Clinical Staging and the Tendency of Malignant Pleural Mesotheliomas to Remain Localized Russell J. Nauta, M.D., Robert T. Osteen, M.D., Karen H. Antman, M.D., and J. Kenneth Koster, M.D. ABSTRACT Thirty-two patients who had been treated for diffuse, malignant pleural mesotheliomas were retrospectively staged according to the system of Butchart. Nineteen of the 2 patients who were seen with disease confined to one hemithorax have died. Twelve patients died without progression to a higher clinical stage, and only 1 patient died of systemic metastases. Nineteen of the 32 patients died of local tumor invasion. Regimens containing Adriamycin (doxorubicin hydrochloride) appeared to prolong the survival of patients with epithelial-type tumors. Combination chemotherapy, designed to treat soft-tissue sarcomas, produced only partial responses in a small number of patients. Malignant pleural mesotheliomas arise from a tissue that is difficult to resect. Except for the diaphragmatic surface, the parietal pleura can be removed easily, but the lung must be sacrificed in order to resect the entire visceral pleura. Mesothelioma is a rare tumor. The clinical diagnosis is often confused with infections or metastases from other organs to the pleura. Histologically, the tumor may resemble a softtissue sarcoma or an adenocarcinoma. The rarity of the tumor, the difficulty of diagnosis, the poor prognosis, and the magnitude of the operation required to resect the entire pleura have made mesothelioma a challenge for modern oncology; palliative therapy has become the rule. The incidence of mesotheliomas appears to be increasing, probably as a result of increased exposure to asbestos during and after World War 1 [l-41. t has been predicted that the disease will increase during the next twenty to thirty years, until the effects of regulatory From the Department of Surgery, Brigham and Women s Hospital, and the Department of Medicine, Sidney Farber Cancer nstitute, Harvard Medical School, Boston, MA. Accepted for publication Nov 30, 1981. Address reprint requests to: Dr. Osteen, Brigham and Women s Hospital, 75 Francis St, Boston, MA 02115. legislation initiated in the early 190s are felt [l-51. The series of patients discussed here was reviewed to determine those features of the disease that might be important for planning therapy. Material and Methods The medical records and radiographs of 32 patients who were treated for diffuse, malignant pleural mesotheliomas at the Brigham and Women s Hospital and the Sidney Farber Cancer nstitute between February, 193, and February, 1980, were reviewed. Patients were classified retrospectively according to the staging system suggested by Butchart and associates []: Stage -tumor confined to the ipsilateral pleura, lung, and pericardium; Stage invasion of the chest wall and mediastinum; Stage 111-penetration of the diaphragm or lymph node metastases; Stage V-distant metastases. Hospital records were reviewed to evaluate the adequacy and effectiveness of diagnostic techniques, the staging system, the results of treatment, and the cause of death. Results Age and Sex Twenty-five men and 7 women were treated. The peak incidence of the disease was during the sixth decade of life. Men had occupational exposure to asbestos more frequently than did women, 0% and 28%, respectively. The median survival for the entire group was 12 months. The median survival for women was 34 months and for men, 10 months. The longer survival of women could not be explained by difference in stage at presentation, since the incidence of men and women in each stage was equal. n Stage, there were 10 men (40%) and 3 women (43%); in Stage 11, 10 men and 3 women; in Stage 111, 3 men (12%) and no women; and in Stage V, 2 men (8%) and 1 woman (14%). 0003-4975/82/0700-05$01.25 @ 1982 by The Society of Thoracic Surgeons
7 Nauta et al: Malignant Pleural Mesotheliomas Table 1. Relationship between Symptoms and Stage Stage Symptom 1 11 v Pain 9 10 1 2 Dyspnea 7 2 1 Pain + dyspnea 2 5 0 0 anumbers are numbers of patients. hall patients had pain or dyspnea. Table 2. nitial Symptoms and Survival of Patients with Pleural Mesothelioma No. of Median survival Svmutom Patients (mo) Dyspnea 17 19 Chest pain 20 14 Dvsunea + uain 7 19 Symptoms All patients had pain or dyspnea, and some had both symptoms. Symptoms correlated with neither the stage of disease (Table 1) nor survival (Table 2). The slight differences in survival presented in Table 2 are not statistically significant, possibly because of the small number of patients in each category. Diagnostic Procedures Examination of pleural fluid samples from 2 patients yielded only two definitive diagnoses of mesothelioma. Two specimens were suggestive of mesothelioma and three were interpreted as malignant tumor. Four definitive diagnoses of mesothelioma were obtained by needle biopsy of the pleura. Twenty-four patients (75%) required open biopsies, including nineteen thoracotomies and two pericardial explorations, to establish the diagnosis. Two patients were thought to have soft-tissue sarcomas, until the diagnosis of mesothelioma was established at postmortem examination. Treatment was delayed for more than 2 months by uncertain diagnoses in 7 patients. n each instance, the delay was caused by inconclusive pathological findings and hesitation to subject the patient to an open biopsy. Histology The survival of patients in this series is compared in Table 3 with that in two other series according to histological subtype of the mesothelioma and the treatment given. Unlike the other two series shown in that table, our patients with epithelial tumors had a shorter survival than patients with the other two histological subtypes. Table 3. Survival by Histological Subtypes and Treatment in Three Series of Patients No. of Survival Series Histology Treatment Patients (mo) Brigham and Women s Hospital Resection 7 7 (median) + Sidney Farber Cancer rradiation 4 8, 8, 21, 145 nstitute [present report] + Resection 3 3, 14, 15 mixed + mixed rradiation 4 11,34,54,53 Memorial [9] Resection 17 21 (median) rradiation 15 8 (median) Resection 1 11 (median) rradiation 7 9 (median) Newcastle upon Tyne [] Pleuro- 9 1 (median) pneumonectomy Pleuropneumonectomy 11 4 (median)
8 The Annals of Thoracic Surgery Vol34 No 1 July 1982 Table 4. Results of Various Therapies in 37 Patients Radiation Presenting Survival Operation Therapy Chemotherapy Stage Histology (mo) Pleurectomy Pleurectomy + chest wall resection x 3 Resection of pleural nodules + pericardiectomy + resection of chest wall nodule Decortication? Amount 3,000 Rads x 2 Gold seeds,000 Rads 1,500 Rads A, AD32 C, vinblastine Hy droxyurea mi tomycin-c, metho trexate, 5-fluorouracil, cis-platinum CCNU, methotrexate, Neocarcinostatin Cis-platinum, CCNU 1 1 v 1 1 V 1 1 11 1 1 11 1 1 1 v 1 1 = not applicable; VCR = vincristen; A = Adriamycin (doxorubicin hydrochloride); = high-dose methotrexate + citrovonun factor; C = cyclophosphamide; CCNU = methyl chloroethyl cyclohexyl nitrosourea; D = dimethyltriazenoimidazole carboximide. *Alive. 14" 3 21 8 8 34 21 57* 22 27 19 49* 2 7 53* 145 34 11 13 15 3 10 4 28 7" 7* 0 7 23*
9 Nauta et al: Malignant Pleural Mesotheliomas Results of Therapy Patients were treated on an individual basis with various combinations of surgical intervention, radiation therapy, and cytotoxic drugs. No single treatment plan was followed. Operative intervention was confined to diagnostic biopsies and limited resections with no pleuropneumonectomies. Chemotherapy usually was given for gross disease, when the induction of complete remission was unlikely. The results of treatment are shown in Table 4. Eight patients received a chemotherapy regimen including Adriamycin (doxorubicin hydrochloride), 50 mg/m2 on day 1, cyclophosphamide, 00 mg/m2 on day 2, and imidazolcarboximide, 4,000 mg/m2 on days 1 and 2, repeated every 21 days. This regimen was begun in 1975, in the belief that mesotheliomas should be treated as if they were soft-tissue sarcomas. With that regimen, 3 patients experienced partial remission, 2 patients had progression, and 3 patients had stable disease for a brief period. The only suggestion of an effect on survival was seen in patients with epithelial tumors. Seven patients with epithelial tumors treated with Adriamycin-containing regimens had a median survival of 19 months, compared with a median survival of 7.5 months for the 12 patients with epithelial tumors who received either chemotherapy regimens that did not include Adriamycin or no chemotherapy at all. Stage Progression and Cause of Death Nineteen of the 2 patients who were seen with disease confined to one hemithorax (Stage or 11) died. Twelve died without clinical evidence of progression to a higher clinical stage, and only 1 patient died of systemic metastases. Progression from Stage, 11, or 11 to a higher stage was observed in 8 of 22 patients with Stage, 1 or 11 and epithelial or mixed histology and 3 of 7 patients with sarcomatous histology. Nineteen patients died of local tumor invasion causing respiratory obstruction and sepsis. Local tumor invasion was complicated by cardiac toxicity from Adriamycin in 1 patient, and radiation pneumonitis in another. Comment The preponderance of men and the longer survival of women in our series are striking. Estrogen-receptor protein was not measured in any of the tumors reported here nor has it been reported by other investigators. The tendency of men to receive a heavier occupational exposure to asbestos raises the possibility of a relationship between survival and dose of the inducing agent. The tendency of the tumor to remain local was demonstrated by the lack of progression in clinical stage and by the predominance of local complications as the cause of death. t is obvious that survival will not be improved unless more effective local control is obtained. The suggestion by Gottlieb and associates [A to treat mesothelioma as a type of soft-tissue sarcoma because of its mesenchymal origin is contradicted by the tendency of mesotheliomas to spread locally rather than to metastasize as do soft-tissue sarcomas. f local control improves, then metastatic disease may become a more predominant feature of the disease. n most instances, a thoracotomy will be required to establish the diagnosis. Since aggressive resections usually should be avoided for metastatic tumors and because the diagnosis of mesothelioma by frozen section may be difficult, it may be necessary to await interpretation of a permanent histological section before proceeding with definitive therapy at a second thoracotomy. Butchart and co-workers [1 reported the treatment of 29 patients with pleuropneumonectomy. Patients were selected for stage and histological subtype, with pleuropneumonectomy reserved for patients with epithelial disease classified as Stage. DeLaria and colleagues [81 reported 2 disease-free survivors at two and four years among 11 patients treated with radical extrapleural pneumonectomy. Both long-term survivors had epithelial-type tumors. Wanebo and associates [9] also reported longer survival of patients with epithelial tumors treated by resection compared with resected sarcomatous tumors. These reports suggest that resection may more favorably affect the course of epithelial tumors, but the number of patients treated by aggressive local therapy is still small and the natural histories of the different tumor subtypes are not known. The role of adjuvant radiation therapy is not well defined. n a nonrandomized series com-
70 The Annals of Thoracic Surgery Vol34 No 1 July 1982 paring operative intervention with radiation therapy, the survival of patients who had radiation treatment was inferior to that of patients who underwent resection [9]. External beam or implant radiation, appropriately combined with resection, may affect survival [lo, 111. The geometric - problem of treating the entire pleural surface with a uniform dose of radiation may impose practical limits on the use of radiation therapy. The partial responses seen in 5 of 13 patients treated with Adriamycin-containing regimens and the apparently improved survival of patients with the epithelial subtype who received Adriamycin both indicate that the drug has an effect on the tumor. The potential for improved survival, by means of surgical resection by pleuropneumonectomy, with radiation therapy to sites of residual disease combined with adjuvant Adriamycin, is under investigation at the Sidney Farber Cancer nstitute. References 1. Selikoff J, Churg J, Hammond FC: Relations between exposure to asbestos and mesothelioma. N Engl J Med 272:50, 195 2. Selikoff J: Perspectives in preclinical management of cancer: initiation of a mesothelioma 3. 4. 5.. 7. 8. 9. 10. 11. therapy research program. Mt Sinai J Med 44: 45, 1977 Manfredi F, Rosenbaum D, Childress RH: Diffuse malignant mesothelioma of the pleura. Am Rev Respir Dis 92:29, 195 Aisner J, Wiernik PH: Malignant mesothelioma: current status and future prospects. Chest 74:438, 1978 McDonald AD, Harper A, Attar OA, et al: Epidemiology of primary malignant mesothelial tumors in Canada. Cancer 2:914, 1970 Butchart EG, Ashcroft T, Barnsley WC, et al: Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura: experience with 29 patients. Thorax 31:15, 197 Gottlieb JA, Baker LH, Quagliana JM, et al: Chemotherapy of sarcomas with a combination of Adriamycin and dimethyltriazenoimadazole carboxamide. Cancer 30:132, 1972 DeLaria GA, Jensik R, Faber LP, Kittle CF: Surgical management of malignant mesothelioma. Ann Thorac Surg 2:375, 1978 Wanebo HJ, Martini NM, Melamed MR, et al: Pleural mesothelioma. Cancer 38:2481, 197 Guttman RJ: Results of radiation therapy in patients with inoperable carcinoma of the lung whose status was established at exploratory thoracotomy. Am J Roentgen01 Radium Ther Nucl Med 93:99,195 Legha SS, Muggia FM: Therapeutic approaches in malignant mesothelioma. Cancer Treat Rev 4:13, 1977