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Hi Bear,
I imagine that get a trial update numbers from the lead managing the study who receives the updates on numbers from CROs. They have enrollment as they participated on that aspect (controlled spending). They get updates information on the overall trial. They don't know the specific PFS or OS on any patient. Anyone who suggests that they do is misinformed.
"The Company remains blinded to all trial data and is only receiving updates on a blinded basis" -- PR in Feb 2017
https://www.nwbio.com/nw-bio-announces-lifting-clinical-hold-dcvax-l-phase-iii-trial-fda-progression-free-survival-events-reached-overall-survival-events-not-yet-reached/
Branko,
The paper is on what is considered an ALL COMERS trial (meaning it didn’t remove/exclude Rapids into the analysis and it didn’t remove any possible PsPD either). Had the study you pasted had the same POST RT MRI exclusion scan to remove the rapids (which gets some psPDs naturally) the KM curve would look slighty different. (The KM Plot that includes the inclusion criteria, might not contain the first 20% of events (rapids) and the last 5% (pseudos), if it were a placebo one; meaning KM curve would only plot events that occur after 20% mark and end by the 95% -- depending on how many it came across). I mention this because exclusion/inclusions can have dramatic effects on median PFS and median OS (which I’m sure you’re aware of). In any event, I just wanted to point out those things before a skeptic does.
That said, it wasn’t why I replied to your post. The study you posted was very helpful because it points to the clinical study mindset around EARLY psuedoprogresson. As you know, there are skeptics who perceive UCLA failed to document progression events of Phase I/II patients properly. Some propose that there should have been “false” progression events recorded on account of eyeballing research paper MRIs (Brad didn’t die, and the two other high TIL patients lived a long time after their Month 2 equivalent scan). And, I often tried to explain, that UCLA radiology team didn’t turn a blind eye, by monitoring Brad’s psueduoprogression, and made no mistake in their clinical progression free survival assessments, the medians were accurate.
From your paper, I hope you don’t mind me pointing this out:
“The study opened for accrual in January 2006 and closed to accrual in June 2008 with a total of 1,173 patients entered (Fig 1). “ —paper
Study accrual occurred well BEFORE RANO was accepted practice, and yet, it investigators during those years were encourage to NOT call progression on patients without the clinical picture early on:
“In light of the recognition of early radiation reactions emulating tumor progression, investigators were encouraged not to declare tumor progression within the first 12 weeks after completion of radiation unless there was either a new lesion or the patient had neurologic worsening.” — paper
Thanks for that! Proof that Month 2 scans were and continue to be treated with care when suspicion of early pseudoprogression is present.
OS10.3 Randomized Phase 3 Study Evaluating the Efficacy and Safety of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma: CheckMate 143
D. A. Reardon A. Omuro A. A. Brandes J. RiegerA. Wick J. Sepulveda S. Phuphanich P. de SouzaM. S. Ahluwalia M. Lim .
Neuro Oncol (2017)
Published: 19 April 2017
Abstract
BACKGROUND: Despite available treatment options for patients (pts) with recurrent glioblastoma (GBM), < 5% of pts survive 5 years beyond initial diagnosis, and no single-agent therapy has demonstrated a survival benefit in the second-line setting, including bevacizumab (bev), which is approved for the treatment of recurrent disease. Nivolumab (nivo), a fully human IgG4 monoclonal antibody that inhibits the programmed death 1 receptor, has provided clinical benefit in multiple cancer types. In cohort 2 of the open-label, phase 3 CheckMate 143 study (NCT02017717), the efficacy and safety of nivo was compared with that of bev in pts with GBM experiencing their first recurrence after prior radiotherapy (RT) and temozolomide (TMZ).
METHODS: Pts with no prior VEGF therapy were randomized 1:1 to receive nivo 3 mg/kg Q2W or bev 10 mg/kg Q2W until confirmed disease progression; pts were stratified by the presence/absence of measurable disease. The primary endpoint was overall survival (OS); secondary endpoints were 12-mo OS rate and investigator-assessed progression-free survival (PFS) and objective response rate (ORR) per Response Assessment in Neuro-Oncology criteria.
RESULTS: At the time of final analyses (Jan 20, 2017), 369 pts were randomized to the nivo (n = 184) or bev (n = 185) treatment arms; of these pts, 182 received nivo and 165 received bev. At baseline, most pts in the nivo (83%) and bev (84%) arms had measurable disease, and 40% (nivo) and 43% (bev) of pts required corticosteroids, with 14% (nivo) and 15% (bev) receiving ≥ 4 mg/day. Deaths were reported in 154 (nivo) and 147 (bev) pts; median OS was 9.8 mo with nivo and 10.0 mo with bev, and the 12-mo OS rate was 42% in both arms. PFS medians were 1.5 mo (nivo) and 3.5 mo (bev). Among evaluable pts treated with nivo (n = 153) or bev (n = 156), ORRs were 8% (nivo) and 23% (bev); duration of response medians were 11.1 mo (nivo) and 5.3 mo (bev). Treatment-related AEs (TRAEs) occurred in 57% (nivo) and 58% (bev) of pts; the most common TRAEs (≥ 10% of pts in either arm; nivo vs bev) were fatigue (21% vs 14%) and hypertension (1% vs 22%). Grade 3–4 TRAEs were reported in 18% (nivo) and 15% (bev) of pts. Serious AEs (all causality) were reported in 46% (nivo) and 35% (bev) of pts; seizure (8% vs 6%) and malignant neoplasm progression (11% vs 7%) were the only serious AEs reported in ≥ 5% of pts in either arm. AEs leading to discontinuation occurred in 10% (nivo) and 15% (bev) of pts.
CONCLUSIONS: Nivo did not demonstrate an improved OS compared with bev in pts with recurrent GBM. The ORR was lower with nivo than bev; however, responses with nivo were more durable. The safety profile of nivo was consistent with that observed in other tumor types. Studies of nivo in combination with RT ± TMZ in pts with newly diagnosed GBM are ongoing.
Unfortunately there really isn't much to give a patient, so the rationale to extend makes sense, particularly if they MGMT status on the patient and patient is stable and healthy following 6 cycles of adjuvant TMZ. That particular abstract was a retrospective analysis of TMZ usage, and not a clinical study. Going up 12 probably can't help all. But stopping at 6 probably doesn't make sense either in most healthy cases. Verdict is still out on the appropriate adjuvant cycles. This study below is more in line what might be expected for patients and the paper explains it well.
Extended adjuvant temozolomide for treatment of newly diagnosed glioblastoma multiforme
Gloria B. Rolda ´n Urgoiti • Amitabh D. Singh • Jacob C. Easaw
Received: 28 June 2011 / Accepted: 15 February 2012 / Published online: 2 March 2012 Ó Springer Science+Business Media, LLC. 2012
Abstract The standard of care for newly diagnosed glio- blastoma multiforme (GBM) is temozolomide (TMZ) che- motherapy given concurrently with radiation for 6 weeks followed by 6 months of adjuvant TMZ.
Originally, patients in Alberta were treated with only six cycles of adjuvant TMZ regardless of clinical status but institutional policy was amended to allow up to 12 cycles of adjuvant therapy for patients experiencing at least stable disease and minimal toxicity. We conducted a population-based analysis to determine if extended adjuvant TMZ treatment (i.e., more than six cycles) confers a survival advantage as compared to the standard six cycles for newly diagnosed GBM patients. Patient data was collected from the Alberta Cancer Registry and patient charts. Progression free—and overall survival was determined in patients receiving six cycles of adjuvant TMZ and compared with that of patients receiving more than six cycles. Patients in whom adjuvant chemotherapy was stopped at cycle six experienced a median survival of 16.5 months, whereas, those who received more than six cycles survived for 24.6 months (p = 0.031). Extended adjuvant therapy was not associated with increased toxicity. In multivariate analysis, adjuvant monthly Temozolomide for more than six cycles was an independent prognostic factor for both progression free—and overall survival. These data suggest extended adjuvant temozolomide (i.e., more than six cycles) should be considered in patients with newly diagnosed GBM.
Introduction
Glioblastoma multiforme (GBM) is the most common of all primary brain tumors and is associated with a median survival (MS) of approximately 5 months without treat- ment [1]. Radiotherapy (RT) remained the standard of care until the publication of a phase III study comparing RT versus RT given concurrently with temozolomide (TMZ) followed by six monthly cycles of adjuvant TMZ [2]. Patients treated with concurrent chemoradiotherapy had a MS of 14.6 months versus 12.1 months with RT alone (p \ 0.001). The survival benefit appeared to be durable as combination therapy maintained its survival advantage over 5 years (9.8 vs. 1.9%) [3].
Despite improved survival with this regimen, the majority of GBM patients will still die within 2 years of their diagnosis. Therefore, in the absence of data, many oncologists treat newly diagnosed GBM patients with more than six cycles of adjuvant TMZ with the hope of improving survival. The reasons underlying for this change in treatment strategy are the absence of effective second line treatments, the minimal toxicity caused by TMZ [4] and the absence of a specific scientific rationale to justify why only 6 months of adjuvant cycles of TMZ was used in the original trial [2].
As a result, many patients in North America and Europe are treated adjuvantly beyond 6 months [5]. The Canadian GBM Treatment Guidelines [6] also advocate for pro- longed adjuvant TMZ in patients with stable or responsive disease and manageable toxicity. However, actual data demonstrating superior efficacy of extended adjuvant therapy beyond 6 months is lacking. This population-based study was designed to evaluate if adjuvant TMZ beyond 6 months improves overall survival as compared to the current standard of 6 months.
Materials and methods
After receiving Ethics Board approval, every patient with GBM diagnosed in Southern Alberta (population 1.8 mil- lion people) from August 2003 to July 2009 was identified by the Alberta Cancer Registry. Their charts were reviewed and information was coded to preserve confidentiality. Initially, patients received up to six cycles of adjuvant TMZ, according to the Stupp protocol [2]. However, due to the relative tolerability of TMZ and absence of effective second line therapies, provincial policy was amended to allow up to 12 cycles of treatment. Therefore, in this study, those patients who stopped treatment at six cycles did so because of the prevalent institutional policy and not due to disease progression.
Progression free survival (PFS) was calculated from the date of initial surgery to progression on MR imaging (where progression was defined as [25% increase in the cross-sectional product of the enhancing tumor) [7] or the date of last contact or death. Overall survival (OS) was calculated from the date of diagnosis to the date of last contact or death. MGMT promoter methylation status is performed routinely at Tom Baker Cancer Centre Trans- lational Labs by methylation specific polymerase chain reaction (MS-PCR) assay, as described elsewhere [8]. MGMT promoter status was typically only available after treatment decisions were made and hence did not influence management. Debulking was defined as any extent of resection excluding biopsy.
PFS and OS were estimated using the Kaplan–Meier method. The distributions of time to events were compared using the log rank test. The factors considered included age [40, KPS [70, debulking, initial treatment, prolonged chemotherapy, and MGMT promoter status. Those factors associated with an event at a p \ 0.1 level in univariate analysis were included in multivariate analysis performed using Cox regression models. Analysis was performed with SAS (Statistical Application System; Version 9.2, SAS Institute Inc, Cary, NC). p-values less than 0.05 were considered statistically significant.
Since this study was designed to evaluate the impact of six cycles versus more than six cycles of adjuvant TMZ on survival, those patients who died or had disease progression before 6 months were excluded from the final analy- sis. For all Kaplan–Meier curves, the graphs start at 6 months after starting adjuvant TMZ.
Results
Overall patient characteristics
A total of 273 patients with newly diagnosed GBM were initially included in this study. Patient characteristics are described in Table 1. Sixty-three percent (n = 171) were male. Median age was 59 years (range; 22–86). At presenta- tion, median KPS was 80 (range 40–100). In 181 cases (66%), initial surgery was either gross total or subtotal resection. Following surgery, 33 patients (12%) did not receive any further treatment, 81 (30%) received only radiotherapy (RT) and 159 cases (58%) received concurrent chemoradiotherapy. After radiation, 115 patients (42%) received adjuvant monthly cycles of TMZ. In this group 60 patients (52%) had radio- logical evidence of disease progression before completing six cycles of adjuvant TMZ and three had disease progression when they completed six cycles.
Patients treated with six cycles or more than six cycles
Patients who received six cycles of TMZ and stopped did so in accordance with the protocol outlined by Stupp et al. [2] and not because of disease progression. Institutional policy was later amended to allow extended adjuvant therapy (i.e., more than six cycles) and was offered to all patients. In the subgroup of patients (n = 52) who com- pleted six or more cycles of adjuvant TMZ without disease progression, 23 (44%) stopped TMZ at six cycles and 29 (56%) received more than six cycles (median 11 cycles, range 7–13) (Table 1).
In these 52 patients, MGMT promoter status was available in 39 patients. The MGMT promoter was meth- ylated in 47% (8/17) and 63% (14/22) in those treated with six and more than six cycles, respectively. MGMT pro- moter status was not used to assign patients into the two treatment groups. Moreover, there was no association between MGMT promoter methylation status and extent of resection, initial treatment, adjuvant chemotherapy or the number of cycles given.
Prognostic factors
In the entire cohort (n = 273), patients who did not receive any postoperative treatment (mostly due to poor KPS) lived a median of 1.4 months (CI 1.1–1.9 months). Those treated with radiotherapy only lived a median of 5.5 months (CI 4.4–6.7 months) compared to 13 months (CI 11–15.1 months) for those who received only concurrent treatment (p \ 0.001).
Patients whose adjuvant TMZ therapy stopped at six cycles (n = 23) had a median survival of 16.5 months, whereas, those that received more than six cycles (n = 29)
survived a median of 24.6 months (p = 0.031). In patients receiving monthly adjuvant chemotherapy, there was no association between KPS and the total number of cycles administered (p = 0.211).
In multivariate analysis for PFS (Table 2), concurrent chemoradiotherapy, MGMT promoter methylation and receiving more than six cycles of monthly chemotherapy were independent prognostic factors. For OS, only con- current treatment and more than six cycles of adjuvant therapy were significant (Table 2). Kaplan–Meier curves comparing six cycles of monthly adjuvant TMZ to greater than six cycles demonstrate significant benefit in the latter group for both PFS (Fig. 1) and OS (Fig. 2).
Discussion
The treatment with the greatest impact on survival for any solid tumor is the therapy used in first line. Once a patient has failed initial therapy, all subsequent treatments are associated with shorter long term survival and potentially increased toxicity. It is therefore essential that the clinical benefit of first line treatment be maximized. Such optimization of treatment has been seen in other cancers such as metastatic colon cancer where initial treatments were effective but required optimization to improve survival and tolerability [9].
Once a study has demonstrated efficacy and is adopted as a standard of care, there is sometimes a dogmatic desire to adhere as closely as possible to the original trial proto- col. While this is often justified, there may be times when it is not. The current standard of care for GBM is concurrent TMZ and RT followed by six cycles of adjuvant monthly TMZ. However, even this protocol has been modified over time to optimize treatment and improve survival. For example, several studies have shown that apparent tumor progression often seen immediately following chemora- diotherapy is actually pseudoprogression in nearly 50% of cases. Therefore, to prevent premature discontinuation from treatment, patients with apparent pseudoprogression are typically treated with chemotherapy for three additional months before reevaluation. Since pseudoprogression had not been considered during the initial study by Stupp et al. many patients were likely prematurely discontinued from treatment resulting in a lower OS.
Similarly, many neuro-oncologists have adapted the Stupp protocol and increased the number of adjuvant cycles of TMZ beyond 6 months. Hau et al. [5] treated patients with newly diagnosed WHO grade III or IV gliomas with a median number of 13 cycles (range 9–40) of adjuvant TMZ, observed a MS of \58.5 months. The prolonged MS described by Hau et al. is due to inclusion of anaplastic gliomas. In the present study, focusing only on GBM patients, we observed a significant increase in PFS and OS when patients were treated with more than six cycles of TMZ. MGMT promoter methylation status was not used to decide on the duration of treatment with TMZ, and we observed that it did not impact on OS (Table 2). Furthermore, there was no significant increase in toxicity with the additional treatment suggesting that this approach is safe [5].
One potential confounding factor is the impact of second line therapies. In this study, treatment at progression included VP16 (Etoposide), CCNU (Lomustine), palliative care or inclusion in trials for recurrent GBM. During the period of the study, Bevacizumab was not available to treat patients with recurrent disease at our centre. However, it is unlikely that the use of these treatments had a significant impact on OS as none of these therapies have been com- pared to each other or demonstrated to elicit a differential survival benefit.
This study has several limitations. The extent of resec- tion in cases of assessment by neurosurgeons is not stan- dardized. Hence we compared debulking (which included gross total and subtotal resection) with biopsy. Moreover, the relatively small number of patients (n = 52) limits evaluation of the impact of MGMT promoter methylation status on survival. Finally, these data are retrospective and therefore the results need to be confirmed in prospective studies.
Our study differs with the recently presented RTOG 0525 randomized phase III clinical trial which compared standard adjuvant TMZ with a dose–dense schedule in newly diagnosed GBM patients [14]. In the present study, we have evaluated the benefit of adjuvant TMZ at the same dose but given for different durations. Our data suggests that extended adjuvant TMZ is safe and increases OS. These findings may be useful in guiding therapy for newly diagnosed GBM.
Magnetic resonance perfusion image features uncover an angiogenic subgroup of glioblastoma patients with poor survival and better response to antiangiogenic treatment
Tiffany T. Liu Achal S. Achrol Lex A. MitchellScott A. Rodriguez Abdullah Feroze Michael IvChristine Kim Navjot Chaudhary Olivier GevaertJosh M. Stuart
Neuro Oncol (2017)
Published: 22 December 2016
Abstract
Background.
In previous clinical trials, antiangiogenic therapies such as bevacizumab did not show efficacy in patients with newly diagnosed glioblastoma (GBM). This may be a result of the heterogeneity of GBM, which has a variety of imaging-based phenotypes and gene expression patterns. In this study, we sought to identify a phenotypic subtype of GBM patients who have distinct tumor-image features and molecular activities and who may benefit from antiangiogenic therapies.
Methods.
Quantitative image features characterizing subregions of tumors and the whole tumor were extracted from preoperative and pretherapy perfusion magnetic resonance (MR) images of 117 GBM patients in 2 independent cohorts. Unsupervised consensus clustering was performed to identify robust clusters of GBM in each cohort. Cox survival and gene set enrichment analyses were conducted to characterize the clinical significance and molecular pathway activities of the clusters. The differential treatment efficacy of antiangiogenic therapy between the clusters was evaluated.
Results.
A subgroup of patients with elevated perfusion features was identified and was significantly associated with poor patient survival after accounting for other clinical covariates (Pvalues <.01; hazard ratios > 3) consistently found in both cohorts. Angiogenesis and hypoxia pathways were enriched in this subgroup of patients, suggesting the potential efficacy of antiangiogenic therapy. Patients of the angiogenic subgroups pooled from both cohorts, who had chemotherapy information available, had significantly longer survival when treated with antiangiogenic therapy (log-rank P=.022).
Conclusions.
Our findings suggest that an angiogenic subtype of GBM patients may benefit from antiangiogenic therapy with improved overall survival.
Leveraging molecular datasets for biomarker-based clinical trial design in glioblastoma
Shyam K. Tanguturi Lorenzo Trippa Shakti H. Ramkissoon Kristine Pelton David Knoff David Sandak Neal I. Lindeman Azra H. Ligon Rameen Beroukhim Giovanni Parmigiani
Neuro Oncol (2017)
Published: 20 February 2017
Abstract
Background.
Biomarkers can improve clinical trial efficiency, but designing and interpreting biomarker-driven trials require knowledge of relationships among biomarkers, clinical covariates, and endpoints. We investigated these relationships across genomic subgroups of glioblastoma (GBM) within our institution (DF/BWCC), validated results in The Cancer Genome Atlas (TCGA), and demonstrated potential impacts on clinical trial design and interpretation.
Methods.
We identified genotyped patients at DF/BWCC, and clinical associations across 4 common GBM genomic biomarker groups were compared along with overall survival (OS), progression-free survival (PFS), and survival post-progression (SPP). Significant associations were validated in TCGA. Biomarker-based clinical trials were simulated using various assumptions.
Results.
Epidermal growth factor receptor (EGFR)(+) and p53(-) subgroups were more likely isocitrate dehydrogenase (IDH) wild-type. Phosphatidylinositol-3 kinase (PI3K)(+) patients were older, and patients with O6-DNA methylguanine-methyltransferase (MGMT)–promoter methylation were more often female. OS, PFS, and SPP were all longer for IDH mutant and MGMT methylated patients, but there was no independent prognostic value for other genomic subgroups. PI3K(+) patients had shorter PFS among IDH wild-type tumors, however, and no DF/BWCC long-term survivors were either EGFR(+) (0% vs 7%, P = .014) or p53(-) (0% vs 10%, P = .005). The degree of biomarker overlap impacted the efficiency of Bayesian-adaptive clinical trials, while PFS and OS distribution variation had less impact. Biomarker frequency was proportionally associated with sample size in all designs.
Conclusions.
We identified several associations between GBM genomic subgroups and clinical or molecular prognostic covariates and validated known prognostic factors in all survival periods. These results are important for biomarker-based trial design and interpretation of biomarker-only and nonrandomized trials.
Importance of the study
GBM and other cancers frequently have genetic aberrations in canonical signaling pathways that are currently being targeted in clinical trials. Genomic biomarkers offer the potential for personalized medicine by identifying patient populations that may be more likely to respond to a therapeutic agent targeting an associated pathway. Effective design and interpretation of biomarker-driven clinical trials require an understanding of the frequency of biomarker subgroups, their overlap, and the intrinsic association with various clinical trial endpoints, however. Here we demonstrate the value of large-scale genomic/clinical data correlation and identify several associations between genomic subgroups in GBM and clinical and molecular prognostic factors that will be useful for clinical trial design and interpretation. We then show how the data pertaining to biomarker frequency, overlap, and endpoint relationships impact the design and simulation of Bayesian clinical trials and discuss the impact on non-adaptive clinical trial design.
Biomarker-driven studies, in which experimental agents are tested within specific genomic or molecular subpopulations, offer a promising approach to trial design to improve efficiency and deliver precision medicine.1 There are many different ways to design such trials—from tumor-specific trials like the biomarker-selected, randomized, controlled Lung Master Protocol (LUNG-MAP) in squamous cell lung cancer2 and the adaptively randomized I-SPY 2 trial in breast cancer,3to the National Cancer Institute’s cross-tumor “basket” trial Molecular Analysis for Therapy Choice (NCI-MATCH).4 The design and interpretation of such trials benefit from biomarker-specific data regarding the relative frequency and degree of overlap between biomarker subgroups, a priori prognostic capacity of subgroups, and the relationship between endpoints for each subgroup. These data can impact decisions regarding eligibility criteria, endpoints, accrual estimates, and selection of appropriate controls. Additionally, this information is essential to generate assumptions for simulations of Bayesian clinical trials to elucidate operating characteristics. The potential to abstract foundational data for biomarker-driven clinical trial design is an underappreciated value of large clinically annotated datasets such as The Cancer Genome Atlas (TCGA),5 as the relative frequency and natural history of genetically defined subgroups with respect to various trial endpoints may not be well characterized.
Despite over 1400 published trials and an increasing number of potential therapies, glioblastoma (GBM) continues to confer poor outcomes with limited therapeutic progress. Work by TCGA and others has identified 3 canonical pathways with recurrent aberrations, including receptor tyrosine kinase signaling and the p53 and retinoblastoma tumor suppressor pathways.5–7 There is much interest in targeting these pathways and the ability to screen for multiple biomarkers with genomic sequencing makes platform trials that test multiple therapies under one master protocol attractive. In fact, the NCI’s Brain Malignancy Steering Committee Targeted Therapies Working Group recommended the development of a multi-arm adaptively randomized clinical trial to efficiently test targeted agents with associated genomic biomarkers,8 and such a trial has recently opened in response: the INdividualized Screening trial for Innovative Glioblastoma Therapy (INSIGhT; NCT02977780). Additionally, there are other biomarker-selected trials that match therapies to tumors with specific aberrations in nonrandomized, uncontrolled studies. Designing biomarker-driven trials in general and interpretation of uncontrolled, single-arm trials, however, may be complicated by the association of specific biomarker subgroup tumor biology and natural history.8,9 This may impact overall survival (OS) and progression-free survival (PFS) times or influence the association between endpoints. The relationship between PFS and OS may differ between therapeutic classes,10 and this potential may exist among biomarker-defined classes.11 To better inform our design choices and simulations for INSIGhT and create a resource to interpret single-arm biomarker-based trial results, we collected and analyzed clinical and genomic data from patients with newly diagnosed GBM from Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC) for associations with relevant clinical covariates, known molecular prognostic factors, and potential clinical trial endpoints and validated significant associations in GBM data from TCGA. Relevant biomarker categories were prospectively hypothesized based on potential interactions with intended agents targeted to epidermal growth factor receptor (EGFR), phosphatidylinositol-3 kinase (PI3K), p53, and cyclin-dependent kinase (CDK) pathways. Furthermore, we characterized the frequency and degree of overlap between biomarker categories to be included on INSIGhT and demonstrated how variations in those factors and survival times would impact clinical trial design through simulation.
Materials and Methods
Datasets and Genomic Assays
The DF/BWCC cohort consisted of patients ≥18 years old with a newly diagnosed GBM and clinical molecular profiling.12 Each patient underwent at least 1 of 3 genotyping assays for genomic profiling: OncoCopy,13 a multiplexed copy number assay based on whole genome array comparative genomic hybridization; OncoMap,14 a targeted and multiplexed mass spectrometry–based mutation genotyping (Sequenom) covering 471 mutations from 41 cancer genes (version 4); and OncoPanel,15 a targeted exome sequencing platform covering 275 cancer genes and 91 select introns across 30 genes to detect somatic mutations, copy number alterations, and structural rearrangements. We disregarded mutations with low (<5%) allelic fraction, with <20 reads of mutant allele on OncoPanel, previously unreported in the COSMIC database, and previously known to be single nucleotide polymorphisms to reduce classification error. OncoCopy data from clinical testing reports were obtained from the medical record under consented and waiver of consent research protocols approved by the Dana-Farber Harvard Cancer Center (DF/HCC) institutional review board (IRB). Somatic mutational profiling was performed with consent for DF/BWCC Profile clinical research studies approved by the DF/HCC IRB. All tests were performed within the Cytogenetics Division (OncoCopy) and Molecular Diagnostics (OncoMap) Divisions of the Brigham and Women’s Hospital Center for Advanced Molecular Diagnostics, a Clinical Laboratory Improvement Amendment (CLIA)–certified laboratory environment. Central histopathologic review was performed on all genotyped tumor specimens at DF/BWCC using standard World Health Organization criteria.16 O6-DNA methylguanine-methyltransferase (MGMT)–promoter methylation status in this cohort was generally assessed using methylation-specific polymerase chain reaction (MS-PCR). Clinical, demographic, pathologic, and follow-up data were collected retrospectively from the medical record following approval from the DF/HCC IRB.
Significant findings from our institutional cohort were validated in data generated by TCGA Research Network available on the TCGA website5,17 and cBioPortal.18 The provisional TCGA GBM dataset was queried for levels 1 and 2 clinical and genomic data related to DNA copy number (HG-CGH-244A), whole-genome next-generation sequencing (Illumina®), conventional sequencing (Sanger), and DNA methylation arrays (Illumina Infinium Human Methylation-27 [HM-27] and HM-450), as previously described.17 Clinically relevant MGMT-promoter methylation status was estimated from cytosine-phosphate-guanine islands using a logistic regression of 2 clinically relevant methylation probes, as previously described.19
Biomarker Subgroups
We prespecified biomarker categories on the basis of genetic aberrations for subsequent analyses based on the Targeted Therapies Working Group recommendations:
1. EGFR: (+) defined as patients with EGFR amplification or mutation;
2. PI3K: (+) defined as patients with PIK3CA mutation/amplification, PIK3R1 mutation, AKT3 amplification, PIK3C2B >1 copy gain, or PTEN dual loss through either homozygous deletion or deletion plus mutation;
3. p53: (+) defined as patients with TP53 mutation;
4. CDK: (+) defined as patients with RB1 wild-type (WT) and CDK4 amplification, CDK6 amplification, or CDKN2A >1 copy loss.
Assignment to biomarker categories was contingent on sufficient data from available molecular analyses. For example, p53(+) could be assessed with either OncoPanel or OncoMap if a relevant mutation was present. P53(-) could only be reliably determined from OncoPanel, since the entire coding region was sequenced, however. Similarly, PI3K(+) could be determined based on OncoMap or OncoPanel if an activating mutation was present, but positivity determined based on copy number and mutation required overlap with OncoCopy.
Statistical Analysis
Patients with isocitrate dehydrogenase (IDH)1 and 2 mutations and/or 1p/19q codeletions were excluded from biomarker subgroup analyses based on the intended eligibility criteria of INSIGhT.8 We evaluated associations between clinical factors and biomarker subgroups using Fisher’s exact test for categorical variables and the Wilcoxon rank sum test for continuous variables. Survival outcomes, including PFS, survival post-progression (SPP), and OS, were estimated for the genomic biomarker, MGMT, and IDH subgroups using the Kaplan–Meier method and compared using the log-rank test. PFS/OS ratio was calculated for patients who had a progression and death. SPP was calculated from time of progression for those patients who had a progression prior to death and censored identically to OS. Progression was defined independently by TCGA and retrospectively by the DF/BWCC cohort through clinical note assessments integrating imaging and clinical status. Pearson correlation coefficients were used to characterize the relationship between PFS, an auxiliary endpoint, and OS to assess for differences in the natural history of disease across biomarker groups among patients who achieved death and progression.
Univariable and multivariable Cox regressions were used to identify clinical factors independently predicting for OS. We then created new models for each biomarker category with significant clinical variables to assess whether biomarker groups independently predicted for OS. All P-values are 2-sided, and analyses were performed using RStudio (version 0.98.1028) running R (version 3.1.0)20 with the survival package.21
To assess the impact of pre-trial genomic biomarker data on clinical trial planning, we assumed various scenarios related to biomarker frequency, overlap, and endpoint distributions into early clinical trial simulations for INSIGhT, a multi-arm, Bayesian adaptively randomized clinical trial currently in development. For the purposes of these comparisons, we assumed the 3 experimental arms above compared against a control arm, with 1 arm showing survival benefit compared with control.
Results
Baseline Patient Characteristics and Frequency of Biomarkers
The DF/BWCC cohort consisted of 265 patients with a median follow-up of 15.4 months overall and 16.8 months among survivors (range: 0.2–197.3 mo). OncoMap data were available for 78 patients, OncoPanel for an additional 157 (no overlap), and OncoCopy for 157 patients (90 patient overlaps with OncoPanel, 37 patient overlaps with OncoMap). Median age was 60 years, 54% were male, and median KPS was 80. MGMT-promoter status was methylated in 95 patients (36%), unmethylated in 82 (31%), and untested in 88 (33%). IDH1/2 were WT in 234 (88%), mutant in 28 (11%), and untested in 3 (1%).
The provisional TCGA dataset consisted of 549 patients with primary GBM diagnosed between 1988 and 2013 with a median follow up of 11.1 months overall and 6.7 months among survivors (range: 0.1–127.5 mo). Overall, median age was 60 years, 61% were male, and median KPS was 80. MGMT-promoter status was methylated in 170 patients (31%), unmethylated in 200 (36%), and unknown in 179 (33%). IDH1/2 were WT in 526 (96%), mutant in 23 (4%).
Fig. 1 illustrates the distribution of biomarker signatures based on IDH1/2 mutation, MGMT-promoter methylation, EGFR, PI3K, p53, and CDK group statuses. Among trial-eligible patients, considered as those without IDH1/2 mutation, p53(+) subclass occurred least commonly, although the 4 primary biomarker groups were otherwise fairly balanced in size. EGFR(+) and CDK(+) seldom occurred in isolation and were more often accompanied by inclusion in other biomarker(+) groups. Specifically, among trial-eligible patients in the DF/BWCC cohort, 33% of patients were EGFR(+) (n = 76), 31% were PI3K(+) (n = 73), 21% were p53(+) (n = 50), and 28% were CDK(+) (n = 66); in TCGA, 48% were EGFR(+) (n = 255), 56% were PI3K(+) (n = 293), 11% were p53(+) (n = 60), and 79% were CDK(+) (n = 413).
Fig. 1
Biomarker status by individual in the DF/BWCC cohorts and TCGA cohorts. Status of IDH, MGMT, EGFR, PI3K, p53, and CDK biomarker groups for each individual patient are arranged in columns in both the DF/BWCC and TCGA cohorts. Trial-eligible GBM patients include those without IDH mutation or 1p/19q codeletion.
Patients with tumors harboring MGMT-promoter methylation were more often female than their unmethylated counterparts in our cohort (54% vs 35%, P = .02) and in that of TCGA (49% vs 34%, P = .005). MGMT-promoter methylated tumors were also more likely to be “multifocal” by imaging report in our dataset (20% vs 8%; P = .04), but this parameter was not available in the dataset of TCGA in order to validate the finding.
Association with Biomarker Subgroups with Known Prognostic Molecular Markers
EGFR(+) (odds ratio [OR] = 7.8, P < .001) and p53(-) (OR = 5.5, P = .002) subgroups were more likely to be IDH WT, and these associations were validated in the TCGA cohort (EGFR OR = 20.1, P < .001; p53 OR = 8.4, P < .001). There were no associations between the genetic biomarker groups and MGMT-promoter methylation status.
Association of Biomarker Subgroups with Clinical Covariates
Overall clinical and prognostic factors and significant associations with biomarker groups are shown in Table 1, excluding patients with IDH1/2 mutations or 1p/19q codeletions. With respect to clinical covariates, patients in the PI3K(+) subgroup were older (median 64.3 y vs 59.7 y, P = .015) and this was also validated in TCGA (median 62.3 y vs 58.8 y, P = .002). P53(+) had smaller contrast-enhancing tumors than the p53(-) group (median 3.8 cm in largest dimension vs 4.2 cm, P = .029) but this could not be validated in TCGA due to data limitations in that dataset. Patients with PI3K(+) tumors also had lower KPS in our cohort (P = .014), but this was not found in the dataset of TCGA. It should be noted, however, that in our dataset the KPS was consistently measured just prior to adjuvant chemoradiotherapy, while the timing of KPS measurements in TCGA was highly variable, limiting the utility.
Table 1
Baseline clinical characteristics and associations with biomarker groups in DF/BWCC
Patient Cohort
DF/BWCC
Biomarker Association*
Total
233
Age , y
Median (IQR)
60.1
(53.2–67.7)
PI3K: (+)64.3 vs (-)59.7; P = .015
Gender
Male
126 (54%)
MGMT: Male (M)46% vs (U)65%; P = .02
Female
107 (46%)
KPS
PI3K(+)
PI3K(-); P = .014
<60
11 (5%)
2 (3%)
4 (4%)
60–80
105 (45%)
46 (65%)
41 (42%)
90–100
97 (41%)
23 (32%)
52 (54%)
Multifocal (%)
No
199 (85%)
Yes
34 (15%)
MGMT: (M)20% vs (U)8%; P = .04
Size (cm)
Median (IQR)
4.2 (3.1–5.3)
p53: (+)3.8 vs (-)4.2; P = .029
Resection (%)
Biopsy
17 (7%)
STR/GTR
207 (88%)
Temozolomide (%)
Received
214 (92%)
Not received
12 (5%)
Alive at 5 y (%)
No
223 (96%)
Yes
10 (4%)
EGFR: (+)0% vs (-)7%; P = .014; p53: (+)10% vs (-)0%; P = .005
OS (mo)
Median (IQR)
20.8
(11.4–50.8)
MGMT: (M)20.0 vs (U)12.8; P = .036
PFS (mo)
Median (IQR)
9.7
(5.7–18.1)
MGMT: (M)11.6 vs (U)6.9; P = .022;
PI3K: (+)9.3 vs (-)10.4; P = .049
Abbreviations: IQR, interquartile range; STR, subtotal resection; GTR, gross total resection, M, methylated; U, unmethylated.
*
Empty values under biomarker associations indicate no significant clinical associations for any biomarker group.
Note: Table includes only patients with wild-type IDH-1/2 and without 1p/19q codeletion.
Association Between Biomarkers and Endpoints
IDH mutant and MGMT-promoter methylated patients demonstrated increased OS, PFS, and SPP in both our cohort and the dataset of TCGA (Table 2, Fig. 2). PI3K(+) patients had shorter PFS in both our cohort (HR 1.42 [95% CI: 1.001–2.00] P = .049) and TCGA’s (HR 1.28 [95% CI: 1.07–1.55], P = .009). EGFR(+) patients were less likely to live 5 years (0% vs 7%, P = .014) as were p53(-) patients (0% vs 10%) in our cohort, but these results could not be recapitulated in TCGA, potentially due to the extremely low rate of 5-year survivors in that dataset (1%). Age, KPS, MGMT-promoter methylation, and the use of temozolomide were all independently associated with OS on multivariate analysis in the DF/BWCC (Table 3). After controlling for these factors, there were no independent associations of genetic biomarker subgroups with survival (Table 4) or with PFS (Supplementary Tables 1 and 3). Notably, the association between PI3K and PFS was no longer significant after correcting for any clinical prognostic factors.
Table 2
Survival and auxiliary endpoints by biomarker group in the DF/BWCC
Table 3
Univariate and multivariate analyses for clinical predictors of overall survival in DF/BWCC
Table 4
Multivariate analyses for overall survival with biomarker groups in DF/BWCC
Fig. 2
Hazard ratios for OS, PFS, and SPP by biomarker subgroups in TCGA and DF/BWCC patient cohorts. *Outcomes across IDH subgroups were compared across the entire cohort. Outcomes across remaining biomarker subgroups were compared across only trial-eligible GBM-patients (IDH WT). Hazard ratios are displayed for positive biomarker status relative to negative status as the baseline, with HR <1 representing a favorable endpoint. Point estimates for the HR are displayed by a square box, scaled to the representative sample size of biomarker (+) patients, with 95% CIs displayed in horizontal bars.
Clinical Trial Simulations Using Biomarker Data
There were 3 major areas for which our genomic biomarker analysis on retrospective cohorts was applicable to the design and simulations for INSIGhT—the overall frequencies for different biomarker groups, the overlap of various biomarker categories, and the relationship of endpoints within given biomarker subgroups. To illustrate the potential impact of these data on design elements of the trial, we first assumed disparate scenarios for each area (frequency, overlap, endpoint) to have a robust comparison of scope and then compared operating characteristics. Our simulations showed the sensitivity of the power (log-rank test) in detecting positive treatment effects for biomarker subgroups and the sensitivity of the resulting biomarker-specific treatment effect confidence intervals.
Independently of the biomarker correlations with each other and the randomization assignment algorithm (Bayesian adaptive, non-adaptive), we observed direct proportionality of the minimum sample size requirements to achieve (60%, 80%, or 90%) power with treatment hazard ratios (HRs) (0.7 and 0.5) in all of our simulations. In these power analyses, the sample size requirement varied between 191 and 920 patients, and the maximal deviation from direct proportionality (sample size = constant/prevalence) with fixed biomarker correlations, treatment effects, and power thresholds that we observed was equal to 13 patients.
We then conducted simulations to compare operating characteristics under varying assumptions of biomarker correlation. The goal of these simulations was complementary to those described for biomarker frequency in the previous paragraph. In this instance, however, we fixed the biomarker prevalence (25% or 50%) and specified scenarios with different correlations between -0.7 and +0.7. The goal was to evaluate the robustness of Bayesian adaptive designs to the biomarker subgroup overlap. In this case, we observed that Bayesian adaptive randomization was sensitive to differences in the degree of biomarker overlap, with power variations up to 6%, demonstrating the importance of appropriate biomarker overlap estimates for design purposes of such trials.
In the last set of simulations, we used the Dana-Farber Cancer Institute biomarker prevalence estimates and defined a set of sensitivity scenarios with different PFS and OS baseline distributions for the control arm, with positive and negative scale variations up to 40% for both PFS times and SPP times. We also included variations limited to single biomarker subgroups. The operating characteristics of the Bayesian adaptive design with fixed treatment effects, obtained using identical time-scale multiplicative constants for control and treatment arms, was not very sensitive to PFS/OS variations. By multiplying PFS and OS by scale factors equal to 40%, we obtained power reductions at most equal to 3%.
Discussion
A growing interest in precision medicine and the availability of targeted agents has heightened interest in genomic biomarker-based clinical trials. Our findings of biomarker category associations with relevant prognostic covariates have some implications for design and interpretation of clinical trials. We found an association of PI3K(+) patients with older age and lower performance status, older age being validated in TCGA. Since age is an independent prognostic factor for adult patients with GBM, single-arm bucket trials using PI3K definitions as eligibility may be erroneously interpreted as poorly performing compared with historical controls if this is not taken into account. PI3K(+) in fact had worse PFS on univariate analysis in our dataset. P53(-) and EGFR(+) genomic subgroups were also associated with being IDH WT. If a single-arm phase II trial designed with a PFS or OS endpoint for agents targeted at these genomic subgroups were conducted and compared with unselected historical controls, we might erroneously conclude a negative result, as the historical control may have included IDH mutant tumors while our genetic selection effectively excluded them without our knowledge. Also of note, both cohorts showed MGMT-promoter methylation to be associated with female gender, which is a novel association to our knowledge that should be validated in future studies.
But while genomics is presumed to be a key determinant of the biology and behavior of tumor growth, we found no independent associations of genomic biomarkers and survival-based endpoints. This suggests that there may be few confounding molecular variables in clinical trials outside of the known factors of IDH mutation, MGMT-promoter methylation, and 1p/19q status. Therefore, while control groups should always be used when evaluating survival endpoints such as PFS and OS, comparison to unselected historical controls in genomic biomarker-selected studies may not have any additional confounding factors based on the biomarker selection as long as clinical covariates and known molecular prognostic factors are considered. Furthermore, should an uncontrolled single-arm study of a targeted agent show a strong prognostic signal related to a genomic biomarker previously shown to have no prognostic value, this may suggest that the biomarker is behaving in a predictive capacity given the new therapeutic context and suggest hypotheses for further testing.
Some studies have identified genomic alterations in EGFR, TP53, PTEN, and CDK4 as negative prognostic biomarkers,22–24 but this has not been consistently replicated or systematically evaluated in other studies.22 Controlling for known clinical covariates is also important when reporting such data. For example, a recently published analysis of TCGA’s glioblastoma and lower-grade glioma datasets identified PI3K mutations to be negatively prognostic for survival.25 Similarly, our study demonstrated an association between PI3K(+) tumors and poorer PFS on univariate analysis of both cohorts. However, significant associations were also seen between PI3K(+) tumors and lower KPS in our cohort and older age in both cohorts, and after controlling for clinical prognostic covariates PI3K was no longer associated with OS or PFS. These findings underscore the need for combined assessment of clinical and biomarker prognostic information.
The prognostic value of any given biomarker may additionally depend on the precise characteristics of its diagnostic assay. For illustration, in the DF/BWCC cohort, MGMT-promoter methylation was assessed primarily by MS-PCR and demonstrated significant associations with female gender, tumor multifocality, and improved PFS and OS. After multivariate adjustment for prognostic clinical factors, MGMT status remained highly prognostic for OS and PFS. In the validation set of TCGA, MGMT status showed similar univariate associations with gender, PFS, and OS; however, survival associations were not significant after multivariate adjustment. This may be due to the use by TCGA of methylation arrays (Illumina HM27K and HM450K) and the potentially imperfect concordance between these assays and the MGMT-STP27 logistic regression model used to categorize MGMT-promoter methylation status,19 a point of importance given that many pathology laboratories are considering adoption of methylation arrays and replacement of MS-PCR MGMT-based assays. More validation and comparison data of these 2 methods are likely needed based on our results. In addition, it is possible that MGMT status was less prognostic overall in TCGA, as fewer patients were treated with temozolomide in TCGA versus the DF/BWCC cohort (52% vs 92%). Finally, the prognostic signal from MGMT may have been overshadowed by more heterogeneous annotation of clinical prognostic factors in TCGA.
Designing clinical trials using an auxiliary endpoint requires knowledge of the relationship between that auxiliary endpoint and more clinically relevant ones, as these relationships may differ according to molecular subtype. Perhaps the best example of this is the relationship between pathologic complete response rate (pCR) and recurrence-free survival in breast cancer where the predictive capability of pCR varies by biologic subtype,26 the knowledge of which was helpful when designing I-SPY 2.3 Having knowledge of the relationships between biomarker-defined subgroups and various clinical trial endpoints would significantly aid clinical trial design by informing specific design choices (such as endpoints or the need for control groups) and by providing biomarker-specific data for operating characteristic analysis such as power and sample size. Past studies and meta-analyses have illustrated correlation between PFS effects and OS effects in GBM,27–29 largely driven by the results from the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada CE.3 study.10,30 But this relationship did not hold in trials of bevacizumab in which effect on progression was not associated with effect on survival.31,32 Our study identified no significant differences in the relationship between PFS/OS ratios or SPP across genomic biomarker subgroups. Additionally, our trial simulations determined that variations in PFS and SPP times would have only a small impact on INSIGhT, and our data could be helpful to support using PFS or a longitudinal model incorporating PFS as an endpoint to inform randomization.33 In contrast, we observed significantly better OS, PFS, and SPP among IDH mutant patients in both cohorts and among MGMT-promoter methylated patients in TCGA. The longer SPP suggests that the prognostic capacity of IDH mutation and MGMT-promoter methylation is retained following recurrence, a result that is particularly relevant for interpreting results of basket trials in patients with recurrent GBM such as NCI-MATCH.4 Furthermore, the lack of evidence supporting differential relationships of endpoints among the subclasses is important for the interpretation of nonrandomized trials with newly diagnosed patients using PFS as a primary endpoint like the Neuro Master Match (N2M2) trial.34
Finally, the relative frequency of biomarker subgroups and their degree of overlap is important for clinical trial design and planning. For non-adaptive studies, knowledge of biomarker frequency is important to estimate accrual rate of specific genomic subgroups, and the frequency and degree of overlap of biomarker categories inform choices with regard to treatment-arm assignment rules. For example, if biomarker groups are relatively frequent and mutually exclusive, assignment rules may simply be to match biomarker groups with agents targeting those aberrations.
Conversely, if there is substantial overlapping of subgroups and some that are relatively rare, algorithms to prioritize or randomize specific treatment arms may be needed. For Bayesian adaptively randomized trials like INSIGhT, the frequency and overlap between biomarker categories directly impact the results of clinical trial simulations that illustrate operating characteristics and how the trial might proceed in the real world. For example, GBM genomic subgroup categories as defined in this study and for INSIGhT are relatively frequent, enabling our preferred design of equal randomization across treatment arms, independent of biomarker subgrouping. This would not be logistically possible if biomarker subgroup frequencies were too low, as randomization to control or a nontargeted treatment arm of a patient with a rare biomarker would make completing the trial for that subgroup challenging. Aside from that design choice, knowledge of biomarker frequency would be used similarly to non-adaptive studies—in both cases the sample size and power are directly related to the biomarker frequency. Furthermore, Bayesian adaptive trial designs such as INSIGhT are impacted by the degree of biomarker overlap, as we found significant variations in power depending on the hypothesized correlations between subgroups. In this manner, the data abstracted from our current study are directly applicable in determining operating characteristics of INSIGhT.
Several limitations exist for this study. First, there are limited preclinical data with targeted agents in GBM to suggest the ideal biomarker categorizations, a priori, and our pathway model may oversimplify the elaborate interconnections and cross-regulation of these pathways in GBM. Additionally, potential differences in the 2 study populations may limit comparison and combined analysis across the sets of TCGA and DF/BWCC. Clinical and molecular factors were also not uniformly defined across our cohort and the validation set of TCGA; for example, in TCGA, KPS could have been defined at multiple time points, while the DF/BWCC cohort uniformly defined KPS postoperatively and prior to radiation therapy. Similarly, inconsistencies in the assessment of MGMT-promoter methylation were discussed above. Progression endpoint identification was also not standardized in either cohort. Nonetheless, these datasets are highly complementary to one another, and the large TCGA dataset was useful for validating our initial findings. Finally, it should be noted that the biomarker subgroupings that were of interest in the current study were not intended to be globally applicable to agents that might target alternative pathways. If there were other biomarkers that were of interest, however, we feel that the general approach and implications of retrospective biomarker analysis for prospective trial planning still hold and should be applied.
In summary, we identified relevant associations between 4 a priori defined genetic subgroups of GBM and known clinical and molecular prognostic factors. After controlling for these factors, there was no association between the genomic biomarker groups and OS, although the PI3K(+) group may have shorter PFS on univariate analysis. Both IDH and MGMT status were not only found to be prognostic initially, but also associated with longer SPP, illustrating a potential differential relationship between endpoints. Clinical trial simulations of both balanced and Bayesian adaptively randomized trials showed the impact of biomarker frequency, overlap, and endpoint relationships on design and operating characteristics. These data represent a foundation to plan and develop innovative genomic biomarker-driven clinical trial designs to accelerate discovery in GBM (currently being used in the development of INSIGhT), and to help interpret findings from genomic biomarker-based basket studies.
CD8+ tumor-infiltrating T cells before and after neoadjuvant therapy correlates with the pathological response in rectal cancer. Shinji Matsutani, Masatsune Shibutani, Kiyoshi Maeda, Hisashi Nagahara, Tatsunari Fukuoka, Ryosuke Amano, Hiroaki Tanaka, Kazuya Muguruma, Kosei Hirakawa, Masaichi Ohira. Osaka City University Graduate School of Medicine, osakasi, Japan. Background: Recently, neoadjuvant therapy (ie. neoadjuvant chemotherapy, neoadjuvant chemoradiationtherapy) for locally advanced rectal cancer has been generally performed. Although in unresponsive cases it may have disadvantages such as tumor progression or delaying surgery, factors predicting the clinical response to neoadjuvant therapy have not been adequately defined. Meanwhile CD8+ Tumor-infiltrating lymphocytes (TILs) have been reported to have a crucial effect in tumor progression and outcome as primary host immune response in various types of cancer, and antitumor immune effect has been reported to contribute to the response to radiotherapy and chemotherapy. The aim of this study was to elucidate the correlation between the local immune status and the effectiveness of the neoadjuvant therapy for locally advanced rectal cancer. Patients and methods: A total of 51 patients who underwent curative operation for locally advanced rectal cancer after neoadjuvant therapy were enrolled. We retrospectively examined the number of CD8+ tumor-infiltrating lymphocytes (TILs) using immunohistochemical staining of pretreatment biopsy samples and resected specimens, and assessed the correlation with pathological response. The grade of tumor response was evaluated according to the definitions in the Japanese Classification of Colorectal Carcinoma. Grade0-1a were defined as “poor response” and Grade1b-3 were defined as “good response”. We set each median value of the number of CD8+ TILs as the cut-off value. Results: For the 26 patients with pretreatment biopsy samples, we classified the the patients into the poor response group (n=14) and the good response group (n=12). Then we set 6.0 as the cut-off value and classified the patients into the high pretreatment CD8+ TILs group (n=14) and the low pretreatment CD8+ TILs group(n=12). Low pretreatment CD8+ TILs were associated with poor response to neoadjuvant therapy (p=0.036). For resected samples (n=51), we classified the patients into the poor response group (n=25) and the good response group (n=26). Then we set 10.8 as the cut-off value and classified the patients into the high posttreatment CD8+ TILs group (n=28) and the low posttreatment CD8+ TILs group(n=23). Low posttreatment CD8+ TILs were also associated with poor response to neoadjuvant therapy (p<0.001). Additionally, the number of pretreatment CD8+ TILs tend to be related to the number of posttreatment CD8+ TILs. Conclusion: In locally advanced rectal cancer patients, T lymphocyte-mediated immune reactions play an important role in tumor response to neoadjuvant therapy, and the quantitative measurement of CD8+ TILs in pretreatment biopsy samples may be a predictor of the clinical effectiveness of neoadjuvant therapy for locally advanced rectal cancer. Moreover, low posttreatment CD8+ TILs were associated with poor response to neoadjuvant therapy.
Human glioblastoma arises from the distant subventricular zone normal appearing but harboring tumor-initiating mutations. Joo Ho Lee,1 Jeong Eun Lee,2 Jee Ye Kahng,1 Junseong Park,3 Seon Jin Yoon,3 Se Hoon Kim,3 Jong Hee Chang,3 Seok-Gu Kang,3 Jeong Ho Lee1. 1Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea; 2Chungnam National University Hospital, Daejeon, Republic of Korea; 3Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea. Glioblastoma multiforme (GBM) is the most devastating and incurable brain tumor. Although the identification of cells with tumor initiating mutations or their location can provide the fundamental basis for understanding disease progression, the origin of GBM remains controversial due to the lack of direct evidence in human GBM patients. Here, we performed ultra-deep sequencing of triple-matched tissues of i) radiologically and pathologically normal subventricular zone (SVZ), which is distant from tumor, ii) GBM tumor, and iii) blood (or normal cortical tissues) from patients with GBM (IDH-wildtype), compared to those with other type of brain tumors such as GBM (IDH-mutant), meningioma, oligodendrgolioma, metastatic brain tumor, and GBM (IDH-wildtype) with SVZ-invasion. Surprisingly, we found that in 55.5% of IDH-WT GBM patients (5 of 9), normal appearing and distant SVZ already contained the low level of GBM mutations such as TP53, EGFR, RB1, PDGRF or TERT variations observed in the matched tumor. Single cell sequencing of GBM tumors and laser capture microdissection analysis of the SVZ show that mutations are enriched in the astrocyte ribbon area, which clonally evolved from the SVZ to the distant GBM tumor. Furthermore, using CRISPR-Cas9 system in the postnatal mouse brain, we showed that neural stem cells with TP53, PTEN, EGFR mutations migrated away from the mutated SVZ site and then formed the high grade malignant glioma in the distant cortical region. Taken together, this study provides the direct evidence that human glioblastoma arises from the distant SVZ that is normal-appearing but harboring tumor-initiating mutations.
Intestinal microbiota may dynamically facilitate the anti-PD-L1 immunotherapy. Jia Xue,1 Zhun Wang,1 Sheng Guo,1 Jie Cai,1 Davy Ouyang,1 Bin Cai,2 Gang Chen,2 Jie Liu,2 Xin Dong,2 Henry Li1. 1Crown Bioscience, Inc., Beijing, China; 2Nanjing Galaxy Biopharmaceutical Co. Ltd., Nanjing, China. Cancer immunotherapies, e.g. the antibody against programmed death ligand 1 (PD-L1), a checkpoint inhibitor, have witnessed great successes in treating certain cancers in recent years. Recent data have also demonstrated that gut microbiota are important modulators on anticancer immunotherapy1,2. Heterogeneity in patient outcome seems to suggest complex communications between microbiota and host antitumor immunity. To this end, we tested an engineered chimeric MC38 mouse cell line, hPDL1-MC38-HuCELL™ via human PD-L1 knock-in procedure, where MC38 CRC syngeneic cell is derived from C57BL/6. After treatment of PD-L1 antibodies (cD7A8 and BMS PD-L1 of different dose regimens), we observed significantly different drug responses among the mice from three different Chinese rodent suppliers: the mice from Vendor 1 showed no tumor progression after treatment with a variety of doses while no favorable response was observed in mice from Vendor 2 and Vendor 3. To deeply study the gut microbiota of these mice, we performed 16S ribosomal RNA sequencing on untreated mice from three groups (5 replicates for each). Global diversity analysis by Quantitative Insights Into Microbial Ecology (QIIME) tool revealed a clear separation in the three sources of mice: the microbiota composition of Vendor 2 and Vendor 1 are relatively closer to each other whereas the Vendor 3 mice are different, suggesting that the main difference seen between Vendor 1/2 and 3 in the original composition of gut microbiota is not the key impact for the observed anti-PD-L1 efficacy, and there should be other complex dynamics impacted anti-PD-L1 treatment, which remains unknown. Moreover, a group of 27 taxa were identified with significant difference in abundance (Kruskal-Wallis test, p-value < 0.05) across the groups, such as Bacteroidaceae, Lachnospiraceae, and Ruminococcaceae, which confirmed the previous data1. In conclusion, intestinal microbiota dynamically facilitate anti-PD-L1 efficacy and reversely anti-PD-L1 treatment could influence reconstruction of gut microbiota. References 1. Sivan A, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015;350(6264):1084-9. 2. Vétizou M, et al., Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015;350(6264):1079-84. 3. Caporaso JG, et al., QIIME allows analysis of high-throughput community sequencing data. Nat Methods. 2010;7(5):335-6.
Cancer stem cell vaccine significantly reduces local tumor relapse and prolongs survival in the adjuvant setting. Fei Liao,1 Yang yang Hu,1 Xin Chen,1 Alfed E Chang,1 Robert E Hollingsworth,2 Elaine Hurt,2 John Owen,1 Jeffrey S Moyer,1 Mark E.P Prince,1 Joel Whitfield,1 Yuxin Chu,3 Qibin Song,3 Max S Wicha,1 Qiao Li1. 1Univ. of Michigan, Ann Arbor, MI; 2MedImmune INC, MD; 3Renmin Hospital of Wuhan University, Wuhan, China. Although surgical resection has been a standard treatment for solid malignancies, therapeutic efficacy is limited by both local and distant recurrence. Effectively preventing local tumor recurrence remains a significant challenge. The existence of micro metastasis at the time of tumor resection represents an even greater therapeutic challenge, since 90% of tumor deaths are due to tumor metastasis. There is increasing evidence that many cancers are driven and maintained by a subpopulation of cells that display stem cell properties. Cancer stem cells (CSCs) can self-renew, mediate tumor growth and contribute to tumor recurrence and metastasis. Targeting CSCs may thus increase the therapeutic efficacy of current cancer treatment. We previously described a strategy to target CSCs using CSC-dendritic cell (DC) vaccination. However, the efficacy of CSC targeted therapeutics may be greatest when they are deployed in the adjuvant setting. In this study, two mouse models were utilized: SCC7 subcutaneous (s.c.) tumors, and a D5 melanoma model. Established s.c. SCC7 tumors were surgically removed from mice followed by treatment using ALDHhigh SCC7 CSC-DC vaccine, which significantly reduced local tumor relapse and prolonged animal survival. This effect was significantly augmented by simultaneous administration of anti-PD-L1 mAb. In the minimal disease setting of D5, ALDHhigh CSC-DC vaccination significantly inhibited tumor growth, reduced spontaneous lung metastases resulting in increased survival. CCR10 and its ligands were down-regulated on ALDHhigh D5 CSCs and in lung tissues respectively in animals subjected to ALDHhigh D5 CSC-DC vaccination. Down-regulation of CCR10 by siRNA significantly blocked tumor cell migration in vitro and metastasis in vivo. T cells harvested from ALDHhigh D5 CSC-DC vaccinated animals selectively killed the ALDHhigh D5 CSCs. There was also evidence of humoral immunological targeting of CSCs. As a result, CSC-DC vaccination significantly decreased the percentage of ALDHhigh cells in residual tumors. These data indicate that, when used in an adjuvant setting, ALDHhigh CSC-DC vaccines effectively inhibit local tumor recurrence, reduce spontaneous lung metastasis, and prolong animal survival; compared with traditional DC vaccines and that simultaneous PD-L1 blockade can significantly enhance this effect.
PP72. IMMUNE INFILTRATION OF TUMOR MICROENVIRONMENT FOLLOWING IMMUNOTHERAPY FOR GLIOBLASTOMA MULTIFORME
Mr Giannis Sokratous Mr Stavros Polyzoidis Prof Keyoumars Ashkan
Neuro Oncol (2017)
Published: 02 March 2017
Abstract
BACKGROUND: Autologous dendritic cell immunotherapy has been proven effective in treating tumours outside the central nervous system. Current evidence from phase I and II trials suggest a similar efficacy for central nervous system tumours as well and that an active immune response against these tumours can be generated.
OBJECTIVE: We aim to review the literature to identify the types of immune responses against gliomas found to be generated by dendritic cell vaccinations and the types of immune cells subsequently infiltrating the glioma microenvironment.
METHODS: A systematic review of the literature was performed by searching the online databases PubMEd, Google Scholar, and EMBASE with use of the keywords intratumoral, infiltration, lymphocytic, vaccination and gliomas.
RESULTS: Seven studies reporting lymphocytic infiltration of gliomas microenvironment were identified. Three studies (42.8%) reported presence of tumour infiltrating lymphocytes in 50%, 50% and 28.6% of included patients respectively in the post-vaccination specimens that were not present in the pre-vaccination samples. The remaining 4 (57.2%) reported an up to six-fold increase in the number of pre-existing lymphocytes following vaccination.
CONCLUSION: Present data indicate that tumour infiltration by lymphocytes can be induced by dendritic cell immunotherapy and that this may positively affect clinical outcome. It still remains unclear which factors influence the above reaction and therefore prediction of response to treatment is still not possible.
ATIM-14. FIRST KOREAN EXPERIENCE OF DENDRITE CELL-BASED IMMUNOTHERAPY IN PATIENTS WITH PRIMARY GLIOBLASTOMA
Jaejoon Lim Kyung gi Cho
Neuro Oncol (2016)
Published: 07 November 2016
Abstract
OBJECTIVE:
Dendritic cells are antigen presenting cells that recognize antigens and trigger an immune response in human immune system. Dendrite cell-based immunotherapy (DCI) has the potential to target and eliminate GBM cells. We evaluated the safety and efficacy of DCI in patients with primary glioblastoma.
MATERIALS AND METHODS:
The dendritic cells sensitized with self-tumor lysate, WT1 and KLH are intradermal injected on upper arm. We administrated the dendritic cells four times every two weeks and twice at intervals of two weeks after the 4weeks of rest period. We followed up patients two years. Treatment response was evaluated with CT and MRI, and immune response was evaluated with T cell proliferation assay and ELISPOT test. The Control group was set up to histological reference (newly diagnosed, standard treatment completed 24 patients).
RESULTS:
Thirteen patients received this immunotherapy. The total 83 related adverse events occurred. The eighty-two (Grade I) and one (Grade II) reactions were not serious adverse effects. Immune response (antigen specific IFN-? and T-cell proliferation) was confirmed. The median progression free survival (PFS) was 15.6 months and the median overall survival (OS) was 28.4 months. DCI led to an extension of PFS (8.2 months; wilcoxon p = 0.084) and OS (16.1 months; wilcoxon p = 0.029) compared to control group. In IDH-1 non-mutation with gross total resection patients group, DCI showed 27 months of survival advantage (wilcoxon p = 0.019) compared to control group.
CONCLUSION:
Dendritic cell-based Immunotherapy in patients with primary glioblastoma is comparative safe and had minor adverse reactions. DCI results in a longer PFS and OS compared to histological reference and well-tolerated. DCI is a good complementary treatment for primary glioblastoma.
PDCT-14. CHEMOTHERAPY BENEFITS SOME BUT NOT ALL HIGH GRADE GLIOMA PATIENTS
Yang Liu Christine Pittman
Neuro Oncol (2016) Published: 07 November 2016
Abstract
BACKGROUND:
Malignant glioma is frequently fatal. The current standard of care prolonged survival in phase III clinical trials. It is unclear though if these survival gains extend to the entire population of glioma patients.
METHODS:
We retrospectively collected patients registered in a population-based database for primary high grade gliomas (HGGs, n = 363) treated in Rochester, NY from 2000 to 2014. We analyzed survival trends and evaluated treatment efficacies for these patients. To externally validate our local population, we also performed survival and medication analysis for glioblastoma (GBM) patients from The Cancer Genome Atlas (TCGA) database.
RESULTS:
The median age at diagnosis was 61 years. The majority of patients were white (94.5%) with GBM (77.7%). Most (84.3%) had died (all causes) during the follow-up interval. Overall, patients who received combination treatment of surgery, RT and chemotherapy have better survival (median 490.0 days) than those who received combination of surgery and RT (median 239.0 days, p<0.001) or surgery alone (median 95.0 days, p<0.001). We further grouped patients into three time periods for comparison: 2000 to 2004, 2005 to 2009, and 2010 to 2014. We found no appreciable differences in the median, 6-month, and 2-year survivals between each time interval (median survival time: 368.0 vs. 360.0 vs. 358.0 days, respectively) for all HGGs. Survival of GBM patients slightly increased, but this was exactly offset by worsening survival rates for grade III patients. While survival did not measurably change, our temozolomide administration increased significantly over the time (42.1% vs. 80.5% vs. 73.1%). Bevacizumab usage rose from 6.3% to 50.3% as well during the time. Similar flat survival trends in the face of increasing chemotherapy use were seen from the TCGA cohort. Our data indicate that chemotherapy, while effective, has benefits to a smaller group of patients than currently receive it.
PP32. GROSS TOTAL RESECTION OF GLIOBLASTOMA MULTIFORME: INFLUENCING FACTORS AND SURVIVAL OUTCOMES - A SINGLE CENTRE EXPERIENCE
Mr Soumya Mukherjee Mr Gnanamurthy SivakumarMr Kenan Deniz Mr Robert Corns Mr Simon Thomson
Neuro Oncol (2017) 19 (suppl_1): i9-i10. DOI: Published: 02 March 2017
Abstract
BACKGROUND: Gross total resection (GTR) of glioblastoma multiforme (GBM) can be variably defined. One definition is tumour residuum < 0.175 cm3 that has notably been used by Stummer and colleagues. We studied factors influencing the extent of resection according to this definition of GTR and attendant overall survival (OS) and functional performance.
METHODS: Consecutive patients who underwent debulking surgery for histologically proven GBM between September 2013 and February 2016 by sub-specialty surgeons at a single institution were included. Data were collected on demographics, tumour location, tumour size pre- and post- debulking using volumetric analysis of magnetic resonance imaging, histology, oncological therapy and functional performance. Survival data and correlations were calculated using Kaplan–Meier and linear regression analyses.
RESULTS: 100 patients were analysed with a mean age of 59.9 years (range, 17 – 85 years), and a male:female ratio of 1:1. Mean tumour size pre- and post - operatively were 37.2 cm3 and 1.78 cm3, respectively, representing a mean 95% extent of resection. Median OS across the cohort was 14.9 months. Pre-operative WHO performance status was 0–1 in 60% of cases and 2 in 37% of cases, and there was no significant change in these proportions post-operatively (p > 0.05). GTR with tumour residuum < 0.175 cm3 was achieved in 66% of small tumours (< 37.2 cm3) whilst in 34% of large tumours (> 37.2 cm3) (p < 0.05). Furthermore, volume of tumour residuum was significantly correlated with pre-operative tumour volume on linear regression analysis (p = 0.01). GTR was achieved in 53% versus 29% of tumours involving a single versus multiple lobes respectively (p = 0.08). There was no difference in the number of GTRs achieved amongst tumours of dominant versus non-dominant lobes. There was no significant difference in median OS between patients who had undergone GTR versus subtotal resection as per Stummer’s definition (15.1 vs 14.9 months, respectively, Log-Rank, p = 0.40). We note that in this cohort nearly two-thirds of patients achieved > 99% extent of resection. Comparison of 24 patients with complete resection versus 52 patients with near total resection (thin rim of enhancement) versus 24 patients with subtotal resection did yield significant differences in survival (15.9 vs 13.2 vs 11.1 months respectively, Log-Rank p = 0.03).
CONCLUSIONS: Factors influencing GTR include pre-operative size of the tumour and involvement of more than one lobe. GTR as per Stummer’s definition does not appear to confer a survival advantage in our cohort but the vast majority of patients had very small tumour residuum. Categorising patients with respect to complete, near total and subtotal resection did yield small but significant differences in survival. Further prospective studies are needed to elucidate the most meaningful definition of gross total resection.
PP56. GLIOBLASTOMA OUTCOMES: THE UCLH / NHNN EXPERIENCE 2010–2016
Dr Michael Kosmin Dr Francesca Solda’ Dr Elena Wilson Dr Jeremy Rees Dr Naomi Fersht
Neuro Oncol (2017) Published: 02 March 2017
Abstract
INTRODUCTION: Chemo-radiotherapy (CRT) after maximal debulking surgery is the standard of care for patients with glioblastoma (GBM). This study reviews patient outcomes at our centre. Published data show worse outcomes for patients who present with GBM through A&E. This study further investigates this phenomenon by analysing outcomes for those patients fit enough to be treated with radical CRT.
METHODS: Patients with GBM operated on between 1 April 2010 and 5 October 2015 at NHNN, and then treated with CRT at UCLH, were included in the study cohort. Data on patient and tumour characteristics, initial patient presentation, CRT treatment and patient outcomes (progression (PFS) and overall survival (OS)) were collected from the electronic patient records and radiotherapy planning systems. Outcome data were censored on 22 March 2016. Survival analysis was performed using logrank test.
RESULTS: 134 patients were included in the analysis (55% male, 45% female). They had a median OS of 16 months, and median PFS of 10 months from start of CRT. 70% patients were alive at 1 year; 41% at 2 years. Improved OS was associated with ECOG performance status (PS=0 vs PS>0; p = 0.00212), type of surgery (biopsy vs partial/complete debulk; p<0.001), and age (<60yrs vs 60yrs; p<0.001). Strong but not statistically significant trends for OS were seen with MGMT status (methylated vs non-methylated; p = 0.053) and sex of patient, with females surviving longer (p = 0.14). 17 patients (13%) with IDH-1 mutation had a significantly improved OS (p=0.0432), with a median OS of 27 months. Patients who presented initially through A&E showed a non-significant trend towards reduced OS (p=0.054). This was not due to a significant difference in PS of this cohort: 41% of A&E presenters were PS 0 vs 47% of those that presented via other routes. There was no effect of tumour size (p=0.065), or time from surgery to CRT (p=0.63). Patients treated with Rapidarc intensity modulated radiotherapy did better than those treated with 3D conformal radiotherapy (p=0.028). Patients who had complete debulking surgery did not do significantly better than those who had partial debulking (p=0.24). Analysis of molecular phenotype showed no effect of Ki67 (p=0.98), EGFR amplification (0.068), or PTEN loss of heterozygosity (p=0.64).
CONCLUSION: The standard GBM prognostic criteria showed the expected trends in our patients. The 13% of patients with IDH-1 mutation had significantly extended OS. Patients who initially present through A&E showed a trend towards worse OS, but not one that was statistically significant. The aggressive phenotype of GBM that leads to rapid deterioration and poorer outcomes after A&E presentation (as described elsewhere) may be associated with a reduction in PS that precludes radical treatment. This cohort would have been excluded from this study of patients treated radically with CRT. Our data showed no correlation between GBM volume at diagnosis and OS. There is no early stage disease; once a GBM is large enough to become symptomatic, its outcomes are not predictable based on its size alone.
IMMU-12. IMMUNOTHERAPY OF WILMS TUMOR 1 PEPTIDE VACCINATION IMPROVE PROGNOSIS OF RECURRENT GLIOBLASTOMA AND DIFFUSE INTRINSIC PONTINE GLIOMA IN CHILDREN
Naoki Kagawa Yoshiko Hashii Ryuichi HirayamaYasuyoshi Chiba Hideyuki Arita Chisato YokotaTakamune Achiha Noriyuki Kijima Yasunori FujimotoNaoya Hashimoto
Published: 31 May 2017
Abstract
BACKGROUND: We have ever proven safety and effectiveness of Wilms tumor 1 peptide (WT1) vaccination for newly-diagnosed or recurrent glioblastomas (GBM) in adult. But pediatric GBM and diffuse intrinsic pontine glioma (DIPG) are known to differ from adult GBM biologically. A pilot study designed to investigate safety and effectiveness of Wilms tumor 1 peptide vaccination for recurrent GBM and DIPG in children was planned.
PATIENTS AND METHODS: HLA-A*2402–positive five children with recurrent malignant glioma (three spratentorial GBMs and two DIPGs) were registered in this clinical study of WT1 immunotherapy. In all children, the tumors were resistant to standard therapy including radiation and temozolomide. Patients received intradermal injections of an HLA-A*2402–restricted, WT1 peptide every week for 12 weeks. Patients with an effective response continued to be vaccinated until tumor progression occurred or performance status deteriorated. Tumor responses were evaluated based on MRI data by RANO (Response Assessment in Neuro-Oncology) criteria. Progression-free survival and overall survival after initial WT1 treatment were analysed.
RESULTS: In all patients, no severe adverse event was observed. The protocol was well tolerated in children. The 6-month progression-free survival rate was 40%. Progression-free survival and overall survival were significantly improved as compared with historical control in Osaka University Hospital. Two patients with supratentorial GBM are still alive more than three years.
CONCLUSIONS:This study showed that WT1 vaccine therapy against recurrent GBM and DIPG in HLA-A*2402–positive children was safe and improved their prognosis. Based on these results, further clinical studies of WT1 immunotherapy in children suffering from newly diagnosed or recurrent malignant glioma should be authorized.
HGG-05. CAN MULTIMODAL IMMUNOTHERAPY REPLACE RADIOCHEMOTHERAPY IN COMPLETELY RESECTED ADULT GBM?
Stefaan Van Gool Dimitri VanhauwaertFranceska Dedeurwaerdere Stefan Pfister Maria LuleiVolker Schirrmacher Wilfried Stuecker
Published: 31 May 2017
Abstract
Adults with GBM always relapse, even after complete resection. Therefore radiotherapy with broad margins around the resection cavity is mandatory part of the initial standard of care for these patients, aimed to maximize the local tumor control. Chemotherapy is aimed as function as radiosensitizer and to prolong disease-free survival. Nevertheless, most patients show local and/or even distant tumor re-occurrence more or less shortly after multimodal primary treatment. Hypotheses for this are the infiltrative character of the tumor cells, the residing non-dividing glioma cancer stem cells, chemoresistance, etc. IOZK was confronted with a patient (EORTC RPA class IV) who refused radiochemotherapy and maintenance chemotherapy after complete resection of a left occipital glioblastoma. Pathology showed tissue necrosis, angiogenesis, mitosis and atypical tumor cell nuclei. Molecular classification revealed glioblastoma, IDH wildtye, subtye RTK I. After immunodiagnostic blood sampling, the patient was treated with multimodal immunotherapy consisting of 2 cycles of 6 days Newcastle Disease Virus (NDV) infusions and local modulated electrohyperthermia (mEHT) sessions plus an autologous DC vaccine loaded with serum-derived NDV/mEHT-induced antigenic microparticles + NDV, and additionally four more treatments with NDV infusions + mEHT. Treatment was conducted without any side effect. We observed the induction of tumor antigen-specific IFN-producing T cells measured upon ex vivo stimulation with autologous DCs loaded with a GBM cell line in ELISPOT. At time of writing, 15 months after resection, the patient remains in complete remission with optimal Karnofsky performance index and good quality of life. The % PFS at 12 months in the Stupp 2005 paper is for the total group of patients with radiotherapy alone 9.1% (95%CI 5.8–12.4m). The patient history points to a potential change in paradigm that microscopic infiltrating GBM tumor cells might be brought under permanent control through the combined action of NDV, mEHT and the induction of memory T cells.
Is more better? The impact of extended adjuvant temozolomide in newly diagnosed glioblastoma: a secondary analysis of EORTC and NRG Oncology/RTOG
Deborah T. Blumenthal Thierry Gorlia Mark R. GilbertMichelle M. Kim L. Burt Nabors Warren P. MasonMonika E. Hegi Peixin Zhang Vassilis GolfinopoulosJames R. Perry
Published: 24 March 2017
Abstract
Background:
Radiation with concurrent and adjuvant (6 cycles) temozolomide (TMZ) is the established standard of postsurgical care for newly diagnosed glioblastoma (GBM). This regimen has been adopted with variations, including extending TMZ beyond 6 cycles. The optimal duration of maintenance therapy remains controversial.
Methods:
We performed pooled analysis of individual patient data from 4 randomized trials for newly diagnosed GBM. All patients who were progression free 28 days after cycle 6 were included. The decision to continue TMZ was per local practice and standards, and at the discretion of the treating physician. Patients were grouped into those treated with 6 cycles and those who continued beyond 6 cycles. Progression-free and overall survival were compared, adjusted by age, performance status, resection extent, and MGMTmethylation.
Results:
A total of 2214 GBM patients were included in the 4 trials. Of these, 624 qualified for analysis 291 continued maintenance TMZ until progression or up to 12 cycles, while 333 discontinued TMZ after 6 cycles. Adjusted for prognostic factors, treatment with more than 6 cycles of TMZ was associated with a somewhat improved progression-free survival (hazard ratio [HR] 0.80 [0.65–0.98], P = .03), in particular for patients with methylated MGMT (n = 342, HR 0.65 [0.50–0.85], P < .01). However, overall survival was not affected by the number of TMZ cycles (HR = 0.92 [0.71–1.19], P = .52), including the MGMT methylated subgroup (HR = 0.89 [0.63–1.26], P = .51).
Conclusions:
Continuing TMZ beyond 6 cycles was not shown to increase overall survival for newly diagnosed GBM.
Your comment about monitoring monitoring for pseudoprogression just needs the word "early" in front of pseudoprogression. Early is the only time the condition can mimic rapid progression. If late pseudoprogression just shows up in any arm of the study it signifies a progression event if it crosses size. Delayed pseudo response to standard of care treatments usually means there is more than just inflammation going on. And so one can hopefully see that there really shouldn't be an exception made for patients who mostly will have no evidence of tumor at baseline to be given a hall pass on their possible progression event. If it looks like and crosses progression later in the study, it should be treated like a progression event. The decision to continue therapy even after progression is where iRANO comes in. But this trial is not following iRANO. It doesn't need to as all patients are eligible to opt-in to open label crossover at that point.
But that approve "early" didn't answer your median question. The short answer is this trial removes patient that lower medians and so you really shouldn't expect a low blended median if the vaccine is delaying progression events. If the main arm were a placebo only trial (meaning dud vaccine) the median would like be anywhere between 10-12 months (depending on % delayed pseudo brings it down).
The long answer. I'm really in a rush so hoping this comes across clear and isn't taken out of context by skeptics. The delay has to do partially with the exclusion criteria. And partially due to vaccine hopefully. This Phase III trial in theory excluded most of the patients that are unresponsive to both chemotherapy and radiation therapy. True rapids have a higher likelihood of being unmethylation patients. But early disease progression patients do not just mean rapidly progression. Sometimes even the smallest change over a successful surgery can capture post radiation MRI result in what appears as tumor. It could mean that the trial is simply removing some patients that are not as responsive to one of those two therapies, meaning radiation or chemo. Both those sets of patients (rapids and eventual progression though not rapid) are the patients that bring down progression free survival medians -- meaning if the study had enrolled those patients, events could have occurred at Month 2, Month 4 and Month 6. If you think about the compassionate use patients, they didn't actually have confirmed documented events before Month 2. Only the patients that didn't make it to the Month 2 scan fit the description of confirmed progression at post RT MRI. And so all in all this study median progression free survival will benefit from removing the worst patients from entering enrollment.
Now understand, in addition to the patients who are completely or partially unresponsive to both radiation and chemotherapy, this trial it also removed a percentage of psuedoprogression prior to enrollment. And by that I mean some MGMT methylation patients who are both responsive to radiation and chemotherapy very early on. Or who were just very responsive to just chemotherapy. But pseudoprogression are not the patients that depress progression free survival median. Psuedos often don't do as well as non-progression patients progression, as sometimes their condition does get a little worse before it gets better, so as a group they may not necessarily have the best progression free survival medians, but they do sometimes do better or the same their non-progression newly diagnosed GBM peers. I would hypotheses that how well psuedos do on both progression and survival is going to depend on how much tumor was removed at initial newly diagnosed surgery. And so if a trial has a high rate of successful surgeries, and most of the patients who contribute early events are removed (relatively few 2, 4 or 6 month event, the non-progressive disease patients won't start recording events until Month 8. If patients in the main arm have had mostly successful surgeries, then the best response these patients are to be stable disease to partial response category. They can't be considered to have complete responses if they had no tumor to start with. If the main arm is responsive to at least radiation or chemo then progression events then they shouldn't start before 6 month scan. If main arm patients are responsive to both radiation and chemotherapy then majority of events start to occur before Month 8. Now T2/FLAIR typically does spot event about a month before it shows up as enhanced tumor and so probably if this were a placebo only trial that enrolled just a high mix of patients who do not have early psuedos scan that progress that progressively gets worse the median would probably fall 10-14 months depending on % of GTR, PR. The higher the blended is, the more likely the vaccine is contributing to the progression delay.
When thinking about how the three groups of patients could possibly do (this retrospective review includes novel therapies) might help show you what I mean on both Median PFS and OS.
RTHP-09. PROGRESSION AND PSEUDOPROGRESSION OF GLIOBLASTOMA MULTIFORME IN THE TEMOZOLOMIDE ERA
Lindsay Rowe John Butman Megan Mackey Joanna Shih Mary Hawes Theresa Cooley Zgela Holly Ning DeeDee Smart Mark Gilbert Kevin Camphausen ... Show more
Neuro Oncol (2016) 18 (suppl_6): vi175-vi176. DOI: https://doi.org/10.1093/neuonc/now212.735
Published: 07 November 2016
Abstract
BACKGROUND:
Standard of care for glioblastoma(GBM) includes temozolomide with radiotherapy. Pseudoprogression has been documented with increased frequency, complicating assessment of early imaging studies after chemoradiation (CRT). MATERIALS: Of 114 consecutive patients receiving CRT for newly diagnosed GBM at our institute between 1998 and 2015, 85 had pre and post-treatment charts and imaging suitable for retrospective evaluation using currently accepted RANO criteria. Patient status was classified at 3 months from baseline post-radiation imaging as, partial response/stable disease(PR/SD), pseudoprogression(PsP), and true progression(TP).
RESULTS:
At the three-month time point there were 37(43.5%) with PR/SD, 16(18.8%) PsP, and 23(27.0%) TP. Nine(10.7%) patients were not evaluable due to early initiation of bevacizumab. Age and sex were equally distributed between groups. Trends toward increased rates of gross total resection in PR/SD, and periventricular location for TP, were seen. Rates of MGMT methylation were 50%(PR/SD), 55.6%(PsP), and 16.7%(TP). Early imaging one month after the post-radiation baseline demonstrated increased contrast enhancement in all PsP cases (none had stabilized or improved), 93.7% had increased tumor perfusion (relative cerebral blood volume), and 50% had increased FLAIR signal. No differences were noted in mean tumor volumes, or location of pseudoprogression in reference to radiation isodose levels. Most importantly, for PR/SD, PsP, and TP, median PFS was 9.80, 9.07, and 4.16 months (p ? 0.0001) and median OS was 27.0, 20.7, and 14.0 months(p = 0.0042), respectively.
CONCLUSIONS:
Contrary to published reports, our data do not demonstrate an improvement in survival outcomes for patients with pseudoprogression compared to stable disease or response on first post-radiation imaging. Our data may be limited by patient numbers but importantly, there were no early imaging characteristics, including perfusion imaging, that differentiated pseudoprogression from true progression. These results underscore the need for continued investigations to develop non-invasive techniques to predict pseudoprogression and accurately predict overall survival.
Abeta,
It is very hard for me to read your post that run off the post on my iPhone.
False. All pseudoprogression are not proneural. Psuedoprogression signifies a positive response to therapy. In the context that we talk about pseudoprogression in GBM, we are mostly discussing early pseudoprogression. This is very important because as far as "false events" it's the Month 2 that we debate. (The patient blogs of late pseudoprogression is more likely to occur in the placebo arm (delayed reaction), and not the vaccine cohort. I've tried to explain that to this iHub before, but fail to have the energy to countlessly explain my logic.)
Early Pseudoprogression is a positive response of standard of care therapy working well resembles rapid progression appearance as it can look like progression on MRI scans. It is treatment-related radiographic changes directly after completion of concurrent chemotherapy and radiation. Adding additional therapy, like the vaccine can make it look worse earlier, particularly the closer it is injected towards radiation. Radiation makes the blood brain barrier more permeable to agents getting through and so once chemotherapy was added up front, the incidents of positive response to therapy started occurring earlier.
Think of pseudoprogression as a positive black and blue on an MRI. Think of rapid progression as a negative black and blue. One represents positive damage and the other represents negative damage. But initially the black and blue might look the same. The way that they tell the two apart is over the course of time. If they take follow-up MRIs, generally, but not always, the psuedoprogression appearance will not get progressively worse. Instead it will stabilize and dissipate and the "mimicking of black and blue progression" disappear over time. Whereas rapid progression black and blue will get progressively worse with time. It can't hid as the appearance of "false progression" for very long. If a patient is a true rapid progression the degree of damage will continue to get worse unless something positive is done about it.
Pseudoprogression doesn't signify a gene type. A therapy that works well can take place in all gene types.
Pseudoprogression is not progression. It is a known phenomenon and it is accounted for early in studies, including in MacDonald. When it is suspected response to INTRODUCTION to any novel treatment a follow confirmation scan is needed. RANO criteria made it mandatory to do retrospective review of early scans.
"Because novel treatments are likely to result in a higher than normal incidence of treatment-related increase in contrast enhancement (“pseudoprogression”, PsP) or decrease in contrast enhancement (“pseudoresponse”, PsR), patients should continue therapy with close observation (e.g. 4-8 week intervals) if there is a suspicion of PsP or PsR. If subsequent imaging studies and/or clinical observations demonstrate that progression in fact has occurred, the date of confirmed progression should be noted as the scan at which the potential progression was first identified. " -- modified RANO paper
Now understand that RANO step above already exists for conventional RANO.
Is it possibly for you to past the Figure 3 in this slide? This shows what a RANO pseudoprogression decision tree looks like starting at this Phase III trial baseline (it adds volume, which this trial doesn't do.)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398984/#!po=51.1765
The crutch of where AVII and I disagree when it comes to pseudoprogression is on the Month 2 scan. We disagree on whether a second scan is needed after TX begins. I perceive it is a must. The trial needs at least 3 scan on every patient before it can rule progression, with Baseline (at Post Radiation MRI) being the first scan. And Month 4 being the third scan. And it is my view that decisions on early progression events need to include a pseudoprogression decision tree.
AVII perceives that confirmation scans are not allowed for any scans that have growth over 25%, period. The decision for Month 2 scan needs to be made on the Month 2 visit. It doesn't matter that psuedoprogression is suspected contributor. He feels that blind central review will make a decision to "false progression" with the first set of scans after treatment (Month 2), and as such, in his opinion if Brad's Month 2 equivalent scans were seen in this Phase III.
However, I want this iHub to think about what we know about the trial enrollment and preliminary results (of when endpoints may have been and may be reached). I think doing so makes it that "false progression" events at Month 2 scan did NOT occur, and that instead, any "true and false progression" patient continued on treatment until Month 4 MRI where their rapid disease was either confirmed as progression and backdated to Month 2 or confirmed as possible psuedoprogression and they continued on treatment until their next scan at Month 6 to monitor their psuedoprogression or non-progression next MRI. It would be at Month 6 that the central imaging review decisions would start to be made and documented on the MRI visit. Month 4 visit would contain retrospective reviews only.
Okay so here is my logic that his speculative assertion is wrong based on the facts as we know it:
-- screening for the trial closed by August 2015.
- The trial enrolled roughly 305 patients by August 2015
-The trial enrolled 331 patients by November 2015.
-- The estimated primary endpoint, consisting of 248 expected progression events, was moved to November 2016.
-- The primary endpoint crossing of 248 and counting events was reported in Feb 2017.
Now if what AVII suggested that "false events" occurred on Month 2, then where are all those early false progression events?
Did we reach 248 progression events sometime shortly after enrollment closed? If AVII were correct and early pseudoprogression were wreaking havoc on this trial, then the trial would have well over 248 patient events roughly 2 months after enrollment closed AT THE LATEST, which means early 2016. It should have occurred earlier than that, but I'll use the latest, since by early 2016, all 331 patients will have reached their Month 2 MRI scan. If what he said occurred, then boom 248 events would have easily been crossed. And we would be waiting a very long time (possibly over 5 years or longer) for a great deal of these Month 2 early "false progression" event patients to convert to death (These would be the high TIL patients that we are talking about.) As a reminder he is proposing that on Month 2, the Brad Silver's of the study, who make it into the main arm, would be "no choice" but ruled progression on the account of "size", no confirmation scan allowed. And yet, we know that a possibly a year after enrollment closed the trial was still waiting for 25% of the study to reach 248 patient events. He understand that the Brad's of the study don't necessarily die. But he perceives they are deemed "progression" patients by central review, even if it is "false progression". AND SO that would mean that in addition to the 25% who have not experienced a progression event, there would be a decent percentage who experienced a "false progression" event (he pointed to 3 patients of the Phase I/II who he feels would be deemed "progression" even if false").
One has to realize that the "false progression" must be in addition to the percentage of progression events that remained outstanding. False progression after all would be mixed in with the primary endpoint events after all. And so, if his theory were accurate -- which hopefully you can see now that it isn't -- between non-progression and false progression, the trial would need to have a very high % of the trial who truly is without a true progression event. Instead of the trial having 25% outstanding events in October, it would have much more if the Brad's of the study scans were misdiagnosed. And as a reminder, according to his rule even placebo patients who display early psuedoprogression at Month 2 would need to be "falsely" removed as well if pseudoprogression showed up on Month 2 scan (which it would since most of can agree that not all the pseudos were removed at exclusion criteria). The trial is randomized by MGMT status, and so the placebo arm would also be at risk for Month 2 removals due to his "no confirmation" at Month 4 rule allowed. Now if 25% of events were outstanding in October 2016, meaning "non-progression" events, that would bring the trial to possibly 40% of combined true non-progression and "false" progression event. That's a very high amount of not real progression events some 15 months after screening (remember all 331 patients needed to enter into screening before it closed in August 2015). Yet, we also know that when progression endpoint was reported, the company expected OS to trigger a few months later. And so, it's virtually impossible that his "false progression" "too bad Charlie" speculative rule is in play. We would be waiting for OS for years from now. Instead 233 death events expected at any time. And so RANO is followed, and is at Month 2 scan it is as ICON states about suspected early pseudoprogression, patients come back at Month 4 to re-evaluate.
What do ICON state about RANO criteria as it relates to Psuedoprogression:
"Pseudoprogression:
-- Enhancement that simulates tumor growth, most often caused by radiation (whole brain or focal).
-- Growth of existing lesions or appearance of new lesions within 12 weeks of completion of radiation therapy may be the result of treatment effects rather than growth of tumor.
-- Continued follow-up imaging can determine whether initial lesion growth was true progression or pseudoprogression.:
-- If lesion continues to enlarge, the initial growth is called true progression.
-- If lesion stabilizes or shrinks, the initial growth is confirmed as pseudoprogression
-- In such cases, the baseline SPD is no longer included when choosing the nadir value for the purposes of determining when progression occurs.
-- Diffusion weighted imaging can help distinguish pseudoprogression from true tumor growth, but its use is still experimental. The use of MR perfusion and spectroscopy is also being explored. "- ICON
ICON central-imaging-core-lab:
http://www.iconplc.com/jp/our-services/imaging/central-imaging-core-lab-/regulatory-expertise/IMI-RANO-Critieria-Booklet-Nov-2011.pdf
Born and raised in LI. :)
This month marks 7 years since Anothony passed away. Always a very hard month for my brother and sister-in-law to get through. They are not actively waiting for the study news. But then again they know (probably because of events surrounding Anthony's case) that he received Placebo. (Could also be the year, as the company was very close to closing the doors -- honestly not sure how they know). Very few patients enrolled back then (11 according to SEC statements). He survived 22 months from the time of his initial diagnosis. For a 22 year old diagnosed patient, that's in line with SoC and multiple surgeries days apart, the second of which was at NYU which had the top-of-line equipment at the time (Stonybrook didn't at the time -- hence why he needed a second, which qualified still as nGBM and entry into the trial). From the time of his randomization it's much less. He was obviously enrolled in the Vanguard period, straight MacDonald -- which is one of the reasons that patient portion of the trial data has specific statistical analysis considerations with how it's incorporated into the full data. Had this trial had RANO at the time, I believe they would have found his recurrence sooner, and the radiologist wouldn't have messed up missing progression in the real month it occurred, about 14 months after randomization. I speculate that they will learn that use of RANO T2/FLAIR in this trial means less in-between visits (at home) progression events. It also should allow patients to not miss the 3 month window (dated from progression) to opt-in for their crossover vaccine. Anyway, it's been a long time coming for me to final see trial closure will be a sigh of relief regardless of the outcome. A few months more and I believe so much will be learned from this trial that will pave the way to change in his GBM patients are treated. So much of the focus on this message board is on the science, the trial particulars, the company and ins and outs the market and the stock. Every once in a while it's good to be reminded that clinical patients contribute standardizing their cancer care -- essentially risking their lives -- for the advancement of science. My sincere heartfelt thanks and appreciation to all the patients who have dedicated their lives to scientific research -- both past and present, deceased and living -- as the contributions you have collectively made continue to change how care is given and received today and all of our tomorrows. Happy 4th of July everyone.
Back to patiently waiting.
Regina
Yes, it should dawn on folks that what I have said all along has been accurate -- 100% so. A confirmation is always used when suspicion of pseudoprogression is at play. Spelled out, crystal clear that nGBM gross total resection patients often have changes in earlier MRI readings that do not signify tumor -- follow-up and monitor scans. Should note, that hasn't changed, as it was something they starting doing from observations that bringing chemotherapy upfront with radiation caused a phenomenon to occur earlier.
Also, years ago I noted that this Phase III trials baseline (Post Radiation MRI) was a very superior start time to begin monitoring response. Many of the changes associates with other GBM standard of care variables are reduced at that time point (go down as adjuvant chemotherapy continue). But there will be psuedos that make it into the main arm like I stated too. And now it seems that it is recommended that all newly diagnosed GBM trials start that time, to standardize them to where this study's baseline begins. It's interesting too that they pick that time point. Why? Well if DCVax-L is approved, therapies that used a placebo control would then to test along with the new standard of care (DCVax-L).
They also note what I've been saying about T2/Flair spotting progression sooner than MacDonald criteria. In this trial, it likely is helping the opt-in crossover patients get their vaccine sooner, and avoid a time to treatment delay that the prior Phase I/II ran into.
And to think so many longs here have jumped on the skeptic bandwagon to think that a "sorry Charlie" approach at Month 2 scan was being done on transient size changes (I.e., Brad's). If that were true then the primary endpoint would have hit years ago as even placebo patients will exhibit pseudoprogression on the Month 2 scan (treatment first testing scan), on the account of residual but delayed affects of concurrent RT/TMZ. But I digress.
Live in NY. Happy everything. :)
Modified Criteria for Radiographic Response Assessment in Glioblastoma Clinical Trials
Benjamin M. Ellingson, 1,2,3,5 Patrick Y. Wen,4 and Timothy F. Cloughesy5,6
Abstract
Radiographic endpoints including response and progression are important for the evaluation of new glioblastoma therapies. The current RANO criteria was developed to overcome many of the challenges identified with previous guidelines for response assessment, however, significant challenges and limitations remain. The current recommendations build on the strengths of the current RANO criteria, while addressing many of these limitations. Modifications to the current RANO criteria include suggestions for volumetric response evaluation, use contrast enhanced T1 subtraction maps to increase lesion conspicuity, removal of qualitative non-enhancing tumor assessment requirements, use of the post-radiation time point as the baseline for newly diagnosed glioblastoma response assessment, and “treatment-agnostic” response assessment rubrics for identifying pseudoprogression, pseudoresponse, and a confirmed durable response in newly diagnosed and recurrent glioblastoma trials.
Introduction
Approximately 89,000 new primary brain tumors are diagnosed in the United States each year, for which 27% are gliomas and 32.8% are malignant [1]. Glioblastoma (GBM) occurs in approximately 46% of gliomas [1] and has a poor prognosis of around 14 months median survival [2] and less than 10% of patients live longer than 5 years from diagnosis [3]. The current standard of care for newly diagnosed GBM patients consists of maximum safe surgical resection followed by external beam radiation therapy plus concomitant and adjuvant temozolomide [2], particularly in patients that demonstrate O6-methylguanine-methyltransferase (MGMT) promoter methylation. At recurrence there is no consensus as to the standard of care as no therapeutic options have produced substantial survival benefit [4].
Although overall survival (OS) is the standard for determining GBM treatment efficacy, using OS as an endpoint when studying new therapeutic strategies can be problematic because of potential influence of therapies prior to or subsequently following the therapy being studied. For example, it is difficult to definitively conclude that bevacizumab has no efficacy in GBM when a large percentage of patients in the placebo arms in both III trials studying efficacy of bevacizumab (i.e. AVAglio and RTOG-0825) eventually crossed over and received bevacizumab (31% in AVAglio [5] and 48% in RTOG-0825 [6]). If bevacizumab increased OS when given at any time during treatment, we may expect both treatment arms to have similar median OS since most patients eventually were treated with bevacizumab, disguising any therapeutic effects of the drug. Together, these results suggest OS may not be a suitable endpoint when studying new therapeutics or when there is a high chance of cross over in the control arm.
To overcome the limitations associated with using OS as the primary endpoint in studies involving new therapeutics, progression-free survival (PFS) and objective response rate (ORR) should be considered important end points [7]. However, PFS and ORR also have challenges, as determination of response and progression using anatomic imaging techniques may suffer from issues associated with measurement variability and discordance in interpretation between radiologists [8]. Therefore, it is important to develop both new response guidelines for identifying these issues as well as new imaging tools for better differentiating treatment-related changes from changes associated with non-responsive, growing tumor.
The goal of this modified response criteria is to meaningfully evaluate radiographic response and progression while simultaneously allowing therapies that may have transient effects on contrast enhancement but therapeutic benefit to be treated equally. This is particularly important in the context of platform trials, where many different therapies may be compared against a common control and there is a significant risk of over or under estimating tumor burden with a single evaluation time point. By allowing patients to stay on therapy longer, a more comprehensive and accurate assessment of therapeutic benefit can be performed on retrospective examination. A universal set of principles and guidelines, rather than treatment-specific response criteria, may allow us to fully understand the possible therapeutic benefits and potential limitations of promising new therapies for patients with GBM.
Brief History of Radiologic Response Assessment in GBM
The formation of new blood vessels, or angiogenesis, is critical for the growth of malignant brain tumors [9–11]. Malignant gliomas with high neovascularity or vascular permeability [12–14] are often associated with higher proliferation rates [15] and higher degree of aggressivity. Because of this association, imaging techniques aimed at identifying abnormal vascularity or vascular permeability, including contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are commonly used for diagnosis and clinical management of brain tumors, as they have been shown to contain the most aggressive portions of the tumor [16, 17].
In 1990, Macdonald et al. [18] introduced the first radiographic response assessment specific to brain tumors by significantly improving upon the Levin criteria [19] and the WHO oncology response criteria [20]. By standardizing the definition of radiographic response using quantitative bidirectional measurements and accounting for corticosteroid use in neurological status, similar to the response evaluation criteria in solid tumors (RECIST) [21], the new “Macdonald criteria” utilized measurements of contrast enhancing tumor size combined with other clinical metrics to determine treatment response and tumor progression by stratifying response into four categories: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). The original Macdonald criteria continues to be the fundamental framework for response assessment and radiographic interpretation of treatment changes in neuro-oncology, having been used for more than 20 years.
Known Limitations for Current Response Criteria
Although contrast enhancement has been used to assess brain tumor response for more than 60 years and contrast enhancement is generally a strong surrogate of brain tumor disease, there are caveats and exceptions that have been discovered as a result of different treatment mechanisms that affect vascular permeability. For example, increased vascular permeability from cytotoxic therapies including radiotherapy and anti-neoplastic treatments have been shown to result in increased contrast enhancement in the context of therapeutic benefit, a phenomena known as “pseudoprogression.” Additionally, clinical studies examining the efficacy of new anti-angiogenic agents have noticed a substantial decrease in contrast enhancement [22–31] resulting in high response rates, ranging from 28 to 63% in bevacizumab [32–34] and 50% in cediranib [31] compared with?<?10% using other chemotherapies [35–38], which translated into prolonged PFS but no difference in OS [31, 32]. It was assumed this high response rate was due to the use of contrast enhancement as the primary tool for evaluation in the Macdonald criteria, which resulted in a “pseudoresponse”[39], where contrast enhancement is falsely reduced due to changes in vascular permeability independent of anti-tumor effect.
In addition to increased response rates, studies examining tumor relapse/progression while on anti-angiogenic agents note a tendency for growth of nonenhancing, infiltrative tumor prior to emergence of contrast enhancement [25]. Approximately 30-40% of patients are estimated to experience non-enhancing tumor progression prior to changes in contrast enhancement [40, 41]. Malignant gliomas are known to contain proportions of both neovascularized and infiltrative tumor [42, 43] and the relative proportions are thought to reflect different biological phenotypes [44–48]. In 2010, expert opinion and examination of these limitations resulted in the creation of a formal Response Assessment in Neuro-Oncology (RANO) criteria [49] to comprehensively reform the Macdonald criteria using previously documented perspectives and approaches [50–52].
Although the RANO criteria corrects for a number of insufficiencies identified in the Macdonald criteria including inclusion of the evaluation of nonenhancing tumor progression and issues associated with pseudoresponse and pseudoprogression, there remain significant limitations to the current standard RANO criteria given recent data. For example, the current RANO criteria requires use of bidirectional measurements of contrast enhancing tumor size, which have been shown to overestimate tumor volume [53] and result in higher reader discordance [8, 54–59], presumably due to differences in head tilt and accurate identification of longest and perpendicular diameter in relatively irregular tumors. Other studies have shown reasonable agreement between bidimensional and volumetric measurements [60, 61], suggesting quick bidimensional assessment of contrast enhancing tumor size may be a practical alternative to more sophisticated volumetric segmentation. Additionally, the thresholds used to define response and progression is relatively arbitrary and not optimized based on scientific data showing the best correlation with survival benefit or time to treatment failure. (Note: The efficacy of these thresholds remains to be sufficiently challenged). Also, the use of thresholds based on “percentage change” with respect to baseline tumor size are significantly biased toward small tumors where relatively low absolute changes in tumor size are interpreted as a large percentage change [61]. This is particularly an issue in newly diagnosed GBM studies, where patients with tiny tumors often progress early due to triggering of progression (PD) when “non-measurable disease”, defined as having the two largest perpendicular diameters of a contrast enhancing target lesion less than 10mm, reaches the subtle threshold of “measurable disease”. Lastly, although changes in non-enhancing disease were added to the RANO criteria in an attempt to identify non-enhancing tumor progression, particularly in the presence of anti-angiogenic therapy, retrospective evaluations in clinical trials have shown it results in PD approximately a month prior to contrast enhancing disease progression [62], does not result in significant differences in prediction of OS [62, 63], and is one of the most controversial aspects of RANO evaluation due to the subjective nature of the interpretation and high adjudication rates. Further, studies have shown that specific aspects of non-enhancing tumor progression (e.g. circumscribed vs. infiltrative T2 changes) result in dramatically different post-progression survival in GBM patients [41], suggesting evaluation of non-enhancing tumor progression using T2 and/or FLAIR may be more complex than once thought and warrant further investigation before it can be properly integrated as an early radiographic endpoint. Further, new immunotherapy agents can also cause inflammation leading to changes in T2 signal intensity that is ambiguous with regard to interpretation of changes in tumor biology.
Updated Strategies for Response Assessment in Neuro-Oncology: Modified RANO Criteria
Based on these various challenges, an update to the current response criteria is necessary in an attempt to establish a general framework for response assessment in neuro-oncology that is agnostic to the mechanism of action of the particular therapy (e.g. anti-angiogenic, anti-neoplastic, immunotherapy, etc.), each of which has its own challenges associated with interpretation of radiographic changes, and is updated based on recent scientific evidence and current clinical convention. In order to advance the RANO criteria and address these challenges we propose the following “modified” RANO criteria for use in evaluating therapeutic efficacy in patients with GBM.
Image Acquisition Requirements
In response to a need for better standardization of image acquisition in GBM clinical trials [64], a recent consensus paper was published outlining an “international brain tumor imaging protocol (BTIP)” (Table1) with recommended sequences and parameters [65]. At the core of this recommended protocol is parameter matched, pre- and post-contrast 3D (volumetric) inversion recovery gradient recalled echo (IR-GRE) images with less than 1.5-mm isotropic resolution, which allows for both bidimensional and volumetric measurements of enhancing tumor. When possible, this protocol should be employed for prospective clinical trials.
table ft1table-wrap mode=article t1
International Standardized Brain Tumor Imaging Protocol (BTIP) minimum image acquisition requirements for 1.5T and 3T MR systems
If volumetric acquisition is not employed, or if retrospective evaluations of existing trial data are performed, then slice thickness plus interslice gap should be less than 5 mm. If the sum of the slice thickness and gap exceeds 5 mm, then slightly modified definitions of measurable disease should be used (e.g. measurable disease?=?largest perpendicular diameters?>?2× slice thickness?+?gap).
Contrast Enhanced T1-Weighted Digital Subtraction Maps for Increased Lesion Conspicuity
Quantification of contrast enhancing tumor size or volume should be performed on contrast-enhanced T1-weighted digital subtraction maps (Fig. 1) in order to increase lesion conspicuity and better predict tumor burden in the presence of reduced vascular permeability as occurs during anti-angiogenic therapy [66] and/or T1 shortening from blood products or calcifications [67, 68]. Further, the American College of Radiology (ACR) recommends this approach for identification and delineation of subtly enhancing bone and soft tissue lesions [69].
Bidimensional and/or Volumetric Measurements
Similar to the current RANO criteria, two-dimensional, perpendicular measurements of contrast enhancing tumor size, excluding the resection cavity along with any cysts or areas of central macroscopic necrosis, should be used for response assessment if volumetric tools are not available. Table 2 outlines suggested volumetric conversions from two- to three-dimensional measurements for consistency in response definitions, as outlined by Chappell et al. [70].
Bidimensional to volumetric definitions [54, 70, 96] of radiographic response and progressionIt is important to note that the field remains conflicted on whether or not enhancing disease should be included in tumor size measurements, or whether it is more appropriate to monitor total enhancing lesion volume, which may include central macroscopic necrosis and any cystic components (but excluding surgically resected tissue). Scientific studies have shown that both approaches for quantifying change in tumor size as a surrogate of treatment response are valuable. Multiple studies utilizing the Macdonald and RANO criteria have shown that change in enhancing disease size using bidimensional measurements, excluding necrosis and cystic components, can be used to predict survival in a variety of therapies. A recent study from the BRAIN trial, a phase II trial of bevacizumab with or without irinotecan in recurrent GBM, confirmed that change in the volume of enhancing disease can be used to predict survival benefit [66]. However, a recent study examining growth rates in treatment naïve presurgical GBMs showed that changes in enhancing disease only may not be reliable, since changes occurring prior to any therapy often showed stable or decreasing tumor enhancing disease volume [61]. Growth rates were universally positive (i.e. growing) when total lesion volume (including central necrosis) were taken into consideration, which appears more realistic given the fast growth trajectory of these tumors during therapeutic intervention. Regardless, future studies are warranted to determine which measurement may be more clinically meaningful or reliable in predicting early response to new therapies.
Definition of Measurable Disease, Non-Measurable Disease, and Target Lesions
Measurable disease should be defined as contrast enhancing lesions with a minimum size of both perpendicular measurements greater than or equal to 10mm (Fig. 2). For example, if the largest diameter is 15 mm but the perpendicular diameter is 8 mm, this would constitute non-measurable disease. Additionally, in the event that the BTIP protocol is not used, if the slice thickness plus interslice gap is greater than 5mm, then the minimum size for both perpendicular measurements should be twice the sum of the slice thickness and interslice gap (e.g. if the slice thickness is 5mm with 1.5mm interslice gap, the minimum tumor size on both perpendicular dimensions should be 13 mm). Up to a total of five target measurable lesions should be defined and ranked from largest to smallest (Fig. 2).
Algorithm for identifying measurable and target lesionsNon-measurable disease should be defined as lesions that are too small to be measured (less than 1 cm in both perpendicular dimensions), lesions that lack contrast enhancement (non-enhancing disease), or lesions that contain a poorly defined margin that cannot be measured or segmented with confidence.
Correction for “Baseline Tumor Volume” in Newly Diagnosed and Recurrent GBM
An abundance of single center, multicenter, and phase I-III trials have confirmed that baseline contrast enhancing tumor size (volume or bidirectional measurements) is a significant prognostic factor contributing to overall survival (OS) in GBM. In newly diagnosed GBM, both extent of resection [3, 71–87] and post-surgical residual volume [83–85, 88–92] have been shown to be prognostic. Similarly, baseline pre-treatment contrast enhanced tumor size has also been shown to be prognostic for OS in recurrent GBM [53, 66, 93]. However, from a clinical trial perspective, post-surgical residual enhancing tumor volume may be a more practical measurement to obtain, as pre-surgical MRI scans are often not available or collected as part of clinical trials because patients are not enrolled until after surgery and diagnosis. Thus, care should be made to make sure baseline tumor size is a stratification factor during randomization (i.e. prospectively balanced across treatment arms) and used as a covariate in statistical models evaluating treatment efficacy.
Post-Radiation MRI Examination as the Reference for Evaluating Radiographic Response in Newly Diagnosed GBM
The current RANO criterion defines the post-surgical MRI scan as the baseline for treatment response evaluation; however, we propose using the post-radiation examination (i.e. the first scan following completion of concurrent radiation therapy and chemotherapies such as temozolomide and/or experimental therapeutics) as the baseline for response assessment because reliability of tumor assessment on the post-surgical MR scans can be problematic for a number of reasons. First, this scan is typically acquired prior to a final pathological diagnosis, thus patients are not yet enrolled in a clinical trial and therefore the imaging protocol may not be consistent with trial recommendations, leading to a mismatch between the baseline and subsequent follow-up time points. Secondly, post-operative MR scans are often contaminated with post-surgical changes including blood products and increased vascular permeability from surgical trauma. Thirdly, steroid dose can be highly variable during this time and may be poorly annotated, as patients are typically not yet enrolled in clinical trials at this point. Additionally, the timing of the post-operative MR scans can be highly variable from patient to patient, depending on the complexity of the surgery and potential intraoperative complications, and institution by institution, as many factors including availability of inpatient MR scanners can lead to different timing of the post-surgical MRI evaluation. This variability inevitably leads to differing degrees of post-surgical artifacts and fluid levels on the resulting images. Together, these factors appear to indicate the post-surgical MRI examination may not be a reliable reference scan for accurately determining radiographic changes, despite post-surgical residual enhancing volume being a significant prognostic factor as outlined above.
Perhaps the most compelling argument for using the post-radiation scan as the baseline for determining response assessment is the highly unpredictable, transient radiographic changes that often accompany the initial chemoradiation phase (i.e. external beam radiation therapy plus concurrent temozolomide) with or without experimental therapeutics. Within 1 month after completion of standard chemoradiation therapy, approximately 50% of patients will experience radiographic changes suggestive of early tumor progression in reference to the post-surgical MRI exam, of which 50% are likely to have pseudoprogression (i.e. 25% of all patients at 1 month post-chemoradiation are estimated to have pseudoprogression) [94]. This proportion of patients with both early progression and pseudoprogression decreases steadily during the subsequent standard adjuvant chemotherapy phase, which forms the basis for current RANO recommendations of excluding patients in recurrent GBM trials who progressed within 3 months after completion of chemoradiation. Many clinicians are reluctant to change therapy based on this examination due to the relatively high incidence of treatment-related radiographic changes directly after completion of concurrent chemotherapy and radiation, and instead use this scan as a new baseline in which to interpret subsequent changes in tumor size. Additionally, experimental therapeutics that significantly alter vascular permeability, including anti-angiogenic and immunotherapies, when used concurrently with radiation therapy and temozolomide often demonstrate dramatic and transient changes in contrast enhancement that quickly stabilize following completion of radiation [95]. Despite the improved lesion conspicuity on T1 subtraction maps in the settings of these therapies, these early changes between the post-surgical, pre-radiation exam and the post-radiation exam may not accurately reflect true changes in tumor burden nor predict long-term survival benefit [95].
Detailed Definitions Used for Modified Radiographic Response Assessment Criteria
Radiographic response should be determined in comparison to the tumor measurements obtained at baseline (post-radiation scan will be baseline for newly diagnosed GBM and pre-treatment scans will be the baseline for recurrent GBM) for determination of response, and the smallest tumor measurement at either pre-treatment baseline or following initiation of therapy for determining progression.
Because novel treatments are likely to result in a higher than normal incidence of treatment-related increase in contrast enhancement (“pseudoprogression”, PsP) or decrease in contrast enhancement (“pseudoresponse”, PsR), patients should continue therapy with close observation (e.g. 4-8 week intervals) if there is a suspicion of PsP or PsR. If subsequent imaging studies and/or clinical observations demonstrate that progression in fact has occurred, the date of confirmed progression should be noted as the scan at which the potential progression was first identified. Definitions for complete response, partial response, progressive disease, and stable disease should be defined as follows for all target lesions.
Complete Response (CR): Requires all of the following:
1. Disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks. The first scan exhibiting disappearance of all enhancing measurable and non-measurable disease is considered “preliminary CR”. If the second scan exhibits measurable enhancing disease with respect to the “preliminary CR” scan, then the response is not sustained, noted as pseudoresponse, PsR, and is now considered “preliminary PD” (note confirmed PD requires at least two sequential increases in tumor volume). If the second scan continues to exhibit disappearance of enhancing disease or emergence of non-measurable disease (less than 10mm bidimensional product), it is considered a durable CR and the patient should continue on therapy until confirmed PD is observed.
2. Patients must be off corticosteroids (or on physiologic replacement doses only).
3. Stable or improved clinical assessments (i.e. neurological examinations).
Note: Patients with non-measurable disease only at baseline cannot have CR; the best response possible is stable disease (SD).
Partial Response (PR): Requires all of the following:
1. ≥50% decrease in sum of products of perpendicular diameters or ≥65% decrease in total volume [54, 70, 96] of all measurable enhancing lesions compared with baseline, sustained for at least 4 weeks. The first scan exhibiting ≥50% decrease in sum of products of perpendicular diameters or ≥65% decrease in total volume [54, 70, 96] of all measurable enhancing lesions compared with baseline is considered “preliminary PR”. If the second scan exhibits PD with respect to the “preliminary PR” scan, then the response is not sustained, noted as pseudoresponse, PsR, and is now considered “preliminary PD” (note confirmed PD requires at least two sequential increases in tumor volume). If the second scan exhibits SD, PR, or CR, it is considered a durable PR and the patient should continue on therapy until confirmed PD is observed.
2. Steroid dose should be the same or lower compared with baseline scan.
3. Stable or improved clinical assessments.
Note: Patients with non-measurable disease only at baseline cannot have PR; the best response possible is stable disease (SD).
Progressive Disease (PD): Defined by any of the following:
1. At least two sequential scans separated by at ≥4 weeks both exhibiting ≥25% increase in sum of products of perpendicular diameters or ≥40% increase in total volume [54, 70, 96] of enhancing lesions. The first scan exhibiting ≥25% increase in sum of products of perpendicular diameters or ≥40% increase in total volume [54, 70, 96] of enhancing lesions should be compared to the smallest tumor measurement obtained either at baseline (if no decrease) or best response (on stable or increasing steroid dose) and is noted as “preliminary PD.” If the second scan at least 4 weeks later exhibits a subsequent ≥25% increase in sum of products of perpendicular diameters or ≥40% increase in total volume of enhancing lesions relative to the “preliminary PD” scan, it is considered “confirmed PD” and the patient should discontinue therapy. If the second scan at least 4 weeks later exhibits SD or PR/CR, this scan showing “preliminary PD” is noted as “pseudoprogression”, PsP, and the patient should continue on therapy until a second increase in tumor size relative to the PsP scan is observed. Note that any new measurable (>10mm x 10mm) enhancing lesions should not be immediately considered PD, but instead should be added to the sum of bidimensional products or total volume representing the entire enhancing tumor burden.
2. In the case where the baseline or best response demonstrates no measurable enhancing disease (visible or not visible), then any new measurable (>10mm x 10mm) enhancing lesions are considered PD after confirmed by a subsequent scan ≥4 weeks exhibiting ≥25% increase in sum of products of perpendicular diameters or ≥40% increase in total volume of enhancing lesions [54, 70, 96] relative to the scan first illustrating new measurable disease. The first scan exhibiting new measurable disease is noted as “preliminary PD.” If the second scan at least 4 weeks later exhibits a subsequent ≥25% increase in sum of products of perpendicular diameters or ≥40% increase in total volume [54, 70, 96] of enhancing lesions relative to the “preliminary PD” scan it is considered “confirmed PD” and the patient should discontinue therapy. If the second scan at least 4 weeks later exhibits SD, CR, PR, or becomes non-measurable, this scan showing “preliminary PD” is noted as “pseudoprogression”, PsP, and the patient should continue on therapy until a second increase in tumor size relative to the “preliminary PD”, or PsP, scan is observed. Note that any new measurable (>10mm x 10mm) enhancing lesions on the subsequent scan following the preliminary PD scan should not be immediately considered confirmed PD, but instead should be added to the sum of bidimensional products or total volume representing the entire enhancing tumor burden.
3. Clear clinical deterioration not attributable to other causes apart from tumor (e.g. seizures, medication adverse effects, therapy complications, stroke, infection) or attributable to changes in steroid dose.
4. Failure to return for evaluation as a result of death or deteriorating condition.
Stable Disease (SD): Requires all of the following:
1. Does not qualify for CR, PR, or PD as defined above. Note this also applies to patients that demonstrate PsR when the confirmation scan does not show PD or PsP when the confirmation scan does not show PR/CR.
2. In the event that corticosteroid dose was increased (for new symptoms/signs) without confirmation of disease progression on neuroimaging, and subsequent follow-up imaging shows that the steroid increase was required because of disease progression, the last scan considered to show stable disease will be the scan obtained when the corticosteroid dose was equivalent to the baseline dose.
Symptomatic Deterioration & Reporting Clinical Status
Patients with global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time, and not either related to study treatment or other medical conditions, should be reported as PD due to “symptomatic deterioration.” Every effort should be made to document the objective progression even after discontinuation of treatment due to symptomatic deterioration. Neurological exam data should be provided to the independent radiologic facility as “stable, better, worse” in case report forms or from study sponsor. Clinical status should be recorded as “worse” if the neurological exam is worse, otherwise the clinical status should be set to “not worse.” In the event that necessary clinical data is not available, clinical status should be recorded as “not available” and that particular time point can only be reviewed for PD (otherwise “non-evaluable”). Neurological data must be within ±7 days of the time-point response date, otherwise the data is considered “not available”.
Steroid Use and Dose
Steroid use should be derived from the concomitant medications on the case report forms and recorded as “Yes”, “No”, or “not available”. A value of “No” should be assigned if, at the time-point, the subject is not on steroids or on physiologic replacement doses only (<1.5 mg dexamethasone or equivalent per day).
Steroid dose should be derived from the concomitant medications on the case report forms. Average steroid dose no greater than 2 mg change from baseline should be abstracted to “stable”. If outside this range the steroid dose should be abstracted to “increased” or “decreased” accordingly. Steroid data should be within ±5 days of the time-point response date, otherwise the data is considered “not available”.
Overall Objective Status
The overall objective status for an evaluation should be determined by combining the patient’s radiographic response on target lesions, new disease, neurological status, and steroid dose/usage as defined in Table
Table3
3 for patients with measurable (>10mm x 10mm) disease. Note that patients with possible PsP or pseudoresponse should be given the Objective Status of “Preliminary Progression” or “Preliminary Response”, respectively. Once PsP, pseudoresponse, or true progression/response are confirmed, the Objective Status can be changed accordingly.
Detailed Modified Radiographic Response Assessment Rubric
In order to provide both clinical guidelines for continuing therapy beyond suspected radiographic progression if the treating physician believes there may be a therapeutic benefit and to provide criteria for defining progression and early drug failure while also allowing for the possibility of PsP and PsR, a modified response rubric similar to those described recently [97] should be employed. Two different rubrics should be used depending on whether the patient is newly diagnosed or enrolled in a trial for recurrent disease.
It is important to note that the primary differences between conventional RANO and the proposed modified criteria are: (1) use of the post-radiation time point as the baseline for response evaluation in newly diagnosed GBM and (2) considering only objectively defined, measurable enhancing disease in the definition of response and progression (i.e. exclusion of qualitatively assessed T2/FLAIR changes).
Newly Diagnosed GBM (Fig. 3)
Fig. 3
Modified radiographic response assessment rubric for management of both pseudoprogression and pseudoresponse in newly diagnosed glioblastomaNewly diagnosed GBM patients will initially undergo a pre-entry MRI scan for initial diagnosis prior to entry in the study and prior to therapy. The post-operative scan [MRI(0)] is desired in order to assess residual enhancing disease volume for use as a covariate in survival analyses, as described previously. Patients will then start on standard or experimental therapy with concurrent radiation therapy (RT). The Post-RT scan [MRI(1)] will be required and used as the baseline scan for which response will be determined.1 Following the first cycles of adjuvant therapy, patients will receive additional required MRI scans [MRI(N)].
Recurrent GBM (Fig. 4)
Fig. 4
Modified radiographic response assessment rubric for recurrent glioblastomaRecurrent GBM patients will undergo a pre-entry MRI scan [MRI(0)] at the time of recurrence. At the time of study entry, two scans to confirm progression should be submitted consisting of at least one scan at the time of progression and one scan at Nadir or baseline. If the patient undergoes surgery (optional), then the post-surgical, pre-treatment MRI can be used as the baseline [MRI(1)], assuming it is obtained?<?72 hours from surgery to reduce post-operative reactive enhancement [91, 98]. (Note: If the post-operative MRI scan is used as the baseline reference, the standardized MRI protocols must be used.) If the patient does not go to surgery or if the start of treatment is?>?21 days from the start of therapy, the patient will undergo a pre-treatment MRI [MRI(1)] scan as the baseline scan for which response will be determined. Following the first cycles of therapy, patients will receive additional MRI scans [MRI(N)].
Details Common to Both Newly Diagnosed and Recurrent GBM
Preliminary Radiographic Progression
If the lesion size has increased ≥25% sum of bidirectional product or ≥40% in volume between MRI Scan 1 and N, these patients should be categorized as “preliminary radiographic progression”. If the investigator believes the patient can safely continue on therapy, then they should continue to treat and acquire a follow-up confirmatory scan [MRI(N?+?1)] at the next scan interval (8 weeks?±?4 weeks from MRI Scan (N) or no less than 4 weeks minimum duration between preliminary PD and confirmed PD scans) to verify tumor growth and progression. For patients with gross-total resection (GTR) and no measurable enhancing disease, preliminary radiographic progression is defined as a transition from no measurable disease to non-measureable (but present) disease (<10mm x 10mm) or measurable disease (>10mm x 10mm). If the investigator feels it is safe to keep the patient on, a confirmatory scan at MRI(N?+?1) should be obtained to verify tumor progression.
Confirmed Progression
If the patient has an increase ≥25% sum of bidirectional product or ≥40% in volume between MRI Scan N and N?+?1, this is “Confirmed Progression”, the patient should stop therapy and the date of radiographic progression is the date of suspected progression, MRI(N). If the patient has SD/PR/CR on MRI(N?+?1) with respect to MRI(N), PsP is confirmed and the patient should continue on therapy. Patients will then continue on therapy and receive additional follow-up MRI scans [MRI(M)]. If the lesion size has increased ≥25% sum of bidirectional product or ≥40% in volume on MRI(M) relative to the smaller of Nadir or MRI(N?+?1), then the patient has “Confirmed Progression”, the patient should stop therapy and the date of radiographic progression is the new date, MRI(M). For patients with no measurable disease at the Post-RT baseline, “Confirmed Progression” will be defined as a transition from non-measurable (but present) disease (<10mm x <10mm) on MRI(N) to measurable disease (>10mm x 10mm) on MRI(N?+?1). For patients with confirmed PsP and no measurable disease at Nadir, “Confirmed Progression” should be defined as a transition from no measurable disease to measurable disease (>10mm x 10mm). In all cases, patients with confirmed progression should stop therapy.
Preliminary & Confirmed Radiographic Response
If a measurable lesion has decreased ≥50% sum of bidirectional product or ≥65% in volume between MRI(1) and MRI(N), these patients should be categorized as “preliminary radiographic responders” and will be monitored for an additional time point and/or treatment cycle. After an additional cycle of therapy (8 weeks?±?4 weeks from MRI(N)), patients will receive a confirmatory MRI(N?+?1). If the lesion(s) have increased ≥25% sum of bidirectional product or ≥40% in volume from MRI(N) (indicating radiographic progression from MRI(N)), this is considered an “unsustained radiographic response” or “pseudoresponse”. The date of radiographic progression for these patients will be MRI(N?+?1) and the patient should stop therapy. Alternatively, if the lesion has not increased from MRI(N), this is considered a “durable radiographic response,” the patient will continue on therapy, and the date of preliminary radiographic progression is the time point of an increase ≥25% sum of bidirectional product or ≥40% in volume (from Nadir) during the remainder of the study. The investigator can then decide whether to continue safely on therapy until progression has been confirmed and at the subsequent time point stop therapy if they feel the patient cannot safely continue therapy.
Stable Disease
If the lesion size has not increased or decreased beyond the set thresholds between Scan 1 and N, the patient is considered “stable.” Such patients will continue on therapy, and the date of preliminary progression is the time point of an increase ≥25% sum of bidirectional product or ≥40% in volume (from Nadir) during the remainder of the study. Upon preliminary progression the investigator can choose to either continue therapy and confirm progression or discontinue therapy. For cases with significant neurologic decline at the time of imaging progression as determined from MRI(N), a confirmatory scan at time point MRI(N?+?1) may not be possible or necessary. For these cases, it is appropriate to define MRI(N) as the progression time point.
Conclusions
Although radiographic response assessment is imperfect and many nuances exist, changes in contrast enhancing tumor are both clinically meaningful and appropriate for evaluating efficacy of new treatments in GBM. The outlined modifications in this report are meant to both build on the strengths of the current RANO criteria while providing potential solutions for many of the common challenges.
Impact of imaging measurements on response assessment in glioblastoma clinical trials
David A. Reardon, Karla V. Ballman, Jan C. Buckner, Susan M. Chang, and Benjamin M. Ellingson
Abstract
We provide historical and scientific guidance on imaging response assessment for incorporation into clinical trials to stimulate effective and expedited drug development for recurrent glioblastoma by addressing 3 fundamental questions: (i) What is the current validation status of imaging response assessment, and when are we confident assessing response using today's technology? (ii) What imaging technology and/or response assessment paradigms can be validated and implemented soon, and how will these technologies provide benefit? (iii) Which imaging technologies need extensive testing, and how can they be prospectively validated? Assessment of T1 +/- contrast, T2/FLAIR, diffusion, and perfusion-imaging sequences are routine and provide important insight into underlying tumor activity. Nonetheless, utility of these data within and across patients, as well as across institutions, are limited by challenges in quantifying measurements accurately and lack of consistent and standardized image acquisition parameters. Currently, there exists a critical need to generate guidelines optimizing and standardizing MRI sequences for neuro-oncology patients. Additionally, more accurate differentiation of confounding factors (pseudoprogression or pseudoresponse) may be valuable. Although promising, diffusion MRI, perfusion MRI, MR spectroscopy, and amino acid PET require extensive standardization and validation. Finally, additional techniques to enhance response assessment, such as digital T1 subtraction maps, warrant further investigation.
Keywords: clinical trials, glioblastoma, imaging, MRI, response assessment
On January 2014, the Jumpstarting Brain Tumor Drug Development Coalition, consisting of the National Brain Tumor Society, The Society for Neuro-Oncology, Accelerated Brain Cancer Cure and the Musella Foundation for Research and Information, in close collaboration with the United States Food and Drug Administration, sponsored a workshop to help evaluate response criteria and endpoints for neuro-oncology clinical trials. This manuscript summarizes the report of Panel 3 for this workshop which was charged with reviewing clinical trial design and its impact on imaging measurement of tumor progression and response to drug therapy.
Why is Imaging Important in the Context of Clinical Trials for Recurrent Glioblastoma?
Although overall survival (OS) remains the gold standard, evaluation of changes in tumor burden using imaging is critical for accurate interpretation of response to a particular therapeutic paradigm, particularly in the context of recurrent disease. Tumor shrinkage and delay of tumor recurrence, as measured by objective response rate (ORR) and progression-free survival (PFS), respectively, are potentially meaningful additional endpoints if they correlate with improvements in either OS or patient well-being. These associations have been frequently established for other malignancies, although the limited consistency has been limited historically for glioblastoma (GBM). One possible explanation for not observing these associations more regularly for GBM is that therapies evaluated to date, with the possible exception of bevacizumab, have been essentially ineffective. Another explanation may be linked with the remarkably adaptive capability of GBM tumors, particularly with regard to the emerging resistance to therapeutic intervention. Nonetheless, a wide spectrum of novel and promising therapeutics are currently in development for GBM patients, and additional innovative treatment strategies continue to emerge as scientific understanding of GBM pathophysiology advances. Radiographic endpoints including ORR and PFS continue to offer attractive, although imperfect, measures of potential antitumor benefit that may help guide development of these approaches forward. Furthermore, in the context of malignant glioma, an inherently and diffusely infiltrative and destructive class of tumors, ORR and PFS are particularly advantageous endpoints because therapeutics capable of shrinking tumors or prolonging PFS would be expected to preserve neurological function and overall quality of life.
In addition to these considerations, PFS and imaging response have a number of advantages over OS. First, these endpoints can be assessed rapidly, which saves time as well as resources. This feature is particularly advantageous given the rapidly increasing number of investigational agents and combinatorial regimens pending clinical evaluation. Second, PFS and imaging response are not impacted by crossover to subsequent therapy. Last, there is evidence to suggest an association between PFS, durable response, and OS in glioblastoma patients, suggesting that imaging response assessment may be a surrogate for clinical benefit as defined by overall patient survival.1–4
Another important consideration with regard to imaging-based endpoints is the variability of historical benchmarks, which can serve as useful benchmarks when assessing new therapeutic interventions. For recurrent GBM, rates of ORR, PFS and OS have remained remarkably consistent across a variety of cytotoxic and biologically based therapies, excluding vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) inhibiting therapeutics. Tables 1 and
2 summarize outcome for phase ≥ II clinical trials conducted with cytotoxic agents and nonangiogenic, biologically based therapeutics, respectively, in recurrent GBM patients over the past 10–15 years. With rare exception, the ORR and PFS rates observed in these trials is ≤5%, with the only observed exception being trials where temozolomide was used at recurrence for patients who did not receive it as frontline therapy. Therefore, the benchmarks established by aggregate historical data for recurrent GBM patients provide a readily available and useful screening comparator for future clinical trials.
Representative recent phase ≥ II clinical trials for recurrent glioblastoma patients evaluating cytotoxic (chemotherapy) agents
Representative recent phase ≥ II clinical trials for recurrent glioblastoma patients evaluating non-angiogenic, biologic-based therapeutics
In summary, imaging-based endpoints of response are particularly relevant for neuro-oncology, and they can decrease the cost and time associated with a clinical trial, are not influenced by crossover, and can quantify effects of therapeutic regimens on tumor growth. Furthermore, historical benchmarks for recurrent GBM provide established yardsticks to gauge antitumor activity. On the other hand, as discussed in detail further in this supplement, accurate determination of progressive intracranial tumor has become increasingly challenging using traditional imaging modalities.
Definition of Standard Imaging Endpoints in Clinical Trials for Recurrent Glioblastoma
Response and Objective Response Rate
Response can be defined as a decrease in tumor size relative to initial tumor burden beyond some predefined threshold. Additionally, a confirmatory scan (see below) may also be necessary for verifying that true response has occurred and thereby exclude pseudoresponse. ORR can be defined as the proportion of patients treated with a drug that demonstrate response.
Durability of Response and Need for Confirmatory Scans
Although radiographic response following administration of a specific agent is always encouraging, agents that are associated with responses that are short-lived are unlikely to be of meaningful benefit to patients. A measure of response duration, or the time from when response was noted to the time of progression, adds value to absolute response rate as it provides a measure of how long the tumor is controlled. Thus, the concept of response duration requires a confirmatory scan to ensure that the response has been sustained for follow-up evaluations.
Progression-free Survival and Time to Progression
Progression can be defined as an increase in tumor size relative to initial tumor burden beyond some predefined threshold. Similar to the definition of objective response, tumor progression may also include a confirmatory scan to exclude possible cases of pseudoprogression. Measures of the time from initial treatment to progression include time to progression (TTP) or PFS. An important distinction between these 2 measures is that TTP refers exclusively to time to tumor progression while PFS also includes time to death from any cause.
Dynamic Growth Estimates for Quantifying Subclinical Benefit
It is conceivable that a drug may have a subclinical benefit for patients by changing dynamic growth patterns of the underlying tumor. For example, the use of doubling time or growth rate based on contrast-enhanced CT has been used in a number of historic studies to quantify changes in growth rates at diagnosis, after therapies, and at tumor recurrence.5–7 Assessment of changes in dynamic growth parameters has been investigated, more so for low-grade than high-grade gliomas, but the underlying principles could be effectively applied to any CNS malignancy. In a recent analysis of 407 newly diagnosed adult low-grade gliomas, the velocity of diametric expansion was shown to be an independent, multivariate predictor for malignant transformation as well as OS,8 while others have shown that changes in velocity of volumetric expansion can predict outcome following radiotherapy or chemotherapy.9,10 Clinical benefit may be quantified in terms of survival gain with the addition of therapy, meaning how the altered growth rate was expected to result in an increase in survival relative to the pretreatment tumor growth trajectory.
Careful assessment of the rate of growth (or response) of a tumor between consecutive scans may provide a measure for subclinical benefit or a means of differentiating true progression (or response) from pseudoprogression (or pseudoresponse). Nonetheless, the potential overall value of such changes will need to be evaluated in a well-designed, prospective trial.
Need for Basic Standardized MRI Acquisition and Postprocessing Methodology
The stability, accuracy, and reproducibility of brain tumor size measurements are intimately tied to MRI acquisition and postprocessing methodology details. In multicenter studies, the heterogeneity of MR scanners and parameters (eg, field strength, gradient systems, manufacturers, sequence parameters, etc.) must be considered. It is well known that minor variations in hardware or sequence timing parameters may result in substantial changes in image contrast between tissues of interest, which can potentially confound interpretation of changes caused by therapy or the disease itself. Further, differences in postprocessing (eg, interpolation/smoothing, digital subtraction, etc.) or measurement techniques (eg, bidirectional, unidirectional, volumetric, etc.) can also increase variability and uncertainty in lesion evaluation. Thus, there remains a significant need for tight control over sequence parameters in the context of multicenter clinical therapeutic trials in order to reduce measurement variability and increase accuracy of response assessment.
Possible Method for Defining a Clinically Meaningful Threshold for Progression for Estimates of PFS and TTP
As mentioned above, the imaging definitions for progression and response are defined relatively arbitrarily. One method of determining an optimal threshold for defining changes in tumor size that is clinically meaningful is to examine the effect a particular threshold has on imaging endpoint time-to-event parameters such as PFS and TTP. Conceptually, the optimal threshold for defining progression would result in a high correlation between these time-to-event imaging endpoints and objective measures of clinical benefit; however, these may be defined (Fig. 1). For example, the percent change in tumor size can be used as a continuous variable that is linked directly with PFS/TTP for each patient. The percentage change in enhancing tumor volume required for determining progression can then be adjusted, each patient's PFS/TTP can be recalculated, and then all patient TTP/PFS information can be correlated with OS (as a measure of clinical benefit). Fig. 2 outlines this process. Note that this strategy could also be used to optimize a threshold for determining response; however, measures of TTP/PFS or endpoints relating to progression will also include patients determined to have stable disease (not just responders), in which case this process will yield slightly different results.
Definition of tumor response to therapy. (A) Definition of time-to-progression (TTP) and/or progression-free survival (PFS). Tumors that are stable or not responding must show an increase in enhancement beyond a specific threshold from baseline to be ...
Example diagram depicting the determination of “optimal”, clinically meaningful thresholds for tumor progression. As the threshold for change in enhancing tumor size is adjusted from 0% to 100%, each individual patient's time-to-progression ...Alternatively, we can explore use of the correspondence index, or c-index, as a measure of optimizing the threshold change in tumor size for determining progression.49 The c-index can be used to define an optimal threshold of change to define progression (rather than the arbitrary cutoff set at 25% increase in bidimensional product as specified by the Response Assessment in Neuro-Oncology [RANO] criteria or Macdonald criteria, for example) by examining the correspondence between progression and survival by continuous assessment or evaluation at set time points. For example, as outlined in Fig. 2, one may propose optimizing the threshold at a 3-month or 6-month evaluation of progression in order to have the highest correspondence with OS or some other objective measure of clinical benefit.
Clinical Trial Entry Criteria for Recurrent Glioblastoma
An important clarification provided by the RANO criteria50 was specification of the degree of radiographic worsening required to define progression in patients being considering for enrollment into clinical trials of salvage therapy. This clarification was included in the RANO criteria to achieve better consistency for patients enrolling into these trials and to specifically reduce the likelihood that patients with minimal evidence of radiographic worsening would be deemed progressive in order to obtain access to investigational therapy. Currently, the RANO criteria specify that patients must show at least a 25% increase in the sum of the products of perpendicular diameters of contrast-enhancing lesions or new enhancing lesions while on stable or increasing doses of corticosteroids to be deemed eligible for salvage therapy clinical trials. Furthermore, based on these criteria, clinical deterioration or increase in corticosteroid dosing alone would not be sufficient to indicate disease progression for entry into clinical trials.
Management of Pseudoprogression During Enrollment
A proportion of patients enrolled in clinical trials for recurrent GBM will have had pseudoprogression at the time of enrollment. Pseudoprogression may alter the interpretation or perception of subsequent drug response, given that pseudoprogression on MRI may improve spontaneously without therapeutic intervention and that such patients typically have a favorable survival. One obvious way to manage the proportion of patients with pseudoprogression is to limit the minimum time from the end of radiation therapy, when patients can be enrolled in trials for recurrent GBM. If we limit patients with disease progression to those who are at least 6 weeks from the end of radiation therapy, we can expect no more than 20% of all patients to have pseudoprogression, with longer intervals from the end of radiation therapy leading to smaller rates of pseudoprogression.51–63
With regard to pseudoprogression itself, the list of therapies potentially associated with this phenomenon is increasing in neuro-oncology and includes radiation boost/reirradiation approaches, locally administered intratumoral therapies, and a wide array of immunotherapies including vaccines, immune checkpoint inhibitors, and T cell therapeutics. One possible approach for identifying patients with pseudoprogression in clinical trials for recurrent disease may be to evaluate several closely spaced scans (eg, the scan that initially identified progression, another scan just prior to enrollment, and then one more scan just prior to initiation of treatment) to quantify changes in tumor volume in order to understand the basal rates of change prior to therapy. Timing for such sequential scanning, however, will require careful planning to minimize the patient's risk of clinical deterioration. For patients with pseudoprogression, stability or improvement in tumor volume may be expected, whereas patients with true progression might show rapid increases in tumor volume consistent with continual, uninhibited tumor growth.
Minimum Tumor Size and Definition of Measurable Disease
As defined by the RANO criteria, measurable disease is defined as bidimensional contrast-enhancing lesions with clearly defined margins on MRI and 2 perpendicular diameters of at least 10 mm that are visible on 2 or more axial slices no farther than 5 mm apart without any interslice gaps. Additionally, the cystic or surgical cavity should not be measured in determining lesion size.
Specification of Known Prognostic Factors
Many prognostic factors may influence disease progression in patients with recurrent GBM. Comparison of outcomes between studies should be considered cautiously because of differences in factors between treatment groups including age, performance status, degree of resection, time from initial diagnosis, degree of prior treatment, extent of neurologic deficits, and tumor volume.
Broad Categorization of Therapeutic Agents
Determination of response to therapeutics is intimately tied to their impact upon vascular permeability because GBM response assessment is currently dependent on contrast uptake as a surrogate for underlying tumor burden. Contrast uptake by malignant gliomas is directly dependent on vascular permeability and vascular surface area. Much of the recent and ongoing clinical research activity for GBM can be divided into 3 categories (Fig. 3): category 1, agents that lack significant impact on tumor vascular permeability including traditional cytotoxic chemotherapeutics, proapoptotic agents, and therapeutics blocking key cell-signaling mediators; category 2, some agents that directly target tumor-associated vasculature and angiogenesis (eg, some inhibitors of VEGF/VEGFR, which tend to reduce contrast agent extravasation (ie, pseudoresponse); and category 3, agents that may impact tumor vessel integrity or alter various cytokines that could increase vascular permeability and lead to worsened contrast uptake independent of underlying tumor growth (ie, pseudoprogression). Possible examples of such agents include radiotherapy, vascular targeting agents, or some immunotherapeutics. Importantly, there are also therapeutic agents in which the distinction between these categories is unknown because the effect of such agents on tumor vascular permeability is unclear.
Fig. 3.
Broad classes of current therapeutic agents, their effect on vascular permeability, and the radiographic consequences.The impact of any therapeutic agent on tumor vascular permeability may be estimated by established techniques that assess changes in tumor vascularity such as dynamic contrast enhancement (DCE) perfusion MR imaging measurement of the transport coefficient, Ktrans.64 It may be prudent to include such assessments as well as other exploratory imaging studies early in the development of investigational agents for GBM, such as phase I studies. Such assessments may help establish whether radiographic responses can be reliably ascertained by changes in contrast uptake as an accurate surrogate for antitumor effect. Furthermore, such assessments may help establish whether radiographic responses can be reliably ascertained by changes in contrast uptake as an accurate surrogate for antitumor effect. However, the distinction of specific changes in permeability that dictate a vascular agent via perfusion have not been established, and variability of DCE-MRI measurements of Ktrans may not be adequate to make this distinction. Ultimately, if impact on tumor vascular permeability cannot be confidently assessed, such therapeutics should be conservatively classified with those that are known to impact tumor vascular permeability.
Modified Response Assessment Rubric
To account for the possibility of both pseudoprogression and pseudoresponse, a modified response assessment rubric can be considered based on the model used for the AVAglio trial (Fig. 4).65 Briefly in this model, the patient initially undergoes a pretreatment MRI scan (MRI [1]) prior to the first cycle of therapy. Following the first cycle of therapy, the patient receives additional MRI scans (MRI[N]). The model expands on that used in AVAglio by incorporating an algorithm for possible pseudoprogression.
Fig. 4.
Modified response assessment rubric for management of both pseudoprogression and pseudoresponse in recurrent GBM clinical trials.
Early Progression
If the lesion size has increased beyond a specific threshold between MRI Scan 1 and N, the patient is categorized as “early progression” and will be monitored for an additional time point and/or treatment cycle. After the next cycle of therapy (or another 4 weeks from Scan N), the patients undergoes a confirmatory MRI scan (MRI[N + 1]). If the patient has an increase in lesion size from MRI Scan N, this is categorized as “true progression,” and the date of progression is the date of MRI Scan N is designated as the date of progression. If the patient has stable or decreasing size on MRI Scan N+1, pseudoprogression is confirmed, the new baseline for subsequent evaluation is MRI Scan N, and the patient continues on therapy.
Early Response
If the lesion size has decreased between MRI Scan 1 and N, the patient is categorized as an “early responder” and will be monitored for an additional time point and/or treatment cycle. After an additional cycle of therapy (or another 4 weeks from Scan N), the patient will undergo a confirmatory MRI scan (N + 1). If the lesion has increased (indicating progression from MRI Scan N), this is considered an unsustained response or pseudoresponse. The date of progression for the patient will be MRI Scan N + 1. Alternatively, if the lesion has not increased from Scan N, this is considered a durable response,” and the patient will continue on therapy. The date of progression is the time point of an increase in lesion size (from smallest lesion size) during the remainder of the study.
Stable Disease
If the lesion size has not increased or decreased beyond the set thresholds between scans 1 and N, the patient is considered stable. The patient will continue on therapy, and the date of progression is the time point of an increase in lesion size (from smallest lesion size) during the remainder of the study. For patients with significant neurological decline at the time of imaging progression as determined from Scan N, a confirmatory scan at time point N + 1 may not be possible or necessary. It is appropriate to define N as the progression time point for these patients.
Corticosteroid Use
Many neuro-oncology patients require systemic corticosteroids, such as dexamethasone, to decrease cerebral edema and improve associated headaches and other neurologic deficits. However, corticosteroids can significantly decrease tumor vasculature permeability and lead to decreased contrast uptake as well as diminished T2/FLAIR signal abnormality. Therefore, current imaging response criteria, including both RANO50 and Macdonald,66 preclude classifying a radiographic response for any patient who has received increased corticosteroid dosing prior to follow-up imaging. Specifically, both RANO and Macdonald criteria specify that a complete response or a partial response can only be assessed if the patient is on a stable or decreased corticosteroid dose. Patients who require an increase in corticosteroid dosing prior to a follow-up brain MRI should be classified as nonevaluable unless they satisfy criteria for either clinical or radiographic progression; they are appropriately classified as “progressive disease” at that time point. Thus, ORR for GBM patients excludes patients requiring increased corticosteroid dosing.
Utility of RANO/Macdonald Criteria for Single-arm Trials for Cytotoxic, Cytostatic, and Antineoplastic Agents That do not Modulate Vascular Permeability
The FDA regards overall radiographic response (defined as the proportion of patients with a tumor size reduction of a predefined amount for a minimum time period) to be a valid endpoint for drug approval because such radiographic changes are felt to directly measure a drug's antitumor activity.67 From a practical perspective, the radiographic response rate includes the sum of partial responses and complete responses and has traditionally excluded stable disease because stable disease may reflect the natural history of a given malignancy rather than actual therapeutic effect. Importantly, the overall value of a given radiographic response rate reflects not only the frequency of such responses but also their magnitude and duration as well as their association with symptom improvement.
From both a clinical and regulatory perspective, duration is a particularly meaningful aspect of radiographic response and is defined as the time from initial response until documented tumor progression. Several anticancer agents have been approved by the FDA based on a primary endpoint of ORR including denosumab for giant cell bone tumors,68 sutent for renal cell carcinoma,69 abraxane for metastatic breast cancer and non–small cell carcinoma,70 vismodegib for basal cell carcinoma,71 and oxaliplatin administered with 5FU/leucovorin for metastatic colorectal carcinoma.72 In their summary statements for these agents, the FDA noted duration of radiographic response to be an important consideration along with ORR frequency. In addition, many of these approvals were based on single-arm trials, indicating that a contemporaneous control arm may not be necessary for an ORR primary endpoint.
In an effort to improve the accuracy of brain tumor response assessment, the RANO criteria were carefully drafted by a multidisciplinary panel of experts in 2010. RANO was specifically developed to address key limitations of the Macdonald criteria,which were originally proposed in 1990 when radiographic responses were originally noted by CT scan in patients with 1p/19q co-deleted anaplastic oligodendroglioma tumors following procarbazine, CCN, and vincristine chemotherapy.73 The Macdonald criteria have served as the standard for radiologic response in neuro-oncology for the past 25 years. The RANO criteria were drafted to add several important considerations to the foundation provided by the Macdonald criteria.
Although the RANO criteria have been widely incorporated into neuro-ooncology clinical trials and standard practice, prospective validation of whether these criteria provide a more accurate measure of tumor assessment than the historical Macdonald criteria has not been undertaken to date. Such a validation study will require a prospective comparison of response assessment measured by Macdonald versus RANO criteria in a setting where Macdonald criteria, which rely exclusively on measurement of contrast-enhancing tumor, are hypothesized to be deficient (eg, a trial evaluating an agent that directly alters vascular permeability). Given that the RANO criteria were developed to build upon response assessment as outlined by the Macdonald criteria, it is anticipated that RANO will be further modified as developing radiologic techniques (including some of those discussed by Panel 2 of this Workshop and reviewed in this supplement) gain widespread applicability and are in turn validated to provide more accurate response assessment capability.
Accurate and reliable radiologic assessment of tumor burden can be challenging for every solid tumor. As discussed by Panel 1 of this workshop and reviewed in this supplement, neuro-oncology patients, and in particular those with malignant gliomas such as GBM, are no exception. Areas of contrast enhancement and associated edema can be difficult to measure accurately on MRI, given their geometric complexity and variable growth patterns including extension along white matter tracts, ependymal surfaces, and neurovascular bundles. Several factors can also worsen MRI findings independent of underlying tumor growth including seizures, stroke, hemorrhage, infection, and treatment-related pseudoprogression. Furthermore, corticosteroids, which are routinely used to decrease symptoms associated with cerebral edema, exert a potent antipermeability effect that can improve tumor-associated MRI findings independent of underlying tumor activity. Based on these concerns, the RANO guidelines appropriately preclude classifying partial or complete radiographic responses when patients have received increased corticosteroid dosing.
Use of ORR as a relevant endpoint for drug approval requires that radiographic response reflect therapeutic antitumor effect. ORR has been traditionally regarded as a reliable measure of therapeutic effect associated with cytotoxic agents because the underlying mechanism of action for these agents directly impacts tumor cell proliferation and/or survival, which in turn translates into shrinkage of responding tumors or growth of nonresponding tumors. Such changes in tumor size in GBM patients have been historically assessed with MRI by delineation of enhancing tumor mass as a surrogate for underlying tumor burden because tumor vessels in the macroscopic portion of the tumor are dysfunctional and leaky. Numerical thresholds for response and progression are in turn defined based on agreed-upon quantifiable parameters of enhancing tumors such as those outlined by RECIST,74 Macdonald criteria,66 or RANO.50
In contrast, agents that directly impact tumor vascular permeability, such as inhibitors of VEGF signaling or some therapeutics targeting other mediators of tumor angiogenesis, confound the ability to determine whether radiographic response reflects therapeutic antitumor effect. Such agents may diminish contrast uptake independent of a bona fide antitumor effect. In these circumstances, changes in enhancing tumor mass, as measured by currently utilized MRI techniques, provide an unreliable surrogate for underlying tumor burden. Similarly, accurate determination of tumor progression is limited.
Therefore, a principal consideration of whether radiographic response reflects a genuine antitumor effect for GBM is the class of therapeutic agent under evaluation. It is the consensus of Panel 3 that ORR and progression can be reliably assessed for therapeutic agents that do not directly modulate tumor vascular permeability. In contrast, agents that directly modulate vascular permeability, such as VEGF/VEGFR inhibitors, preclude the ability to accurately assess tumor burden and determine progression as functions of enhancing tumor mass with currently available assessment techniques. In summary, presently employed radiologic techniques and response assessment criteria can be reliably used to assess ORR as a measure of antitumor activity for GBM therapeutics, except for those that impact tumor vascular permeability.
Consensus Statement – Objective response rate is an appropriate endpoint for single-arm trials of cytotoxic, cytostatic, and antineoplastic agents that do not directly modulate vascular permeability
The rate of ORR, as assessed by currently available imaging techniques, is a valuable and rapidly assessed endpoint for single-arm studies in recurrent GBM patients that can support accelerated drug development of promising new agents. As previously discussed, the historical benchmarks of ORR for traditionally cytotoxic agents and biologically based therapeutics (excluding those directly targeting VEGF/VEGFR), provide well-established and consistent comparator data to support the evaluation of promising, similarly classified therapeutics in future single-arm clinical trials. The following factors are important considerations for ORR rate as an endpoint for GBM trials:
1. The class of therapeutic agent evaluated should exclude those that directly impact tumor vessel permeability.
2. The study population is limited to patients with recurrent glioblastoma and in whom recurrence is consistently defined by established parameters such as those specified by the Response Assessment for Neuro-Oncology (RANO) criteria;
3. The duration of radiographic response is an important indicator of meaningful antitumor effect and associated clinical benefit.
In addition, factors that add further value to a durable ORR rate include:
1. Increased rates of overall tumor shrinkage in study participants, as reflected by waterfall or spider plots;
2. Reproducibility across studies and investigators;
3. Confirmation by an independent review panel of expert neuroradiologists;
4. Correlation with overall survival (this must be validated in an appropriately randomized clinically trial);
5. Correlation with additional measures of clinical benefit (ideally, this would also be validated in an appropriately randomized clinically trial).
Additional Efforts of High Potential Value
Going forward, a critical priority to enable more effective use of imaging-based endpoints for neuro-oncology clinical trials includes a mandate for neuroradiologists and imaging scientists to generate guidance on optimized, standardized parameters for routine MRI sequence acquisition and processing. An effort to bring together imaging scientists, radiologists, neurosurgeons, radiation oncologists, and neuro-oncologists to develop a standardized MRI protocol is currently underway. Once defined, widespread implementation of such protocols will facilitate informative comparisons across imaging datasets along with more ease of interpretation by regulation agencies.
Another important effort, to be undertaken in parallel, should focus on assessing the clinical utility of advanced imaging techniques. A general strategy to evaluate the potential value of such imaging approaches will likely include a 2-step process. The first step should include a retrospective evaluation to assess the clinical merit of a specific advanced imaging technique using existing imaging and clinical datasets. If such a retrospective analysis suggests that a specified advanced imaging technique offers potential value for outcome assessment, the second step might involve a prospective evaluation of such a technique within a planned clinical trial. This step would provide an opportunity to proactively interrogate whether the data generated by the advanced imaging technique provide significant incremental value above the data generated by standard/routine imaging techniques. In our supplemental material, we provide an example of a 2-step strategy using T1 digital subtraction maps, a promising approach for evaluating response in patients undergoing treatment with therapeutic agents that directly alter vascular permeability.
Conclusions/Future Considerations
1. The discussion generated by this workshop provides a framework to further address neuroimaging challenges and prioritize strategies for moving forward.
2. A forum building on the RANO working group experience should prioritize standardization of acquisition and postprocessing parameters of routinely performed MR imaging in order to generate uniform imaging standards for incorporation into clinical trials and ultimately into daily practice.
3. Retrospective and prospective validation of RANO response assessment should be undertaken, including separate evaluations for agents that are known to alter, as well as not alter, tumor vascular permeability.
4. Retrospective and prospective evaluation should also be undertaken to further evaluate the impact of additional advanced imaging techniques including diffusion, perfusion and T1-subtraction mapping approaches. Separate evaluations should be performed for agents that are known to alter, as well as not alter, tumor vascular permeability.
Supplementary Material
Supplementary material is available online at Neuro-Oncology (http://neuro-oncology.oxfordjournals.org/).
Funding
This work, summarizing discussion led by Panel 3 of the “Jumpstarting Brain Tumor Drug Development Coalition and FDA Clinical Trials Neuro-Imaging Workshop” held on January 30, 2014, was supported by general funding provided by National Brain Tumor Society, The Society for Neuro-Oncology, Accelerated Brain Cancer Cure and the Musella Foundation for Research and Information.
Again, not true. She is only the lead investigator at UCLA when it comes to having insight about specific GBM patients in the trial, it ends there. UCLA's consent form specifically references that site enrolling approximately 28-patients in the Phase III. Both consent forms that I have for UCLA pertaining to the Phase III (different consent years) state the same thing on the first page:
"The approximate number of subjects to be enrolled at UCLA is 28." -- UCLA consent form
http://neurosurgery.ucla.edu/Workfiles/Site-Neurosurgery/Brain_Tumor_Program/11-000686-%20Main%20ICF%2007Nov2012.pdf
http://neurosurgery.ucla.edu/Workfiles/Site-Neurosurgery/Brain_Tumor_Program/DCVax%20Consent.pdf
Linda Liau may know a bit more than the NW Bio, as the Sponsor has absolutely no patient eCFR involvement. They hired someone to medically oversee the study. And that person is not Linda Liau. They have effectively kept degrees of separation for both the Company and UCLA from gaining access to blinded information. It's a well designed system in my opinion. They also have hired 2 CROs to respectively cover the US and abroad. But it's safe to know that her clinical usage access is limited to hearing the same blinded overall trial data that is reported to the sponsor. Each clinical site has their own principal investigator and she is not the designee who goes site to site checking on patients. I know you want to perceive that the blind has somehow been revealed to her, but you will find that the protocol is very clear that she is out of patient loop beyond the 28-patients treated at UCLA. She does have access to the Phase II 60-patient UCLA study that has been running somewhat simultaneous to this trial, so yes, she can get a better glimpse to how patients are responding to therapy. In that trial all patients receive the vaccine. They trial is basked though on which patients receive the placebo cream. And she also know how the remaining Indeterminate patients are doing.
Sections from the protocol which make it clear to me that she only has access to her site, UCLA. Again, she is not listed as someone who has access to any other clinical site data:
You're perception is wrong. The trial has not suffered any unblinding. Again, I never claimed anyone is looking at vials in an unblinded fashion. Obtaining the percentage of patients within the overall study have had access to their vaccine supply does not signify unblinding.
Having the percentage of patients who have had access to their vaccine at some point in this study is not information that enables an investigator to even know who was on vaccine before open label. The study is randomized 2:1. And that means 67% percent of patients were on vaccine from the start and 33% of placebo patients were not at the start. If she learned that that usage percentage number went to 86% of the trial it is then very easy to determine they exact percentage of placebo crossover patients that opted to join the open label crossover.
The math:
2:1 randomization of 331 patient enrollment means 221 vaccine: 110 placebo
86% of 331 patient enrollment received their vaccine at some point in the study. That equals 285 patients who had access to at least 1 injection.
285 patients - 221 vaccine patients = 64 placebo patients who had access to at least 1 injection after crossover.
110 placebo patients - 64 placebo patients who had access to at least 1 injection after crossover = 47 who did not.
64 placebo crossovers / 110 placebo patients overall = 58% placebo crossover
47 placebo non-crossovers / 110 placebo patients overall = 43% placebo non-crossover
That 86% clinical study usage doesn't give Linda Liau the percentage of crossover patients. That 86% clinical study usage doesn't tell her whether vaccine patients opted to receive their vaccine after progression. That 86% clinical study supply doesn't tell how many vaccine patients progressed. That 86% only tells that 64 placebo patients have progressed. But given the trial was very close to 248 patient progression events, it would be information that anyone who realize blind or not. Again, that 86% clinical supply usage is simply a % of patients who at one point or another had at least access to one injection of their vaccine supply. She has no idea if any of the vaccine patients opted to crossover or not. She has no idea how many of the possible 47 placebo non-crossover patients opted out. She had no idea the placebo to vaccine events of PFS. She has no idea how many injections any patients received. That 86% (almost 90% now) doesn't tell her any blinded information. Open label is not blind. But it doesn't mean she could have conversations with patients on what therapy the patient was on initially. This trial has very few serious adverse events. And that means that there were very few, if any, emergency unblinded to the site lead investigator (not the study one).
They know anyone who received any vaccine after progression and opted in open label crossover is on DCVax-L. But as the lead investigator she remains blind and has no idea what initial treatment patients were on before progression.
"All patients (from either arm) who receive DCVax-L after progression do so on the same basis -- patients and investigators remain blinded and do not find out which arm they were in initially" -- page 9 slide.
https://www.nwbio.com/NWBio_ASCO_Update_On_Trials_6-5-17.pdf
You're reading context, and clearly inappropriate context. Linda Liau is not raiding clinical study supply records to find out who received product and who didn't. I pasted that section of the protocol to show that the information about progression and crossover is recorded in this study. It is very easy for those monitoring the study on behalf of the Company to get an update on clinical supply usage from the vendor. In fact they received such information and Linda Liau passed it along to conference attendees months ago. She created a nifty slide that figured out the exact % of placebo patients that crossover at the date of her slides. She didn't include information on how many patients had not progressed in that slide. But, the fact remains it is how I stated, she got overall trial data, nothing patient specific, and nothing "unblinded". Even those monitoring the study on behalf of the sponsor received clinical study supply usage in a blind fashion.
Here is part of an old post of mine about what Linda Liau stated and how the Compassionate stated makes my point for me. :)
**
Koman, thanks for transcribing. I had my own copy, but do appreciate it. Mutual respect. Before I begin, I want to paste it again:
Minute 34: Slide Speaking about Trial Design Lesson
"Post Radiation MRI scan, if the patients had progressive tumor they were put in this separate information arm. And the thought about that and what we saw from prior Phase I/II trial is that if patients had bulky disease; or actually not even bulky disease, progressive disease, those patients didn't respond as well. Because if your tumor is growing exponentially, you don't have enough time to mount an immune response to the tumor. And those patients at least what we saw did not derive much benefit. So that was the rationale, for EXCLUDING what we call "early progressors". Unfortunately what we have learned over the years is that determination of "early progressors" is difficult because of the issue of "pseudoprogression". So there may have been some patients who should not have been excluded or vice versa. "-- Linda Liau
Her comments above around PSEUDOPROGRESSION had to do with the trial design randomization "exclusion" flaw.
Do you not agree?
Koman, you said: So LLiau CLEARLY states that these PROGRESSIVE patients are removed at the baseline MRI which is determined by an INDEPENDENT CENTRALIZED LAB as my other transcript suggested. There was no clinical determination at that baseline scan as far as I can tell and it was purely done by reading a MRI scan to avoid bias.
I say: LLiau states that both true progression and some pseudoprogression patients were removed at baseline which was determined by an Independent Centralized Lab.
When I read her comments I interpret them as the inclusion/exclusion criteria:
Due to the trial design rationale, they sought to specifically remove rapid progression patients, BEFORE THEY ATTEMPTED RANDOMIZATION. Unfortunately in the process they EXCLUDED some psuedoprogression patients (INDETERMINATES) who should have been randomized in the trial.
The determination of "early progressors" is difficult to make "early on" in the study, as they can tell which is which. In the Compassionate Use Information Arm they needed subsequent scan to tell if the patients had progressive disease. We would later learn many did NOT have progressive disease, as Linda Liau noted, when referring to the failed enrollment patients:
"THERE MAY HAVE BEEN SOME PATIENT WHO SHOULD NOT HAVE BEEN EXCLUDED and vice versa".
Those are her words in "quotes", not mine. And is quite clear that removing rapids caused them to lose patients who did not have progressive disease. And in an effort to keep the pseudoprogression in the main trial, they may have let some possible rapids progressions in the trial (whose tumors didn't cross that size barrier). The exclusion criteria was based on size, a strong line in the sand to avoid selection bias. That we agree on.
You are calling those patients who failed main trial enrollment as recurrence (PROGRESSION). BUT the reality is that they were EXCLUDED because of actual or apparent early progression. Again her comments were specifically about Central Review unbiased removal of possibly "true and false" Progression based on Tumor Progression changes after surgery (A new lesion ≥ 1 cm or tumor growth ≥25% after post-surgery MRI) when compared to 6 weeks later after Chemo Radiation scan. Using that baseline scan as the cut-off EXCLUDED both rapid progression and pseudoprogression. LLiau's comments were regarding the attrition of patients at Post Radiation Baseline MRI scan. Meanwhile they only ever meant to remove true progression of disease prior to 2012. Again she said the trial design, “there may have been some patients who should not have been excluded” and by excluded, she means from the main trial enrollment. She did not ever say that psuedoprogression patients were removed due to progression in the trial. It was before enrollment that she pointed to and referenced.
OFF the 55 Compassionate Use Arm abstract confirms her suggestion:
We treated 55 rGBM patients with autologous dendritic cells pulsed with autologous tumor cell lysate (DCVax®-L) in an “Information Arm” outside of our Phase III clinical trial. 51 of these 55 patients were not eligible for the trial because they had actual or apparent early progression (recurrence) at a Baseline Visit at the end of 6 weeks of daily radiotherapy and chemotherapy after surgical resection of their brain tumor. 4 of the patients were not eligible for the trial for other reasons (e.g., insufficient doses of DCVax-L).
The changes from after surgery MRI to Post Radiation Baseline MRI does not capture TRUE progression. It only captures patients who MIGHT have progressive disease. It didn’t matter if the 55 Patients were Recurrent Patients or not. Those patients were removed, because of trial's design exclusion criteria in an effort to enroll patients who fit this:
"The primary objective of this study is to compare progression free survival (PFS) between patients in the DCVax-L cohort and patients in the placebo cohort in patients with no evidence of disease progression at baseline." -- protocol
You calling the scans official "Progression", does not make it so. Again, these 55 were eliminated because between Surgery Scan and Post Radiation Scan (Baseline) the INDEPENDENT CENTRAL REVIEW IMAGING TEAM failed some Patients AT BASELINE VISIT based simply on SIZE. The size criteria was the evidence of possible disease progression:
• A new lesion ≥ 1 cm or tumor growth ≥25% at Baseline scan 6 weeks after Surgery Scan
As I mentioned before, in an effort to enroll patients with "no progressive disease" at baseline, they eliminated pseudoprogression (not real progression) while the protocol called for SPECIFICALLY looking for early progression patients. Progression of disease always needs to be confirmed by a confirmation scan; and because patients didn’t really have a starting one after chemoradiation treatment, the BASELINE scan is the ONLY one that can confirm PROGRESSION STATE. IT IS THE ONLY SCAN USED IN THIS TRIAL TO CONFIRM PROGRESSION. Incidentally, the Compassionate Use, Informational Arm abstract confirms this.
As AVII is aware, Psuedoprogression is not true progressive disease, instead it is true responsiveness to therapy. They eventually understood that might be removing some Psuedoprogression patients, and it is why they opened the pseudoprogression enrollment in 2012 to capture progression on some of those screening excluded patients. It is understood they EXCLUDED some patients due the evidence progression at baseline, they still needed to confirm whether the patients had progression or not.
Again from the 55 Compassionate Use Informational Arm abstract, what we know as fact:
Patients re-imaged at Month 2 after Baseline Visit to confirm either actual disease progression or pseudo-progression (patients categorized by independent medical imaging company)
Methods: Disease progression (recurrence) was determined through MRI imaging at the Baseline Visit and at Month 2 thereafter. All images were reviewed and analyzed by an independent specialized medical imaging company. Each image was reviewed separately by two independent reviewers, and any material differences were resolved by a third independent reviewer. Reviews were conducted using both RANO and McDonald criteria. OS data is available for all 51 patients. Baseline and Month 2 images are available so far for 46 of the 51 patients.
Based on comparison of the Baseline and Month 2 images, the independent medical imaging company classified the 46 patients into the following 3 groups. The other 5 patients were unclassified, due to lack of available images.
* 20 Rapid-Progressor Patients: A new lesion ≥ 1 cm or tumor growth ≥25% at Baseline and at Month 2
* 25 Indeterminate Patients: Stable disease, modest progression and/or regression, or measurements still unclear
* 1 Pseudo-Progressor: Month 2 image showed resolution of most of the prior appearance of tumor growth
http://www.nwbio.com/NWBT_ITOC_poster_3-25-15.pdf
The psuedosprogressions were not wreaking havoc on the study the way that AVII suggested. INSTEAD AS LINDA LIAU SUGGESTS, SOME WERE EXCLUDED FROM THE STUDY AND SOME WERE NOT. UNDERSTAND THAT LLIAU TOLD US THAT THERE WERE PSUEDO WHO CENTRAL REVIEW DETERMINED THAT >25% TUMOR GROWTH ON THEIR BASELINE SCAN (WHEN COMPARED TO POST SURGICAL SCAN) AND THEY WERE EXCLUDED FROM MAIN ENROLLMENT. AND WE ALL AGREE THAT THERE WILL BE PSUEDOS WHO HAD < 25% TUMOR GROWTH ON THEIR BASELINE SCAN (WHEN COMPARED TO POST SURGICAL SCAN).
IT IS THE POST SURGICAL SCAN THAT IS USED FOR TRIAL DESIGN EXCLUSION CRITERIA STARTING BASELINE. IT IS THE POST RADIATION BASELINE SCAN THAT IT IS COMPARED TO IN ORDER TO MAKE THAT IN-OR-OUT OF THE MAIN ENROLLMENT DETERMINATION. BUT WHEN IT COMES TO THE PSUEDOPROGRESSION PATIENTS PROGRESSION TEST, IT IS THE BASELINE VISIT SCAN THAT USED AS A STARTING MEASURE FOR THE PROGRESSION DETERMINATION. THE BASELINE VISIT SCAN IS WHERE TREATMENT OR PLACEBO CHANGES BEGIN TO BE MEASURED. AND I REPEAT, NOT ONE INDETERMINATE BASELINE VISIT SCAN WAS LABELED AS A TRUE PROGRESSIVE STATE AT MONTH 2 COMPARISON.
THE PSUEDO THAT PASSED MAIN TRIAL INCLUSION/EXCLUSION CRITERIA (< 25% TUMOR GROWTH PRIOR TO ENROLLMENT) would have been randomized fairly 2:1 (randomization occurs based on MGMT promoter status). We both know Central Review REMOVED patients on SIZE CHANGES BEFORE ENROLLMENT (measured from Post Surgical Scan to Post Radiation MRI Baseline Scan). We both know that they will continue to do unbiased assessment based on SIZE CHANGES AFTER ENROLLMENT (tumor growth measurement to begin from Baseline Visit Scan). AND I REPEAT WHEN CENTRAL REVIEW LOOKED AT THE 55 FAIL SCREENED PATIENTS AND USED BASELINE SCAN AS THE STARTING POINT, THE INDETERMINATES (LIKELY PsPDs) DID NOT HAVE.
--- A new lesion ≥ 1 cm or tumor growth ≥25% at Baseline and at Month 2
INSTEAD, WHEN MEASURED FROM BASELINE VISIT SCAN, 25 Indeterminate Patients READINGS WERE: Stable disease, modest progression and/or regression, or measurements still unclear.
AND I ARGUED REPEATEDLY that just like their 25 Indeterminate peers -- whose disease either shrunk, grew a little (not enough for progression) or were stable disease -- the randomized main arm PsPD would experience the same PSPD non-progression baseline scan comparison outcome.
So yes, it is exactly like I interpreted it. And I stated, the “likely PsPD” in the Indeterminate cohort (outside the study) who were on vaccine were confirmed as NON-PROGRESSION patients by Month 2 scan. None of the 25 INDETERMINATE patients tumors grew to a officially be called PROGRESSION. NOT ONE. The "likely psPDs" who were excluded from enrollment were officially cleared of their POSSIBLE PROGRESSION STATE and called INDETERMINATES. NO PROGRESSIVE DISEASE WAS DETERMINED BY MONTH 2 IN ANY OF THOSE 25 INDETERMINATE PATIENTS. They couldn’t be confirmed “officially” PsPD because patients were put on vaccine therapy that confounded the baseline scan data. And so Linda Liau likes to call them “likely” PsPDs.
IT IS VERY EASY TO PROVE THAT IF ANY OF THOSE "likely PsPD” INDETERMINATE COMPASSIONATE USE ARM patients had been enrolled and randomized IN THE MAIN ARM many would be without a progression event. WHAT WE KNOW FOR A FACT IS not a single one would have been removed for “PROGRESSION” at month 2 (MEASURED FROM BASELINE). Some would become progression patients on follow-up scans. BUT, the fact remains that the patients who are PsPD and who are living 3+ years, she stated that many of those patients have not seen a PROGRESSION EVENT -- according to LLIAU. THAT ALONE TO ME PROVES THAT AVII IS WRONG. HAD HE BEEN CORRECT, then the VERY BEST RESPONDERS PSPDS IN THAT ARM (LONG TAIL SURVIVORS LIKE BRAD) would have CENTRAL REVIEW CONFIRM THEM AS PROGRESSION AT ONE POINT OR ANOTHER. YET THAT DID NOT OCCUR. LINDA LIAU KNOWS MORE THAN AVII, AND SHE SAID THEY HAVE NOT HAD A PROGRESSION EVENT. SHE CAN'T BE CALLED BIASED, AS SHE IS NOT THE ONE MAKING THE "NO PROGRESSION" DETERMINATION. SIMPLY LOOK AT THE INFORMATIONAL DATA AND YOU WILL SEE, the Indeterminate patients were removed for mimicking signs of progression disease but not for actually having confirmed disease progression. WE DO NOT HAVE THE PROGRESSION MONTH FOR THE INDETERMINATE PATIENTS THAT PASSED. BUT WE CERTAINLY HAVE CONFIRMATION THAT THE ONES THAT ARE ALIVE HAVE NOT SEEN A PROGRESSION EVENT. CLEARLY Psuedoprogression is not confirmed progression. WHETHER INSIDE OR OUTSIDE OF TRIAL ENROLLMENT, the PsPD patients will need to have Progression of Disease from their BASELINE VIST SCAN, and if that didn’t happen to the very responsive PsPDs in the INDETERMINATE ARM (AT MONTH TWO SCAN) it certainly will be difficult to prove it will happen to the possible psPD randomized patients. As for psPD wreaking havoc after enrollment, it’s just biased interpretation of LLiau’s words (BOSCH'S TOO) and conjecture on skeptics part. CONJECTURE AND NO PROOF, IMHO.
Yes, AVII and I have agreed to disagree. Considering he's rehashing the past, this iHUB probably deserves a short recap on my perspective. First thing to clear up is that RANO was very much in effective when this trial resumed in 2011. Very much so. The non-enhanced disease portion is RANO is being used which automatically means they are following RANO.
And I perceive AVII has misinterpreted her comments about the exclusion criteria to mean more than it is. If anyone needs me to repost her comments verbatim, I'll be happy too. She spoke of Central Revuew having no choice of removing patients due to SUSPICION of "evidence of disease" as they didn't have the clinical picture. Everyone knows that at least 3 scans in any GBM study is needed to determine what is going on. And at the exclusion criteria determination they only had 2 scans. Central Review will not treat suspicion of early psuedoprogression as automatic progression. Even in those PsPD cases they did not find on the patients next scan that any of the Indeterminate arm fit the description of disease progression. On the third scan a large percentage of the compassionate use arm could not be confirmed for progression -- it was Indeterminate on 25 patients.
In order to be considered progression, the main arm scans would have needed to grow from BASELINE. AVII gets that. As do I. But I also get that earlier on in the study, they won't be so quick to judge the reaction to the vaccine. They will want a third scan. The baseline POST MRI SCAN is considered the very first scan for the main arm. The POST SURGICAL MRI scan is the screening criteria baseline. It has no relevance as to whether main arm patients can be determined "progression". However, for the compassionate use arm patients, that post surgical scan remains important. That constituted as scan one for the Indeterminate arm patients. But that didn't mean the excluded patients had confirmed progression. Scan #3 was needed to determine what was going on. Yet, the Indeterminate patients -- who possibly had the highest TIL of study recruitment (when considering both screening failure and passes) -- and who incidentally started vaccine, well their scans did not SWELL an additional 25% over their POST RADIATION MRI scan. Had those Indeterminate patients been in the main arm, their residual mass, seen at BASELINE, would have needed to grow an additional 25% for them to be considered PROGRESSIVE disease. What we know for sure is that NONE of the pseudoprogression, that might have been in the Indeterminate Arm, outside the study, grew an additional 25% by that next scan which was meant to be the confirmation scan. Some may have grown later on, when the patients truly progressed, but not one Indeterminate patient scan grew an additional 25% after initiating vaccine. But none, not one, grew an additional 25% over BASELINE.
As a reminder, we already are privy to just how patients outside of the main arm faired on vaccine after BASELINE scan. And then there is the fact that Linda Liau reported late last year that none of the 10 Indeterminate patients, who remained alive at the time, had experienced an event. To quote her "not even progression." And so for AVII to suggest that the patients who were in the main arm, who were not excluded at BASELINE for their POST SURICAL scan changes (it being less than 25%) would suddenly suffer a worse fate then the INDETERMINATE patients and SWELL 25% over their new BASELINE scan (the POST RADIATION one) after receiving vaccine well that's not contrary to rationale to me. At all.
To recap, that point: The Indeterminate patients scans with evidence of disease (greater than 25% growth) at BASELINE exclusion scan didn't grow 25% above BASELINE exclusion scan and so one shouldn't expect the patients with less evidence of disease (less than 25% growth) at BASELINE inclusion scan to grow 25% above BASELINE inclusion scan for starting the same vaccine schedule. Anyone who suggests that MONTH 2 scan is going to be removing patients for vaccine growth needs to look hard at the Indeterminate Arm to just see that MONTH 2 scan didn't grow residual disease greater than 25%.
Now, I finished discussion measurable disease. Let's move on and discuss non-measurable disease. Non-residual disease that can't be measured as they do not fit disease measurement size (I.e, those found on T2-FLAIR), does not have a 25% elimination rule. Those scans are monitored for changes. And so those scans AUTOMATICALLY require a significant change in growth, if the appearance of a T2-FLAIR shows up after INITIATION of vaccine. Those scans are subjectively monitored.
From the protocol it states this about non-enhanced lesion:
• "Unequivocal progression of non-measurable disease (either non-enhancing disease seen only on T2/FLAIR images or enhancing disease not meeting size criteria for measurability), such that there is confidence that tumor growth has occurred;44 Radbruch et al. 2010: Neuro Oncol. 2011 Dec 6."--Phase III protocol RANO
Here is what RANO criteria states about non-enhanced lesions SIZE (hint: not measured, monitored):
"4.2. Non-enhancing Lesions
In addition to enhancing lesions, non-enhancing lesions on T2/FLAIR images are reviewed when evaluating GBM response. Non-enhancing lesions ARE NOT measured but instead are monitored for changes in size. It is important to note that the extent of the non-enhancing component of the tumor can be difficult to determine since localized swelling and damage caused by radiation have a similar radiographic appearance. Changes in T2/FLAIR signal that suggest presence of an infiltrating tumor include mass effect, infiltration of the cortical ribbon, and location outside of the radiation field. " -- RANO criteria
Also, before leaving this topic, I must point out that AVII looked at Brad's scans and compared the changes starting from first to his third scan. That won't be done inside this Phase III trial. Brad's very first scan represents a screening criteria scan. The Post RADIATION scan is the baseline in this study. Just as it was the baseline in his. One needs to compare only Brad's THIRD to his SECOND scan. And one UCLA took at 2 weeks after starting the vaccine does not constitute the SECOND scan. It's too early of a scan to determine progression. The vaccine regiment literally would be causing changes then. UCLA only had treated a handful of patients before Brad, so they took a bunch of scans at various points to get a sense of what was going on internally. And so AVII should not be using one that is only 2 weeks after the vaccine was administered. Anyone who wants to eyeball it need the one that was taken 2 months after the vaccine baseline. And we know that AVII does not have that one. Beyond that there also is the fact that AVII is looking at Brad's non-enhancement T2-FLAIR disease changes and eyeballing it for size changes, when there is no "size elimination" fast rule for T2-FLAIR. It is a retrospectively reviewed scan. Period.
It should also be understood that RANO criteria is simply modified MacDonald and having a pseudoprogression decision tree (to determine whether scans seen early on are or are not progression) well it is something that evolved over time after careful observation that adding TMZ upfront increased the incidence of pseudoprogression seen earlier on. The Neuro-oncology community didn't change any size rules of what constitutes progression. The only difference is that RANO incorporates a NON-ENHANCEMENT disease component. It captures progression about 1.2-1.4 months earlier than MacDonald.
It should also be understood that the neuro-oncology is on the look out for ways to distinguish early progression from early pseudoprogression. ICON, the image specialist in this trial, will be on the look out for psuedoprogression and not call any main arm a progression patient prior to having at least 3 scans on the patients. Month 2 is the second scan. Any suspected progression at Month 2 won't be determined progression until the next scan, at Month 4. There needs to be confidence that what they are looking isn't a false progression event. And so the first scan after BASELINE is automatically respectively reviewed. Automatically. They need to see WORSENING of a scan after initiating therapy. And to see WORSENING they need to review the Month 4 scan. If they find on Month 4 that the scan got worse (25% for enhancing disease, and subjective determination for non-enhancement disease) they will determine that the Month 2 scan was confirmed progression. But if it doesn't get worse, then the patient will continue to their Month 6 scan to assessment. Scans will no longer need to be retrospectively reviewed after that point as they will have the clinical MRI storyline picture.
What do ICON state about RANO criteria as it relates to Psuedoprogression:
"Pseudoprogression:
-- Enhancement that simulates tumor growth, most often caused by radiation (whole brain or focal).
-- Growth of existing lesions or appearance of new lesions within 12 weeks of completion of radiation therapy may be the result of treatment effects rather than growth of tumor.
Continued follow-up imaging can determine whether initial lesion growth was true progression or pseudoprogression.:
-- If lesion continues to enlarge, the initial growth is called true progression.
-- If lesion stabilizes or shrinks, the initial growth is confirmed as pseudoprogression
-- In such cases, the baseline SPD is no longer included when choosing the nadir value for the purposes of determining when progression occurs.
-- Diffusion weighted imaging can help distinguish pseudoprogression from true tumor growth, but its use is still experimental. The use of MR perfusion and spectroscopy is also being explored. "- ICON
AVII would like this iHUB to believe that after enrollment that this trial goes out of its way to remove the very patients that RANO looks to keep in. He is wrong. And so is anyone else who agrees with him. :)
The following question is from ASCO SEP, Second Edition: • A 55 year old man presented with syncope, a history of lightheadedness which had worsened over several months, and mild personality changes. Imaging revealed a right frontal mass measuring 7.3 by 6.3 cm which was associated with a 1.9 cm midline shift. He underwent resection followed by standard temozolomide/radiation. Four weeks after the conclusion of combined therapy he is being seen in the office with a repeat MRI, just prior to the start of cycle one of temozolomide at 150 mg/m2, 5/28 days. Clinically the patient is doing well. His energy has returned. He has no complaints of lightheadedness and his wife is relieved to report that he seems like himself. The MRI, however, shows an increase in enhancement surrounding the surgical cavity as well as at the inferior aspect of that cavity. The next step in his treatment should be: a)• • Bevacizumab 10 mg/kg every 14 days. b)• • Participation in a clinical trial. c)• • A discussion of hospice. d)• • Continue with temozolomide 5/28 as planned.
Answer: Continue with temozolomide 5/28 as planned. • Rationale : • Pseudoprogression describes the frequently observed, non-tumor related increase in enhancement on MRI following initial radiation or chemoradiation to the brain. These radiologic changes, appearing in the first 12 weeks following the completion of chemo/radiation, do not prompt a change in the therapeutic plan and resolve with time. Persistent increases in enhancement may prompt a biopsy to determine the presence of viable tumor.
I never wrote anything about vial coding. Not one thing. Prior to this post, I never even used those words in any of my posts to my sincere knowledge.
It's obviously a no-no to go look at the patients' vials. On that we agree. You suggested that I implied that in order to gain the % of patients who have had access to their vaccine, at any point trial, that they needed to raid the vials. I did no such thing. It's a naughty no no to go retrieve clinical study supply vial data. We agree on that. But I kind of thought you understood that we agreed on that point, but clearly you think I oppose that logic of it being a naughty no-no as you're suggesting we have opposing viewpoints on the subject, and yet, we do not. We agree, it is not okay to get patient efficacy data in an on-going double-blinded trial. It never crossed my mind that you would read my posts and think I suggested that they would do such a dishonest thing. Meanwhile, I trust that they got the % data in one of their clinical trial update, the same way they get PFS and OS information -- legitimately and wholeheartedly "blind" to efficacy data.
Having said that, since you mentioned vials, I should make it clear that no one in the company is getting vial information usage on any patients when they get information on the study supply usage. They simply received an update on the percentage of patients in the overall trial that have had access to their vaccine supply at one point or another in the study. But that data is absent of anything that can be directly linked to any patient. For instance, they don't know how many of those vaccine vials were used before or after progression events. They have no idea how many vaccine vials any specific patient received. They received no "unblinded" efficacy data.
They also received an update on the number of injections used in the overall trial. They know how many vials were used on the 331 patients in the trial. But that data is absent of anything that can be directly linked to any patient. For instance, they don't know how many of those vaccine vials were used before or after progression events. They have no idea how many vaccine vials any specific patient received. They received no "unblinded" data.
I hope that clears it up for you.
The company has maintained all along that they have been blind to all clinical trial efficacy data. The only representative from the company that might have had any inkling to screening aspects, such as leukaphersis -- results of which would documented in the patients electronic case file reports (eCFR) -- is Marnix. And from what I can understand, NW Bio, as the Sponsor of the trial, hired someone to oversee monitoring clinical sites adherence to the Phase III protocol. And that means, they were not aware they would be flagged for putting placebo patients at risk.
From the protocol:
"17.3. DOCUMENTATION
The PI and study staff has responsibility for maintaining a comprehensive and
centralized filing system containing all study-related documentation. These files must
be suitable for inspection by the Sponsor, the FDA, and/or other applicable
regulatory agencies/competent authorities at any time, and should consist of the
following elements: patient files (complete medical records, laboratory data,
supporting source documentation, and the Informed Consent); study files (the
protocol with all amendments, copies of all pre-study documentation, and all
correspondence between the Competent Authorities, IRB/EC, site, and Sponsor);
and drug accountability files, containing a complete account of the receipt and
disposition of the study drug.
17.4. ACCESS TO SOURCE DATA
The PI will permit the sponsor's representatives to monitor the study as frequently as
the sponsor deems necessary to determine that protocol adherence and data
recording are satisfactory. The eCRF and related source documents will be reviewed
in detail by the sponsor’s representative at each site visit. Only original source
documents are acceptable for review. This review includes inspection of data
acquired as a requirement for participation in this study and other medical records as
required to confirm information contained in the eCRF, such as past history,
secondary diagnoses, and concomitant medications. Other study records, such as
correspondence with the sponsor and the Competent Authorities, and IRB/EC and
screening and drug accountability logs will also be inspected. All source data and
study records must also be available for inspection by representatives of the FDA or
other regulatory agencies.
17.5. DATA COLLECTION
Electronic case report forms must be completed and submitted for each patient
enrolled in the study. Any changes or corrections made to the eCRF must be
subsequently reviewed and electronically signed by the PI. All data fields in the
eCRF must be completed to avoid queries.
17.6. PROTOCOL INTERPRETATION AND COMPLIANCE
The procedures defined in the protocol are carefully reviewed by the PI and his/her
staff prior to the time of study initiation to ensure accurate representation and
implementation. Protocol amendments, if any, are reviewed and implemented
promptly following IRB/EC and relevant Competent Authorities approval. The
Sponsor is responsible for submitting protocol amendments to the FDA as described
in 21 CFR § 312.30 (Protocol Amendments) and other regulatory agencies according
to national, state or local requirements. The Sponsor, or its designee, is always
available to answer protocol- or patient-related questions.
17.7. STUDY MONITORING AND DATA COLLECTION
A representative from the Sponsor will visit the study center periodically to monitor
adherence to the protocol, applicable FDA regulations and/or other regulatory
agencies national, state or local requirements, and the maintenance of adequate and
accurate clinical records. Electronic case report forms are reviewed to ensure that
key safety and efficacy data are collected and recorded as specified by the protocol.
The Sponsor or its designee is permitted to access patient medical records,
laboratory data and other source documentation as needed to appropriately monitor the trial.[/quote]"
Once the trial screening hold didn't lift in the Month they perceived it might, they made the decision not to reveal what was going on behind the curtain. I think the decision was based on wanting to avoid the suggesting that something was wrong with the study design. I don't know if you were invested at the time, but both skeptics and the media were suggesting the study didn't have enough patients to reach the finish line. And the company was also doing back to back raises/dilutions. In my opinion, I believe they decided that saying less would be the best course of action. They did reveal though, within SEC statements, that the screening hold might not lift, and that they might not be allowed to screen more patients, but they never came out and said it. After a certain point, resuming screening no longer mattered. And as I predicted they eventually came out and stated that enrollment was closed and that screening would not resume, stating something along the line that it didn't make sense to go through the costly and time consuming process to reinitiate sites to resume screening. What was unclear though, was whether the primary endpoint had already been crossed at the time they revealed both screening and enrollment was closed.
As for JJ's comment about the placebo patients getting their own activated cells back, well he is wrong. The patients get Dendritic Cell precursors back. The study Placebo has no affect on patients immune function, according to the Company.
See below:
SEC 10K 2008 NW Bio Statement: "Placebos to look indistinguishable from various kinds of pills have been made for decades, but creating a placebo to be indistinguishable from living cells in a vial (such as the living immune cells that comprise DCVax) was a new and difficult challenge. Not only must the placebo look indistinguishable from the DCVax visually, it must also not have any positive functional action of its own that would muddy the trial results. After considerable work, the Company succeeded in developing such placebo arrangements and re-designing the Phase II trial to accommodate them, including nearly doubling the number of patients (from 140 to 240 patients). The Company obtained a new FDA clearance and re-approvals by all the clinical sites, and commenced the new Phase II trial in early 2009."
Okay, gotta run. Enjoy the 4th. :)
Not true. See page 9 of the Bosch's ASCO slides, it states:
"All patients (from either arm) who receive DCVax-L after progression do so on the same basis -- patients and investigators remain blinded and do not find out which arm they were in initially" -- page 9 slide.
https://www.nwbio.com/NWBio_ASCO_Update_On_Trials_6-5-17.pdf
Once patients progress, they are at physician choice of care. It is only up until the primary endpoint (or PFS) that patient care need to be standard.
From the protocol:
"Study Procedures for Crossover (Open Label) Option:
Patients who, wish to continue in the study after confirmation of disease progression, will have the option to receive DCVax-L under the crossover/open label option of the study (except in rare cases where they were originally randomized to DCVax-L and have exhausted their supply). Patients enrolled into the crossover arm will be required to follow the same study visit schedule as patients enrolled into the treatment arm of the study (Appendix A1). Patients MAY BE treated with any additional established therapies, and the administration guidelines should be referenced as described below. Labs will be collected prior to the first immunization of a patient following crossover as specified in 8.4 Labs. A negative urine pregnancy test must be obtained for all female subjects of child bearing potential prior to receiving the immunization.
Treatment Schedule after Confirmed Progression and Crossover
• Patients will receive up to 10 DCVax-L injections at days 0, 10, 20, and months 2, 4, 8, 12, 18, 24 and 30.
Day 0 is the date of the first immunization and must occur within 3 months of crossover (date of confirmation of disease progression). For the immunizations at days 10 and 20, the variance may be ±2 days but the minimum interval between injections must be at least 9 days. For the immunizations at months 2, 4, 8, 12, 18, 24, and 30 the variance can be ±1 week with a minimum interval of 6 weeks between injections. Vitals are recorded every 30 minutes for 2 hours post injection.
Guidelines for Combination Therapy Approaches:
If chemotherapies other than temozolomide are combined with DCVax-L following crossover, the following guideline should be used:
• A 21 day window surrounding DCVax-L immunizations (10 days before and 10 days after the day of vaccination), during which no chemotherapies (with the exception of
temozolomide) should be given, is advised;
• Keeping the corticosteroid dose as low as tolerated within the 21 day window around vaccine administration is recommended.
Treatment Schedule and Procedures:
Follow the schedule of events outlined in Appendix A1, and in Section 8.1 of this
protocol as appropriate within the patient’s treatment plan.
Treatment Discontinuation Due to no Study Drug Availability:
• If the crossover patient is receiving DCVax-L and no more study drug isavailable, the patient will discontinue from active treatment, have an End of Treatment (EOT) visit, Section 8.5, and will be followed for survival. Follow-up will be conducted through quarterly phone calls per Sections 11 and 14.5 of the
protocol.
• An explanation for discontinuing treatment is recorded for each patient on the
appropriate eCRF.
8.5. END OF TREATMENT (EOT) VISIT SCHEDULE AND PROCEDURES (ALL
PATIENTS – RANDOMIZED AND CROSSOVER):
• EOT Visits for all patients who discontinue from the study should occur at least 7
days, but ≤ 30 days, after the last immunization and prior to beginning other treatment. Procedures to be performed during the EOT Visit include:
• Physical Exam
• Neurological Exam
• Vital Signs
• KPS
• MRI of brain
• CBC and Differential
• Blood Chemistry - Comprehensive metabolic panel, including electrolyte balance,
and hepatic and renal functions
• Serum markers of Autoimmune disease (anti-DNA)
• Urinalysis
• AE Assessment
• Concomitant Medication
8.6. EMERGENCY UNBLINDING PROCEDURES
• Site to contact the Medical Monitor
• Upon review and approval by the Medical Monitor the site will call or log onto the IXRS to unblind the patient.
• It is important that only the investigator be unblinded. The patient and all other
personnel are to remain blinded including NWBT and the CRO personnel
• CRAs who become cognizant of the unblinded information during monitoring visits are not permitted to share this data with others to ensure that aggregate treatment
assignment data cannot be assembled prior to the scheduled endpoint analyses
8.7. ADMINISTRATION OF DCVAX-L OR PLACEBO
Over the course of the study patients will receive up to 10 DCVax-L or placebo injections at days 0, 10, 20, and at months 2, 4, 8, 12, 18, 24 and 30. Some patients may not receive 10 immunizations due to insufficient material. Patients who have
exhausted all doses of DCVax-L are switched to placebo. This switch will not be communicated to the patient or physician to maintain blinding.
For injections at day 0, the variance may be +2 days. For injections at days 10, 20 and at month 2, the variance may be ±2 days but the minimum interval between injections must be at least 9 days. Thereafter, the variance can be ±1 week with a minimum interval of 6 weeks between injections.
At the clinical site, two vials of DCVax-L or placebo are thawed at room temperature for each immunization. Study drug should be administered as soon as possible after thaw; No more than 1 hour should elapse between thawing and administration. For each immunization, two separate i.d. injections of approximately 0.15 mL (150 ul) each are given via an insulin syringe with minimal dead space to deliver a total of 2.5 million tumor lysate antigen-loaded DC (DCVax-L) or autologous MNC (placebo).
Injection volume is patient specific and the Certificate of Analysis (C of A) should be referenced. Injections are administered in the upper arm (alternating arms at each treatment visits). If subcutaneous injection occurs, this should be recorded on the eCRF, and the injection SHOULD NOT be repeated. The patient is observed for 2 hours after administration of each injection with vitals (heart rate, respiration rate, and blood pressure) taken pre-injection and every 30 ± 5 minutes and only recorded (as AEs) if considered clinically significant.
9. PATIENT EVALUATION
9.1. ON-STUDY CLINICAL EVALUATIONS
Clinical evaluations take place according to the Schedule of Events (Appendix A).
Follow-up visits should be scheduled to occur once every two months, ±7 days for vaccination visits and ±14 days for all other study visits. For this purpose, all visits after month 2 are considered follow-up visits. The window between these visits
should be as close to 2 months as possible, no less than 6 weeks, and no more than 12 weeks. The following tests and procedures are completed, although not all tests may be done at each visit; see the detailed study timeline in Appendix A.
• Physical Examination
• Neurological Exam
• Vitals (every 30 minutes for 2 hours post injection)
• KPS
• MRI of brain with and without contrast every 2 months ±2 weeks, with a minimum of 6 weeks between scans
• Optional tumor burden tests: Other imaging modalities, conforming to local
regulation, may be performed at the investigator’s discretion, if necessary as part of standard care or if necessary to confirm tumor progression as indicated by MRI
• Hematology: CBC, differential, platelets
• Serum Chemistries: including calcium, magnesium, SGOT, SGPT, alkaline
phosphatase, LDH, total bilirubin, BUN, creatinine, electrolytes, and glucose
• Serum markers of Autoimmune disease (anti-DNA)
• Immune monitoring (Immune monitoring samples will not be drawn for patients
enrolled in the crossover study arm)" -- protocol
And:
"Additionally if patients in either cohort develop tumor recurrence at any point during the trial, they will then have the option of receiving DCVax-L following a specific process that crosses them over to the IMP arm. From this point onwards subjects will be in the open label follow up arm, but without unblinding the previous trial data. Patients are monitored regularly by physical and neurological examination, blood tests and MRI imaging to evaluate effects and side effects. Immune responses are also tested for by blood withdrawals at baseline and follow up visits. " -UK paper from DCVax-L investigators about DCVax-L
The protocol:
All randomized patients receive up to 10 immunizations of DCVax-L or autologous MNC (placebo cohort) at days 0, 10, 20, and at months 2, 4, 8, 12, 18, 24 and 30)
following recovery from surgery and radiation with concurrent temozolomide 1 Sanghera et al. 2010. Can J Neurol Sci. 2010 Jan;37(1)36-42; Topkan et al. 2011: Am J Clin Oncol 2011 Mar 10;
Gunjur et al. 2011: J Med Imaging Radiat Oncol. 2011 Dec;55(6):603-10. chemotherapy.
All immunization dates are calculated from day 0 (the date of the first immunization). Some patients may not receive 10 immunizations due to insufficient material; in these cases immunizations will be replaced with placebo while maintaining the blind. Patients who elect to receive DCVax-L immunizations post confirmed disease progression and crossover will restart the immunization schedule and may receive a total of more than 10 immunizations during the course of the study.
For each immunization, patients will receive two intradermal injections (i.d.) of approximately 150µl (0.15mL) containing 1.25 million cells each (DCVax-L or MNC) in an outpatient setting. Injection volume is patient specific and the Certificate of Analysis (C of A) should be referenced. Patients are observed for acute toxicity every 30 minutes for 2 hours post-injection."
You're wonder how Linda Liau knows how many patients cross over, and the simple answer is clinical study supply. It's very easy to monitor if patients vaccine supply has been touched.
From the protocol:
"Clinical Drug Supply:
• Clinical Drug Supply vendor is notified that a patient has confirmed disease progression. Refer to the IXRS manual for further details."
By the way, no arrogance on my part. I'm not arrogant, although I could see how you read the tone and come to that assumption. I was trying to be concise in my thoughts but remain uninvolved. I never meant to imply you yourself couldn't discuss it. Certainly, you can discuss it all you want. The topic is new to some, but it's old to most.
As for your perspective, you can't bring new perspective to ME on this topic. Sorry, but you can't. And that doesn't imply arrogance. Instead it's debate exhaustion. It gets old. I've been researching this study for years, since my nephew was a patient. Debated the topic with shorts and longs alike and so I meant and continue to mean the RANO and PsPD "false progression" (within the first 3 months of study entry) topic is done for ME. Gone silent mostly as there really is no point other than to wait. Unless there is new news, I've got nothing that I feel is new to discuss. The results will speak for themselves. And so I wait. And just like the past, those who were wrong in their conjecture statements will be set straight. I only started replying to the conjecture statements of others (LTFU) and then came across your post which seems to find merit with the skeptic review points. I simply offered my brief perspective. I've always been of the mindset that folks should formulate their own opinions. Not trying to force feed anyone mine. I honestly didn't expect to engage with you on the topic but you then thought you brought something new to me. And, perhaps I was a bit harsh, let you know you didn't. Anything you write to me, on old news, has been debated time and time again. Most of my thousands of post are on this message board. Anyway, the topic is done for me.
By all means discuss with others without going back to see the loads of data on the subject that might help you gain a clear perspective for yourself. I honestly shouldn't of tried to set you on a track to back-track to find it to then formulate your own opinion. I simply know I'm not interested in rehashing the topic and so I should just let your post be. You think you understand the debate and so you're free to feel as though you do. I'll let your posts be regardless of whether my opinions are the same or differ.
And I really wasn't trying to get you trust my opinion. But your free to assume because it's a message board everyone has stock movement intentions. Yes, i'm invested, but I know the study might not be a PFS slam dunk, I always perceived that it might be close (don't need to rehash that either). I'm patiently waiting for overall survival news. I'm much more interested in getting to the end of the study and learning the study results then the day to day movements. It's more personal to me.
Good luck.
More off an old post of mine:
He can write <cough all he wants and rewrite PFS history, using his eyesight to but he can't change the prior trial's OS. He can plant suggestions that investigator made mistakes in recording of prior events and study median but without proof it's just accusations and conjecture. He can talk all he wants about futility, but his low PFS theory is based on PsPD passing size perimeters, that means the therapy is working well. If it's working well they should see long-tail. And if the therapy were not working well we wouldn't be waiting for a primary endpoint update as Linda Powers told annual meeting shareholder attendees, scans need to read and tumors carefully measured. Well death requires no MRI reading.
But let's chat about changes in tumor size on an Immunotherapy and the clinical signals of ilpilumumab:
-- it demonstrated a relatively low conventional (shrinking of tumors) response rates: (10-15% in melanoma)
But then as they Investigators were going through their observations, efficacy was distinctively different:
-- they noticed survival improvement more than their 10-15% response rate initially was suggesting as.
That suggested that there must another benefit beyond the conventional response (same observation as other immunotherapies).
Case studies showed mixed examples of efficacy benefit. Axel Hoos described verbatim:
1)Included conventional response patterns: after initial treatment: tumors shrink
2)included case patterns where after initial treatment: Tumors grow, and then subsequently shrink; predominantly because Lymphocytic infiltration into the tumor; makes the lesion larger, for the T cells can then acts against the tumor cells that leads to shrinkage
3) included case with patterns where the immune system is in some form of equilibrium state with the tumor; and leads to prolonged stabilization of disease. That may over time lead to a conventional response but it may take time to a year or more for that to happen.
4)included cases with patterns where actually new lesions appear while other lesions disappear or shrink. Those patterns are particularly interesting because suggest they that micro metastatic tumor cell deposits in different tissues that once detected by the immune system may actually lead to a visible lesion on a CAT scans, that previously did not exist, because T cells accumulate around the micro metastatic tumor cell and make that a visible lesion. Those lesion are usually small and they are transient. They go away with time, once the T cells do their job.
Conventional Responses is:
-- Tumor shrinkage
Immunotherapy benefit go above and beyond conventional responses of "shrinking" mass that might be there. To look only at conventional response rate is faulty as it doesn't give a true picture of response benefit.
"5. Delayed vaccine effect
As a consequence of their immunological mechanisms of action, cancer vaccines may require considerable time after administration to induce immunity. Therefore, tumors in subjects treated with cancer vaccines may show early progression followed by subsequent response. This potential phenomenon should be considered in the design of later phase clinical trials, particularly if nonclinical data or early phase clinical trials suggest that the phenomenon exists and time-to- event endpoints are used. Due to delayed effect of the vaccine, the endpoint curves may show no effect for the initial portion of the study. If the vaccine is effective, evidence of the effect may occur later in the study. This delay in the effect may lead to an average effect that is smaller than expected and thus may require both an increase in sample size to compensate for the delay and a careful assessment of trial maturity for the primary analysis. In addition, possible violation of the proportional hazards assumption should be considered when selecting a statistical method for the primary analysis. " -- FDA on vaccines
But trial was not enrolling the patients with established tumors. Not to mention this trial more than doubled the 110 events it initially was set to review in PFS, so they appear to cover the "sample size" to compensate for any potential delay effect. And so expected to see more cases of #3 and some cases of #4, when dormant cells wake up elsewhere.
3) included case with patterns where the immune system is in some form of equilibrium state with the tumor; and leads to prolonged stabilization of disease. That may over time lead to a conventional response but it may take time to a year or more for that to happen.
4)included cases with patterns where actually new lesions appear while other lesions disappear or shrink. Those patterns are particularly interesting because suggest they that micro metastatic tumor cell deposits in different tissues that once detected by the immune system may actually lead to a visible lesion on a CAT scans, that previously did not exist, because T cells accumulate around the micro metastatic tumor cell and make that a visible lesion. Those lesion are usually small and they are transient. They go away with time, once the T cells do their job.
Remember with DCVax-L Phase III there shouldn't be established tumors, as it's an intent for gross total resection patients that they remove. This trial was designed to remove ALL EVIDENCE OF DISEASE PROGRESSION at baseline. And this study design was to find patients who qualify for a GTR. It doesn't mean they will always get it, but with state of the article surgical equipment, the rates of GTR should be high. Tumor debunking is known to decrease immunosuppressive cytokines such as TGFB. As such, this study will more than likely experience a higher disease stabilization as it WILL not be enrolling the type of patients that the ilpilumumab trial enrolled --melanoma patients with established tumor mass. And so there shouldn't be a need to "shrink" tumors and cause immune "swelling" first effect like the DCVax-Direct trial encounter leading to possible "false" progression. The PsPD in thar made it passed main trial screening should not have tumors. They have Blood Brain Barrier (BBB) enhancements, of a therapy working well, which isn't the same thing as a TUMOR that is growing. And PsPD after enrollment can be determined by other imaging modalities, which this trial uses. It is a "enhancement" condition that clears itself in time. It is not disease progression.
Here is an example of what we should expect to see as far as MRI imaging on disease progression. This is a recurrent DC enrolled study. The patients that had lower disease tumor volume had significantly longer PFS and OS. The recurrent trial OS median was at 8 months (range: 5–107 mo). IF a KM Curve for all patients were created, there would be a long-tail response for a nice percentage of the GBM patients, as the median OS doesn’t tell the story. OS times of the 15 rGBM patients with immune first-injection increase in NK cells responders survival times in RED -- many of the rGBM patient had disease progression early on: 7.5 mo.; 12.5 mo.; 51 mo. ; 7 mo.; 11.5 mo; 25 mo.; 16.5 mo.; 5 mo.; 17.5 mo.; 16.5 mo.; 7 mo.; 6 mo.;
Dr Hoos is speaking about a different disease that is at a metastatic state and already has tumor mass that was present. It isn't a case where there was no evidence of disease to start. Of course, they are going to find clustered of tumor cells in other areas of the body which he is referencing in his disease.
A very small percentage of GBM tumor masses will be big enough on the MRI to produce a new lesion. But I do happen to agree that is the only place they will find possible early events. If you read my post you'd see I mentioned it time and time again. But the topic that was focused in your post was witinin the field of radiation. As I said the topic was debated so many times, you can't bring anything new to it. Even your perspective is old.
The rest of what you wrote is not important. Your entitled to have a vocal opinion.
With RANO criteria, which this trials uses after randomization, a progression event can not be called within the first 3 months, unless growth it is outside the field of radiation, as it is understood that what might be pseudoprogression response. If this trial had early progression events, there would be no way that the PFS endpoint was reached in November 2014. It would have triggered earlier IMHO. This RANO aspect has been debated ten times over, you will have to review the old posts to see both arguments. Subject done.
As for the clinical hold, Bosch's latest ASCO slides does mention insufficient Leukapheresis as a reason for screening failure. It is a known fact from reading patients blogs that several patients needed to do go through the procedure several times to make the product for the study. And so I stated it before, and I will state it again, that I perceive that the study design was too optimistic on the amount of product it could rationally make for the study once the trial lowered the white blood count inclusion criteria for Germany. Doing so, and then needing to do several leukaphersis may have put placebo patients (who were not getting their WBC infusion back prior to progression) at risk. Remember, they needed to make both 10 placebo and at least 5 vaccine supply for each and every patient. And while the consent form did make it clear the patients might need to undergo the procedure several times, having the patients go through the process would mean their immune function would be altered. I think it's every six months to a year that the study would be reviewed (regulators just showing up to monitor the study). And I imagine on a yearly review (from Germany's entry into the study (June 2014)) once it became apparent that the patients were being subjected to multiple attempts, that raised a red flag on the "screening" aspect of the study; and the IRB may have wanted to look into the issue and halted "screening". The company albeit perceived it as temporary, a check up. Yet, if the patients counts were too suppressed from blood work review -- again study had lowered WBC the prior year -- the screening step to make both the placebo and vaccine product for those patients may have been too optimistic of a study design and patients were at risk of a suppressed immune function, simply to be in the study. Placebo patients do not get their activated white blood cells back until they cross over. And so the company was no allowed to screen additional patients and only allowed to continue with the patients that had already signed first consent.
I also imagine they put a limit on the number of leukaphersis the study could do. What was meant as an exception (more than one) probably became more of the norm for the patients who had lower WBCs. And if they did need to go through the process several time, that certainly could have caused an issue -- a time to treatment delay on when patients could start treatment (it should be around 3 months) and to fail screen too many times over that failure to obtain enough product could mean the regulators were concerned the study design caused the trial to essentially cherry pick patients. After reviewing I perceive they accepted it as okay, because screening always occurred before the 2:1 blinded randomization. But they were still not allowed to screen additional patients, as not to put patients immune system under duress to simply enter this study.
**Note, this screening concern is not as much of a concern after the study, because if the product is approved then patients won't have to worry about having enough WBC drawn to make placebo product. Plus, vaccine recipients do get their own cells back on a schedule.
Just to be clear about what I mean by this, I will elaborate.
His assumption is to take NW Bio's "some" lost to follow-up when referring to the trial ending and surpassing 233 death events, and suggest that it may be in fact "significant", but prior to the PFS endpoint. However, patients and their doctors are blind to the patients treatment arm prior to progression. And so if a patients (regardless of the arm they would be blindly randomized into) were to event their first year in the study, one would think they might make the assumption that they were in the placebo arm, and would eagerly want their confirmed vaccine upon crossover. Now we have no idea how many did event the first year. But we do know that just over 50% of the placebo arm ended up crossing over. It could be that many of the vaccine patients were turned away (due to insufficient supply over 5 injections) and then some subsequently stopped reporting in every two months. That's possible. But clearly, the fact that over 50% of the patients that made up 35% of the initial 2:1 randomization (2 vaccine to 1 placebo), I think it's safe to assume that folks did not drop out of the study before attempting to get their crossover to open label vaccine. Hence why I think it's highly unlikely that the "some" Lost to Follow-up study drop outs prior to OS event suddenly be turned into "significant" before the primary endpoint. Anyone who suggests this is just not considering the percentage of placebo to vaccine crossover facts objectively IMHO.
Now if PFS hit late, after the first year in the study (which would mean a 15 month or more PFS event, due to randomization being typically about 3 months after initial nGBM screening) then I would imagine that neither the blinded to treatment placebo or the vaccine patient would consider dropping out prior to their progression event. After all, to survive without progression sons 15 months after surgery is generally a statistic that less than 30% of healthy patients partake. No reason to stop reporting in and possibly risk receiving an injection that is helping the patients. Remember prior to projgression-- for blinded vaccine patients - if the product runs out, the patients injections are just switched to blinded placebo product. Anyway, in my opinion it is highly unlikely that a long tail PFS patient would decide to drop out.
Unlikely scenario. Perhaps you haven't considered that there is the fact that almost 90% of the trial received the vaccine before or after PFS. If memory serves, Linda Liau stated it was 86% percent. And so if there were to be lost to follow-up in the PFS group, then I would reason that number would not be as high.