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

Dr. Paul Sugarbaker's reviewon management of the peritonealsurface component ofgastrointestinal cancer represents alifetime of experience with an aggressivetherapeutic approach to patientshistorically considered poor surgicalcandidates. This strategy combinestumor-directed peritoneal stripping(peritonectomy) and major abdominalvisceral organ resection, with"heated intraoperative intraperitonealchemotherapy" followed by "earlypostoperative intraperitoneal chemotherapy,"to improve outcome in patientswith seemingly fatal disease.The manuscript is thorough, informative,and reasonable. It provides historicalbackground, a discussion of thepathophysiology of peritoneal carcinomatosis,a rationale for pursuing thisapproach, a description of surgical technique,drug administration, and patientselectioncriteria, and a discussion ofselected results in the literature. Morbidity,mortality, and ethical considerationsare also briefly mentioned.Verwaal et al Study
This is a timely review in light ofthe recent randomized trial comparingcytoreductive surgery and heated intraoperativeintraperitoneal chemotherapy(experimental therapy) tosystemic chemotherapy and palliativesurgery (standard therapy) incolorectal cancer patients with peritonealdisease.[1] In this study byVerwaal et al, patients receiving experimentaltherapy achieved a survival advantage over those managed withstandard therapy (median survival =22.3 vs 12.6 months, P = .032), albeitwith significantly higher mortality(8% in the experimental group). Becausethe two arms in this trial differedin treatment intent, type of surgery, andchemotherapy regimens, the comparisonsare difficult to interpret. Still, theoverall message suggests a potentiallymodest benefit of the experimentalcombined treatment for selected patientswith peritoneal metastases fromcolorectal cancer over standard palliativecare.As with all provocative trials, thestudy by Verwaal et al raises morequestions than answers. Is the relativelymodest gain in life expectancyworth the morbidity and mortality associatedwith the treatment? Is extentand completeness of peritonectomy, afunction of surgical technique or astatement on tumor biology? How aggressiveshould we be with these patients,and what morbidity and mortalityare acceptable? When combinedwith peritonectomy, what advantagedoes intraperitoneal chemotherapytruly provide over systemic chemotherapy?Presumably, these and otherqueries will be addressed in the nearfuture by the American College ofSurgeons Oncology Group.Gynecologic vsGastrointestinal Disease
The combination of surgicaldebulking and cytotoxic chemotherapyto treat peritoneal disease is afamiliar concept in the world ofgynecologic oncology. In stage III andIV ovarian neoplasms, acceptabledebulking requires the reduction of peritonealdisease volume to less than 2 cm(optimal debulking is less than 0.5 cm)in any given focus within the peritonealcavity. Surgery is followed by systemicchemotherapy, and this combination isassociated with a survival benefit oversystemic therapy alone.[2] This approach to the treatment of advancedovarian cancer is successful for severalreasons: Many advanced ovarian neoplasmsremain confined to the peritonealcavity; many ovarian neoplasms arechemoresponsive; and the tumor nodulesare often soft and somewhat penetrableby these agents.Unfortunately, gastrointestinal tractmalignancies rarely meet these criteria,especially in the face of regionalmetastases. In fact, in some instances,we are still struggling to achieve significantlong-term survival when treatingprimary disease (eg, pancreaticadenocarcinoma). Aggressive regionaltherapy remains unproven in mostmalignancies including sarcoma andpancreatic, gastric, colorectal, andbreast cancers.[3-7] Clearly, however,some patients survive in excess of expectancy,and most clinicians rememberthese notable exceptions. Thesecases represent the positive tail of thebell curve and do not provide theentire picture.Limitations ofCombined Treatment
Two obvious limitations of combinedtreatment are the developmentof systemic disease and poor responseto intraperitoneal chemotherapy-both of which hinder this approach tomalignancies of the gastrointestinaltract. These limitations have beendemonstrated in numerous experimentalmodels of intraperitoneal chemotherapyand gene therapy for carcinomatosis.Usually, the only success seenwith these models is when intraperitonealtherapy is administered hoursor days after tumor cells have beeninjected into the abdominal cavity,prior to significant tumor cell implantationand division.[8]Another interesting parallel to considerregarding tumor biology andperitoneal metastases is that of portsite recurrence following laparoscopic procedures in patients with cancer.After a few early case reports, someauthors raised the concern that insufflatingthe abdomen with carbon dioxidewould spread microscopic peritonealdisease, allowing it to implanton fresh surgical wounds associatedwith trocar sites. Subsequent datahave refuted these concerns, and portsite recurrences are no longer thoughtto be primary determinants of patientoutcome, but rather, markers of anoverall worse biology.[9] Similarly, asurgeon's ability to perform completecytoreduction (CC-0 or CC-1) is likelyto be a function of tumor biology, andthe more aggressive malignancies thatare more likely to invade do not lendthemselves to optimal cytoreduction.Conclusions
Finally, the author makes the pointthat hepatic resection was accepted asstandard therapy for some patientswith colorectal cancer metastaseswithout phase III data, suggesting thatcombined therapy for peritoneal carcinomatosismay be ethical by similarlogic. Although this point is somewhatvalid, the cost of treatment to the patientshould not exceed or even equal the benefit provided. In the case ofpartial hepatectomy, the procedure isgenerally well tolerated, and certainlysome cures are achieved followinghepatic metastectomy.The risk/benefit profile of combinedtherapy is still being defined. Onthe other hand, patients with peritonealcarcinomatosis are usually devoidof attractive options, and provided theytruly understand the potentially devastatingrisks and modest benefitsahead, combined treatment and otherinvestigational approaches should continueto be evaluated in protocol settings.I applaud Dr. Sugarbaker's effortsin defining a therapeutic niche.

Disclosures:

The author has no significantfinancial interest or other relationshipwith the manufacturers of any products or providersof any service mentioned in this article.

References:

1.

Verwaal VJ, van Ruth S, de Bree E, et al:Randomized trial of cytoreduction and hyperthermicintraperitoneal chemotherapy vs systemicchemotherapy and palliative surgery inpatients with peritoneal carcinomatosis ofcolorectal cancer. J Clin Oncol 21:3737-3743,2003.

2.

van der Burg ME, van Lent M, Buyse M,et al: The effect of debulking surgery after inductionchemotherapy on the prognosis in advancedepithelial ovarian cancer. GynecologicalCancer Cooperative Group of the European Organization for Research and Treatment ofCancer. N Engl J Med 332:629-634, 1995.

3.

Nguyen TC, Sohn TA, Cameron JL, et al:Standard vs radical pancreaticoduodenectomyfor periampullary adenocarcinoma: A prospective,randomized trial evaluating quality of lifein pancreaticoduodenectomy survivors. JGastrointest Surg 7:1-11 (incl discussion), 2003.

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Bonenkamp JJ, Hermans J, Sasako M, etal: Extended lymph-node dissection for gastriccancer. Dutch Gastric Cancer Group. NEngl J Med 340:908-914, 1999.

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Bruch HP, Schwandner O, Schiedeck TH,et al: Actual standards and controversies onoperative technique and lymph-node dissectionin colorectal cancer. Langenbecks Arch Surg384:167-175, 1999.

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Fisher B, Redmond C, Fisher ER, et al:Ten-year results of a randomized clinical trialcomparing radical mastectomy and total mastectomywith or without radiation. N Engl JMed 312:674-681, 1985.

7.

Rosenberg SA, Tepper J, Glatstein E, etal: The treatment of soft-tissue sarcomas of theextremities: Prospective randomized evaluationsof (1) limb-sparing surgery plus radiationtherapy compared with amputation and (2) therole of adjuvant chemotherapy. Ann Surg196:305-315, 1982.

8.

Bennett JJ, Kooby DA, Delman K, et al:Antitumor efficacy of regional oncolytic viraltherapy for peritoneally disseminated cancer.J Mol Med 78:166-174, 2000.

9.

Shoup M, Brennan MF, Karpeh MS, etal: Port site metastasis after diagnosticlaparoscopy for upper gastrointestinal tractmalignancies: An uncommon entity. Ann SurgOncol 9:632-636, 2002.