Excellent. Most likely psPDs in the Indeterminate data. I wonder, why it is then that you made no attempt to correct DoGood on his interpretation of the Compassionate Arm Data? He's under the impression that their are no psPD in the CUA. I suspect Flipper shares your honest interpretation of the data as well.
Did you review the Brandees comparison study they used for their DCVax-L comparison data? That Brandees paper, "MGMT Promotor Methylation Status Can Predict Incidence and Outcome of Psueduoprogression After Concomitant Radiochemotherapy in Newly Diagnosed Glioblastoma" Patients was release on May 1, 2008 in the Journal of Clinical Oncology (JCO). Do you think GBM oncologist at any of the CUA clinical sites potentially read it? I ask, because the following reference is within:
It has not yet been demonstrated that maintenance chemotherapy prolongs the survival of patients with solid tumors. However, prolonged TMZ therapy can substantially deplete MGMT, thus providing the rationale for continuous treatment. In the present study, patients who received less than six TMZ cycles had an OS of 13.7 months, while those who received > six TMZ cycles had an OS of 34.8 months (P .0001). However, in view of the presence of several factors that may have influenced the duration of maintenance therapy, we decided not to perform a multivariate analysis of this datum, also in view of the nonrandomized nature of our trial.
This Phase III study is going on at multiple sites during the Compassionate Use Arm enrollment years 2011 - 2012. And each clinical site, as you will agree, will likely not be following the same treatment plan upon progression. Patients within the CUA, and patients who fail the study, can get more than six TMZ cycles. Any GBM doctor would likely understand the highlighted selection above, and if they read it, they may prescribe additional chemotherapy upon progression, do you agree? Did you consider the affects of additional treatments, and how it might positively skew DCVax-L Indeterminate data and subsequent bullish chart?
Yesterday I posted a link to a TMZ study, that I myself just recently stumbled upon within the Journal Neuosurgical (JNS) paper released December 2014, "Long-term therapy with temozolomide is a feasible option for newly diagnosed glioblastoma: a single-institution experience with as many as 101 temozolomide cycles". Iwasadiver prompted me to explore just how big of a difference TMZ is making since its approval into the standard of care (2005). I found this JNS paper fascinating, it covers much of the subject of TMZ dosing (Stupp protocol) verses TMZ dosing long-term (Stupp + TMZ). Have you considered deviations from STUPP protocol upon PFS in both your bullish and bearish analysis at all? I remember reading Linda Liau and Robert Prins paper on the DCVax-L Phase I/II. One of their theories was that DCVax-L someone altered the patients DNA to somehow make susceptible to chemotherapy. The topic has been addressed many times, it's bullish. This could be possible, it's being tested at crossover, and before PFS. Yet, in keeping to the true spirit of "objectivity", which I strive for, I must state TMZ additional cycles is turning out to be big "CONFOUNDING" factor; one that I hope will ultimately be found to be small, and one that leads to vaccine+ chemotherapy synergy, and will allow more "Brad-like" cases of long-life survival. My perception is that you have a harder time seeing the "cons" of data, unless there's no way to refute the facts; and so I repeat the prior question, altered slightly before you read further: Do you think GBM oncologist at any of the Phase III clinical sites potentially read the JNS 2014 TMZ long-term therapy study? And a few more follow-up questions: Considering that a large majority of the patient in this trial were enrolled between 2008 - 2014, do you believe it is reasonable to assume that upon PFS event, GBM oncologist might prescribe additional TMZ cycles if a study proved it was worthwhile? This TMZ long-term therapy factor, could explain Linda Liau's comment about the median survival of GBM patients being closer to 2 years, and why that is. Have you considered that Linda Liau's comments about "patients are living longer", perhaps has nothing to do with the vaccine but everything to do with TMZ? (But, yes, again it could be synergy of vaccine + chemotherapy additional cycles, but it might not be.)
An excerpt from the JNS paper for you to consider in your "objective" viewpoints on how the deviation from STUPP and additional TMZ cycles positively affects survival, without a shadow of a doubt. To me, these patients could literally be Phase III patients, as their surgical procedure matches this trial's intention (GTR, use of iMRI, etc.). Group A represents additional cycles of Stupp (>6 up to 101)(OS range 18 - 101 months), and Group B is Stupp protocol (OS range 2 - 17 months):
ABSTRACT: OBJECT The objective of this study was to report the authors' experience with the long-term administration of temozolomide (TMZ; > 6 cycles, up to 101) in patients with newly diagnosed glioblastoma and to analyze its feasibility and safety as well as its impact on survival. The authors also compared data obtained from the group of patients undergoing long-term TMZ treatment with data from patients treated with a standard TMZ protocol.
METHODS A retrospective analysis was conducted of 37 patients who underwent operations for glioblastoma between 2004 and 2012. Volumetric analysis of postoperative Gd-enhanced MR images, obtained within 48 hours, confirmed tumor gross-total resection (GTR) in all but 2 patients. All patients received the first cycle of TMZ at a dosage of 150 mg/m2 starting on the second or third postsurgical day. Afterward, patients received concomitant radiochemotherapy according to the Stupp protocol. With regard to adjuvant TMZ therapy, the 19 patients in Group A, aged 30–72 years (mean 56.1 years), received 150 mg/m2 for 5 days every 28 days for more than 6 cycles (range 7–101 cycles). The 18 patients in Group B, aged 46–82 years (mean 64.8 years), received the same dose, but for no more than 6 cycles. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was analyzed for both groups and correlated with overall survival (OS) and progression-free survival (PFS). The impact of age, sex, Karnofsky Performance Scale score, and Ki 67 staining were also considered.
RESULTS All patients but 1 in Group A survived at least 18 months (range 18–101 months), and patients in Group B survived no more than 17 months (range 2–17 months). The long-term survivors (Group A), defined as patients who survived at least 12 months after diagnosis, were 51.3% of the total (19/37). Kaplan-Meier curve analysis showed that patients treated with more than 6 TMZ cycles had OS and PFS that was significantly longer than patients receiving standard treatment (median OS 28 months vs 8 months, respectively; p = 0.0001; median PFS 20 months vs 4 months, respectively; p = 0.0002). By univariate and multivariate Cox proportional hazard regression analysis, MGMT methylation status and number of TMZ cycles appeared to be survival prognostic factors in patients with glioblastoma. After controlling for MGMT status, highly significant differences related to OS and PFS between patients with standard and long-term TMZ treatment were still detected. Furthermore, in Group A and B, the statistical correlation of MGMT status to the number of TMZ cycles showed a significant difference only in Group A patients, suggesting that MGMT promoter methylation was predictive of response for long-term TMZ treatment. Prolonged therapy did not confer hematological toxicity or opportunistic infections in either patient group.
CONCLUSIONS This study describes the longest experience so far reported with TMZ in patients with newly diagnosed glioblastomas, with as many as 101 cycles, who were treated using GTR. Statistically significant data confirm that median survival correlates with MGMT promoter methylation status as well as with the number of TMZ cycles administered. Long-term TMZ therapy appears feasible and safe.
Having just read the above TMZ abstract, will you considered the possibility that maybe "some of the overall survival time" that in the past was credited sole to the vaccine, in part belongs to TMZ additional cycles? Will you consider that some of the survival in the Indeterminate group perhaps belongs to TMZ additional cycles?
Having read the above, do you think that maybe "all of the extended survival time" that was credited to vaccine might instead be a combination of all the confounding factors that I and others have posted on in the past (i.e., UCLA expertise, iMRI, TMZ, TLR, etc.)? I personally think that's a fair "objective" conclusion, that it is possible the overall survival belongs to the a combination of all the confounding factors. How much credit goes to DCVax-L, I do not know. That is what this Phase III study is meant to test.
I will say this, I believe those involved in the DCVax-L study read both 2008 JCO and 2014 JNS papers, as many of the patients who progressed on Phase I/II deviated from the Stupp protocol (Brad Silver as you may well know, received TMZ cycles for 2 years straight.). We may never find out how many cycles a particular patient receives in this Phase III or any of it's arms (i.e, CUA Indeterminates). This study is clear about one thing, upon progression the Protocol allows the departure of STUPP, and if it includes additional TMZ cycles it can be positively affected. But, given that TMZ long-term therapy is a confounding factor, what we have seen within the prior vaccine results might end up only being an illusion of "long-term vaccine" survival, to which that the credit belongs mostly to this "long-term TMZ feasibility approach" in patients.
See Phase I/II DCVax-L data below on pre-and-post progression TMZ:
