Excess premature (3-month) mortality in advanced pancreatic cancer could be related to fatal vascular thromboembolic events. A hypothesis based on a systematic review of phase III chemotherapy studies in advanced pancreatic cancer

Introduction. An at least 3-month expected survival is a common inclusion criterion in cancer treatment trials, including advanced pancreatic cancer phase III studies. Published survival curves for advanced pancreatic cancer however seem to reflect a substantial survival shortfall. We wanted to assess the strength of this observation and search for an explanation by reviewing the literature. Methods. A Medline and EMBASE search was done for chemotherapy or chemotherapy based phase III studies in advanced pancreatic cancer published since 1997. Similar search was done at the American Society's of Clinical Oncology web site for abstracts presented since 2000. Three months mortality was based on the survival curves presented. Results. Fourteen papers and five abstracts met our criteria and are included in our review. Six thousand two hundred and twelve patients participated in these trials and 1 447 (23.3%) died in the first 3-month period. Figures were worse in patients with metastases and poorer performance status. Assuming that most deaths during treatment happened during the first 3-months, cause of death was reported in only 40 cases (2.8%). Progressive cancer was reported as cause of death in 21 of these cases. Less frequent causes of death were reported to be infections, 'complications of cancer', thromboembolic events and renal failure. Discussion. Overall treatment-related deaths represent a very small percentage of the deaths happening during the 3-month period, and are unlikely to be under-reported given the Good Clinical Practice oversight of these trials. Progressive cancer is likely to be an important cause of early mortality but given the very select nature of the trial-related population this cannot explain the phenomenon of 3-month early death burden of 23.3%. Our hypothesis, supported by multiple autopsy series, is that early death burden in advanced pancreatic cancer trial patients is likely to be due to under-reported vascular thromboembolic events. Thromboprophylaxis needs to be addressed in future trials.