80%–85% of pancreatic cancer patients present with advanced non-resectable tumors that respond only poorly to most chemotherapeutic agents
The safety and efficacy of the angiographic instillation of encapsulated allogeneic cells overexpressing cytochrome P450 in combination with low-dose systemic ifosfamide administration has now been evaluated in 27 patients in total. These patients were successfully treated in four centers by three different interventional radiologists, arguing strongly that the treatment can be successfully used in different centers. The safety of the intra-arterial delivery of the capsules and the lack of evidence that the patients developed an inflammatory or immune response to the encapsulated cells or encapsulation material was shown in all 27 patients. The ifosfamide dose of 1 g/m2/day used in the first trial was well tolerated by all patients. In contrast, the ifosfamide dose of 2 g/m2/day used in the second trial was poorly tolerated in most patients. Since the median survival in the first trial was 40 weeks and only 33 weeks in the second trial, this strongly suggests that there is no survival benefit to increasing the dose of ifosfamide, and indeed, a lower dose is beneficial for quality of life and the lack of side effects. This is supported by the one-year survival rate in the first trial being 38%, whilst that in the second trial was only 23%. However, taking the data from both trials together, a total of nine of the 27 patients were alive after one year, and two of these nine patients were alive for two years or more.
pancreatic cancer is the fourth leading cause of cancer death in the USA with a median survival of only six months and a dismal five-year survival rate of 3%–5% [2,3,4]. Survival is better for those with malignant disease that is localized to the pancreas and is thus amenable to surgical resection, since at present, this offers the only chance of a cure. However, 80%–85% of patients present with advanced non-resectable tumors that respond only poorly to most chemotherapeutic agents
The American Cancer Society’s estimates for pancreatic cancer in the United States for 2018 are:
About 55,440 people (29,200 men and 26,240 women) will be diagnosed with pancreatic cancer.
Thus, of the 27 patients that were evaluable from both of our trials, the majority (16) showed stable disease. There were two patients in the first trial that showed partial responses where their tumors were reduced in size by more than 50%, and four additional patients from the second trial showed a minor response (reduction in size between 25% and 50%), with one of these patients (2-4) showing a 47% reduction in tumor size at Week 10, although this reduction was not maintained at Week 16. The tumor status for a further four patients in the second trial showed progressive disease, and the status of the remaining five patients could not be determined, either due to death or the patient dropping out of the study.
Interestingly, the majority of the survival benefit was exhibited early on, with the patients eventually succumbing to the disease at a similar rate to the historic controls. This suggests that a prolongation of the survival benefit might be achieved if additional cycles of ifosfamide are given to the patients. The one-year survival rate in the first trial was 36%, which is twice that of gemcitabine (Table 5). In contrast, the one-year survival for the second trial was 23% and is possibly attributable to the side effects of the higher dose of ifosfamide.
The increased dosage of chemotherapy did also not bring any additional benefit with respect to parameters of efficacy, such as tumor reduction, improvement of median survival or quality of life. Thus, we can conclude that the lower dose of 1 g/m2 gave a better tolerability and associated therapeutic benefit than the higher dose.
An encouraging finding in the second trial is that the encapsulated cells could be delivered to the vasculature leading to the pancreatic cancer in four independent centers. Although skill is required to deliver the encapsulated cells via supra-selective catheterization of these vessels, this demonstrates the general applicability of this treatment. In the meantime, we have also developed a more robust, GMP-compliant manufacturing of encapsulated cells, as well as a freezing protocol that allows the encapsulated cell product to be shipped all over the world and also to be stored for at least one year at -80 °C [45,46], which should facilitate the use of this product.
In 2013, von Hoff and colleagues reported the results of a phase 3 study of a combination therapy consisting of protein-bound paclitaxel (commonly referred to as Abraxane) plus gemcitabine. In this study, the median survival was 8.5 months, as compared to 6.7 months for gemcitabine (Table 6), and again, treatment-related adverse events of Grade 3 or higher were reported for the combination therapy [54].
Summary of recent trial data for pancreatic cancer treatments. The median survival that was observed in the two clinical trials summarized in this publication is 10 months, and treatment-related side effects are limited, particularly in the first study employing 1 g/m2/day (Table 6). The data suggest that future trials, possibly using additional cycles of low (1 g/m2) ifosfamide, may be warranted, since the encapsulated cells maintain viability in animal studies, even after a number of cycles of ifosfamide. Moreover, the inclusion of other chemotherapeutic or prodrug activating enzymes or even other antitumor agents, such as anti-angiogenic agents, may allow patient-specific tumor treatments that circumvent any pre-existing or treatment-induced resistance
Pancreatic cancers generally consist of heterogeneous cells and include cells with properties of stem cells that express aldehyde dehydrogenase (ALDH), an enzyme that is associated with resistance to chemotherapy [56,57]. Recent publications suggest that use of disulfiram, an irreversible inhibitor of ALDH [58], or dasatinib, a potent inhibitor of SRC family kinases and ABL kinases [59], in combination with chemotherapeutic drugs may be able to address this problem and slow the growth of pancreatic tumors. Such agents thus may be useful in combination with encapsulated cells plus low-dose ifosfamide.
Encapsulated Cells Expressing a Chemotherapeutic Activating Enzyme Allow the Targeting of Subtoxic Chemotherapy and Are Safe and Efficacious: Data from Two Clinical Trials in Pancreatic Cancer J. Matthias Löhr, Stephan L. Haas, [...], and Walter H. Gunzburg
Article information Pharmaceutics. 2014 Sep; 6(3): 447–466. Published online 2014 Aug 11. doi: 10.3390/pharmaceutics6030447 PMCID: PMC4190529 PMID: 25116885 J. Matthias Löhr,1,2 Stephan L. Haas,1,2 Jens C. Kröger,3 Helmut M. Friess,4 Raimund Höft,5 Peter E. Goretzki,6 Christian Peschel,7 Markus Schweigert,8 Brian Salmons,9,* and Walter H. Gunzburg9,10 1Gastrocentrum, Karolinska University Hospital, Hälsovägen 1, SE-141 86 Stockholm, Sweden; E-Mails: es.ik@rhol.saihttam (J.M.L.); ed.xmg@saaH.tS (S.L.H.) 2Department of Medicine II, University Hospital Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer, D-68135 Mannheim, Germany 3Institute of Diagnostic und Interventional Radiology, University Medicine Rostock, Ernst-Heydemann-Strasse 6, D-18057 Rostock, Germany; E-Mail: ed.kcotsor-inu.dem@regeork.naitsirhc-snej
Survival is better for those with malignant disease that is localized to the pancreas and is thus amenable to surgical resection, since at present, this offers the only chance of a cure. However, 80%–85% of patients present with advanced non-resectable tumors that respond only poorly to most chemotherapeutic agents
The size of the primary tumor was measured prior to starting the treatment and at Weeks 10 and 20 post-treatment [37,38]. The tumor did not grow any further during this observation period in any of the treated patients in the phase 1/2 trial Two of the 14 patients treated in this trial (Patients 2 and 8)
Encapsulated Cells Expressing a Chemotherapeutic Activating Enzyme Allow the Targeting of Subtoxic Chemotherapy and Are Safe and Efficacious: Data from Two Clinical Trials in Pancreatic Cancer J. Matthias Löhr, Stephan L. Haas, [...], and Walter H. Gunzburg
Abstract Despite progress in the treatment of pancreatic cancer, there is still a need for improved therapies. In this manuscript, we report clinical experience with a new therapy for the treatment of pancreatic cancer involving the implantation of encapsulated cells over-expressing a cytochrome P450 enzyme followed by subsequent low-dose ifosfamide administrations as a means to target activated ifosfamide to the tumor. The safety and efficacy of the angiographic instillation of encapsulated allogeneic cells overexpressing cytochrome P450 in combination with low-dose systemic ifosfamide administration has now been evaluated in 27 patients in total. These patients were successfully treated in four centers by three different interventional radiologists, arguing strongly that the treatment can be successfully used in different centers. The safety of the intra-arterial delivery of the capsules and the lack of evidence that the patients developed an inflammatory or immune response to the encapsulated cells or encapsulation material was shown in all 27 patients. The ifosfamide dose of 1 g/m2/day used in the first trial was well tolerated by all patients. In contrast, the ifosfamide dose of 2 g/m2/day used in the second trial was poorly tolerated in most patients. Since the median survival in the first trial was 40 weeks and only 33 weeks in the second trial, this strongly suggests that there is no survival benefit to increasing the dose of ifosfamide, and indeed, a lower dose is beneficial for quality of life and the lack of side effects. This is supported by the one-year survival rate in the first trial being 38%, whilst that in the second trial was only 23%. However, taking the data from both trials together, a total of nine of the 27 patients were alive after one year, and two of these nine patients were alive for two years or more.
Keywords: pancreatic cancer, cytochrome P450, cell therapy, encapsulation, ifosfamide, safety, efficacy, bioencapsulation, targeting chemotherapy, low dose, quality of life 1. Introduction Even though substantial progress has been made in unraveling the biology behind the development of pancreatic cancer, there has been little change in the success of treating this devastating tumor [1]. Pancreatic cancer is the fourth leading cause of cancer death in the USA with a median survival of only six months and a dismal five-year survival rate of 3%–5% [2,3,4]. Survival is better for those with malignant disease that is localized to the pancreas and is thus amenable to surgical resection, since at present, this offers the only chance of a cure. However, 80%–85% of patients present with advanced non-resectable tumors that respond only poorly to most chemotherapeutic agents [5]. Recent evidence suggests that pancreatic cancer develops at a similar speed to other tumor types, and it has been estimated that it takes about 12 years from the start of tumorigenesis to the formation of a primary pancreatic cancer, with a further seven years being needed for the seeding and development of metastatic disease [6]. Moreover, the primary tumor appears to be mix of genetically distinct subclones of which only one type gives rise to metastases, suggesting that the disease has a stem-cell origin [6,7].
The introduction of gemcitabine in 1997, which rapidly became the gold standard for the treatment of pancreatic cancer, was a milestone for this tumor type, as well as later on for other tumors, despite its modest effect on the median survival of patients suffering from this disease [3]. Since then, a number of combinations with gemcitabine, as well as new chemotherapeutic agents and/or gene and cell therapies are being developed as potential therapies to treat this tumor type (reviewed in [1,8,9,10]).
Ifosfamide is a chemotherapeutic agent with a long established history of clinical use that was approved some years ago for use in pancreatic cancer patients (Baxter Product Monograph: IFEX Ifosfamide for injection, [11]), but serious toxicity-related side effects have precluded its use at conventional doses (2.5–3 g/m2/day) [12,13]. Mid-range doses of ifosfamide (1.8–2 g/m2/day) result in less toxicity and partial treatment responses in the range of 60% with rare complete remissions [14,15,16], whereas low dose ifosfamide treatment (≤1.6 g/m2/day) results in non-severe toxicity, but is accompanied by, at best, rare, mostly partial treatment responses (≤33%) [17,18].
Like many chemotherapeutic agents, ifosfamide is a prodrug, i.e., it is not tumor toxic per se, but upon metabolization by cytochrome P450 enzymes (mainly those that are expressed in the liver), it is converted into short-lived tumor toxic metabolites [19,20,21]. The short half-life of these metabolites in plasma, however, necessitates relatively high systemic levels of ifosfamide to achieve therapeutic, tumor toxic metabolite levels in the tumor. At the same time, these doses cause debilitating and unacceptable side effects [22]. Moreover, there are a number of different cytochrome P450’s, some of which produce metabolites that are neurotoxic due to the chloroacetaldehyde (CAA) catabolite [23,24,25]. Cytochrome 2B1 (CYP2B1), the rat isoform of the human cytochrome 2B6 [26], is particularly efficient at producing mainly only the tumor toxic and not the neurotoxic metabolites [27].
Some years ago, we and others argued that local tumor activation of ifosfamide, i.e., in the proximity of the tumor, combined with relatively low-dose (1 g/m2/day) ifosfamide, should result in local high levels of cytotoxic activity and, at the same time, only minimal systemic side effects [28,29,30]. Local activation of prodrugs has been achieved in animal models of pancreatic cancer after delivery of enzyme encoding genes (suicide genes) using virus vectors [9]. We have taken a different approach in that we have used genetically modified allogeneic cells to over-express CYP2B1 at the site of the tumor. This has necessitated the encapsulation of these cells, so that they are confined to the site at which they should act, as well as to protect them from the host immune system and to also prevent their replication, so that they are not killed by the activated prodrug [28,31,32].
The cells have been encapsulated in cellulose sulfate capsules [33], since this biomaterial is inert. Cells within the capsule survive and thrive for long periods, and upon implantation, they show good biocompatibility. Moreover, due to their flexibility and robustness, the cell-containing capsules (Figure 1A) can easily be injected through a needle or catheter without bursting, and they can specifically be delivered to the pancreas by the tumor vasculature under angiography (Figure 1B) [34,35,36].
Figure 1 Figure 1 (A) schematic of placement of capsules in vessels leading to the pancreatic tumor using supraselective angiography with a catheter being inserted into a vessel in the groin, followed by low-dose ifosfamide administration given intravenously (IV); (B) ... Initial data from a first clinical trial, approved and performed in Germany [36], has been published previously [37,38,39]. This article aims to provide an update and overview of the safety and efficacy results obtained in patients from two clinical trials, the first involving 14 patients treated at a single clinical center and a second one involving 13 patients treated at four clinical centers in two European countries.
2. Results of Clinical Trials All but two patients in the first trial were diagnosed with Stage IV disease, with the other two having Stage III disease. In the second study, 12/13 of the patients were classified as Stage IV with one patient being diagnosed as Stage III.
The first trial involved 14 patients were treated at one clinical center, the Department of Internal Medicine, Division of Gastroenterology and Endocrinology, University of Rostock, and all of them received 1 g/m2 ifosfamide. The patients in the second trial were treated at four different centers and received 2 g/m2. Thus, taken together, a total of 30 patients (17 males and 13 females) were enrolled in the two studies. The age ranged from 43 to 78 years old with an average age of 61.5 years of age. However, in the first study, three patients could not be treated (two due to infections and one because angiography was not successful), and so, a total of 27 patients (16 male and 11 female) have actually been treated to date with the encapsulated cells followed by ifosfamide.
2.1. Objectives of the Two Clinical Trials The primary aim of the first phase 1/2 trial was to assess the safety and tolerability of the angiographic instillation of encapsulated, genetically modified cells into the tumor in patients with non-resectable pancreatic carcinoma Stages II to IV. The secondary objective was to obtain a description of the clinical effects of the cell-therapy compared to patients given the best available treatment in the years prior to the study (historical data) with respect to response, survival, failure-free survival and progressive disease. This trial protocol was approved (20 March 1998, Protocol No. 23) by the working party for gastrointestinal oncology (AGO) of the German Gastroenterology Society (DGVS), as well as by the state ethics committee (approval on 7 May 1998, Reg. No. I MPG 1/98; registration on 10 July 1998, AMUSt 20a/610.1) and the federal ethics committee (approval on 6 July 1998, Az.: 854.052, Protocol No. 16; registration on 6 July 1998, Reg. No. 4013824). It was registered with the state authority, as well as the federal authority.
The primary objective of the second, phase 2 clinical trial was to determine tumor response rate defined by stable disease (SD), partial remission (PR) and complete remission (CR) and the clinical benefit (Karnofsky score, body weight, pain) of the treatment with encapsulated cells followed by ifosfamide in patients with non-resectable pancreatic cancer. The secondary aim of this study was to determine the time to progression, tumor response, duration of partial or complete remission, time of symptom-free survival, survival time and quality of life. In addition, another secondary aim of this study was to evaluate the safety and tolerability of the treatment regimen with special attention being paid to the appearance of pancreatitis or immediate-type allergic reactions. The protocol was approved by the state ethics committee (Votum der Ethikkommission der Ärztekammer Mecklenburg-Vorpommern, 8 November 1999), as well as by the German Medical Association committee (9 July 1999, registration number 4015446) for somatic gene therapy (Votum des Wissenschaftlicher Beirats der Bundesärztekammer/Kommission Somatische Gentherapie) and was registered with the Mecklenberg-Vorpommen Health office (Gesundheitsamt) and the Federal Institute for Drugs and Medical Devices (Bundesamt für Arzneimittel und Medizinprodukte (BfArM)). It was also approved by the working party for gastrointestinal oncology (AGO) of the German Gastroenterology Society (DGVS).
In the first study, an appropriate artery leading into the tumor (Table 1) could be supra-selectively cannulated in 14 of the 17 patients entering the study. Two patients developed severe infections before the start of the trial and had to be treated by other means, whilst angiography was not successful in one patient due to an unusual blood vessel architecture. In contrast, in the second study, all patients could be given capsules via supra-selective angiography (Table 1). Thus, when considering both trials together, a final total of 16 males and 11 females were successfully administered encapsulated cells. However, whereas in the first study, all patients, except one (i.e., 13/14 patients), received the planned dose of 300 cell-containing capsules (with one patient only receiving 250 capsules); the number of capsules given in the second trial varied from 160 up to 450 capsules (Table 2).
Table 1 Table 1 Vessels targeted for encapsulated cell instillation. Table 2 Table 2 Patient overview from the two clinical trials. All of the patients in the first trial received ifosfamide at a dose of 1 mg/m2, whereas a dose of 2 mg/m2 was given in the second trial according to the label instructions, i.e., on Days 2, 3 and 4 and Days 23, 24 and 25 post capsule administration, plus an isodose of mesna to protect against urotoxicity. Table 2 shows an overview of the patients, as well as the location of the centers involved in the clinical trials, the dose of encapsulated cells that the patients received and the subsequent dose of ifosfamide. The patients were then followed for a variety of parameters associated with safety, as well as efficacy.
2.2. Safety Parameters and Results The safety analysis concerned three aspects of the treatment, i.e., angiography, capsule instillation and chemotherapy.
On average, angiography took approximately 40 min [37]. Most frequently, the encapsulated cells were instilled through the Arteria pancreaticoduodenalis (A. gastroduodenalis) (Table 1). More than one vessel had to be used for instillation of the encapsulated cells in only one patient in the first trial, but this was necessary in five patients in the second trial. None of the 14 patients had any acute complaints during angiography. The quality of the angiographic intervention was estimated as “good” in 13 patients (92.9%) and as “intermediate” in one patient (No. 12). The administration of the encapsulated cells was also well tolerated in the second trial.
In the first trial, acute toxicity or allergic reactions were not observed after instillation of the encapsulated cells and in the follow up neither abdominal symptoms nor were blood biochemical changes suggestive of pancreatitis observed. There were also no signs of allergic reactions (eosinophil count) or hemorrhagic cystitis (urine sticks). One patient showed increased serum lipase levels 15 days after encapsulated cell instillation, but this was attributed to the disease rather than to capsule instillation.
In the second trial, there were also no signs of allergic reactions (eosinophil count) or hemorrhagic cystitis (urine sticks) after the encapsulated cells had been implanted. Two patients had increased lipase at baseline; in one patient, lipase measurements decreased to a level that was no longer considered as clinically relevant. In another patient, whose lipase measurements fluctuated between normal and elevated levels, the final measure was assessed as clinically not relevant. However, a CT scan of this patient suggested a possible pancreatitis in three assessments after therapy (Weeks 7, 10 and 14). Nevertheless, no clinical report for pancreatitis is available, nor was a specific treatment initiated.
In conclusion, the safety analyses did not reveal any clinically relevant risk associated with the instillation of encapsulated cells. Especially, there were no clinically relevant signs of pancreatitis, and no allergic reactions were registered.
However, with respect to the third component of the treatment, the dose of 2 g/m2 of ifosfamide was found, as expected, to be toxic in the majority of patients in the second phase 2 trial, necessitating one patient to receive a reduced dose during the second cycle. In contrast, the dose of 1 g/m2 was well tolerated by all patients in the first trial.
The toxicity profile experienced by patients in the phase 2 trial reported in this paper is in line with the findings of Ajani and colleagues who performed a phase 2 trial in 31 patients with pancreatic cancer who had not received prior chemotherapy and who were treated with a median ifosfamide dose of 2 g/m2/day (range, 1.5 to 2 g/m2/day) administered intravenously (IV) over one hour for five consecutive days with mesna [16]. The most common toxic effects included nausea and vomiting, malaise, anorexia and mild hematuria. Mesna offers an adequate protection against uroendothelial injury caused by ifosfamide. However, unlike the study reported here, the data from Ajani and colleagues suggest that ifosfamide alone is only marginally active against cancer of the pancreas and appears to be of minimal value in the treatment of patients with this tumor. Indeed in the Ajani study, only one patient of the 30 evaluable patients achieved a complete remission (more than 26 months), and another patient had a partial remission (four months). The median duration of survival of all patients from the start of ifosfamide therapy was only three months (range, one to more than 26 months) [16]. A more recent study that employed ifosfamide 2.5 g/m2 and mesna together with mitomycin C was prematurely stopped because of a median survival of only 3.7 months that was accompanied by high levels of Grade 3–4 toxicity [40]. Taken together, these studies and our two studies suggest that the encapsulated cells improve median survival, but that benefit is achieved by using 1 gm/m2/day ifosfamide without the toxicities experienced by patients receiving 2 g/m2/day.
2.3. Serious Adverse Events Although 11 serious adverse events (SAEs) were recorded in seven patients during the study period for the phase 1/2 clinical trial, none of these SAEs were deemed to be treatment related (i.e., due to instillation of the encapsulated cells or to the ifosfamide treatment) and were rather attributed to the underlying disease and/or the effects thereof [37,38]. Importantly, the delivery of the encapsulated cells to the vasculature leading to the tumor did not result in any obvious allergic or inflammatory responses, and none of the patients developed pancreatitis at any time during the course of the clinical study. Elevated amylase levels were detected in some patients, but they appeared to be a result of the tumor infiltration of the pancreas and limited obstructive (chronic) pancreatitis, and no further increase was measured after the angiographic procedure to place the encapsulated cells [38]. A single AE in one patient (increased lipase activity observed on Day 15 after capsule instillation) may have been possibly related to the angiographic administration procedure [38].
A total of 16 SAEs in eight patients was documented in the second trial, including the three SAEs leading to death (Table 3). A detailed description of each SAE from this trial is given in Table 3, the most common of which were obstructions. Importantly, none of these SAEs were attributed to the instillation of the encapsulated cells. Patient 2-5 showed signs of neurological impairment, i.e., drowsiness, nocturnal enuresis, mild somnolence, on the second day of the first chemotherapy cycle. There were no other signs of neurological dysfunction. He was treated with additional hydration (infusions with isotonic saline and glucose). This SAE was deemed to be due to the treatment with ifosfamide. From the SAE analysis, there was no evidence of pancreatitis or any allergic responses at any time during the course of the study.
Table 3 Table 3 Documented deaths and serious adverse events (SAEs) in the phase 2 trial. All of the patients in the phase 2 trial experienced between five and 19 adverse events (AEs), with a median number of nine AEs per patient. There were 6 AEs (5.6%) rated as life-threatening, 10.2% as severe, 28.7% as moderate and 53.7% as mild. Importantly, none of the AEs was thought to be related to the administration of the encapsulated cells, but 44 (mainly mild to moderate in intensity, only two severe) were related to ifosfamide at the higher 2 g/m2 dose. The most frequent AEs were the toxicities of the chemotherapy, namely alopecia (in 76.9% of all patients), anemia (69.2%), leucopenia (61.5%), vomiting and nausea (53.9% each) or encephalopathy (23.1%). Other AEs were new or worsened symptoms of the underlying disease, like abdominal pain (53.9%), weight decrease (30.8%), bile duct stricture or intestinal obstruction (23.1%). Compared to the baseline status, a total of 65 events fulfilled any of the National Cancer Institute (NCI) common toxicity criteria (NCI toxicities); of these, 46.2% had Grade 1, 40% Grade 2, 9.2% (six events) Grade 3 and 4.6% (three events) Grade 4 (multiple counts per patient possible). Decreased leucocyte counts and alopecia (in 76.9% of all patients), nausea (61.5%), vomiting (53.9%), decreased granulocyte counts (46.2%) and decreased hemoglobin (38.5%) were documented. Grade 3 nausea was experienced by two of the patients during chemotherapy; Grade 3 leucopenia was noted in four patients. Grade 4 toxicities were decreased leucocytes and increased serum blood urea nitrogen (BUN) in one patient and decreased granulocytes in another. In total, five patients experienced Grade 3 or Grade 4 NCI toxicities.
2.4. Tumor Reductions The size of the primary tumor was measured prior to starting the treatment and at Weeks 10 and 20 post-treatment [37,38]. The tumor did not grow any further during this observation period in any of the treated patients in the phase 1/2 trial (Table 4). Two of the 14 patients treated in this trial (Patients 2 and 8) showed a partial response (PR), characterized by a more than 50% reduction in tumor volume (Table 4). The remaining 12 patients showed a stable disease (SD) with tumor sizes in the range of 50%–125% of the initial size (Table 4) [37]. Of these 12 patients, two demonstrated a minor response (MR), i.e., tumor reduction by 25% to 50%.
