Pharmacology of chemotherapy treatments for peritoneal metastases: optimizing and augmenting HIPEC

Cancers that occur within the abdomen or pelvis have three different routes of dissemination: hematogenous metastases (usually to the liver), lymphatic metastases, and metastases to peritoneal surfaces. In many patients, disease progression at the resection site or spread to peritoneal surfaces may occur. Eliminating peritoneal surface spread will impact on the survival of these cancer patients, in whom a prominent cause of death is peritoneal metastases. Also, eliminating local-regional treatment failure may facilitate benefits from control of systemic metastases. Prior to the use of the combined treatment of cytoreductive surgery (CRS) and perioperative chemotherapy, peritoneal metastases were uniformly fatal, eventually resulting in intestinal obstruction over months or years and a fatal outcome with progression of intraabdominal cancer. The new approach of combining CRS with hyperthermic intraperitoneal chemotherapy (HIPEC) to treat peritoneal metastases offers hope for long-term survival in this group of patients.

This new combined treatment is always dependent on complete CRS from long-term benefit. This surgical intervention, which includes visceral resections and peritonectomy procedures, optimally results in the complete, visible resection of all cancer within the abdomen and pelvis. These dissections include the total parietal peritonectomy, left upper quadrant peritonectomy, greater omentectomy plus splenectomy, right upper quadrant peritonectomy, pelvic peritonectomy plus rectosigmoid colon resection, and cholecystectomy plus lesser omentectomy with peritonectomy of the omental bursa. A right colon resection or total abdominal colectomy may also be required. Resections are performed where peritoneal metastases are present.

Along with CRS, HIPEC is an integral part of the surgical procedure. This approach involves conceptual changes in both the route and timing of chemotherapy administration. The intraperitoneal route assures a high concentration of anticancer therapy at the peritoneal surfaces, and the perioperative timing has several advantages. With HIPEC, hyperthermia can be used to enhance cytotoxicity and improve drug penetration. In addition, the surgeon manually distributes the chemotherapy solution either from within the peritoneal space (open method) or externally (closed method) to improve the distribution of heat and drugs. The perioperative timing thereby improves responses and reduces complications. Because chemotherapy is administered after CRS, all of the malignancy, except microscopic residual disease or tiny nodules on small bowel surfaces, has already been surgically removed. Therefore, the limited penetration of chemotherapy (approximately 1 mm into tissues) may eradicate all tumor cells.

A notable change from prior nomenclature involves the term “peritoneal metastases” to replace the term “peritoneal carcinomatosis”; the term “peritoneal metastases” is used because it implies a treatable condition, such as lymph nodal metastases, liver metastases, and lung metastases. Peritoneal metastases can be quantified, with the extent directly correlating with treatment success. Historically, the term “peritoneal carcinomatosis” carries with it the connotation of a terminal condition that always lead to the patient’s death regardless of treatment and should no longer be used.

This multi-authored monograph collects the thoughts of world opinion leaders in the combination of CRS and HIPEC for treatment of peritoneal metastases. It originated as a satellite symposium of the 10th International Congress on Peritoneal Surface Malignancies held in Washington, DC, November 17–19, 2016. This was the 10th biennial conference of the Peritoneal Surface Oncology Group International (PSOGI). The principal authors of the manuscripts presented in this multi-authored monograph were the presenters at the PSOGI Satellite Symposium.

All of the authors recognize the great progress in the management of peritoneal metastases that has been achieved to date. However, they all also recognize that treatment failures are still all too common. Using the most up-to-date information, the eight manuscripts seek to optimize and augment the use of HIPEC or other perioperative intraperitoneal chemotherapy treatments such as pressurized intraperitoneal aerosolized chemotherapy (PIPAC) in the management of peritoneal metastases. De Bree and colleagues have defined for us the pharmacologic advantages expected with intraperitoneal chemotherapy delivery as part of a surgical procedure to remove abdominal and peritoneal tumor deposits [1]. Sophisticated mathematical models for this intraperitoneal drug delivery are provided by Ceelen et al. [2].

There are new approaches to intraperitoneal drug delivery for definitive treatment of peritoneal metastases. PIPAC has generated great interest because it can be used repeatedly and because the access of an aerosol to intraperitoneal spaces will greatly exceed that of a liquid solution. Pocard and colleagues have presented the favorable pharmacokinetics that predicts clinical utility for PIPAC [3]. Morris and colleagues are showing us how to eliminate the mucinous component of mucinous peritoneal metastases [4]. This provides a whole new platform for chemotherapy access and long-term patient survival. The improved packaging of drugs for intraperitoneal delivery in a nanomicellar package described by Kitayama provides greatly prolonged access as compared to a soluble chemotherapy agent [5]. The new field is just beginning to explode.

The current approach which itemizes the intraperitoneal drugs, duration of treatment, and dosimetry is provided by the near incredible accomplishments of the French group to improvements in the management of peritoneal metastases. In addition, van der Speeten et al. working from a pharmacologic but also a practical perspective provides us with a series of drug regimens expected in our current state of knowledge to provide us with an optimal outcome [6].

Finally, realizing that CRS and HIPEC are not universally successful, far from it, the possible addition of normothermic intraperitoneal chemotherapy to CRS and HIPEC is presented. The high-grade diseases that repeatedly fail CRS and HIPEC within the peritoneal space are ovarian cancer, gastric cancer and malignant peritoneal mesothelioma. An overview of the use of normothermic intraperitoneal chemotherapy long-term (NIPEC-LT) for ovarian cancer, gastric cancer, and peritoneal mesothelioma was provided by Sugarbaker [7].

In all of the chapters, the reader will note that peritoneal metastases are not evaluated as an isolated part of a disease process. Rather, the disease, whether it is ovarian cancer, colorectal cancer, appendiceal malignancy, gastric cancer, or peritoneal mesothelioma, is discussed in a comprehensive manner. The rationale, results to date and future prospects for integrating CRS and HIPEC into the disease process are evaluated. This publication seeks to promote CRS, HIPEC, and NIPEC-LT for the comprehensive management of these abdominal and pelvic diseases. The increased use of these combined treatment modalities by the multidisciplinary team and the prompt referral of patients appropriate for definitive management are the major goals of the authors of the monograph. This special issue should satisfy the needs of the peritoneal surface oncology centers seeking the most up-to-date, complete, and practical coverage of this emerging technology.