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EDITORIALS |
From the Department of Surgery, Division of Surgical Oncology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Correspondence: Address correspondence to: Andrew M. Lowy, MD, The Barrett Cancer Center, University of Cincinnati Medical Center, 234 Goodman Street, Cincinnati, OH 45219-0772; Fax: 513-584-0459; E-mail: lowyam{at}healthall.com
In this issue of the Annals of Surgical Oncology, Culliford et al.1 present a thought-provoking article regarding the treatment of patients with peritoneal metastases from carcinoma of the colon and appendix.
There are three central theses put forth by the authors:
The authors review the outcome of 64 patients treated with surgical debulking and intraperitoneal chemotherapy (FUDR and Leucovorin). The median survival of the group was 34 months and the 5-year survival rate was 28%. There were no treatment-related mortalities and morbidity was generally minor. Complete gross resection of peritoneal metastases was the only factor associated with long-term survival. Pestieau and Sugarbaker2 recently reported remarkably similar findings in a cohort of 104 patients with colorectal carcinoma treated with cytoreductive surgery, intraperitoneal hyperthermic chemotherapy, and early postoperative intraperitoneal 5-FU. Using a different intraperitoneal chemotherapy regimen, Pestieau and Sugarbaker’s group also found that the ability to achieve complete cytoreduction was the most significant predictor of outcome.
Although Culliford et al. have demonstrated that long-term survival is achievable for some patients with peritoneal metastases from colon carcinoma, the retrospective nature of the study makes any conclusions about the impact of therapy risky. It is certainly conceivable, perhaps even likely, that favorable tumor biology may have played a larger role in the outcome of this cohort than did the therapy itself. The patient cohort represents those treated at Memorial Sloan-Kettering Cancer Center over a 12-year period. One would assume they represent far less than 1% of patients with colon carcinoma treated at Memorial during that period, though the denominator is not specified. To their credit, the authors readily acknowledge the probable impact of biology and patient selection on their results. The similar findings of the Pestieau and Sugarbaker group argue that biology and perhaps surgical cytoreduction are more important than the specific peritoneal chemotherapy regimen. It is unfortunate that the authors have not provided any information as to the selection criteria that were used to place patients on this treatment regimen. Were there exclusion criteria such as history of prior bowel obstruction, perforated malignancy, etc.? What performance status was considered acceptable for these patients? Although the authors provide numerical data on recurrence and survival, no specifics of the patterns of failure are provided. This would at least provide a measure of the effectiveness of this treatment regimen in achieving "local" disease control in the peritoneum.
The limitations of the current study are common to most retrospective analyses. The importance of the paper lies in the paradigm it presents: that of using surgery as adjuvant to what has been considered the more "standard treatment" of peritoneal metastases, chemotherapy. As the authors point out, surgical debulking or cytoreduction of peritoneal metastases has been successfully applied in the management of ovarian carcinoma. Ovarian carcinoma differs from most other gastrointestinal malignancies in two significant ways, however. The pattern of metastasis is largely limited to the peritoneum and most importantly, response rates to cytotoxic chemotherapy are significantly higher. Again, this is not the first investigation of its kind. It is timely, however. With the ever increasing array of chemo- and biologic therapies, we can reasonably expect systemic treatment of gastrointestinal malignancy to improve significantly in the coming years. As our ability to effect tumor biology with molecular targeted agents increases, surgical cytoreduction may soon become a strategy that is rationally applied to an ever-increasing number of patients with peritoneal metastases.
The question then becomes, where do we go from here? Clearly, further evaluation of this treatment strategy is warranted. Surgical oncologists are uniquely positioned to take the lead in these investigations. The pat answer of proceeding to prospective, randomized trials to examine the role of surgical cytoreduction is certainly premature, however. Although prospective, multi-institutional trials are certainly desirable, the Culliford et al. study highlights several critical issues regarding the methods by which we study new therapies for peritoneal metastases. Within one study, the authors have included both patients with pseudomyxoma peritonei from appendiceal carcinoma and patients with colon carcinoma. Although analysis of various subsets revealed no change in their conclusions, clearly the design of prospective trials must aspire to uniformity so as to minimize the biases introduced by tumors with vastly differing biologic behavior. Our current staging systems lack the specificity to distinguish patients with disseminated carcinomatosis from those with a few peritoneal implants. Pestieau and Sugarbaker have attempted to quantify the extent of peritoneal metastases with a "Peritoneal Cancer Index." Classification schemas such as this need to be evaluated, refined, and correlated with our best imaging tools to allow the enrollment of patients with similar degrees of tumor burden. What endpoints should be used in these studies? For patients with colon carcinoma, survival may be entirely appropriate, whereas for patients with low-grade appendiceal tumors, this may not be practical. Given the profound negative impact of disseminated peritoneal metastases on quality of life, clearly future studies should include quality of life measures as endpoints. Finally, despite the grave clinical problem it poses, there has been remarkably little basic research into the molecular characteristics of tumors that metastasize preferentially to the peritoneum. This is despite the fact that, in perhaps no other site, is there a greater volume of tumor available for study. Future trials should be linked with more basic work so that we can gain insight into the molecular changes that prompt some gastrointestinal cancers to spread preferentially to the peritoneum versus to other sites. Hopefully, such studies will eventually provide rational targets for the development of novel intraperitoneal therapies to which surgical cytoreduction could serve as an effective adjuvant.
Received for publication August 22, 2001. Accepted for publication September 4, 2001.
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