Patients with malignant pleural mesothelioma have a poor prognosis. Until recently, attempts to improve survival of patients using surgical therapy alone have been disappointing. Trimodality treatment using maximal cytoreductive surgery followed by adjuvant chemotherapy and radiation has increased survival up to 46% at 5 years in selected patients.¹ It is extremely difficult to achieve a microscopically complete resection with surgery alone.² Although metastases can occur distantly, the recurrence pattern in malignant pleural mesothelioma is predominantly locoregional. In Sugarbaker's analysis of a large cohort of patients undergoing extrapleural pneumonectomy (EPP), microscopic tumor involvement at the surgical margin played a significant role in survival, which supports the need for improved locoregional control.¹ The use of intracavitary chemotherapy has been studied in abdominal malignancies as a method of locoregional control.³ Sugarbaker and colleagues studied heated intracavitary chemotherapy for gastrointestinal malignancies.^4,5 A series of studies at Brigham and Women's Hospital was conducted to treat malignant pleural mesothelioma using this innovative technique. This methodology was applied to both EPP and pleurectomy and decortication (P/D) in selected patients. Techniques for hyperthermic intraoperative chemotherapy (HIOC) are presented along with its complications and pitfalls.

GENERAL PRINCIPLES

With intracavitary administration, chemotherapy agent enters the tumor cells directly by diffusion, which minimizes the toxic systemic effects of IV administration. The depth of penetration of the chemotherapeutic agent is limited to several millimeters deep to the surface of the cavity.⁶ Thus cytoreduction of the tumor to microscopic levels is very important if one is to achieve maximal benefits for this modality of treatment. Complete contact with any surface that might sequester cancerous cells from the chemotherapeutic agent is extremely important. The optimal timing of intracavitary chemotherapy lavage is immediately after resection of the tumor. This ensures maximal exposure of residual cancerous cells to the chemotherapy before there is development of adhesions or fibrinous exudates and while the volume of residual tumor is small enough to be penetrated by the agent.

Cisplatin is the chemotherapeutic agent used in our lavage protocol. The drug binds covalently to various macromolecules, including DNA, the apparent target.⁷ The effects of cisplatin on mesothelioma have been studied in the past, and it can be combined with cytoprotective agents or other drugs.^8,9 The concentration of the drug with regional administration is up to 50-fold higher than with IV administration.¹⁰ Ratto and colleagues showed that levels of cisplatin given into the pleura are higher with hyperthermic perfusion than with normothermic perfusion.¹¹ Heat increases cell permeability, alters cellular metabolism, and improves membrane transport of drugs. This has been demonstrated in animal and human studies.^12,13 A synergistic effect of hyperthermia and cisplatin has been demonstrated.^14,15 Intracavitary cisplatin and its benefits in thoracic malignancies have been studied in the past for both EPP and P/D.^11,16

Two cytoprotective agents are used during HIOC. Sodium thiosulfate is a neutralizing agent with the ability to protect stem cells and reduce the nephrotoxicity of cisplatin. It is believed that the drug binds covalently to cisplatin, forming an inactive complex.¹⁷ Fluid administration is kept to a minimum as a consequence of the risk and high mortality associated with the development of postpneumonectomy pulmonary edema. This relative state of hypovolemia combined with cisplatin exposes the kidneys to significant risks. The administration of thiosulfate intravenously concurrently with intracavitary cisplatin protects against nephrotoxicity.^10,18,19  Amifostine is another cytoprotective drug used with this protocol that mitigates cisplatin-induced neutropenia as well as nephrotoxicity.

PATIENT SELECTION

The same general principles for selecting EPP patients apply to patients being selected for EPP plus HIOC. The aim is to offer curative surgery, which cannot be achieved by leaving macroscopic residual disease. Elderly frail patients or those with renal impairment are not offered HIOC. Patients with normal renal function who are not candidates for EPP because of poor pulmonary reserve or other contraindications are offered P/D plus HIOC.

PREOPERATIVE ASSESSMENT

A pulmonary function test is performed, and if indicated, a quantitative ventilation/perfusion scan or pulmonary stress test also is done. Mandatory chest CT scan and MRI are performed preoperatively to exclude unresectable or metastatic disease. A PET scan can be helpful in this regard. An echocardiogram is recommended with estimation of the pulmonary systolic pressure to exclude elements of pulmonary hypertension. Cardiac clearance is required if the patient has a history of cardiac disease or abnormal ECG or stress test. We routinely perform preoperative lower extremity noninvasive Doppler studies to exclude deep vein thrombosis (DVT). For patients diagnosed with DVT, an inferior vena cava filter is placed prophylactically.

Since patients who receive HIOC have a higher incidence of DVT, prophylactic subcutaneous heparin (5000 units) is started three times a day preoperatively. All patients should get a bowel prep the night before surgery. HIOC patients are admitted the night before surgery and kept well hydrated to minimize the toxic effects of cisplatin on the kidneys.

TECHNIQUE

To maximize patient and staff safety, it is necessary to establish a multidisciplinary "heated chemotherapy" team that meets regularly to develop guidelines for this novel therapy. Safety courses are required for all staff participating in patient care. A special method has been designed for drug delivery and disposal in the OR, as outlined below.

The initial preparation and positioning of the patient have been described in the surgical technique chapters on P/D (Chap. 102) and EPP (Chap. 103). Surgical resection achieves macroscopic cytoreduction of the tumor, leaving 1 cm³ or less of residual tumor to be treated with intracavitary cisplatin lavage. The anesthesia team is responsible for synchronizing the administration of key cytoprotective agents (to reduce the systemic toxicity of cisplatin) during pivotal steps of the surgical resection and ensuing lavage. At the moment the specimen is removed from the field, the anesthesiologist is instructed to administer amifostine at a dose of 910 mg/m². This timing provides for a period of 30 minutes between the amifostine dose and the cisplatin lavage. After the chest cavity is lavaged with the maximally tolerated dose of heated intracavitary cisplatin in dialysate (Baxter, Deerfield, MA), the anesthesia team administers an IV bolus of sodium thiosulfate (4 g/m²), followed by a 6-hour infusion of 12 g/m² sodium thiosulfate. This agent is key to protecting against intravascular volume depletion and to sustaining a urine output of 100 mL/h both during the lavage and for 1 hour afterward.

Removal of the diaphragm during surgical resection permits the lavage to circulate in the ipsilateral hemithorax as well as the abdomen, a site of locoregional recurrence. It is best to achieve adequate hemostasis (including the use of argon beam cautery) before HIOC is initiated. Once hemostasis is achieved, the rib retractor is removed, and the entire thoracic cavity is scrubbed with a Betadine-soaked sponge, avoiding vital structures such as the heart. Special attention should be drawn to areas once laden with dense tumor, such as the costophrenic sulcus, or areas that may have been contaminated during the procedure, such as the subscapular region and the skin or soft tissues bordering the incision. After the Betadine scrub, the field is rinsed first with a basin of warm water and then one of warm saline. This routine is performed three times. Thereafter, the field is pulse irrigated with a total of 9 L of warm fluid consisting of 3 L of dilute Betadine in water (using 10 mL of Betadine in 3 L of water), followed by 6 L of saline.

Hemostasis is again ensured before setting up the HIOC apparatus (Fig. 104-1). The thoracotomy incision is approximated at both ends by using a no. 2 nylon running suture, leaving a small aperture in the center of the wound (Fig. 104-2). This permits access for the surgeon to place a double-gloved hand into the thorax and evenly distribute the perfusate. The Omni retractor (Omni-Tract, Minneapolis, MN) is secured to the surgeon's side of the table. Interrupted no. 2 nylon sutures then are placed at selected points along the wound aperture, and the edges of the wound are lifted onto the Omni wishbone arms so as to create a funnel that prevents spillover of the intracavitary chemotherapy. A 28F straight thoracostomy tube is carefully guided by the surgeon's hand into the pelvis and serves as an inflow catheter. A 36F angled thoracostomy tube is placed at the apex of the pleural space to collect the perfusate and return it to the pump. Both drains are attached to the cardiopulmonary bypass machine, thereby completing the perfusion circuit. Towels are placed in the gutter on either side of the patient and 3M adhesive incise drapes are applied over the entire field to create a seal and prevent escape of lavage fluid from the field. A slit is made in the plastic shield, which permits the surgeon to monitor the perfusate level (Fig. 104-3). Once HIOC is initiated, the inflow and outflow perfusate temperatures are monitored constantly and maintained at 42°C. The entire field should be submerged in the solution. The edges of the wound that are not bathed by the perfusate should be constantly irrigated by the surgeon with a properly labeled bulb syringe that is discarded at the end of the lavage. Constant communication between the surgeon and perfusionist ensures that the level of the lavage in the chest cavity is appropriate. A smoke evacuator is used to pull air from beneath the plastic cover and pass it through an activated charcoal filter to prevent any possible contamination of air in the OR by chemotherapy aerosols.

After 1 hour of HIOC lavage, the patient is placed in a severe Trendelenburg position, and the perfusate is drained out of the field back into the perfusion circuit. The volume of perfusate returned to the circuit is scrutinized, and different maneuvers are performed to maximize the return of perfusate. These include displacing the omentum or gently sweeping perfusate retained in the pelvis or in between bowel loops into the field. Leaving behind a significant amount of perfusate will increase the systemic absorption of cisplatin and toxicity.

Before the diaphragm and pericardium are constructed, attention is turned to hemostasis. The bronchial stump can be buttressed with surrounding tissues (e.g., pericardial remnant or parathymic fat) or with a tongue of omentum that enters through an aperture fashioned in the Gore-Tex diaphragm patch (W.L. Gore and Associates, Flagstaff, AZ) (see also Fig. 103-19). This omental flap is constructed most easily by stapling endo-GIA vascular loads (2.9 mm) across part of the omentum while the abdomen is fully exposed (after HIOC, before the diaphragm patch is undertaken) (see also Fig. 103-16).

Before the incision is closed, a final check for hemostasis is performed. We often use an aerosol 9F fibrin sealant across the thoracic cavity (Evicel, Ethicon, Inc., Somerville, NJ) to assist with firm hemostasis. A 12F Rob-Nel (Dover, Rob-Nel, Kendall, Inc., Mansfield, MA) catheter is left in the thoracic cavity to permit access to the space postoperatively. Once the wound is completely closed, air is withdrawn through the Rob-Nel catheter for medialization of the mediastinum. Current guidelines call for the withdrawal of 750 mL from the right thoracic space in a female, 1000 mL in a male, and 500 mL from the left thoracic space in a female, 750 mL in a male. The preceding serves as a guideline only, however, because the evacuation of air should be aborted early if any suggestion of hemodynamic instability develops as a consequence of excessively negative intrathoracic pressure. Beyond the immediate evacuation of fluid in the OR, the Rob-Nel catheter is used in the ensuing day(s) to withdraw postoperative fluid and correct for mediastinal shift, as well as to reduce intrathoracic pressures. The trend of intrathoracic pressures is monitored, and any sudden rise in pressure should be managed by urgent withdrawal of intrathoracic fluid to avoid potential compression on the mediastinum and vena cava.

Once the patient is turned supine and the double-lumen endotracheal tube is exchanged for a single-lumen tube, bronchoscopy is repeated at the end of the procedure to visualize the bronchial stump and to clear secretions from the dependent remaining lung.

POSTOPERATIVE CARE

The immediate postoperative goal is to extubate the patient in the OR, except for patients undergoing P/D, who usually require some positive-pressure ventilation and thus are kept intubated overnight. Minimizing positive-pressure ventilation and leaving adequate chest tube drains in place facilitates apposition of the lung to chest wall, in turn, reducing the amount of bleeding from raw surfaces of the lung.

The protocol for postoperative management is similar for EPP and EPP plus HIOC, but there are some important differences. HIOC patients must be well hydrated. For the first 12 hours, the patient receives 100 mL/h of 1 L of sterile water with 3 ampules of sodium bicarbonate added. For the next 12 hours, the hydration fluid is changed to 100 mL/h of normal saline (D₅/NS). Thereafter, the IV rate and type are tailored to the patient's electrolytes, urine output, and ability to tolerate oral intake.

The nasogastric tube is kept in place until bowel sounds return. The patient's ability to swallow is assessed at bedside before oral intake is instituted. To reduce the risk of aspiration, indirect laryngoscopy and vocal cord visualization occasionally are indicated if there is a suspicion of palsy or paresis. A speech and swallow evaluation is indicated if the patient has a hoarse voice or when aspiration is suspected at bedside swallow evaluation.

The trend of using Rob-Nel catheter pressure measurement aids in postoperative management, with aspiration of the pleural space, if necessary. The need for aspiration should be correlated with the clinical picture. We recommend aspirating no more than 200–300 mL at a time to avoid pulmonary edema or complications of acute respiratory distress syndrome. The catheter is usually removed in 2–3 days depending on the frequency and necessity of aspiration. Strict bed rest is observed for the first postoperative day, followed by dangling in bed on postoperative day 2. Active ambulation starts on postoperative day 3. Once the patient is being actively ambulated, the patient usually is ready to be transferred to the telemetry or step-down thoracic intensive care unit. Routine daily chest x-rays are ordered to assess for mediastinal shift.

The postoperative management is similar to that for routine EPP, but extra attention must be paid to renal function and the development of DVT. A routine lower extremity noninvasive Doppler study is performed weekly if the patient is kept in-house to detect asymptomatic DVT. If DVT is diagnosed, anticoagulation is started promptly, and partial thromboplastin times are monitored closely until the international normalized ratio is therapeutic on Coumadin. The development of pulmonary embolism in a pneumonectomy patient could have catastrophic consequences.

We continue to advocate early and frequent ambulation, chest physiotherapy, optimal pain control with an epidural catheter initially, and bedside flexible bronchoscopy when secretion clearance is inadequate.

PROCEDURE-SPECIFIC COMPLICATIONS

Our initial studies with HIOC lavage produced an operative mortality rate comparable with our previously published mortality rate of 3.4% for EPP alone.^20,21 The incidence of major morbidity was higher in all categories except atrial fibrillation and was determined to be directly attributable to complications of DVT and diaphragmatic patch failure.³ To counteract the incidence of DVT, we introduced prophylactic subcutaneous heparin preoperatively, as described earlier, and continued this regimen postoperatively three times a day with routine weekly Doppler study. HIOC patients are also kept well hydrated commencing immediately after chemotherapy lavage.

Diaphragmatic patch failure can result in herniation of abdominal contents into the thorax. The higher incidence of patch failure may be attributed to violation of the peritoneal cavity (necessary to permit abdominal lavage) and swelling of the abdominal viscera after exposure to hyperthermic chemotherapeutic lavage. Increased cephalad pressure on the patch results in dehiscence. To correct this problem, we doubled the size of the Gore-Tex patch by stapling two patches together, as shown in Fig. 104-4 and as described in Chap. 103. This creates a dynamic patch that permits sufficient upward movement to accommodate for swelling of the abdominal viscera and reduces tension on the sutures to prevent them from pulling away from the chest wall. By using this approach, the diaphragmatic patch failure rate was subsequently reduced from 12% to 3.4%.

For the remainder of the complications, including atrial fibrillation, constrictive pericarditis, cardiac tamponade, cardiac arrest, myocardial infarction, acute respiratory distress syndrome, tracheostomy, pulmonary embolism, vocal cord paralysis, aspiration, and empyema, the difference was not statistically significant between the two groups.

In our phase I–II study, patients who underwent P/D plus HIOC had a higher mortality and renal toxicity rate but comparable or better rates for other complications. An apparent dose-related survival benefit was identified and is undergoing further investigation. Twenty patients with epithelial tumors had a 26-month median survival. In terms of the morbidity and mortality, given the dire clinical circumstances of this patient cohort (more advanced age, lower forced expiratory volume in 1 second, and inability to withstand pneumonectomy because of limited cardiopulmonary reserve), P/D plus HIOC is a feasible option.²²

SUMMARY

HIOC can be administered safely and effectively in concert with EPP or P/D. The aim of this treatment is to decrease or delay the rate of recurrence and potentially improve long-term survival in patients with malignant pleural mesothelioma.

EDITOR'S COMMENT

Hyperthermic intraoperative chemotherapy is feasible despite adding one and a half hours to the overall operating time and requiring more liberal use of volume administration intra- and postoperatively. It may have a role in other thoracic malignancies as well, such as thymoma with pleural metastasis.

–LZ

REFERENCES