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Ann Thorac Surg 2001;72:366-370
© 2001 The Society of Thoracic Surgeons

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Original article: general thoracic

Resection and perfusion thermochemotherapy: a new approach for the treatment of thymic malignancies with pleural spread

^a Departments of Thoracic Surgery and Oncology, Sheba Medical Center, Tel Hashomer, Israel
^b Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Address reprint requests to Dr Yellin, Department of Thoracic Surgery, Sheba Medical Center, Tel Hashomer, Israel 52621
e-mail: ayellin{at}sheba.health.gov.il

Presented at the Poster Session of the Thirty-seventh Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 29–31, 2001.

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
Background. Thymoma and thymic carcinoma with pleural spread have a high rate of locoregional recurrence and poor prognosis. Maximal debulking coupled with aggressive local treatment could offer a chance for cure. This study evaluates the early and midterm results of operation and hyperthermic pleural perfusion with cisplatinum for thymic malignancies.

Methods. Fifteen patients (11 men), 20 to 67 years old (10 thymoma, 4 thymic carcinoma, 1 carcinoma in thymic cyst) underwent resection and hyperthermic pleural perfusion between 1995 to 2000. All had pleural spread proven before or intraoperatively. Six of the thymoma cases were recurrent. Current operation included resection without pleurectomy (9 patients), resection with pleurectomy (5), and extrapleural pneumonectomy (1 patient) with intraoperative hyperthermic pleural perfusion in all. Intrapleural temperature reached 40.3°C to 43°C. The total dose of cisplatinum was 150 mg or more in 14 patients.

Results. Complete resection (R0) was achieved in 10 patients, subtotal (R1) in 3, and partial (R2) in 2. There was no operative mortality, no hemodynamic or respiratory disturbances during perfusion, and no hematologic, neurologic, or renal complications. Complications consisted of significant bleeding (2 patients), fever (2), and air leak (1 patient). Two patients with thymic carcinoma died after 27 and 34 months, and 1 is alive with no evidence of disease at 54 months. Two patients with thymoma died after 7 and 36 months. Eight are alive after 9 to 70 months. Four patients (all R0) are alive without local recurrence more than 60 months after operation and hyperthermic pleural perfusion.

Conclusions. Operation and thermochemotherpy is feasible and safe in patients with thymic tumors. This method seems to offer excellent local control for patients with stage IV-a thymic malignancies. Midterm results suggest that operation plus hyperthermic pleural perfusion may lengthen survival in stage IV-a thymoma.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
Aggressive surgical approach is considered the mainstay of therapy for thymic malignancies. All patients with thymoma, except those with clinically, grossly nonresectable tumors or with spread beyond the thorax, are recommended to undergo operation for as complete resection as possible. The presence of intrapleural metastases does not negate operation. Nevertheless, despite complete resection, recurrence in all stages of thymoma is not uncommon ranging between 10% and 40% in different series [1–3]. Epithelial thymoma, thymic carcinoma, and advanced stage were recognized as risk factors for recurrences [4]. Thymoma with pleural spread (stage IV-a) carries a high risk for locoregional recurrence and poor outcome. Five-year survival rates were reported to range between 33% and 46% in different series [5, 6]. The prognosis of thymic carcinoma is even poorer but as this tumor is rare it is impossible to discuss survival rates in advanced stages. Recently, new multimodality protocols including aggressive chemotherapy were found to be effective in locally advanced thymomas [7–11].

The present study evaluates the feasibility, early and midterm results of an aggressive, locoregional multimodality approach consisting of maximal debulking, hyperthermia, and perfusion with cisplatinum in the management of thymic malignancies with pleural spread.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
From February 1995 to February 2000, 59 patients with thymic malignancies underwent operation in Sheba Medical Center. Forty three patients were in stages I–III. There were 16 patients in stage IV-a. One of them was found to have an unresectable tumor at operation and therefore, did not undergo hyperthermic pleural perfusion (HPP). Fifteen patients underwent resection combined with intraoperative HPP with cisplatinum. There were 11 men and 4 women. Patients’ age ranged from 20 to 67 years (median, 53 years). The underlying neoplasms were thymoma, 10 patients (mixed type, 5 patients; lymphocytic, 3; epithelial, 2); thymic carcinoma, 4; papillary carcinoma in a thymic cyst, 1 patient. All thymomas and thymic carcinomas were classified as stage IV-a according to Masaoka staging system [12]. In the only patient with carcinoma in a thymic cyst, the pleural spread was iatrogenic, caused during a thoracoscopic attempt to resect a presumably benign cyst. Myasthenia gravis was present in 5 patients: thymoma, 4; thymic carcinoma, 1. Eight patients received various chemotherapy combinations before operation: 3 of them for recurrent thymoma and 5 for de novo diagnosis. All had partial response. Seven patients had previous surgical procedures: 5 underwent presumed complete resection of thymoma 2 to 14 years before the present operation, and 2 underwent partial resection 1 and 7 months previously: 1 for a thymic cyst and 1 for thymoma. Patients were included in the study if they had thymic malignancy with proven pleural spread (either unilateral in 14 or bilateral in 1), without extrathoracic metastases, a cardiorespiratory reserve allowing the required resection, and normal creatine clearance test. All patients were advised of the investigational nature of the treatment and signed an informed consent. Patients had a complete preoperative history and physical examination, complete blood count, liver function tests, renal function tests (including creatine clearance test), electrocardiogram, chest roentgenogram and computed tomographic scan. Magnetic resonance imaging was performed when the extent of mediastinal involvement was not clear from the computed tomographic scan. All had pulmonary function test, and lung quantitative perfusion scan when pneumonectomy was planned. Echocardiogram and cardiac isotope scans were done when indicated.

Postoperatively patients had chest roentgenograms done on days 1, 3, and 7. Blood count was repeated on days 1, 3, 7, 14, and 21. Creatine clearance test and neurologic assessment were done on postoperative days 2 and 7.

Follow-up was done every 3 months. Computed tomographic scan was performed every 6 months. Magnetic resonance imaging was performed to differentiate between pleural scarring and tumor recurrence. The follow-up was updated on December 31, 2000.

Surgical procedure
Double lumen endotracheal tubes were used to ventilate all patients. Patients were monitored with electrocardiograms, arterial line, pulse oximeter, end-tidal CO₂, intraesophageal temperature measurement, and urine output. The patients that underwent thoracotomy and were placed in a lateral decubitus position during operation were repositioned to supine for the perfusion. The surgical approach was through a sternotomy in 7 patients when there was a bulky mediastinal tumor and thoracotomy in 8. In patients whose tumors were resectable, maximal attempts were done to remove all gross tumor. Operation consisted of extended extrapleural pneumonectomy in 1 patient, tumor resection without pleurectomy in 8, and resection with pleurectomy in 6 patients. Two intercostal drains, 28F each, were placed in the pleural space: one ventrally for outflow drainage and the other dorsally for inflow. The drains were secured with loose 4/0 absorbable sutures to the chest wall. After closure of the chest, the patients were turned to a supine position and the perfusion was started as described later. During operation the patients received generous fluid and blood replacement, maintaining an adequate blood pressure and high urine output.

Complete resection (R0) was defined as macroscopic and microscopic removal of all gross tumor, subtotal (R1) as minimal residual disease, and partial (R2) as macroscopic incomplete resection.

Perfusion technique
Fourteen patients underwent unilateral HPP and one bilateral HPP. A standard roller pump and heat exchanger were used. The extracorporal circuit was primed with lactated ringer solution. In patients in whom pneumonectomy was not performed, the lung was kept in partial collapse. Fluids were flowed through the dorsal drain until all air was removed from the pleural space through a sidearm in the outflow pipe, and then the initial heating perfusion was begun. Circulation flows of 1,000 to 2,000 mL/min with an inflow temperature of 42°C or higher were required to maintain the desired temperature. Cisplatinum was added when the outflow temperature stabilized. The intrapleural temperature ranged from 40.3°C to 43°C, median 40.8°C (Table 1). Initially it was measured directly with an intrapleural thermometer. Because it was found to be equivalent to the average of the inflow and outflow temperatures, it was thereafter measured indirectly, attempting to avoid another source of potential contamination. Since August 1999 we have used a modified heat exchanger that allows temperatures as high as 45°C and we also adjusted the cisplatinum dose to a standard of 100 mg/m². Those changes took place in the last 4 patients.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
Complete resection (R0) was achieved in 10 patients, R1 in 2, and R2 in 3 patients. There were no technical problems during the perfusion period. Neither hemodynamic nor respiratory instability was noticed. The maximal systemic temperature reached 38°C with an increase of 0.7°C to 3.2°C (median, 2.0°C). Creatine clearance, which was measured before and postoperatively, was found unchanged in all patients. There was no neurologic toxicity.

One patient was found on the fifth postoperative day to have monocytic leukemia related to previous chemotherapy for his thymoma (Table 1). There was one case of prolonged air leak that stopped spontaneously after 7 days. There were two cases of significant postoperative bleeding, in one rethoracotomy was required. Two additional patients had fever that subsided spontaneously and did not prolong hospitalization. The median postoperative hospital stay was 7 days (range, 5 to 14 days). There were two late complications consisting of respiratory insufficiency. In one patient it occurred 3 months after operation, related partially to a myasthenic crisis and partially to diaphragmatic paresis and, in the other patient, it appeared 1 month after the operation due to a myasthenic crisis associated with delayed wound infection. Fourteen patients were included in the survival analysis; 1 patient with thymic carcinoma was lost to follow-up. The follow-up ranged between 7 and 70 months (median, 34 months.) Ten patients are alive 10 to 70 months after operation. All patients with thymoma or thymic carcinoma that survived are free of disease, except one who has a suspected contralateral pleural recurrence. There is no evidence of ipsilateral pulmonary or pleural disease in all survivors. The patient with carcinoma in a thymic cyst had an ipsilateral chest wall recurrence 16 months after the operation and underwent re-resection and radiation. Four patients died 7 to 36 months after operation. Three of them died from local and systemic disease progression (thymic carcinoma, 2; thymoma, 1), and one from complications related to chemotherapy for monocytic leukemia. The 3-year and 5-year actuarial survival rates for the entire group and for the thymoma patients are 70%, 55% and 90%, 70%, respectively (Fig 1).

View larger version (14K): [in this window] [in a new window]   Fig 1. Survival of patients undergoing resection and thermochemotherapy.

	Comment

Top Abstract Introduction Patients and methods Results Comment References

In view of the fact that complete tumor eradication plays a major role in prevention of tumor recurrence and as most of the relapses in advanced stages of thymoma are locoregional, we hypothesized that aggressive local treatment consisting of maximal resection and intraoperative perfusion thermochemotherapy may improve survival. Regional antitumor therapy has been used for some malignancies with encouraging results. This therapeutic approach has a valid theoretical basis. Compared with conventional systemic therapy, it may have the advantage of directly exposing the tumor to a higher concentration of the drug while less toxic systemic effects could be expected. Although intravesical and intrathecal chemotherapy have already clear indications, the role of intrapleural chemotherapy has still to be defined. At present only case reports, or small controlled clinical studies have been published.

We chose cisplatinum for our study because its antitumoral effects and pleural pharmacokinetics are highly predictable and were studied most extensively. Rusch and colleagues [20] examined the pharmacokinetics of intrapleural cisplatinum and mitomycin when given to patients after pleurectomy for malignant pleural mesothelioma. They found that peak plasma levels are reached within 1 hour of intrapleural administration. Peak plasma levels measured after intrapleural chemotherapy approximated those reportedly during systemic administration of both drugs at similar doses. However, the mean peak cisplatinum and mitomycin levels, and their mean areas under the concentration time curve were significantly higher in the pleural fluid than in the plasma. There was a three- to fivefold advantage for pleural-to-plasma areas under the concentration time curve for both drugs. Thus, intrapleural cisplatin-based chemotherapy has a distinct local pharmacologic advantage. One of the clinical implications of Rusch’s study is that the same precautions practiced during intravenous treatment (eg, prehydration) are needed while administering intrapleural cisplatinum. Ratto and associates [21] studied the effects of the extent of resection and perfusion temperature on cisplatin pharmacokinetics in the treatment of malignant mesothelioma. Cisplatin was given intrapleurally in a similar method described by us. In a small group of patients they found that systemic drug concentrations were greater after pleurectomy/decortication than after pleuropneumonectomy. They also found that local tissue/perfusate ratio of platinum concentrations tended to be higher after hyperthermic perfusion than after normothermic perfusion.

The efficacy of hyperthermia in the treatment of malignant neoplasms has been demonstrated in vitro and in vivo. The use of hyperthermia in the pleural space is limited to 43°C, as there is an increased risk for the development of pulmonary edema above this temperature. Combining hyperthermia with antitumoral drugs may produce an additive effect. Furthermore, enhancement of the drug cytotoxicity was found when intrapleural mitomycin and cisplatinum were heated to 40°C to 42°C for 1 hour. There are three proposed explanations for the synergism between hyperthermia and cisplatinum: (1) an increased level of drugs within cells; (2) significant enhancement of the DNA cross-linking effect of the drugs; and (3) heat-induced inhibition of DNA repair.

The present study consists of a limited number of patients with several thymic malignancies. This group harbored many poor prognostic factors: pleural spread (all patients), thymic carcinoma (3), and recurrent disease (6 patients). Thermochemotherapy was feasible in all patients, achieved without mortality and with acceptable morbidity. The relatively high 3-year and 5-year survival rates of 70% and 55% for the entire study population and 90% and 70% for the thymoma patients, are at least comparable and apparently higher than that reported in the other series. All the survivors and 1 patient who died after 3 years from an unrelated cause, did not have ipsilateral pleuropulmonary relapse. Thus, 11 patients (79%) have had complete local control for periods ranging from 10 to 70 months. This fact may predict a survival benefit in the long term follow-up.

Although some of our patients achieved midterm to long-term disease-free survival with operation and thermochemotherapy alone, we believe that in light of the recent studies demonstrating a high response rate to systemic chemotherapy, the management should also include this modality. Ideally, a multicentric study including pleural chemotherapy should be instituted to examine the additive effect of HPP, but practically it seems almost impossible.

In summary, HPP is a feasible, easy to perform, and safe technique in patients with thymic malignancies. Resection plus HPP can achieve a high local control in thymoma stage IV-a. Results to date suggest a survival benefit in patients with thymoma. Although not evaluated in our study, it seems that neoadjuvant therapy has a place in the management of these malignancies and should be combined with aggressive local treatment, as reported here.

	References

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