Lack of efficacy of streptozocin and doxorubicin in patients with advanced pancreatic endocrine tumors.

To the Editor: We read with great interest the article by McCollum et al in the October 2004 issue of the American Journal of Clinical Oncology, which highlights the lack of efficacy of chemotherapy based on the combination of streptozotocin and doxorubicin in the treatment of advanced pancreatic endocrine tumors. We suggest an alternative explanation to justify the difference between the results observed by Moertel et al and those stated by the authors in the discussion. Although the nature of these tumors has been commonly considered indolent, current knowledge in this field suggests that advanced pancreatic endocrine tumors have a broad spectrum of behavior with a widely variable prognosis. In the year 2000, the World Health Organization revised the pathologic classification, and it now considers different tumor types according to their clinical behavior and pathology. Moreover, the determination of proliferation index by the immunohistochemical Ki67 assay is being introduced into standard diagnostic pathology reports. This proliferation index has been shown to correlate well with the development of metastases and is thus a clear predictor of survival. We lack the information on the proliferation indices of the patients included in the article by McCollum et al, but we can speculate on the characteristics of these patients when looking at the overall survival of this population. These patients may have had advanced tumors with a low proliferation index, which would justify the prolonged median survival observed (20.2 months) and a poor objective response rate to the cytotoxic treatment (ORR 6%) reported in the article. When Moertel et al published their original manuscript, the efficacy of giving somatostatin analogs along with interferon was still under investigation; thus, inclusion of patients who were resistant to those active treatments was not an option. Consequently, most if not all of the patients had not yet received any kind of therapy before the study medication. In the article by McCollum, only 2 patients out of a total of 16 had received other treatments previously. On the other hand, in the article published by Saltz et al that was cited in the discussion, 6 patients out of a total of 16 had received previous chemotherapy or immunotherapy. An important proportion of patients were thus refractory to previous treatments. We consider that the results of McCollum et al differ from the data reported by Moertel et al for 3 important reasons. First, the patients included in the study belonged to a restricted subgroup (possibly tumors with low proliferative index) with a prolonged survival but a poor response rate to chemotherapy. Second, a substantial number of patients had been treated previously with active agents used in this setting as somatostatin analogs and interferons. Third, the methodology used to evaluate the response, which accepts the biologic response as a reduction in the values of the hormonal assays of at least 50% and the clinical measurement of hepatomegaly, has now been abandoned. At our institution, patients with advanced disease and low proliferative index ( 10%) receive immunotherapy, either alone or in combination with somatostatin analogs, as first-line treatment. Because combination of the 2 drugs has additive and synergistic effects, we prefer this option for most of our patients. We use somatostatin analogs alone only for patients with poor performance status, mainly to achieve control of the symptoms related to peptide production. We reserve chemotherapy treatment for patients with more aggressive tumors with high proliferative index ( 10%) or for those patients with low proliferative tumors that have failed to respond to noncytotoxic treatments, which is an algorithm for treatment that is very similar to the recent guidelines published by the Nordic Neuroendocrine Tumor Group. We and others support determination of the proliferation index to better define the treatment of patients with pancreatic endocrine tumors. In addition, we believe that the determination of proliferative index should be included as an eligibility criterion or as a stratification factor for future clinical trials in patients with advanced pancreatic endocrine tumors. This would avoid the inclusion of patients with different tumor profiles and natural histories, which may seriously bias the outcome of these studies.