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.

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.

A careful preoperative assessment of the patient’s pulmonary reserve and cardiac function is mandatory. Patient-related factors associated with increased operative risk for pulmonary complications include preexisting pulmonary disease, cardiovascular disease, pulmonary hypertension, dyspnea upon exertion, heavy smoking history, respiratory infection, cough (particularly productive cough), advanced age (>70 years), malnutrition, general debilitation, obesity, and prolonged surgery. Therefore, cessation of smoking 2 weeks (and preferably 6 weeks) before resection is advised. Risk assessment is a complex process for determining the patient’s resectability and operability. Resectability in patients with malignant pleural mesothelioma refers to the amount of lung tissue (e.g., pneumonectomy) and tumor that can be completely removed without the risk of developing postoperative respiratory insufficiency. It depends directly on the volume of the remaining lung tissue (i.e., pulmonary reserve). Operability is the patient’s ability to survive the proposed procedure, whether EPP or P/D, and this depends primarily on the patient’s comorbid conditions.

While no single test can effectively predict intraoperative and postoperative morbidity and mortality from pulmonary complications, candidates for EPP should have ppoFEV₁ >1000 mL, systolic pulmonary artery pressure <35 mm Hg plus right atrial pressure of approximately 10 mm Hg, and diffusion capacity of the lung for carbon oxide (D_{L CO}) >40. Candidates for P/D should have minimal disease and sufficient cardiopulmonary reserve to withstand the procedure. Both groups of patients must have a glomerular filtration rate (GFR) >60 mL/min/1.73 m² (normal range 90–120 mL/min/1.73 m²) in order to receive the hyperthermic intraoperative chemotherapy lavage (HIOC).

Pulmonary function testing is performed, including a quantitative ventilation/perfusion scan and pulmonary stress test (6-minute walk test). Chest CT scan with intravenous contrast and chest MRI are performed preoperatively to exclude unresectable or metastatic disease. A PET scan can be helpful in demonstrating extrathoracic sites. An echocardiogram is recommended with estimation of the pulmonary systolic pressure to exclude pulmonary hypertension. Surgery is contraindicated in patients who have had a myocardial infarction (MI) within the previous 3 months. Patients with a remote history of MI should undergo a myocardial perfusion study with sestamibi, and cardiac clearance should be obtained. We routinely perform preoperative lower extremity noninvasive Doppler studies to exclude deep vein thrombosis (DVT) and perioperative pulmonary embolism. For patients diagnosed with DVT, an inferior vena cava filter is placed prior to the surgery. Patients receiving heated chemotherapy are admitted the night before surgery and undergo DVT prophylaxis, bowel prep, and overnight intravenous hydration to prevent cisplatin nephrotoxicity.

Pulmonary function testing comprises four elements of the preoperative evaluation: (1) pulmonary spirometry, (2) quantitative ventilation/perfusion (V/Q) scan, (3) pulmonary hemodynamic response testing, (4) exercise testing.

Pulmonary spirometry is affected by height, age, weight, sex, race, and thoracic deformities, as well as arterial oxygenation and diffusion capacity. It is important to remember that although pulmonary spirometry and arterial oxygenation help to predict mortality, they are not good predictors of postoperative complications. D_{L CO} is a more sensitive predictor of postoperative complications. The diffusing capacity is a measure of the conductance of the CO molecule from the alveolar gas to Hb in the pulmonary capillary blood. The transfer of the CO molecule is limited by both perfusion and diffusion. CO (and oxygen) must pass through the alveolar epithelium, tissue interstitium, capillary endothelium, blood plasma, and red cell membrane and cytoplasm before attaching to the Hb molecule. D_{L CO} is directly proportional to VA (alveolar ventilation) in a single breath. Therefore, factors that affect D_{L CO} are low hemoglobin level, low lung volume, previous lung resection, thoracic cage abnormalities (e.g., kyphoscoliosis), as well as patients with chronic obstructive pulmonary disease (COPD), emphysema, chronic pulmonary hypertension, and interstitial lung disease. D_{L CO} may also be reduced temporarily in patients with pneumonia, interstitial infiltrative disorders, and alveolar proteinosis (Table 123-1). The importance of obtaining an inspiratory vital capacity (IVC) greater than 90% of the best measured VC from the day of the test cannot be overemphasized. The inability to achieve an IVC of greater than or equal to 90% of the largest VC measured that day must be noted. Patients with low D_{L CO} should not be considered candidates for extrapleural pneumonectomy. Thus, decreased D_{L CO} is an important and independent predictor of postoperative complications, even in patients without COPD.

Quantitative ventilation/perfusion (V/Q) scan is useful for predicting postoperative lung function. A calculated postoperative FEV₁ (ppo FEV₁%) of <40% is associated with a 50% mortality rate. The absolute minimum ppoFEV₁ in patients undergoing pneumonectomy is 1000 mL.²¹

Pulmonary hemodynamic response testing includes the measurement of pulmonary artery pressure and pulmonary vascular resistance. Pulmonary artery hypertension (PAH) carries a high mortality rate, and therefore it is important to determine its potential reversible causes (Table 123-2). Pulmonary artery pressure can be estimated by a transthoracic or transesophageal echocardiogram, but right heart catheterization may be indicated if the echocardiogram does not produce an accurate measurement. Normal pulmonary artery blood pressure is 20/10 mm Hg (mean 15) at rest at sea level. Pulmonary arterial systolic pressure rises gradually with age, and each 10-mm Hg increase is associated with a 2.7-fold greater risk for mortality. Systolic pulmonary artery pressure >35 mm Hg is associated with a 10-fold decrease in survival rate, and pulmonary vascular resistance >190 dyne is associated with a 90% mortality rate.