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.
In a certain sense, treatment selection by professionals is easier in early or late stage pancreatic cancer (ductal adenocarcinoma of the pancreas) because the options tend to be narrower: early yields surgery; late leans toward chemotherapy alone. The middle stages II and III, or locally advanced, potentially resectable pancreatic cancer, etc. tend to be more problematic in terms selecting the optimal course of action among the array of initial treatment options. The term that Farnell, et al. use for assessing this treatment option situation in the article reviewed is “poorly defined.”
The authors, all from the surgical service at the Mayo Clinic in Rochester, Minnesota, retrospectively reviewed a nine-year period beginning in 2002 for the outcome of survival duration in patients with stage 3 pancreatic cancer in the U.S. National Cancer Data Base, dividing them into those who received neoadjuvant therapy as the initial treatment modality with an intention for subsequent pancreatic cancer surgery, or as having received surgery first with adjuvant therapy to come later. The results were published in the October 2016 issue of the journal Surgery.
Almost 600 patients in these two categories were identified, about two-thirds in the neoadjuvant pancreatic cancer group and the rest in the surgery first group. However, over a quarter of the neoadjuvant patients were unable to receive pancreatic cancer surgery due to preoperative attrition, leaving 273 patients who were able to undergo both neoadjuvant therapy and pancreatic surgery. In the surgery first group approaching 14% of patients did not receive adjuvant therapy leaving 186 patients with pancreatic cancer who received both modalities.
The overall survival of these two groups with pancreatic cancer was 20.7 months for the neoadjuvant therapy group, and 13.7 months for the surgery first group (P = .0012).
This is an impressive survival advantage for state 3 patients with pancreatic cancer receiving neoadjuvant therapy prior to surgery, although the high rate of those unfortunately unable to ultimately receive the planned surgery is noted. This is a commendable and good step forward in trying to provide illuminating light in the otherwise somewhat murky area of the optimal treatment strategy for the presenting middle stages of pancreatic cancer. More research in this area is needed, including teasing out options for different circumstances, and ultimately involving prospective studies.
Dale O’Brien, MD
Criteria for exclusion of patients from surgery for pancreatic cancer (ductal adenocarcinoma of the pancreas) include detection of distal metastases including those noted in the liver (also known as the hepatic organ). However especially over the past decade, there have been a number of studies aimed at trying to discern whether liver lesions alone should rule out pancreatic cancer surgery for every patient – or might careful selection based on chemotherapy response or multimodal therapy possibly including hepatic surgery treatment yield access to surgery and possible survival advantage?
The outcomes of such studies have been mixed. For example, an article in the December 2007 issue of the journal Cancer by Johns Hopkins University researchers showed no advantage by including hepatic metastases in the greater scope of surgical targets in pancreatic cancer surgery, whereas in 2008 German authors presented a review of the medical literature in the journal Digestive Surgery which indicated that there might be such a survival advantage in select such patients with pancreatic cancer.
But 2016 produced at least four studies (including the article-under-review; with a link at the end of this blog entry) from international researchers (including one Johns Hopkins researcher) which address the issue of concomitant surgery of hepatic metastatic lesions along with more standard pancreatic cancer in select patients, or standard pancreatic cancer surgery under select circumstances (significant response to chemotherapy).
The article under review was authored by researchers from Vita-Salute University in Milan, Italy and from Università Politecnica delle Marche in Ancona, Italy. They published their results in the October 2016 issue of the European Journal of Surgical Oncology, the official journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. The authors retrospectively examined the outcomes at their two institutions of pancreatic cancer patients who had who had undergone chemotherapy for hepatic metastases without evidence of extra-hepatic metastases, and who had acceptable personal performance status. 127 patients were identified (76 male and 51 female), had been treated with chemotherapy, and followed with regular CA 19-9 levels.
After treatment, 19 of these patients demonstrated a complete or partial radiological response of their pancreatic cancer; each of these patients additionally showed major biochemical response defined as a significant reduction of CA 19-9 levels. On subsequent evaluation, seven patients were excluded from pancreatic cancer surgery due to further studies that located increased liver or peritoneal metastases, or in one case a significant rise of CA 19-9 levels after the chemotherapy had ended. Laparotomy was performed on twelve patients with a full pancreaticoduodenectomy completed on 11 patients (one was found to have peritoneal metastases at surgery). In this sub-group of eleven patients with advanced pancreatic cancer who later underwent surgical resection, the median survival duration was 46 months as compared to 11 months for the patients with pancreatic cancer who were unable to undergo surgery (P< 0.0001).
This is a quite interesting study that begins to challenge existing orthodoxy in the context of the effectiveness of new chemotherapy regimens for the treatment of pancreatic cancer. The recent research concerning possible advantages of hepatic surgery or multimodal treatment for pancreatic cancer with hepatic metastases in select patients will be left for another time. But for now, perhaps it is enough to highlight this tentative conclusion that identifies significant-response-to-chemotherapy as a marker to possibly negate the absolute exclusion of pancreatic cancer patients with hepatic metastases for surgical resection. Obviously more research is needed, but this is an intriguing outcome worthy of further consideration, with accolades given from this vantage to the authors.
Dale O’Brien, MD