123: Intracavitary Hyperthermic Chemotherapy for Malignant Mesothelioma

Introduction

The rising incidence of malignant mesothelioma worldwide has intensified the search for treatment strategies to extend disease-free survival.¹ To date, the best survival has been observed in patients undergoing multimodality therapy with surgery, either extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D), plus chemotherapy and/or radiation therapy.^2–7 Seminal work at the Washington Cancer Center and Brigham and Women's Hospital led to the development of innovative surgical techniques to accomplish macroscopic complete resection, along with intracavitary lavage with hyperthermic platinum-based chemotherapy for local control. The rationale for hyperthermic intraoperative thoracoabdominal chemotherapy has been previously described, with particular emphasis on malignant peritoneal mesothelioma.⁸ This chapter describes the thoracic delivery of heated intraoperative chemotherapy for patients with malignant pleural mesothelioma (MPM), along with special advice on perioperative pitfalls and complications.

General Principles

Intracavitary administration of heated chemotherapy (at 42°C) increases the intracellular uptake of drugs, thus minimizing the systemic side effects and maximizing the therapeutic effect. To accomplish maximal delivery of drug at the time of surgery, the chemotherapy lavage is performed after complete macroscopic resection, irrespective of whether the surgeon is operating in the chest or in the abdomen. Factors that may limit the depth of penetration include temperature, residual tumor, fibrinous exudate, excessive bleeding, clotting, and the intracavitary volume of perfusate.

Platinum-based chemotherapy has been used safely in many thoracic and abdominal protocols.⁹ The drug binds covalently to various macromolecules, including DNA, the apparent target.¹⁰ The effects of cisplatin on mesothelioma have been studied in the past, and it can be combined with cytoprotective agents or other drugs to minimize toxicity.^11,12 The concentration of the drug with regional administration is up to 50-fold higher than with IV administration. ¹³ Ratto et al.¹⁴ showed that levels of cisplatin given into the pleura are higher with hyperthermic perfusion than with normothermic perfusion. Heat increases cell permeability, alters cellular metabolism, and improves membrane transport of drugs. This has been demonstrated in animal and human studies.^15,16 A synergistic effect of hyperthermia and cisplatin has been demonstrated.^17,18 Intracavitary cisplatin and its benefits in thoracic malignancies have been studied in the past for both EPP and P/D.^14,19

Sodium thiosulfate and amifostine provide renal protection during heated chemotherapy. Sodium thiosulfate is a neutralizing agent that has the ability to protect stem cells and reduce the nephrotoxicity of cisplatin. It is thought to bind covalently to cisplatin, forming an inactive complex.¹³ The administration of thiosulfate intravenously concurrently with intracavitary platinum-based agents protects against nephrotoxicity.^13,20,21 We favor colloids over crystalloids for volume replacement in the intraoperative and early postoperative period to avoid the development of postpneumonectomy pulmonary edema and renal failure.

Patient Selection

A careful preoperative assessment of the patient's pulmonary reserve and cardiac function ...