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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