Since the May 12, 2011 New England Journal of Medicine article that reported the possible superiority of the 5-FU based four-drug FOLFIRINOX regimen over gemcitabine in the treatment of metastatic pancreatic cancer (ductal adenocarcinoma of the pancreas), researchers have been at work trying to discover the best use of this information – and ways to perhaps improve on it. A case in point is the blog entry just prior to this one (FOLFIRINOX for neoadjuvant therapy in pancreatic cancer).
Also, we have reported on research of chemotherapy combinations that contain similar but fewer drug agents, such as the ones termed OFF and SOX. These are essentially modified FOLFIRINOX regimens. But there has arisen the term “Modified FOLFIRINOX Regimen” by which researchers appear to mean that tiny (to date) body of research on smaller tweaks to the standard FOLFIRINOX combination: oxaliplatin – 85 mg per M2 (body-surface area); irinotecan – 180 mg/ M2; leucovorin, 400 mg/M2; and fluorouracil (5-FU) – 400 mg/M2 given as a bolus followed by 2400 mg/M2 given as a 46-hour continuous infusion.
El-Rayes and colleagues at Emory University have published a study involving such a modified FOLFIRINOX regimen in the November 2013 issue of the journal Pancreas. They postulated that eliminating the bolus portion of the 5-FU and adding hematopoietic growth factor to FOLFIRINOX might continue to provide the efficacy of the drug-combination while improving the safety profile of the side-effects. They looked at 60 patients with pancreatic cancer in various stages of disease who were treated using this modified combination.
The authors found that the median overall survival duration for these patients with metastatic pancreatic cancer treated with this modified FOLFIRINOX regimen was 9.0 months. Also, importantly, the safety profile DID appear to be improved. The researchers suggest that this regimen can be given more safely than standard FOLFIRINOX, and without losing efficacy.
This is an interesting finding demanding further research.
Dale O’Brien, MD
The idea behind treating surgically unresectable and borderline resectable pancreatic cancer (ductal adenocarcinoma of the pancreas) with chemotherapy or chemoradiation is that some minority of cases will thereupon improve to the point of now being deemed amenable to surgery, with its typically more favorable outcome. This is generally the point then of so-called neoadjuvant therapy.
As the 5-FU based four-drug FOLFIRINOX regimen appears to show improved outcomes for advanced pancreatic cancer over gemcitabine alone, Bahary and colleagues at the University of Pittsburgh used FOLFIRINOX as neoadjuvant therapy in unresectable and borderline resectable pancreatic cancer. The results were published in the September 2013 issue of the Journal of Surgical Oncology.
The researchers treated 21 such pancreatic cancer patients with the drug combination; seven patients were then able to progress to surgery (two of these patients were initially found to have been unresectable). An additional two patients were deemed fit for surgery who were treated with both FOLFIRINOX and stereotactic body radiation therapy.
The authors found the results of FOLFIRINOX neoadjuvant treatment for surgically unresectable and borderline resectable pancreatic cancer as encouraging. This approach is certainly worthy of further study.
Dale O’Brien, MD
In what appears to be a season of blockbuster conceptual research results in the cancer medical literature, comes a recent study involving leukemia cells but which has implications for the entire spectrum of cutting edge cancer treatment. The general current prevailing thought on the origin of cancer is that a pattern of gene mutations or epigenetic changes emerge – that initiates signaling miscues to the normal orderly growth pathways of a cell – thus launching subsequent rapid and erratic cellular division and growth: cancer.
The present study takes the above as a starting point, but in a heretofore unknown (to this author) minor strain of research over the last few years – asks the questions: are these genetic mutations physically uniform throughout a tumor, and does the mutation profile of the tumor remain uniform over time? Of course, their answers are no and no. They cite research primarily from the last two years, but going back until 2008 demonstrating that there exists genetic diversity within a single tumor – and they indicate that “intraclonal genetic and phenotypic diversity is an inherent feature of [cancer].”
The implications of this concept are large, in that much of the idea of personalized medicine and targeted therapy is aimed at specific genetic patterns. If such a pattern is not uniform throughout a tumor then the results of the therapy may not be effective, or could possibly be ameliorated.
Greaves and colleagues primarily from The Institute of Cancer Research in London E-published the results of their research on November 6th 2013 in the journal Genomics Research that offers an in-depth view of genetic diversity in leukemia cells. In a multi-stage procedure the authors used state-of-the-art technologies to undertake single cell whole genome DNA sequencing, repeated in approximately three hundred cells. This was done for an individual with leukemia, and later for two other leukemia patients. The results showed not merely the expected mutations, but a large range of genetic mutations, and which were seen to be distributed in a manner which suggested sub-clonal populations (as identified by mutation patterns). These data were sorted and placed into a tree-and-branch clonal phylogeny by algorithm which physically demonstrated the relationships and temporal evolution of the DNA mutation patterns. In effect, these results showed that the individual patients did not have “leukemia” but in fact (rather astoundingly) had between two and ten genetically distinct leukemias.
Interestingly, the authors refer to their research process in such terms as “interrogating” clonal genetic complexity, in the sense that the DNA profile might perhaps be coaxed (through similar observation) to tell the story of what has happened to the cell over time. The researchers make the point that the beginning of disorderly cell division and growth due to DNA mutations in cancer increases the likelihood of subsequent DNA mutations in the same tumor / cell line. They indicate that leukemia is less likely to be complex in these matters than carcinoma (one might insert here “pancreatic cancer”). Finally, with all of the potential problems that these results confer to the idea of personalized medicine (treatments aimed at a patient’s tumor profile) the authors’ offer some promise in the sense that future doctors on understanding a more complex picture of the underpinnings of a given tumor, may be more likely to treat the “founder lesion” rather than a clonal branch or even a more minor clone – thus conferring more likely success in therapy.
This is large concept work – shown in meticulous, brilliant detail. It is actually rather breathtaking science that reveals again the unexpected at the cutting edge of medicine; plaudits to these researchers.
Dale O’Brien, MD