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Chemotherapy for Resectable and Advanced Pancreatic Cancer

Chemotherapy for Resectable and Advanced Pancreatic Cancer

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/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

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