Commentary (Kooby): Managing the Peritoneal Surface Component of Gastrointestinal Cancer

Dr. Paul Sugarbaker's review on management of the peritoneal surface component of gastrointestinal cancer represents a lifetime of experience with an aggressive therapeutic approach to patients historically considered poor surgical candidates. This strategy combines tumor-directed peritoneal stripping (peritonectomy) and major abdominal visceral organ resection, with "heated intraoperative intraperitoneal chemotherapy" followed by "early postoperative intraperitoneal chemotherapy," to improve outcome in patients with seemingly fatal disease. The manuscript is thorough, informative, and reasonable. It provides historical background, a discussion of the pathophysiology of peritoneal carcinomatosis, a rationale for pursuing this approach, a description of surgical technique, drug administration, and patientselection criteria, and a discussion of selected results in the literature. Morbidity, mortality, and ethical considerations are also briefly mentioned. Verwaal et al Study
This is a timely review in light of the recent randomized trial comparing cytoreductive surgery and heated intraoperative intraperitoneal chemotherapy (experimental therapy) to systemic chemotherapy and palliative surgery (standard therapy) in colorectal cancer patients with peritoneal disease.[1] In this study by Verwaal et al, patients receiving experimental therapy achieved a survival advantage over those managed with standard therapy (median survival = 22.3 vs 12.6 months, P = .032), albeit with significantly higher mortality (8% in the experimental group). Because the two arms in this trial differed in treatment intent, type of surgery, and chemotherapy regimens, the comparisons are difficult to interpret. Still, the overall message suggests a potentially modest benefit of the experimental combined treatment for selected patients with peritoneal metastases from colorectal cancer over standard palliative care. As with all provocative trials, the study by Verwaal et al raises more questions than answers. Is the relatively modest gain in life expectancy worth the morbidity and mortality associated with the treatment? Is extent and completeness of peritonectomy, a function of surgical technique or a statement on tumor biology? How aggressive should we be with these patients, and what morbidity and mortality are acceptable? When combined with peritonectomy, what advantage does intraperitoneal chemotherapy truly provide over systemic chemotherapy? Presumably, these and other queries will be addressed in the near future by the American College of Surgeons Oncology Group. Gynecologic vs Gastrointestinal Disease
The combination of surgical debulking and cytotoxic chemotherapy to treat peritoneal disease is a familiar concept in the world of gynecologic oncology. In stage III and IV ovarian neoplasms, acceptable debulking requires the reduction of peritoneal disease volume to less than 2 cm (optimal debulking is less than 0.5 cm) in any given focus within the peritoneal cavity. Surgery is followed by systemic chemotherapy, and this combination is associated with a survival benefit over systemic therapy alone.[2] This approach to the treatment of advanced ovarian cancer is successful for several reasons: Many advanced ovarian neoplasms remain confined to the peritoneal cavity; many ovarian neoplasms are chemoresponsive; and the tumor nodules are often soft and somewhat penetrable by these agents. Unfortunately, gastrointestinal tract malignancies rarely meet these criteria, especially in the face of regional metastases. In fact, in some instances, we are still struggling to achieve significant long-term survival when treating primary disease (eg, pancreatic adenocarcinoma). Aggressive regional therapy remains unproven in most malignancies including sarcoma and pancreatic, gastric, colorectal, and breast cancers.[3-7] Clearly, however, some patients survive in excess of expectancy, and most clinicians remember these notable exceptions. These cases represent the positive tail of the bell curve and do not provide the entire picture. Limitations of Combined Treatment
Two obvious limitations of combined treatment are the development of systemic disease and poor response to intraperitoneal chemotherapy- both of which hinder this approach to malignancies of the gastrointestinal tract. These limitations have been demonstrated in numerous experimental models of intraperitoneal chemotherapy and gene therapy for carcinomatosis. Usually, the only success seen with these models is when intraperitoneal therapy is administered hours or days after tumor cells have been injected into the abdominal cavity, prior to significant tumor cell implantation and division.[8] Another interesting parallel to consider regarding tumor biology and peritoneal metastases is that of port site recurrence following laparoscopic procedures in patients with cancer. After a few early case reports, some authors raised the concern that insufflating the abdomen with carbon dioxide would spread microscopic peritoneal disease, allowing it to implant on fresh surgical wounds associated with trocar sites. Subsequent data have refuted these concerns, and port site recurrences are no longer thought to be primary determinants of patient outcome, but rather, markers of an overall worse biology.[9] Similarly, a surgeon's ability to perform complete cytoreduction (CC-0 or CC-1) is likely to be a function of tumor biology, and the more aggressive malignancies that are more likely to invade do not lend themselves to optimal cytoreduction. Conclusions
Finally, the author makes the point that hepatic resection was accepted as standard therapy for some patients with colorectal cancer metastases without phase III data, suggesting that combined therapy for peritoneal carcinomatosis may be ethical by similar logic. Although this point is somewhat valid, the cost of treatment to the patient should not exceed or even equal the benefit provided. In the case of partial hepatectomy, the procedure is generally well tolerated, and certainly some cures are achieved following hepatic metastectomy. The risk/benefit profile of combined therapy is still being defined. On the other hand, patients with peritoneal carcinomatosis are usually devoid of attractive options, and provided they truly understand the potentially devastating risks and modest benefits ahead, combined treatment and other investigational approaches should continue to be evaluated in protocol settings. I applaud Dr. Sugarbaker's efforts in defining a therapeutic niche.