O. Anthony Stuart

Surgically directed chemotherapy: Heated intraperitoneal lavage with mitomycin C

This chapter reported the pharmacokinetics and the toxicities of mitomycin-c (MMC) when administered as a hyperthermic intraperitoneal lavage after surgical resection of advanced primary or recurrent gastrointestinal cancer. Pharmacologic studies were performed in 10 patients and all adverse reactions were recorded in 20 patients. These 20 patients had advanced gastrointestinal malignancies with peritoneal carcinomatosis and underwent cytoreductive surgery prior to intraperitoneal lavage. Heated (42 degrees C) intraperitoneal mitomycin C was used in a lavage technique with 30 mg/3 1 of drug for 2 hours. The fluid was distributed throughout the abdominal cavity by vigorous external massage of the abdominal wall. This resulted in approximately 70 percent (21 mg) drug absorption from the perfusate. Urine output of MMC averaged 2.5 mg during the 2 hour procedure. Median peak blood levels of 0.25 micrograms/ml (range 0.11-0.41 micrograms/ml) were observed at 45-60 minutes into the procedure. Morbidity was low and was mainly related to the surgical procedures (prolonged ileus, postoperative fistulas) with mild to moderate drug-related myelosuppression. This new method of delivery of MMC and 5-FU should be explored in phase II clinical trials.

Systemic Chemotherapy prior to Cytoreductive Surgery and HIPEC for Carcinomatosis from Appendix Cancer: Impact on Perioperative Outcomes and Short-Term Survival

Background and Objectives. Systemic chemotherapy administered prior to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal mucinous adenocarcinoma of appendiceal origin (PMCA) is associated with a significant rate of histological response. The impact of preoperative systemic chemotherapy (PSC) on intraperitoneal tumor burden, completeness of cytoreduction, and perioperative complications is unknown. Methods. We analyzed prospectively collected data from our HIPEC database. Thirty-four patients with PMCA were prospectively recruited and treated with PSC. Perioperative variables and survival in this group of patients were compared against 24 patients with PMCA who did not receive PSC. Results. Ten of 34 patients (29%) receiving PSC had a complete or near complete histological response. Patients receiving PSC had a lower peritoneal carcinomatosis index, required fewer peritonectomies and visceral resections, and achieved complete cytoreduction more frequently compared to patients with no preoperative chemotherapy. The incidence of perioperative complications and survival were not significantly different between the two groups. However, patients with complete histological response had better overall survival compared to patients without complete response. Conclusions. Preoperative systemic chemotherapy in appendix-originated PMCA is associated with a significant rate of histological response which may reduce the tumor burden, facilitate less aggressive and more complete CRS, and improve short-term survival in patients with a significant histological response.

Pharmacologic rationale for treatments of peritoneal surface malignancy from colorectal cancer

The peritoneal surfaces of the abdomen and pelvis are important sites for the dissemination of gastrointestinal and gynecologic malignancy. Transcoelomic dissemination of cancer cells gives rise to carcinomatosis, which, without special treatment, is a fatal manifestation of these diseases. To treat peritoneal carcinomatosis, cytoreductive surgery removes gross disease plus perioperative intraperitoneal and perioperative intravenous chemotherapy eradicates microscopic residual disease and chemical compatibilities. Chemotherapy agents are administered either by the intraperitoneal or intravenous route, based on their pharmacologic properties. A peritoneal-plasma barrier, which retards the clearance of high molecular weight chemotherapy from the peritoneal cavity, results in a large exposure of small cancer nodules on abdominal and pelvic surfaces. Tissue penetration of the intraperitoneal chemotherapy is facilitated by moderate hyperthermia (41-42°C). Targeting of intravenous chemotherapy to the peritoneal surface is facilitated by the intraperitoneal heat. A constant dose of chemotherapy agent and volume of carrier solution, based on body surface area, allows prediction of systemic drug exposure and systemic toxicity. Timing of the hyperthermic chemotherapy as a scheduled part of the surgical procedure to uniformly expose all peritoneal surfaces is crucial to success.

Strategies for management of the peritoneal surface component of cancer: cytoreductive surgery plus perioperative intraperitoneal chemotherapy

Background. A prominent part of treatment failure of gastrointestinal and gynecologic malignancy is dissemination to peritoneal surfaces. This has been associated with a limited survival and no reliable treatment strategies. Methods. A review of the natural history of carcinomatosis was performed and a rationale for intraperitoneal chemotherapy was sought. The pharmacology of chemotherapy administration into the peritoneal cavity was reviewed. Results. The technology of perioperative intraperitoneal chemotherapy requires the administration of drugs along with moderate hyperthermia in the operating room as a planned part of the surgical procedure. The solution in which the chemotherapy is diluted has an effect upon the drug clearance from the peritoneal cavity. Also, the volume of the carrier solution affects the exposure of cancer nodules on peritoneal surfaces. Conclusions. New combinations of intraperitoneal chemotherapy administration when combined with optimal surgical technology for maximal chemotherapy effects should result in benefit to patients with peritoneal surface dissemination of gastrointestinal and gynecologic malignancy.

Pharmacokinetics of the peritoneal-plasma barrier after systemic mitomycin C administration

The peritoneal plasma barrier (PPB) is a pharmacologic entity of importance for treatment planning in patients with malignant tumors confined to the abdominal cavity. We have examined the pharmacokinetics of the PPB by sampling abdominal fluid following intravenous mitomycin C (MMC) administration. The study included 15 cycles of treatment in seven patients with peritoneal carcinomatosis from colorectal cancer. Five patients were studied twice and one patient was studied three times for a total of 15 cycles. Patients were treated with intraperitoneal 5-fluorouracil (5-FU) at 20 mg/m2 in 11 of fluid. Between 250 and 500 ml of ascites remained after the 23 hour intraperitoneal dwell. On day 3, MMC (12 mg/m2) was administered intravenously as a 2-hour continuous infusion in 200 ml of dextrose solution. The concentration of MMC was determined in plasma, peritoneal fluid, and urine by high performance liquid chromatolography (HPLC) at frequent intervals for 8 hours. The area under the curve (AUC) for plasma as related to peritoneal fluid was three times greater for plasma in one cycle, two times greater for plasma in three cycles, 1.5 times greater for plasma in five cycles, and the same in six cycles. AUC ratios showed a correlation with the extent of peritoneal stripping at the prior surgical procedure 6 weeks to 14 weeks previously. We conclude that malignant ascites may be less exposed to chemotherapy than systemic tumor nodules when the intravenous route of drug administration is used. This inadequacy is even more pronounced in patients who have had extensive abdominal surgery.

Gastrointestinal Complications in 147 Consecutive Patients with Peritoneal Surface Malignancy Treated by Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy

Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is increasingly used in the treatment of peritoneal carcinomatosis from gastrointestinal malignancies. The purpose of this study is to reevaluate the incidence of gastrointestinal events and identify risk factors associated with this treatment approach. Between January 1, 2006 and December 31, 2009, 147 patients with appendiceal and colorectal carcinomatosis were treated. Gastrointestinal events were analyzed. The overall incidence of grade I–IV gastrointestinal events was 17%. There were 4 grade III gastrointestinal events that occurred in 4 patients and 11 grade IV gastrointestinal events that occurred in 8 patients. On univariate analysis of grade I–IV events a statistically significant association was observed with the following variables: histological grade, peritoneal cancer index (PCI), small bowel resection, colorectal anastomosis, and the number of anastomoses performed per patient. By multivariate analysis, PCI was identified as the only independent risk factor for gastrointestinal complications. CRS combined with a uniform HIPEC regimen is associated with a 17% gastrointestinal morbidity rate (grade I–IV). The frequency of gastrointestinal complications was associated with a large extent of disease measured by PCI (>30).

Intraperitoneal Gemcitabine Chemotherapy Treatment for Patients with Resected Pancreatic Cancer: Rationale and Report of Early Data

Currently, the surgical management of pancreas cancer is recognized around the world as inadequate. Despite a potentially curative R0 resection, long-term survival is rare. There is a strong rationale for the use of chemotherapy in the operating room to reduce local-regional of recurrent/progressive disease. Gemcitabine monotherapy administered by an intraperitoneal route in the operating room with hyperthermia and then for long-term treatment postoperatively has a pharmacologic basis in that the exposure of peritoneal surfaces to intraperitoneal gemcitabine is approximately 200–500 times the exposure that occurs within the plasma. A standardized treatment with intraoperative and long-term chemotherapy that is well tolerated would greatly facilitate further improvements in pancreas cancer treatment and may lead the way to an evolution of more successful treatment strategies of this dread disease. The aim of this paper is to present the early data on a protocol in progress in patients with resected pancreatic cancer.

Pharmacokinetic Study of Perioperative Intravenous Ifosfamide

The use of cancer chemotherapy and hyperthermia as part of a surgical procedure in the management of patients with peritoneal carcinomatosis has gained prominence in recent years with selected patients showing benefit. Patients with peritoneal surface malignancy following cancer resection were treated with intraperitoneal hyperthermic (41.5–42.5°C) cisplatin and doxorubicin combined with the infusion of systemic ifosfamide chemotherapy. The concentrations of ifosfamide and 4-hydroxyifosfamide were determined in plasma, peritoneal fluid, urine, and when possible, within small tumor nodules less than 1 cm. Plasma concentrations of ifosfamide exceeded peritoneal fluid levels of ifosfamide during the 90 minutes of chemotherapy infusion. Both ifosfamide and 4-hydroxyifosfamide could be recovered from peritoneal tumor nodules throughout the 90 minutes of ifosfamide continuous infusion and exceeded plasma concentrations. 4-Hydroxyifosfamide within peritoneal surface cancer nodules suggested a favorable pharmacologic endpoint in the study of ifosfamide administered in the operating room.

Hyperthermic Intraperitoneal Chemotherapy with Melphalan: A Summary of Clinical and Pharmacological Data in 34 Patients

Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment option for peritoneal metastases. The optimal agents for HIPEC have not been established. Melphalan is a drug with broad activity and a favorable profile for intraperitoneal application. The purpose of this study is to review our experience using melphalan for HIPEC. Pharmacologic data was obtained. Thirty four patients who underwent CRS for peritoneal metastases received melphalan for HIPEC between 2003 and 2011. The first 10 patients received 70 mg/m2; subsequent 24 received 60 or 70 mg/m2. The mean PCI was 21 ± 7. Twenty-eight patients (83%) had a CC score of 1 or 2. The mean length of stay was 18 ± 2 days. Nine patients (26%) had a grade 3 and 6 (17%) had grade 4 morbidity. There were no postoperative deaths. The pharmacologic analysis of plasma to peritoneal fluid levels of melphalan showed an AUC ratio of 33 while the tumor nodules to peritoneal ratio was 8. Melphalan is an acceptable agent for use in HIPEC. The morbidity of intraperitoneal melphalan at the dose of 60–70 mg/m2 appears acceptable. Further studies comparing the effectiveness of melphalan and other HIPEC agents are needed.

Pharmacokinetics of Hyperthermic Intrathoracic Chemotherapy following Pleurectomy and Decortication

In patients with pseudomyxoma peritonei or peritoneal mesothelioma, direct extension of disease through the hemidiaphragm may result in an isolated progression of tumor within the pleural space. We monitored the intrapleural and plasma levels of mitomycin C and doxorubicin by HPLC assay in order to determine the pharmacokinetic behavior of this intracavitary use of chemotherapy. Our results showed a persistent high concentration of intrapleural drug as compared to plasma concentrations. The increased exposure for mitomycin C was 96, and the increased exposure for doxorubicin was 241. When the clearance of chemotherapy from the thoracic cavity was compared to clearance from the abdomen and pelvis, there was a considerably more rapid clearance from the abdomen as compared to the thorax. The pharmacologic study of intrapleural chemotherapy in these patients provides a strong pharmacologic rationale for regional chemotherapy in this group of patients.