In the mid-1980s, the Colorectal Cancer Section of the Surgery Branch, National Cancer Institute, Bethesda, MD was negotiating heavily concerning a protocol to test the efficacy and safety of the resection of 1–3 liver metastases in patients with colon or rectal cancer. We eventually piloted an IRB-approved trial testing long-term intraperitoneal 5-fluorouracil as an adjuvant to complete resection . For several logistical reasons, the final results of approximately 60 patients were never published. We use the same strategy, 12 full months of intraperitoneal 5-fluorouracil as an adjuvant for patients with resected poor prognosis primary colon or rectal cancer . Maximal doses of intravenous 5-fluorouracil were compared to maximal doses of intraperitoneal 5-fluorouracil. In retrospect, we got the expected result. There was a marked decrease in local-regional failure but no survival advantage. With the chemotherapy-induced control isolated to the peritoneal space, a malignancy with metastases limited to the peritoneal space seemed a logical next step . With pseudomyxoma peritonei, we were treating gross disease so we had to invent the peritonectomy procedures to get the intraperitoneal 5-fluorouracil to be effective . The combination of no hematogenous metastases, cytoreductive surgery (CRS) and intraperitoneal mitomycin C and 5-fluorouracil was an astounding success . As greater numbers of patients with low-grade appendiceal mucinous neoplasms were treated a 100% lethal disease process was converted to 80% survival at 20 years . Results with another malignancy with metastases confined to the peritoneal spaces were likewise spectacular. Malignant peritoneal mesothelioma was taken from a median survival of 1 year to 80% survival at 20 years .
Unfortunately, our rapid progress for long-term survival from CRS and perioperative chemotherapy was stalled when peritoneal metastases from colon cancer, gastric cancer, and ovarian cancer were treated [8, 9]. The resilience of our commitment to succeed with control of peritoneal metastases from the more common abdominal and pelvic malignancies is currently being tested. In randomized trials for ovarian and gastric cancer, the perioperative chemotherapy has some efficacy [10, 11]. While for colon cancer, the chemohyperthermia intraperitoneal was not of benefit . Currently, we are controlled by the PCI: less than 10 for gastric cancer, less than 17 for colorectal cancer and confusing for ovarian cancer because of inconsistent use of neoadjuvant chemotherapy.
In some of our efforts to control peritoneal metastases, we must adapt to failure. In other instances, be content with limited success with our local-regional approach. Now 35 years into this effort, it is apparent that we recognize our strengths and weaknesses. There are some amazing accomplishments. Complete CRS is a really powerful tool for treatment for peritoneal metastases patients. Complete visible resection of all visible disease really works and should always be the surgeon’s goal if it can be completed safely . A second strength is our positive results with perioperative intraperitoneal chemotherapy in patients with positive cytology. The hyperthermic intraperitoneal chemotherapy (HIPEC) and extensive washing of peritoneal surfaces can eliminate tumor cell reimplantation after CRS . This causes limited benefits with ovarian and gastric cancer [10, 11].
There are, unfortunately, some fundamental weaknesses with HIPEC which is our current mainstay of treatment after CRS. I am convinced that intraperitoneal chemotherapy is being asked to perform over and above that which translational science would predict. Intraperitoneal chemotherapy in an aqueous solution with or without heat enters tissues by simple diffusion. This results in drug penetration of a fraction of a millimeter into cancerous tissue. Also, if the cancer nodule is vascularized, the chemotherapy is rapidly removed from tumor into the body compartment. Consequently, with HIPEC, only single cells or minute nodules should be expected to develop apoptosis. Perhaps only nonvascularized nodules are eradicated. This response assumes that a complete cytoreduction precedes HIPEC. Not only is the chemotherapy penetration and retention within peritoneal metastases severely restricted, the chemotherapy that has entered the cell has a low response rate. For example, mitomycin C has a durable response rate of approximately 20% for previously untreated metastatic colon cancer. Add a low volume of disease as expected after complete cytoreduction, increased drug concentration from intraperitoneal drug administration, and heat. The durable response may reach 20–40%. Unfortunately, even with optimal delivery of chemotherapy into the peritoneal metastases, apoptosis may not result because the cancer cells have natural or acquired resistance. Not surprising, then, that 30% is the long-term survival expected with CRS and HIPEC for colon cancer peritoneal metastases.
I am convinced that perioperative intraperitoneal chemotherapy can be made maximally effective. In order to achieve the best outcome, one needs the cytoreduction to be complete (no visible residual disease) and prolonged exposure of the combined intraperitoneal and intravenous cytotoxic agents active in a majority of patients. Valuable lessons are to be learned from the successes of systemic chemotherapy in the last 30 years: progress will be the result of long-term multidrug regimens that are founded in extensive translational science.
In this special issue of Visceral Medicine, we take a hard look at peritoneal dissemination with gastric cancer, colorectal cancer, ovarian cancer, at a new treatment modality currently being explored (pressurized intraperitoneal aerosolized chemotherapy) and at prevention of peritoneal metastases. It is part of the resilience of the global effort to control peritoneal metastases.
Conflict of Interest Statement
The author has no conflicts of interest.
Administrative and secretarial support was provided by the Foundation for Applied Research in Gastrointestinal Oncology.
Paul H. Sugarbaker was responsible for all aspects of this editorial.