In late March 2017, the French biotech firm Erytech presented results of a IIb clinical trial of eryaspase (trade name: GRASPA) which is the enzyme l-asparaginase encapsulated in red blood cells as added to gemcitabine or FOLFIRINOX treatment regimens for patients with advanced pancreatic cancer (ductal adenocarcinoma of the pancreas), versus these standard therapies alone. The results of this phase II clinical trial demonstrated survival promise (more below).
L-asparaginase is an interesting drug agent from a number of standpoints. Asparagine is a non-essential amino acid that plays in important role in human brain function and in ammonia physiology. In 1953, the observation was made that lymphomas in rats and mice were reduced in size when exposed to guinea pig serum. It was later found that the causative factor in the serum was the enzyme asparaginase. Since that time, l-asparaginase has emerged as a stalwart in the treatment especially of blood tumors with under-expressed asparagine synthetase, most notably acute lymphoblastic leukemia (ALL).
The primary trade names for l-asparaginase in the U.S. are Elspar and Kidrolase. The main side effects of the drug are chills & fever, nausea & vomiting, other GI upset, allergic reaction, and neurotoxicity. There is a pegylated form of l-aspariginase termed Oncaspar. Pegylation involves attaching or amalgamating polyethylene glycol to the drug, in order to increase its effective duration, or to reduce side effects.
Solid tumors that also tend to show low levels of asparagine synthetase (and thus, which may be promising targets for asparaginase) include ovarian and pancreatic cancers. But, in 1980 Lessner and colleagues from the University of Miami published the results of a Phase II clinical trial in Cancer Treatment Reports whereby ten patients with advanced pancreatic cancer were given l-aparaginase alone. There was no evidence of efficacy, and side-effects included mental confusion and blood coagulopathy. The conclusion was that l-asparaginase “seems to have no value in advanced pancreatic carcinoma.”
However, despite these earlier findings, Dr. Daniel Von Hoff in his concluding keynote speech as President of the American Association of Clinical Research in year 2000 in San Francisco, pointed out that l-asparaginase was a potential intriguing agent for the treatment of pancreatic cancer. On a personal note, the author of this Pancreatica Blog entry was involved in an early study of l-asparaginase in guinea pigs as a first-year medical student working with colleagues at the Ellis Fischel Cancer Center in Columbia, Missouri.
The study in question built on Phase I clinical trial research by Bachet and other French colleagues as published in the October 2015 issue of the journal Pancreas, which noted that the twelve patients with a diagnosis of advanced pancreatic cancer who were given one dose of eryaspase at 25-150 IU/kg appeared to tolerate the drug agent well. Also, these researchers examined more than 500 resected and live pancreatic cancer tumors for the expression levels of asparagine synthetase, which was adjudged to be low in 79.4% of cases.
The present study by principal investigator Professor Pascal Hammel, MD, PhD of Beaujon Hospital in Paris, France and his French colleagues examined the outcomes of 140 patients with metastatic pancreatic cancer for 2nd line treatment who were randomized 2:1 to either the FOLFIRINOX or gemcitabine (defined as standard of care treatment) PLUS eryaspase arm, or to the standard of care arm without eryaspase. The overall survival of the arm for the 2nd line treatment of advanced pancreatic cancer including eryaspase was 26.1 weeks, and the standard of care only arm was 19.0 weeks.
Interestingly, the survival advantage obtained regardless of asparagine synthetase expression level (AS), though the researchers noted that the AS may be prognostic in pancreatic cancer treated by asparaginase, promising further study. The results of this work are being prepared for meeting submission and publication.
These preliminary results by Hammel, et al. are intriguing and carry the effect of resurrecting the enzyme l-asparaginase, now as a potential part of a chemotherapy regimen for advanced pancreatic cancer. These are early days for this treatment, however. It will be a matter of great personal interest to follow the progress of this agent as peer review is applied, and with more definitive testing. Perhaps one might be forgiven for additionally wondering if pegylated l-asparaginase also might be worthy of consideration as an adjunct to standard chemotherapy regimens?
Mathews, Brown, Riley, O’Brien; Comparative Study: kinetics of the enzyme l-asparaginase in several tissues of Cavia Cobaya; International Journal of Biochemistry, August 1971, Issue 10, Vol 2, 473-476.
Dale O’Brien, MD
The radiation component of adjuvant chemoradiation after surgery for ductal adenocarcinoma of the pancreas (pancreatic cancer) took a turn toward controversy beginning about year 2000 with results of the Gastrointestinal Tract Cancer Cooperative Group of the EORTC demonstrating minimal survival improvement of adjuvant chemoradiation over chemotherapy alone (1999). These findings were punctuated with the release of the preliminary results of the European Study Group for Pancreatic Cancer (ESPAC-1) in meetings beginning as early as the next year. These and subsequent ESPAC studies and published articles called into question the results from 1985 and 1987 of the US-based Gastrointestinal Tumor Study Group (GITSG) which had established chemoradiation as the adjuvant standard for post-surgical therapy for pancreatic cancer.
It was also year 2000 that saw published Phase II clinical trial results in the American Journal of Surgery by Vincent Picozzi Jr., MD, et al. of the Virginia Mason Medical Center, which introduced the creative and intensive adjuvant regimen for pancreatic cancer consisting of 5-FU infusion, bolus cisplatin (weekly), external-beam radiation, and subcutaneous interferon-α. The rationale for the use of interferon was that it was a known antineoplastic biologic, augmented the effects of certain other chemotherapy drug agents including 5-FU and likely cisplatin, and acted as a sensitizing agent in regard to radiation. This regimen appeared to be a highly exciting development with improved two-year overall survival rates in these pancreatic cancer patients at 84%, in comparison to 54% with a GITSG-style protocol. However even in this initial publication, the authors noted that the toxicity of the regimen was seen as “moderate to severe” with 53% of interferon-receiving patients experiencing a grade 3 or 4 higher NCI defined gastrointestinal toxicity. 35% of the patients required hospitalization as a result of treatment side-effects, though there were no fatalities due to therapy in the interferon arm of pancreatic cancer patients.
The adjuvant radiation vs. chemoradiation controversy in post-surgical pancreatic cancer has continued and is not fully resolved. And the subsequent promise of the specific Virginia Mason adjuvant chemoradiation interferon-α regiment was later tempered by an American College of Surgeons Oncology Group clinical trial which demonstrated a median overall survival of 25.4 months, although 95% of the pancreatic cancer patients developed a grade 3 or 4 toxicity, and 44% were unable to finish all treatment phases of the therapy. Virtually all subsequent research has found very high occurrence of serious side-effects related to the adjuvant interferon regimen. And the survival advantages to pancreatic cancer patients conferred by this regimen as seen in published articles have been uneven. Thus, the excitement related to the introduction of this adjuvant treatment combination for pancreatic cancer has waned. And the number of recent related publications has been rather sparse.
However, two recent studies have increased the profile and added twists to the possible utility of this intriguing and intensive regimen for the adjuvant treatment of pancreatic cancer.
First, Picozzi and colleagues published a follow-up including long term survival statistics in the February 2016 issue of the Annals of Surgery on those with pancreatic cancer who had received the adjuvant interferon-based chemoradiation therapy. They found that the overall five-year survival was 42%, and ten-year survival was 28%. The median overall survival was seen as 42 months. Of the original 43 patients with pancreatic cancer, 9 had lived beyond ten years, with 7 of these currently showing no evidence of disease. Further, that 70% of the cohort had experienced a Grade 3 or 4 treatment side-effect, with 42% requiring hospitalization.
The second recent research study was reported out by Hawkins and his colleagues primarily from the Washington University School of Medicine in the February 2017 edition of HPB, the official journal of the International Hepato Pancreatico Biliary Association. These researchers too offer long term results based on a Phase II clinical trial using a modified version of the Virginia Mason adjuvant interferon regimen in patients who underwent pancreatic cancer surgery. Their modifications, aimed at reducing the side-effects of the original regimen, included using 3-D conformal radiation, reducing the dosage of 5-FU and cisplatin, and substituting gemcitabine for 5-FU in the add-on post chemoradiation phase. In their cohort of 53 patients, they found that the overall five-year survival of these pancreatic cancer patients was 26%, and the ten-year survival was 10%. The median overall survival was found to be 25 months. 68% of these patients developed a grade 3 or 4 toxicity, and long term complications related to treatment were found to be high. The authors were surprised to find as many treatment side-effects despite their intentional attempts to limit them. They question the small gains in longevity and survival in pancreatic cancer given this approach, as compared to the heavy price paid in the toxic effects of the therapy. And the researchers conclude by suggesting that the protocol “will need to be carefully reformulated” to hold on to the survival advantages while trying to minimize the “early and late toxicities.”
It is interesting that this regimen for the adjuvant chemoradiation treatment of pancreatic cancer introduced some 17 years ago is still a matter of interest and possibility, though it is difficult to add much to the thoughtful observations of Hawkins, et al.
More Here: https://www.ncbi.nlm.nih.gov/pubmed/28162923
More Here: https://www.ncbi.nlm.nih.gov/pubmed/25775069
Dale O’Brien, MD
One of the observations that physicians often made when the standard of care treatment typically consisted of the chemotherapy drug agent of gemcitabine alone, was that many patients with pancreatic cancer (ductal adenocarcinoma of the pancreas) seemed to feel better after the initiation of treatment. In the past five years with the since widely deployed four-drug fluorouracil based regimen called FOLFIRINOX and with the introduction of the combination regimen of gemcitabine plus Abraxane for advanced pancreatic cancer, can this reassuring expressed attitude still be held as more or less true?
This is the question that Solheim, and his fellow Norwegian authors from the Trondheim University Hospital tried to address in a study published in the March 2016 issue of Critical Reviews in Oncology / Hematology. Winnowed down from 872 abstracts, they reviewed 36 published study-and-trial-results to examine whether the overall patient sense of well-being was improved or worsened by chemotherapy treatments in the face of advanced pancreatic cancer, and somewhat apart from the specific side-effects of drug regimens. They looked for reported changes in health-related quality of life (QOL) including especially pain, and cachexia (pathologic weight loss or wasting) from the start of treatment of the pancreatic cancer, and between treatment arms within the research studies. Sparse and inconsistent reporting by the original studies, as well as patient attrition, thwarted definitive conclusions. Nevertheless, the researchers uncovered some interesting results.
Fourteen of the studies of treatment effects on patients with advanced pancreatic cancer reported out changes in QOL of patients over time. Five of these fourteen studies (35%) showed improvements in QOL in at least one treatment arm. Three studies (21%) reported worsened QOL in at least one treatment arm. In seven studies (50%) QOL measures were noted as stable over time. The authors conclude that chemotherapy can stabilize and even improve QOL factors for patients with pancreatic cancer. The important caution here is that assessments were based on patients who remained in the studies – not the entire population. The majority of patients discontinued treatments presumably often due to toxicity or progression of their pancreatic cancer and were not assessed, making definitive conclusions problematic.
The authors also intentionally reviewed the effects of chemotherapy and that of pain related to pancreatic cancer. Most treatment arms utilizing chemotherapy reported patient improvement of pain, often measured by pain scales and/or by changes in analgesic dosage. Only two treatment arms (of eight total) reported worsened pain over time compared to that at the point of enrollment. The conclusion of improved pain control with chemotherapy in advanced pancreatic cancer was stronger than that of general QOL, especially for treatment regimens that improved overall survival.
Cachexia (physical wasting) was inadequately and typically not addressed by the studies. The authors were unable to draw any conclusions about the effect of chemotherapy in pancreatic cancer treatment in terms of cachexia due to differing definitions of weight gain, exclusion of patients losing weight, missing details, and other factors.
The researchers offered interesting observations about the FOLFIRINOX regimen alone, and in contrast to gemcitabine and gemcitabine combination therapy in the treatment of advanced pancreatic cancer, although there were no observations related to the use of the gemcitabine plus Abraxane regimen. They addressed a study on the effects of FOLFIRINOX whereby a number of QOL symptoms appeared to be improved by the chemotherapy including anorexia, insomnia, constipation, emotional functionality, and general health status. They noted in another study that the time until deterioration of pain status was significantly longer with FOLFIRINOX than in the study arm treated with gemcitabine alone.
In terms of gemcitabine and gemcitabine combination therapy for the treatment of pancreatic cancer, the authors cited a study whereby mood, sense of physical well-being, functional performance, and coping efforts were improved over time compared to that at the initiation of chemotherapy. They noted that in those of the seven (of total 24) studies that did pain assessment, gemcitabine appeared to be related to a 50% reduction in pain or a reduction in analgesics in about a quarter of patients compared to about 5% of those receiving fluorouracil.
This somewhat rare look at patient quality of life issues in advanced pancreatic cancer was hindered by incomplete and inconsistent reporting from the studies in question. But, it appears that stabilization of health-related quality of life and improved pain control tended to be shown in the patient populations who remained under chemotherapy treatment. And the authors also found that quality of life improvements during therapy tended to be more strongly correlated with the more effective treatment regimens.
This is an engaging view with a somewhat reassuring albeit tentative conclusion. Chemotherapy with all of if its side effects can provide a possible upside in quality of life measures in advanced pancreatic cancer. It may be difficult, but we wonder if future studies might additionally consider creative means of trying to capture quality assessments of patients who are forced to leave treatment. And it will be interesting to see where the gemcitabine plus Abraxane regimen fits into this provisional understanding.