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.
Since the mid-1990s, teams affiliated with Dr. Daniel Von Hoff have ushered in two of the three key advances in the first-line treatment of advanced pancreatic cancer (ductal adenocarcinoma of the pancreas). This includes seminal work from a research institute affiliated with the University of Texas at San Antonio on the development of gemcitabine for the treatment of pancreatic cancer, AND per published article in 2013 as acting lead of an international consortium presenting the MPACT study results that represented a formal introduction to the advantages of gemcitabine plus Abraxane (nab-paclitaxel) in the treatment of metastatic pancreatic cancer. The other key advance was the 2011 article in the New England Journal of Medicine by French researchers demonstrating the survival advantage of the 4-drug regimen known as FOLFIRINOX over gemcitabine alone in the therapy for advanced pancreatic cancer.
Now another treatment improvement from a new Von Hoff team that appears, at least thus far, to offer potential further increased survival advantage. First in the April 2015 American Association for Cancer Research (AACR) annual meeting, and later at the January 2017 Gastrointestinal Cancers Symposium (American Society of Clinical Oncology – ASCO) Von Hoff’s team from HonorHealth Research Institute in Scottsdale, Arizona and other institutions, including fellow researchers Gayle S. Jameson, Erkut Borazanci and other authors, have reported out the rolling results of an ongoing Phase Ib/II clinical trial that assess the addition of cisplatin to the original gemcitabine plus Abraxane regimen in the treatment of metastatic pancreatic cancer (clinical trial: NCT01893801).
In the 2015 AACR meeting, the researchers published their work in a meeting abstract entitled, “High complete and partial response rate in a phase Ib pilot trial with cisplatin plus albumin-bound paclitaxel and gemcitabine in patients with advanced pancreatic cancer.” Under the rationale that pancreatic cancer not infrequently demonstrates abnormalities in DNA repair that may tend to respond to such entities as platinum salts, they added cisplatin to the gemcitabine plus Abraxane chemotherapy regimen for patients with stage IV pancreatic cancer. Ten patients with advanced pancreatic cancer were enrolled with two showing a complete response, six showing a partial response, one offering stable disease, and one demonstrating progression of their pancreatic cancer. Four patients had serious adverse side effects including sepsis/pneumonia, bacteremia, clostridium difficile colitis, and neutropenic fever/pneumonia. Despite the sobering events profile, the clinical results were encouraging enough for the researchers to move forward to the stage II status of the clinical trial.
In the 2017 Gastrointestinal Cancers Symposium, the research team both published an abstract and presented their further results in a Poster Presentation, “A phase Ib/II pilot trial with nab-paclitaxel plus gemcitabine plus cisplatin in patients with stage IV pancreatic cancer.” The 25 patients in three U.S. sites met inclusion criteria including being diagnosed with stage IV pancreatic cancer between December 2013 and July 2016. All of the patients were treated with the three-drug regimen. 20% had their tumor resected. 18 of the 25 patients had a greater than 30% reduction in the pancreatic cancer tumor size. The median survival to date (at the time of presentation) was 16.5 months, with 20% alive at 24 months. 40% of the patients experienced a grade 4 adverse effect including primarily such conditions as thrombocytopenia, anemia, neutropenia, infection, or substantive diarrhea.
Dr. Erkut Borazanci indicated that there appears to be, “something related to ‘BRCA-ness’ in pancreatic tumors,” referring to the positive response that patients with BRCA1 or BRCA2 genetic-mutation-related cancers tend to have to platinum drugs (and perhaps PARP inhibitors). Please note our Pancreatica Blog on this topic Here.
These preliminary survival outcome results with the cisplatin + gemcitabine + Abraxane regimen for advanced pancreatic cancer are remarkably encouraging, to say the least. The adverse effects of this chemotherapy regimen though are rather profound, and would require serious management and care. One interesting finding was the high number of patients who became available for surgery during the course of the treatment (the authors have indicated that a separate study of this outcome is anticipated). It is important to note that these are meeting results with a small number of patients, and the results are not yet published in a peer-reviewed journal. It will be highly interesting to see if the outcomes of this treatment approach hold up in a Phase III trial, and as peer reviewed. If so, the current Von Hoff team will have again succeeded in changing the landscape of the treatment for advanced pancreatic cancer.
Proceedings: AACR 106th Annual Meeting; April 18-22, 2015; Philadelphia, PA; Cancer Res 2015;75(15 Suppl):Abstract LB-003. doi:10.1158/1538-7445.
2017 Gastrointestinal Cancers Symposium, ASCO, San Francisco; J Clin Oncol 35, 2017 (suppl 4S; abstract 341); Poster Session B Board #F11.
Dale O’Brien, MD
Every person is different; every situation is different; every cancer is different. So, the decision about which treatment is right for an individual patient with pancreatic cancer (ductal adenocarcinoma of the pancreas) by their health care team is highly complex. Here we present the work of published research that examines factors related to two of the most common chemotherapy regimens in use for advanced stage pancreatic cancer.
A December 2016 study in the World Journal of Gastroenterology by Kattan et al. compared information from the phase III clinical trial reported out in the New England Journal of Medicine article in 2011 that measured the 4-drug FOLFIRINOX regimen favorably against the use of gemcitabine alone in metastatic pancreatic cancer WITH information from the phase III clinical trial reported out in the New England Journal of Medicine article in 2013 that measured gemcitabine plus Abraxane favorably against the use of gemcitabine alone in metastatic pancreatic cancer. The authors addressed such topics as study design, efficacy, toxicity, effects on quality of life, and the cost effectiveness of these two regimens, based on these two key studies.
In general, patients with pancreatic cancer who received FOLFIRINOX were somewhat younger and more robust, on balance, than those from the gemcitabine + Abraxane trial (the FOLFIRINOX study used ECOG standards, and the gemcitabine + Abraxane study used Karnofsky measures). These factors could have skewed the results in the latter trial to more side effects and toward reduced clinical response rates. This is a very important point to keep in mind in considering these studies.
Characteristic FOLFIRINOX G + Abraxane
Duration 2005 – 2009 2009 – 2012
# Patients 171 431
Location France multinational
Age, min-med-max 25-61-76 27-62-86
Performance status 37-62-1 16-77-7
The FOLFIRINOX study in regard to its cohort appeared to show better efficacy in comparison to the pancreatic cancer patient cohort in the gemcitabine + Abraxane study. This latter study included patients from North America, Australia, and Eastern and Western Europe. A subgroup analysis of Canadians in this study demonstrated an overall pancreatic cancer survival duration of 11.9 months, pointing to possible outcome differences between countries involved.
Characteristic FOLFIRINOX G + Abraxane
Overall Response Rate 31.6% 23%
PR 31% 23%
SD 38.6% 27%
DCR 70.2% 48%
PFS1/2 (mos) 6.4 5.5
OS1/2 (mos) 11.1 8.5
1-yr Overall Survival 48.4% 35%
TOXICITY & QUALITY of LIFE
For the first two months of treatment, the FOLFIRINOX study seemed to show improved overall patient health status by relieving several pancreatic cancer symptoms (except diarrhea). The Gemcitabine + Abraxane study did not assess quality of life, but the regimen appeared to improve quality-adjusted survival in metastatic pancreatic cancer compared to the use of gemcitabine alone.
Adverse Event FOLFIRINOX G +Abraxane
Neutropenia 45.7% 38%
Thrombocytopenia 9.1% 13%
Anemia 7.8% 13%
Fatigue 23.6% 17%
Peripheral Neuropathy 9% 17%
Diarrhea 12.7% 6%
Alopecia (grade 2) 11.4% 50%
Here we use 2014 Medicare average sales prices for the three pancreatic cancer treatment regimens. The bottom row assumes that patients continued until progression per key study results (each with their own unique demographics). The UK’s National Health Service has rejected Abraxane due to cost.
Cost Gemcitabine FOLFIRINOX G + Abraxane
Monthly Cost $1,363 $7,234 $12,221
PFS1/2 (mos) 3.7 6.4 5.5
Cost to progression $5,043 $46,298 $67,216
Both FOLFIRINOX and Gemcitabine plus Abraxane improve the duration of survival compared to gemcitabine, which had been the standard of care for advanced pancreatic cancer. It is difficult to compare these drug regimens as the patient populations are different and, to date, no study has done a direct comparison in pancreatic cancer. But this idea of comparing the Phase III clinical trial results of the two treatment regimens is a very clever one by Kattan and colleagues. Until more direct data are available, one has the sense from comparisons such as this, that FOLFIRINOX may offer slightly better efficacy, with comparable or possibly slightly more intense side effects. But direct comparative data are not yet available. So, as Paul Simon says, we are left with “hints and allegations” until that time. The costs of these regimens for advanced pancreatic cancer are surprisingly high.