Carcinoma of the pancreas re mains an imposing threat to health and life, with the majority of patients presenting with advanced disease and, in most cases, dying from it. Surgical, radiation, and chemotherapy treatments have demonstrated limited efficacy in this disease. Drs. Berlin and Rothenberg concisely yet thoroughly review the data on the utility of chemotherapy at each stage of disease. We would like to expand and emphasize the discussion in several areas.
Impact of Trial Design on Assessment of Activity
Low frequency of objective remission and difficulty in assessing response in pancreatic cancer has led to the use of survival and clinical benefit response as primary measures of outcome. Drs. Berlin and Rothenberg correctly call attention to the impact of stage distribution on the survival of patients with "advanced" pancreatic cancer entered into a clinical trial. As exemplified by the three trials of the gemcitabine(Drug information on gemcitabine)/fluorouracil (5-FU) combination, reported differences in survival (medians of 4.4, 7, and 11 months) might be explained by the percentage of enrolled patients with nonmetastatic disease (0%, 46%, and 61%, respectively). This example serves to remind investigators of the need to pay careful attention to disease stage and suggests caution when making comparisons between studies.
Apparently conflicting study results also contribute to the confusion regarding the utility of adjuvant chemoradiotherapy. Data from the Gastrointestinal Tumor Study Group (GITSG) reported a significantly improved median survival of 21 months with adjuvant chemoradiation vs 11 months with best supportive care. More recently, the European Organization for Research and Treatment of Cancer (EORTC) found no statistically significant survival benefit with chemoradiotherapy in their randomized study.
Why did the trials differ in their conclusions? In the EORTC trial, 20% of patients randomized to the treatment arm did not receive treatment, which likely had an impact on the non-statistically significant but improved median survival of 24.5 months in the treatment arm vs 19 months in the control arm. In addition, patients in that trial received only 4 weeks of chemotherapy, whereas patients in the GITSG trial received 5-FU for 2 years. Perhaps most importantly, both studies were underpowered, leading us in the first instance to doubt a positive study, and in the second, to dismiss a clinically meaningful benefit due to lack of statistical significance.
We believe adequately powered, well-designed studies with contemporary regimens administered for an appropriate length of time, if performed, would demonstrate a benefit for adjuvant therapy in pancreatic cancer following curative resection.
Markers of Response Need to Be Reevaluated