Commentaries on Articles
A ray of hope for patients with advanced small bowel and ampullary adenocarcinomas
Carcinomas of the small bowel and ampulla of Vater (also referred to as periampullary carcinoma) are relatively uncommon cancers. The prognosis of resected periampullary cancers is better than pancreatic-biliary tumors; however patients with advanced stage disease have a poor outcome. The 2 year survival is less than 10%. Small bowel and periampullary carcinomas are traditionally not considered very chemo-responsive tumors. However, the nihilistic approach of oncologists to advanced periampullary carcinomas needs reconsideration in the light of the recent publication of a Phase II study of capecitabine and oxaliplatin (CAPOX) in advanced adenocarcinoma of small bowel and ampulla of Vater in the June 2009 issue of Journal of Clinical Oncology (Overmann et al, J Clin Oncol 2009;27:2598-2600).
The institutional review board approved prospective study was conducted at the M.D.Anderson Cancer Center, Houston from November 2004 to July 2007. CAPOX was administered as a 21 day cycle with oxaliplatin 130 mg/m2 on day 1 and capecitabine 750 mg /m2 twice a day from day 1 to day 14 .The primary end point was overall response rates as per the standard RECIST criteria and secondary end points were overall survival, time to progression and toxicities. A total of 31 patients with advanced small bowel and ampullary carcionomas were accrued in the study over a 3 year period. Eighty three percent of the patients had metastatic disease; 96% of patients had good performance status (ECOG 0 OR 1) and 40% of patients had ampullary carcionomas. A total of 175 cycles of CAPOX were administered, of which 69% could be given at the full planned doses. Most dose reductions (mainly of oxaliplatin) were due to fatigue and peripheral neuropathy. The treatment was well tolerated; the most common severe adverse effects were fatigue (30%), diarrhea (10%), neuropathy (10%) and neutropenia (10%). The efficacy analyses showed a surprising degree of activity for the CAPOX regimen. The complete response rate was 10%, the partial response rate was 40% for an overall response rate of 50%. The responses were sustained – the median time to progression was 9.8 months and the median overall survival was 20.3 months.
Most previous studies of chemotherapy in advanced small bowel carcinomas have been retrospective in nature with response rates ranging from 0-37% with 5-FU based single agent or combination chemotherapy. The only previous prospective study (Gibson et al, Oncologist 2005;10:132-137) evaluated FAM chemotherapy, which resulted in response rate of 18% and overall survival of 8 months. A particular feature of the current study was the lower than usual dose of capecitabine that resulted in less dose reductions and interruptions and possibly contributed to the good response rate and prolonged duration of response. The recently published TREE study in metastatic colorectal cancer also suggested that the tolerability and efficacy of the CAPOX regimen is improved with reduced-dose capecitabine (J Clin Oncol 2008;26:3523-3529). The other notable feature of this study was the lower response rate in ampullary carcinomas (33%) compared to small bowel carcinomas (61%). Although a definitive explanation for this observation is not available the plausible hypotheses include the heterogeneous epithelium of origin and the expression of the caudal-type homeodomain transcription factors 1 (CDX1) and 2 (CDX2) in small bowel carcinomas. However further research into the molecular classification and predictive markers in periampullary carcinomas are required.
Although the small sample size of this study precludes a definitive conclusion about the efficacy of the CAPOX regimen in small bowel and periampullary carcinomas, it is certainly a valuable piece of information for physicians caring for these patients. Future studies are likely to evaluate the role of targeted therapies in combination with chemotherapy.
Dr. Nirmal Raut, Medical Oncologist
Dr. Sudeep Gupta, Medical Oncologist