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The role of extrapleural pneumonectomy in malignant pleural mesothelioma
Volume 102,
Number 1
July 1991
THORACIC AND CARDIOVASCULAR SURGERY The Journal of
J
THORAC CARDIOYASC SURG
1991;102:1-9
Original Communications
The role of extrapleural pneumonectomy in malignant pleural mesothelioma A Lung Cancer Study Group trial Malignant pleural mesothelioma is usually a fatal cancer for which operation has been the mainstay of treatment because chemotherapy and radiation are relatively ineffective. The choice of operation for malignant pleural mesothelioma remains controversial. Extrapleural pneumonectomy has been advocated because it allows complete removal of gross tumor and can be associated with long-tenn survival. To evaluate extrapleural pneumonectomy, we conducted a prospective muitiinstitutional trial in patients with biopsy-proved previously untreated malignant pleural mesothelioma. Criteria for extrapleural pneumonectomy were (1) potentially completely resectable unilateral disease by computed tomography scan, (2) predicted postresection forced expiratory volume in 1 second> 1 LIsee, and (3) no other major medical problems. Patients who were not candidates for extrapleural pneumonectomy had a more limited operation with or without adjuvant tberapy or had nonsurgical treatment From September 1985 to June 1988 83 eligible patients (64 male, 19 female) were entered. The mean age for all patients was 59.7 years. Only 20 of the 83 patients (24%) underwent extrapleural pneumonectomy. Three of these 20 patients (15%) died postoperatively. The recurrence-free survival was significantly longer for the patients undergoing extrapleural pneumonectomy than for the other two groups (p = 0.03), but there was no difference in overall survival among the three groups. In univariate analyses, epithelial versus sarcomatoid and mixed histologic findings and platelet count <400,000 were associated with a better overall survival (p = 0.02), and perfonnance status (Kamofsky <80) was
Valerie W. Rusch, MD (by invitation), New York, N.Y., Steven Piantadosi, MD, PhD (by invitation), Baltimore, Md., and E. Carmack Holmes, MD, Los Angeles, Calif.
From Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York, N.Y., the Department of Oncology Biostatistics,Johns Hopkins Oncology Center, Baltimore, Md., and the Department of Surgery, UCLA School of Medicine, Los Angeles, Calif. Supported by Grant CA 36045 from the National Cancer Institute.
Read at the Seventieth Annual Meeting of The American Association for Thoracic Surgery, Toronto, Ontario, Canada, May 7-9, 1990. Address for reprints: Valerie W. Rusch, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. 12/6/26077
2 Rusch, Piantadosi, Holmes
The Journal of Thoracic and Cardiovascular Surgery
predictive of recurrence (p = 0.02). In a multivariate analysis, histologic findings, sex, age, extrapleural pneumonectomy, weight loss, and performance status all bad no significant impact on survival. Extrapleural pneumonectomy was associated with a greater likelihood of relapse in distant sites tban were limited operation and nonsurgical treatment We conclude tbat (1) only a small proportion of aU patients with malignant pleural mesothelioma are candidates for extrapleural pneumonectomy, (2) extrapleural pneumonectomy carries a significant operative mortality and does not seem to improve overall survival compared with more conservative forms of treatment, (3) extrapleural pneumonectomy alters the patterns of relapse, and (4) factors previously thought to have an impact on survival in other series did not affect outcome in this trial.
Dffuse malignant pleural mesotheliomais an uncommon malignancy. Only 2000 to 3000 cases occur annually in the United States, 1 but it posesa significantproblem because there is no standard therapy for this usually fatal disease. All forms of treatment, and in particular the role of surgical resection,remain controversial.Some authors favor supportive care alone, and others advocate aggressive multimodality treatment combining extrapleural pneumonectomy with postoperative chemotherapy or radiation or both.' The assessment of any treatment regimen is compounded by the lack of formal TNM staging system and a poor understanding of the prognosticfactors in this disease. Because radiation and chemotherapy in mesothelioma are relatively ineffective in malignant mesothelioma.l? surgical resection has been considered the mainstay of treatment. Two very different operations have commonly been performed: pleurectomy/decortication and extrapleural pneumonectomy (also termed pleuropneumonectomy). Pleurectomy/decortication carries an operative mortality rate of 2% or less but is by definition an incomplete resection.s" It has been used alone for palliation, or with radiation or chemotherapy for treatment. Extrapleural pneumonectomy is theoretically attractive because it allows complete resection of all gross disease and has occasionally been associated with survival in excess of 2 years. It carries a higher risk than pleurectomy/ decortication, however, with reported operative mortality rates ranging from 9% to 30%.2 The Lung Cancer Study Group (LCSG) brought together several institutions that were geographically located in areas in which mesotheliomawas prevalent. In addition, the LCSG brought together a group of surgeons whose practice was dedicated to general thoracic surgery and who had collaborated extensively in previousclinical trials. The LCSG was therefore in an excellentpositionto perform clinical trials in malignant mesothelioma. As a first step, the LCSG decided to evaluate the role of extrapleural pneumonectomy.The aims of this initialtrial were to determine (1) what proportion of all patients with malignant mesothelioma might be candidates for extra-
pleural pneumonectomy,(2) the morbidity and mortality of this operation in a multiinstitutional setting, (3) the impact of this operation, in the absence of adjuvant postoperative treatment, on disease-freeand overallsurvival, and (4) the patterns of relapse.
Materials and methods Patients were eligible if they had biopsy-proved previously untreated malignant mesothelioma and did not have another active malignant tumor. The trial had two arms: an extrapleural pneumonectomy arm and a registry arm. The trial was approved bytheinstitutional review board ofeach oftheparticipating institutions, andinformed consent was obtained from all patients before entryin the study. Patients were candidates for the extrapleural pneumonectomyarmif (I) thetumor was confined toonehemithorax andthe preoperative computed tomographic (CT) scan indicated that extrapleural pneumonectomy would allow complete resection of all gross disease, (2) pulmonary function tests arid ventilation/ perfusion lung scan predicted a postresection forced expiratory volume in I second greater than I L/sec, and (3) the patients had nosignificant cardiovascular disease or other major medical problems. Extrapleural pneumonectomy was defined as en bloc resection of the parietal and mediastinal pleura, the lung, hemidiaphragm, and ipsilateral halfof the pericardium. Diaphragmatic and pericardiaI reconstruction was performed according to the surgeon's preference. Patients who underwent extrapleuraI pneumonectomy didnotreceive anyadditional treatment unless they developed recurrent disease. A baseline CT scan of the chest and upper portion of the abdomen was obtained 6 weeks postoperatively. Follow-up of the patients continued every 3 months by physical examination and CT scan of the chest and upper portion of the abdomen. Additional laboratory tests and scans were obtained as clinically indicated. If the patient was thought to have recurrent disease by examination or CT scan, anattemptwas made toobtain a confirmatory biopsy specimen. Patients deemed to have recurrent disease were treated at the discretion of their physician. Patients who were operated onwith the intent to perform an extrapleural pneumonectomy butwere found tohave anincompletely resectable tumor at thoracotomy were taken off-study from the extrapleural pneumonectomy arm and were followed intheregistry armofthetrial. These patients could then receive additional nonoperative treatment at the discretion of their physician. Patients who were not candidates for extrapleural pneu-
Volume 102
Malignant pleural mesothelioma
Number 1 July 1991
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monectorny were entered on the registry arm of the study and treated according to the preference oftheir physicians. Patients in this arm ofthe study were also given by serial physicalexaminations and CT scans of the chest and abdomen. The major statistical end point of this study was to estimate the postoperative recurrence and survival rates in patients with mesothelioma. Secondary objectives were to estimate the perioperativemorbidity and mortality and the importance of several prognostic factors on long-term outcome. Event time distributions were estimated by the product limit method.f The significance of categoric prognostic factors was assessed with the log rank statistic." and the significanceof continuously distributed factors was assessed in the proportional hazards regression model." Confidence limits on estimated proportions were determined by means of exact binomial methods. Results From September 1985 to June 1988, 86 patients were entered on study. Three patients were deemed ineligible because the final pathology review revealed metastatic adenocarcinoma. These three patients have therefore been excluded from analysis. None of them underwent an extrapleural pneumonectomy. Of the 83 eligible patients, 64 were male and 19 female. The mean age for the entire group was 59.7 years. Fifty-four patients (65%) had known asbestos exposure. At the time of this analysis, 77 of the 83 patients had had central review of their pathology slides to verify the mesothelioma cell type. Epithelial mesothelioma was seen in 34 patients (44.2%) and was the most common histologic finding. Twenty-nine patients (37.7%) had mixed findings histologically, whereas six (7.8%) had sarcomatoid mesothelioma and eight (10.3%) had an indeterminate cell type.
For the purposes of further analysis, the 83 patients were divided into three groups according to the type of surgical procedure performed: (1) complete resection of all gross disease by extrapleural pneumonectomy (EPP group); (2) incomplete resection of all gross disease by a more limited operation than extrapleural pneumonectomy, usually a pleurectomyjdecortication (LO group); (3) any surgical procedure performed strictly to obtain a biopsy specimen with no subsequent surgical treatment (NST group). The EPP group included 20 patients, the LO group 26 patients, and the NST group 37 patients. The mean ages in the groups were 56.7 years in the EPP group, 61.5 years in the LO group, and 61.1 years in the NST group. There was no significant difference in the mean age of the three groups. The reasons that patients did not undergo extrapleural pneumonectomy were as follows: concurrent medical problems severe enough to prohibit major surgery, eight patients (9.6%); extrathoracic tumor, nine patients (10.8%); inadequate pulmonary function, 27 patients (32.5%); and disease that was thought by the operating surgeon to be too locally advanced to allow complete resection, 45 patients (54.2%). Some patients had more than one reason that precluded extrapleural pneumonectomy. Of the twenty patients in the EPP group, three died postoperatively (15%, 95% confidence limits 3% to 38%). One patient died of multiple pulmonary emboli, and two died of respiratory failure that led to multisystem failure. Four patients, two in the group that died postoperatively and two in the group that survived, had a bronchial stump leak and associated empyema. All four patients had
The Journal of
4
Rusch. Piantadosi, Holmes
Thoracic and Cardiovascular Surgery
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Fig. 2. Recurrence-free survival analyzed by surgical status for the 83 eligible patients. EPP. Extraplcural pneumonectomy.
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Fig. 3. Overall survival for all 83 eligible patients.
undergone a right pneumonectomy. Eight of the twenty patients (40%, 95% confidence limits 19% to 40%) developed arrhythmias that were severe enough to require medication. In one patient the arrhythmia was ventricular, while in seven patients it was atrial. One patient required reexploration to control postoperative bleeding. The median follow-up was 421 days in the EPP group, 301 days in the LO group, and 327 days in the NST group. The recurrence-free survival for all 83 patients is
shown in Fig. I, and the recurrence-free survival by surgical group is shown in Fig. 2. The recurrence rate per person-year was 0.616 in the EPP group, 1.48 in the LO group, and 1.63 in the NST group. The recurrence-free survival was significantly longer in the EPP group (p = 0.03) than in the other two groups. This difference in recurrence-free survival may not represent a true comparison of surgical effect because it was not adjusted for differences in prognostic factors.
Volume 102 Number 1
Malignant pleural mesothelioma
July 1991
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Fig. 4. Overall survival analyzed by surgical status for the 83 eligible patients. EPP, Extrapleural pneumonectomy.
Table I. Initial sites of recurrent or progressive disease analyzed by operation status for the 83 eligible patients Biopsy only Diaphragm Chest wall
Mediastinum Pleura Ipsilateral lung Nodes Contralateral ehest Abdomen Other Second primary
3 15 3 10 I
3 3 3 4 0
Table II. All sites of disease at time of last follow-up analyzed by operation status for the 83 eligible patients
LO
EPP
4 9 4 9 3 1 3 3 7 1
1 4 3 I
0 5 5 5 6
0
The overall survival for the 83 eligible patients is shown in Fig. 3. The median survival for the entire group was 10 months (318 days). The survival by surgical group is illustrated in Fig. 4. The death rate per person-year was 0.545 in the EPP group, 0.757 in the LO group, and 0.807 in the NST group. The estimated proportion of patients survivingat 2 years was 33% in the EPP group (95% confidencelife table limits 14%to 54%),20% in the LO group (12% to 46%), and 18.5% in the NST group (8%to 32%). There was no significant difference in the death rates among the three groups (p > 0.05). Several factors were analyzed to determine whether they had any impact on recurrence-free or overall survival. These included cell type, sex, age, weight loss, performance status, platelet count, and extrapleural pneu-
Diaphragm Chest wall Mediastinum Pleura Ipsilateral lung Nodes Contralateral chest Abdomen Other Second primary
Biopsy only
LO
EPP
5 19 7 13 2 5
9 15 11 14 9 9
8
6
11 9 2
7 11 2
2 4 5 2 0 7 7 10 9 0
monectomy. In univariate analyses, epithelial histologic type conferred a better overall survival than did other cell types (p = 0.02). Elevated platelet count (>400,000) was associated with a significantly poorer survival (p = 0.04) but was not prognostic for recurrence. Performance status (Karnofsky scale <80) was predictive of recurrence but had no impact on survival. By multivariate analysis, however, none of these factors had any influence on recurrence-free or overall survival. The first sites of recurrent or progressive disease for each of the three groups of patients are shown in Table I. All of the sites of disease at the time of last follow-up are shown in Table II. To examine this from another perspective, we grouped diaphragm, chest wall, mediastinum, pleura, and ipsilateral lung together as locally
6
The Journal of Thoracic and Cardiovascular Surgery
Rusch, Piantadosi, Holmes
Table III. Number ofpatients who had local only, distant only, or local plus distant disease as their initial site of recurrent or progressive disease Biopsy only Local only Distant only Local plus distant
20 4 4
LO
EPP
13 3
2 6 5
6
recurrent disease, and nodes, contralateral chest, abdomen, and other were considered distant disease. Patients were then categorized according to whether disease developed locally, in distant sites,or in both localand distant sites. The number of patients who had recurrent or progressive disease in each area, both initiallyand at the time of last follow-up, is listed in Tables III and IV. Relapse occurred predominantly in distant sites in the EPP group, whereas initiallythe LO group and especiallythe NST group,had mainlyprogression oflocaldisease. Ultimately, though, distant disease developed in a large proportion of the LO and NST groups as well. Discussion
The role of surgical resection, and especially of extrapleural pneumonectomy, in the management of pleural mesothelioma is controversial. Most of the previously published series make it difficult to assess the impact of extrapleural pneumonectomy becausethey are retrospective,involve small numbers of patients treated overmany years, have unclear eligibility criteria for extrapleural pneumonectomy, and use highlyindividualized regimens of radiation or chemotherapy (or both) postoperatively.I- II The LCSG believed that extrapleural pneumonectomyshould be evaluated prospectively in a multiinstitutional setting where a large number of patients could be accrued over a short period of time. Thorough pathologic evaluation with immunohistochemistry or electron microscopy (or both) was required to exclude patients who had metastatic adenocarcinoma. Specific eligibility criteria for extrapleural pneumonectomy were set and included the routine use of CT scans for preoperativestaging.This provided an assessment of the applicabilityof extrapleural pneumonectomy to the overallpopulation of patients with malignant mesothelioma. Most important, the outcome of complete surgical resection alone was determined in the absence of adjuvant postoperative treatment. The patientsentered on this trial weremiddleaged and predominantly male. The majority of them had known asbestos exposure. This reflects the fact that several
Table IV. Number ofpatients who had local only, distant only, or local plus distant disease at time of last follow-up Biopsy only Local only Distant only Local plus distant
8 4
16
LO
EPP
9 I 12
0
5 8
LCSG-participating institutions are located in areas where there are asbestos mines or industries using large amounts of asbestos. Thus patients included in this study are similar to those in other series, and to patients with mesothelioma in general.I Becausemost other seriesare retrospective, it has been hard to determinewhat proportionof the total numberof patients with mesothelioma might truly be candidatesfor an extrapleural pneumonectomy. This proportion seems to vary strikinglyfrom one seriesto the next. In a 20-year review of patients with mesothelioma treated at the Dana Farber Cancer Institute, only 16 of 136 (11.7%) underwent extrapleural pneumonectomy.I? Likewise, in a 19yearcombinedexperience fromOntario and Quebec,only 23 of 332 (6.9%) patients underwent extrapleural pneumonectomy.P In contrast, 29 of 46 (63%) patients reported on by Butchart and colleagues 14, 15 and 33 of 56 (59%) patients reported on by DaValle and colleagues" qualified for extrapleural pneumonectomy. In our series only 20 of 83 (24%) patients underwent extrapleural pneumonectomy. The remainder did not meet the eligibility criteria becauseof either inadequate cardiopulmonary reserveor locally advanced disease. This is not surprising given the average age of these patients and their potential for underlying pulmonary disease related to smokingand asbestosexposure. Becauseall patients with mesothelioma seen at LCSG-participating institutions wereevaluatedprospectively and placedon thisstudy,the proportion of patients who are truly suitable for extrapleuralpneumonectomy ismorelikely to beaccurate than in retrospective series. Our data suggest that only a minority of patients with mesothelioma qualify for this operation at the time of diagnosis. The operativemortality of extrapleural pneumonectomy has alsovariedwidely. In the firstmajor seriesofthese operationsreported by Butchart and colleagues 14 in 1976, the operativemortality rate was 30%. Operative mortality rates have been lowerin more recent studies but have ranged from 10%to 20%in severalseries.i' 15 The lowest mortality rate to date has been 9% (3/33 patients) reported by DaValle and coworkers." Thus the mortal-
Volume 102 Number 1 July 1991
ity in this series is consistent with what has been described previously. The LCSG has previously reported a mortality rate of less than 7% for patients undergoing pneumonectomy for lung cancer.!? Thus our operative mortality for extra pleural pneumonectomy probably reflects the greater magnitude of the operation compared with a standard pneumonectomy rather than just the multiinstitutional nature of the study. Lower mortality rates may be achievable in a single institution if very stringent patient selection is used. To assess the impact of any treatment for mesothelioma, one must understand the natural history of the disease and the outcome after supportive care alone. Unfortunately such information is sparse. Assessment of treatment results is made even more difficult by the lack of a reproducible TNM-based staging system and by the highly individualized approach to treatment of mesothelioma. Law and coworkers" compared the outcome of64 patients treated with supportive care alone with that of 52 patients with clinically similar stage disease who received a variety of active treatments. There was no difference in survival between the two groups. The median survival from the onset of symptoms was 18 months, and seven patients survived more than 4 years." More recently Hulks, Thomas, and Waclawski'? reviewed the outcome of 68 patients managed with supportive care alone. The overall median survival was 30 weeks from the time of diagnosis. Patients who presented with pain had a median survivalof 22 weeks, whereas those who presented with dyspnea had a median survival of 44 weeks, probably reflecting the extent of disease at the time of diagnosis. The longer median survival reported by Law and coworkers" may represent the difference between measuring survival from the time of onset of symptoms compared with the time of diagnosis, since diagnosis is frequently delayed 3 months or more in patients with mesothelioma.13 Histologic findings did not affect survival in either of these two studies. Enthusiasm for any type of treatment must be tempered, therefore, with the knowledge that patients with mesothelioma can occasionally survive a year or more with supportive care alone. The operative morbidity and mortalityof extra pleural pneumonectomy is acceptable if it leads to prolonged survival. In the original reports by Butchart and associates.lv 15 only 9% (3/33 patients) survived 2 years or longer after extrapleural pneumonectomy. In the experience of Da Valle and coworkers," the 2-yearsurvival rate was 24% and the 3-year survival rate, 15% (5/33 patients). Half of the patients received adjuvant radiation or chemotherapy. Worn-? has also reported a series of 62 patients whose 2-year survival rate was 37% and 5-year survival rate was 10% after extrapleural
Malignant pleural mesothelioma 7
pneumonectomy. At the Dana Farber Cancer Institute, the 136 patients treated from 1965 to 1985 had a median survival of 16 months. The 14 patients who underwent extrapleural pneumonectomy and received postoperative chemotherapy appeared to have a significantly better survival.12 In the combined Ontario and Quebec review of 332 patients, the 23 patients who underwent extrapleural pneumonectomy did not have a better survival than the remainder of the group. Their 2-year survival rate was 17%.13 Thus the 2-year survival rate of 33% and median survival of 10 months seen after extrapleural pneumonectomy alone in our study are similar to what has been reported previously, even with adjuvant postoperative therapy. Comparison of the EPP group with the remainder of the study group is hazardous because this was not a randomized study. Nonetheless, the EPP group did not have a better overall survival even though they may have had more limited disease and may have been better-risk patients initially. The experience with extra pleural pneumonectomy can be contrasted with the experience with pleurectomyI decortication. Although the LO group in our trial includes mostly patients who had a pleurectomy/decortication, the study was not designed to evaluate this surgical procedure. We have not attempted to analyze this group in detail because it comprises a heterogeneous group of patients who underwent different surgical procedures and received various forms of treatment postoperatively. The largest and most uniform experience with pleurectomyI decortication, albeit retrospective, comes from the Memorial Sloan-Kettering Cancer Center. In a series of 64 patients operated on from 1972 to 1981, the operative mortality rate was 1.8%.6 All of the patients who had pleurectomy /decortication received postoperative external-beam radiation to the involved hemithorax. Radioactive implants were used to areas of gross residual disease that could not be resected by pleurectomy/decortication. From 1976 to 1988, 105 patients were treated in this manner. Forty-one patients received only external-beam radiation and 54 patients required both an implant and external-beam radiation. For the entire group, the median survival was 12.6 months, and the 2-year survival rate was 35%. Patients who required an implant of three or more sites had a median survival of 9,9 months and a 0% 2-year survival rate. A select group of 27 patients, however, who had pure epithelial histologic findings and who did not require an implant had a median survival of 22.5 months and a 2-year survival rate of 41%.21 Thus pleurectomy /decortication seems to be a safer operation than extra pleural pneumonectomy. At this point it is unclear what treatment might lead to a better survival rate.
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8 Rusch, Piantadosi, Holmes
The conflicting information with respect to the impact of a wide variety of treatments on survival underscores our ignorance of the prognostic factors in this disease and the lack of a uniform TNM-based staging system. Cell type, sex, age, performance status, weight loss, duration and type of symptoms, ability to resect all gross disease, and platelet count have all been variously cited as prognostic factors. Among published series, the correlation of these factors with survival has been variable, but epithelial cell type and good performance status seem the most consistently predictive of a better outcome.v 7,12,22,23 Factors such as the type of symptoms or the ability to resect all gross disease may simply reflect the local extent of disease (i.e., the "T status" of the primary tumor) rather than be true prognostic factors. Although univariate analysis showed that cell type, platelet count, and performance status had a significant effect on survival or recurrence in our trial, none of these factors emerged as significant in a multivariate analysis. Our ability to design clinical trials and to evaluate the outcome of therapy will probably not improve until we are able to select a more homogeneous group of patients to study. In turn, this requires continued evaluation of possible prognostic factors and a better staging system than the one proposed by Butchart and associates'? in 1976 and still in use today. Of note are the patterns of recurrence and disease progression in this trial. Patients who underwent extrapleural pneumonectomy had the greatest tendency toward the development of distant disease. In the past mesothelioma was thought to be primarily a problem oflocally recurrent disease.i" More recently, though, several autopsy series have demonstrated that pleural mesothelioma is widely disseminated at the time of death. I 3, 25, 26 The patterns of progression and relapse in this trial underscore the fact that mesothelioma rapidly becomes a systemic disease, especially when control of local disease has been possible initially. Eventually, effective treatment regimens for malignant mesothelioma must address the problem of systemic disease as well. In summary, extrapleural pneumonectomy appears to be a treatment option for a minority of patients with malignant pleural mesothelioma. It retains a substantial morbidity and mortality. As the sole initial treatment for mesothelioma, it confers an overall survival similar to that reported previously even with adjuvant therapy, and it is no better than lesser operations such as pleurectomy. Although local recurrence can in patients who undergo extrapleural pneumonectomy, the disease tends to relapse mainly in distant sites. Extrapleural pneumonectomy may still be an appropriate treatment option for a very select group of patients with mesothelioma, but it does not
offer optimal treatment for the majority of patients with this disease. REFERENCES I, McDonald AD, McDonald rc. Epidemiology of malignant mesothelioma. In: Antman K, Aisner J, eds. Asbestosrelated malignancy. Orlando: Grune & Stratton, 1987:3155. 2. Shemin RJ. Surgical treatment of pleural mesothelioma. In: Antman K, Aisner J, eds. Asbestos-related malignancy. Orlando: Grune & Stratton, 1987:323-37. 3. Antman KH, Li FP, Osteen R, et al. Mesothelioma. Cancer Updates 1989;3:1-16. 4. Alberts AS, Falkson G, Goedhals L, Vorobiof DA, Van Der Merwe CA. Malignant pleural mesothelioma: a disease unaffected by current therapeutic maneuvers. J Clin Oncol 1988;6:527-34. 5. Brady LW. Mesothelioma-the role for radiation therapy. Semin OncoI1981;8:329-34. 6. McCormack PM, Nagasaki F, Hilaris BS, Martini N. Surgical treatment of pleural mesothelioma. J THoRAc CARDIOVASC SURG 1982;84:834-42. 7. Martini N, McCormack PM, Bains MS, Kaiser LR, Burt ME, Hilaris BS. Pleural mesothelioma. Ann Thorac Surg 1987;43:113-20. 8. Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81. 9. Mantel N, Haentzel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Nat! Cancer Inst 1958;22:719-48. 10. Cox DR. Regression models and life tables [With discussion]. J R Stat Soc B 1972;34:187-220. II. Martini N, Rusch VW. Comprehensive approach to diagnosis and management of pleural mesothelioma. In: Deslauriers J, ed. International trends in general thoracic surgery; vol 6. St. Louis: CV Mosby-Year Book [In press]. 12. Antman K, Shemin R, Ryan L, et al. Malignant mesothelioma: prognostic variables in a registry of 180 patients, the Dana Farber Cancer Institute and Brigham and Women's Hospital experience over two decades, 1965-1985. J Clin OncoI1988;6:147-53. 13. Ruffie P, Feld R, Minkin S, et al. Diffuse malignant mesothelioma of the pleura in Ontario and Quebec: a retrospective study of 332 patients. J Clin OncoI1989;7:115768. 14. Butchart EG, Ashcroft T, Barnsley WC, Holden MP. Pleuropneurrionectomy in the management of diffuse malignant mesothelioma of the pleura. Thorax 1976;31:1524. 15. Butchart EG, Surgery of mesothelioma of the pleura. In: Roth JA, Ruckdeschel JC, Weisenburger TH, eds. Thoracic oncology. Philadelphia: WB Saunders 1989;566-83. 16. DaValle MJ, Faber LP, Kittle CF, Jensik RJ. Extrapleural pneumonectomy for diffuse malignant mesothelioma. Ann Thorac Surg 1986;42:612-8.
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17. Ginsberg RJ, Hill LD, Eagan RT, et al. Modern thirty-day mortality for surgical resections in lung cancer. J THORAC CARDIOVASC SURG 1983;86:654-8. 18. Law MR, Gregor A, Hodson ME, Bloom HJG, TurnerWarwick M. Malignant mesothelioma of the pleura: a study of 52 treated and 64 untreated patients. Thorax 1984;39:255-9. 19. Hulks G, Thomas JS, Waclawski E. Malignant pleural mesothelioma in western Glasgow 1980-1986. Thorax 1989;44:496-500. 20. Worn H. Moglichkeiten und Ergebnisse der chirurgischen Behandlung des malignen Pleuramesothelioms. Thoraxchirurgie 1974;22:391-3. 21. Mychalczak BR, Nori 0, Armstrong JG, Martini N, Harrison LB. Results of treatment of malignant pleural mesothelioma with surgery, brachytherapy, and external beam irradiation. Proceedings of the Twelfth Mid-Winter Meeting of the American Endocurietherapy Society, Dec. 6-9, 1989. 22. Chahinian AP, Pajak TF, Holland JF, Norton L, Ambinder RM, Mandel EM. Diffuse malignant mesothelioma. Ann Intern Med 1982;96:746-55. 23. Adams VI, Krishnan KU, Muhm JR, Jett JR, Ilstrup OM, Bernatz PE. Diffuse malignant mesothelioma of pleura: diagnosis and survival in 92 cases. Cancer 1986;58: 154051. 24. Nauta RJ, Osteen RT, Antman KH, Koster JK. Clinical staging and the tendency of malignant pleural mesotheliomas to remain localized. Ann Thorac Surg 1982;34:6670. 25. Roberts HG. Distant visceral metastases in pleural mesothelioma. Br J Dis Chest 1976;70:246-50. 26. Adams VI, Unni KK. Diffuse malignant mesothelioma of pleura: diagnostic criteria based on autopsy study. Am J Clin Pat hoi 1984;82: 15-23.
Lung Cancer Study Group This study was conducted by the Lung Cancer Study Group (LCSG). The institutions and principal and co-principal investigators participating in this study included the following:Albany Medical College, Albany, N.Y.: John C. Ruckdeschel, MD, and Martin McKneally, MD, PhD. Fred Hutchinson Cancer Center, Seattle, Wash.: Lucius Hill, MD, Nevin Murray, MD, BillNelems, MD, and Valerie W. Rusch, MD. Hopital Laval, Quebec, Quebec, Canada: Jean Deslauriers, MD. Illinois Cancer Council, Chicago, Ill.: Paul Thomas, MD. Johns Hopkins Oncology Center, Baltimore, Md.: Steven Piantadosi, MD, PhD, (group statistician). UCLA, Los Angeles, Calif.: E. Carmack Holmes, MD, (group chairman), and Robert Figlin, MD. Universityof Colorado, Denver, Colo.: Michael Johnston, MD, and Paul Bunn, MD. University of Texas, San Antonio, Tex.: Frederick L. Grover, MD. University of Toronto, Toronto, Ontario, Canada: Ronald Feld, MD, and Robert Ginsberg, MD. Data management for this study was performed by Infor-
mation Management Services, Inc., Rockville, Md.: William H. Lake, Jr., Sherrill Long, and Barbara Harrington.
Discussion Dr. Haney Pass (Bethesda. Md.). Dr. Rusch has presented a carefully designed study to look at the natural history and surgical options in patients for mesothelioma, and the manuscript is going to serve as a reference for this disease in the future. The implications of the study are that extrapleural pneumonectomy will provide a longer disease-free survival but possibly not overall survival. The real differences between the two groups that had surgical options needs to be carefully examined. We have tried to increase total control after radical resection of pleural malignancies by using intraoperative photodynamic therapy along with radical surgical resection. Photodynamic therapy involvesthe use of a photosensitizer that is given to the patient before the operation. The activation of this sensitizer by light then causes cell death in order to try to increase local control after resection. We use a 0.02% intralipid base solution, after resection and debulking of disease to 5 mm thickness, to fill the chest and to use for light delivery. The light isdelivered from an argon pump dye laser by way of specially modified endotracheal tubes. Intralipid is also put into the ends of the endotracheal tubes, and then these actually serve as light bulbs. (Slide) The light is delivered to all aspects of the chest after radical resection of the tumor. We then treat to 1500 J /cm 2, a dose that is cytotoxic to lung cancer cells. We are now performing a phase I trial to define the maximum tolerated dose of light that we can deliver to the pleura after radical resection, leaving only 5 mm of debulked disease. I have two questions, Dr. Rusch. You have had considerable experience in managing these patients with this operation; you have mentioned the high mortality. Because you have completed your learning curve, are there certain ideas or techniques that you can impart to us that may be useful in the performance of this operation? Second, you mention that systemic disease is more prevalent in the patients with extra pleural pneumonectomy. Do you imply that the performance of the operation may in some way contribute to systemic disease, or is it that debulking is never achieved in your control group and the patients die of their local disease before the progressive systemic disease develops? Dr. Rusch. Dr. Pass, the work that you are doing currently is very exciting and may provide some new therapeutic leads in this disease. It may be applicable both after pleurectomy/decortication and after extrapleural pneumonectomy, and, therefore, may be useful in the majority of patients who have this disease. This is not a common operation, there is something of a learning curve to doing it, and lower mortality rates may be achievable with more stringent patient selection and perhaps in a single-institution setting. A close examination of the patterns of systemic disease will show that relapse occurs first in the patients treated by extrapleural pneumonectomy, predominantly in distant sites, but that relapse ultimately occurs in the other groups of patients as well. It is a matter of difference in timing, and I think it simply underscores that effective systemic treatment is needed as well in mesothelioma.
Number 1
July 1991
THORACIC AND CARDIOVASCULAR SURGERY The Journal of
J
THORAC CARDIOYASC SURG
1991;102:1-9
Original Communications
The role of extrapleural pneumonectomy in malignant pleural mesothelioma A Lung Cancer Study Group trial Malignant pleural mesothelioma is usually a fatal cancer for which operation has been the mainstay of treatment because chemotherapy and radiation are relatively ineffective. The choice of operation for malignant pleural mesothelioma remains controversial. Extrapleural pneumonectomy has been advocated because it allows complete removal of gross tumor and can be associated with long-tenn survival. To evaluate extrapleural pneumonectomy, we conducted a prospective muitiinstitutional trial in patients with biopsy-proved previously untreated malignant pleural mesothelioma. Criteria for extrapleural pneumonectomy were (1) potentially completely resectable unilateral disease by computed tomography scan, (2) predicted postresection forced expiratory volume in 1 second> 1 LIsee, and (3) no other major medical problems. Patients who were not candidates for extrapleural pneumonectomy had a more limited operation with or without adjuvant tberapy or had nonsurgical treatment From September 1985 to June 1988 83 eligible patients (64 male, 19 female) were entered. The mean age for all patients was 59.7 years. Only 20 of the 83 patients (24%) underwent extrapleural pneumonectomy. Three of these 20 patients (15%) died postoperatively. The recurrence-free survival was significantly longer for the patients undergoing extrapleural pneumonectomy than for the other two groups (p = 0.03), but there was no difference in overall survival among the three groups. In univariate analyses, epithelial versus sarcomatoid and mixed histologic findings and platelet count <400,000 were associated with a better overall survival (p = 0.02), and perfonnance status (Kamofsky <80) was
Valerie W. Rusch, MD (by invitation), New York, N.Y., Steven Piantadosi, MD, PhD (by invitation), Baltimore, Md., and E. Carmack Holmes, MD, Los Angeles, Calif.
From Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York, N.Y., the Department of Oncology Biostatistics,Johns Hopkins Oncology Center, Baltimore, Md., and the Department of Surgery, UCLA School of Medicine, Los Angeles, Calif. Supported by Grant CA 36045 from the National Cancer Institute.
Read at the Seventieth Annual Meeting of The American Association for Thoracic Surgery, Toronto, Ontario, Canada, May 7-9, 1990. Address for reprints: Valerie W. Rusch, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. 12/6/26077
2 Rusch, Piantadosi, Holmes
The Journal of Thoracic and Cardiovascular Surgery
predictive of recurrence (p = 0.02). In a multivariate analysis, histologic findings, sex, age, extrapleural pneumonectomy, weight loss, and performance status all bad no significant impact on survival. Extrapleural pneumonectomy was associated with a greater likelihood of relapse in distant sites tban were limited operation and nonsurgical treatment We conclude tbat (1) only a small proportion of aU patients with malignant pleural mesothelioma are candidates for extrapleural pneumonectomy, (2) extrapleural pneumonectomy carries a significant operative mortality and does not seem to improve overall survival compared with more conservative forms of treatment, (3) extrapleural pneumonectomy alters the patterns of relapse, and (4) factors previously thought to have an impact on survival in other series did not affect outcome in this trial.
Dffuse malignant pleural mesotheliomais an uncommon malignancy. Only 2000 to 3000 cases occur annually in the United States, 1 but it posesa significantproblem because there is no standard therapy for this usually fatal disease. All forms of treatment, and in particular the role of surgical resection,remain controversial.Some authors favor supportive care alone, and others advocate aggressive multimodality treatment combining extrapleural pneumonectomy with postoperative chemotherapy or radiation or both.' The assessment of any treatment regimen is compounded by the lack of formal TNM staging system and a poor understanding of the prognosticfactors in this disease. Because radiation and chemotherapy in mesothelioma are relatively ineffective in malignant mesothelioma.l? surgical resection has been considered the mainstay of treatment. Two very different operations have commonly been performed: pleurectomy/decortication and extrapleural pneumonectomy (also termed pleuropneumonectomy). Pleurectomy/decortication carries an operative mortality rate of 2% or less but is by definition an incomplete resection.s" It has been used alone for palliation, or with radiation or chemotherapy for treatment. Extrapleural pneumonectomy is theoretically attractive because it allows complete resection of all gross disease and has occasionally been associated with survival in excess of 2 years. It carries a higher risk than pleurectomy/ decortication, however, with reported operative mortality rates ranging from 9% to 30%.2 The Lung Cancer Study Group (LCSG) brought together several institutions that were geographically located in areas in which mesotheliomawas prevalent. In addition, the LCSG brought together a group of surgeons whose practice was dedicated to general thoracic surgery and who had collaborated extensively in previousclinical trials. The LCSG was therefore in an excellentpositionto perform clinical trials in malignant mesothelioma. As a first step, the LCSG decided to evaluate the role of extrapleural pneumonectomy.The aims of this initialtrial were to determine (1) what proportion of all patients with malignant mesothelioma might be candidates for extra-
pleural pneumonectomy,(2) the morbidity and mortality of this operation in a multiinstitutional setting, (3) the impact of this operation, in the absence of adjuvant postoperative treatment, on disease-freeand overallsurvival, and (4) the patterns of relapse.
Materials and methods Patients were eligible if they had biopsy-proved previously untreated malignant mesothelioma and did not have another active malignant tumor. The trial had two arms: an extrapleural pneumonectomy arm and a registry arm. The trial was approved bytheinstitutional review board ofeach oftheparticipating institutions, andinformed consent was obtained from all patients before entryin the study. Patients were candidates for the extrapleural pneumonectomyarmif (I) thetumor was confined toonehemithorax andthe preoperative computed tomographic (CT) scan indicated that extrapleural pneumonectomy would allow complete resection of all gross disease, (2) pulmonary function tests arid ventilation/ perfusion lung scan predicted a postresection forced expiratory volume in I second greater than I L/sec, and (3) the patients had nosignificant cardiovascular disease or other major medical problems. Extrapleural pneumonectomy was defined as en bloc resection of the parietal and mediastinal pleura, the lung, hemidiaphragm, and ipsilateral halfof the pericardium. Diaphragmatic and pericardiaI reconstruction was performed according to the surgeon's preference. Patients who underwent extrapleuraI pneumonectomy didnotreceive anyadditional treatment unless they developed recurrent disease. A baseline CT scan of the chest and upper portion of the abdomen was obtained 6 weeks postoperatively. Follow-up of the patients continued every 3 months by physical examination and CT scan of the chest and upper portion of the abdomen. Additional laboratory tests and scans were obtained as clinically indicated. If the patient was thought to have recurrent disease by examination or CT scan, anattemptwas made toobtain a confirmatory biopsy specimen. Patients deemed to have recurrent disease were treated at the discretion of their physician. Patients who were operated onwith the intent to perform an extrapleural pneumonectomy butwere found tohave anincompletely resectable tumor at thoracotomy were taken off-study from the extrapleural pneumonectomy arm and were followed intheregistry armofthetrial. These patients could then receive additional nonoperative treatment at the discretion of their physician. Patients who were not candidates for extrapleural pneu-
Volume 102
Malignant pleural mesothelioma
Number 1 July 1991
3
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monectorny were entered on the registry arm of the study and treated according to the preference oftheir physicians. Patients in this arm ofthe study were also given by serial physicalexaminations and CT scans of the chest and abdomen. The major statistical end point of this study was to estimate the postoperative recurrence and survival rates in patients with mesothelioma. Secondary objectives were to estimate the perioperativemorbidity and mortality and the importance of several prognostic factors on long-term outcome. Event time distributions were estimated by the product limit method.f The significance of categoric prognostic factors was assessed with the log rank statistic." and the significanceof continuously distributed factors was assessed in the proportional hazards regression model." Confidence limits on estimated proportions were determined by means of exact binomial methods. Results From September 1985 to June 1988, 86 patients were entered on study. Three patients were deemed ineligible because the final pathology review revealed metastatic adenocarcinoma. These three patients have therefore been excluded from analysis. None of them underwent an extrapleural pneumonectomy. Of the 83 eligible patients, 64 were male and 19 female. The mean age for the entire group was 59.7 years. Fifty-four patients (65%) had known asbestos exposure. At the time of this analysis, 77 of the 83 patients had had central review of their pathology slides to verify the mesothelioma cell type. Epithelial mesothelioma was seen in 34 patients (44.2%) and was the most common histologic finding. Twenty-nine patients (37.7%) had mixed findings histologically, whereas six (7.8%) had sarcomatoid mesothelioma and eight (10.3%) had an indeterminate cell type.
For the purposes of further analysis, the 83 patients were divided into three groups according to the type of surgical procedure performed: (1) complete resection of all gross disease by extrapleural pneumonectomy (EPP group); (2) incomplete resection of all gross disease by a more limited operation than extrapleural pneumonectomy, usually a pleurectomyjdecortication (LO group); (3) any surgical procedure performed strictly to obtain a biopsy specimen with no subsequent surgical treatment (NST group). The EPP group included 20 patients, the LO group 26 patients, and the NST group 37 patients. The mean ages in the groups were 56.7 years in the EPP group, 61.5 years in the LO group, and 61.1 years in the NST group. There was no significant difference in the mean age of the three groups. The reasons that patients did not undergo extrapleural pneumonectomy were as follows: concurrent medical problems severe enough to prohibit major surgery, eight patients (9.6%); extrathoracic tumor, nine patients (10.8%); inadequate pulmonary function, 27 patients (32.5%); and disease that was thought by the operating surgeon to be too locally advanced to allow complete resection, 45 patients (54.2%). Some patients had more than one reason that precluded extrapleural pneumonectomy. Of the twenty patients in the EPP group, three died postoperatively (15%, 95% confidence limits 3% to 38%). One patient died of multiple pulmonary emboli, and two died of respiratory failure that led to multisystem failure. Four patients, two in the group that died postoperatively and two in the group that survived, had a bronchial stump leak and associated empyema. All four patients had
The Journal of
4
Rusch. Piantadosi, Holmes
Thoracic and Cardiovascular Surgery
Surgical Group
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36 25 20
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3
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Fig. 2. Recurrence-free survival analyzed by surgical status for the 83 eligible patients. EPP. Extraplcural pneumonectomy.
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1000
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Fig. 3. Overall survival for all 83 eligible patients.
undergone a right pneumonectomy. Eight of the twenty patients (40%, 95% confidence limits 19% to 40%) developed arrhythmias that were severe enough to require medication. In one patient the arrhythmia was ventricular, while in seven patients it was atrial. One patient required reexploration to control postoperative bleeding. The median follow-up was 421 days in the EPP group, 301 days in the LO group, and 327 days in the NST group. The recurrence-free survival for all 83 patients is
shown in Fig. I, and the recurrence-free survival by surgical group is shown in Fig. 2. The recurrence rate per person-year was 0.616 in the EPP group, 1.48 in the LO group, and 1.63 in the NST group. The recurrence-free survival was significantly longer in the EPP group (p = 0.03) than in the other two groups. This difference in recurrence-free survival may not represent a true comparison of surgical effect because it was not adjusted for differences in prognostic factors.
Volume 102 Number 1
Malignant pleural mesothelioma
July 1991
>-
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37
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29
12 10 11
18 15
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Fig. 4. Overall survival analyzed by surgical status for the 83 eligible patients. EPP, Extrapleural pneumonectomy.
Table I. Initial sites of recurrent or progressive disease analyzed by operation status for the 83 eligible patients Biopsy only Diaphragm Chest wall
Mediastinum Pleura Ipsilateral lung Nodes Contralateral ehest Abdomen Other Second primary
3 15 3 10 I
3 3 3 4 0
Table II. All sites of disease at time of last follow-up analyzed by operation status for the 83 eligible patients
LO
EPP
4 9 4 9 3 1 3 3 7 1
1 4 3 I
0 5 5 5 6
0
The overall survival for the 83 eligible patients is shown in Fig. 3. The median survival for the entire group was 10 months (318 days). The survival by surgical group is illustrated in Fig. 4. The death rate per person-year was 0.545 in the EPP group, 0.757 in the LO group, and 0.807 in the NST group. The estimated proportion of patients survivingat 2 years was 33% in the EPP group (95% confidencelife table limits 14%to 54%),20% in the LO group (12% to 46%), and 18.5% in the NST group (8%to 32%). There was no significant difference in the death rates among the three groups (p > 0.05). Several factors were analyzed to determine whether they had any impact on recurrence-free or overall survival. These included cell type, sex, age, weight loss, performance status, platelet count, and extrapleural pneu-
Diaphragm Chest wall Mediastinum Pleura Ipsilateral lung Nodes Contralateral chest Abdomen Other Second primary
Biopsy only
LO
EPP
5 19 7 13 2 5
9 15 11 14 9 9
8
6
11 9 2
7 11 2
2 4 5 2 0 7 7 10 9 0
monectomy. In univariate analyses, epithelial histologic type conferred a better overall survival than did other cell types (p = 0.02). Elevated platelet count (>400,000) was associated with a significantly poorer survival (p = 0.04) but was not prognostic for recurrence. Performance status (Karnofsky scale <80) was predictive of recurrence but had no impact on survival. By multivariate analysis, however, none of these factors had any influence on recurrence-free or overall survival. The first sites of recurrent or progressive disease for each of the three groups of patients are shown in Table I. All of the sites of disease at the time of last follow-up are shown in Table II. To examine this from another perspective, we grouped diaphragm, chest wall, mediastinum, pleura, and ipsilateral lung together as locally
6
The Journal of Thoracic and Cardiovascular Surgery
Rusch, Piantadosi, Holmes
Table III. Number ofpatients who had local only, distant only, or local plus distant disease as their initial site of recurrent or progressive disease Biopsy only Local only Distant only Local plus distant
20 4 4
LO
EPP
13 3
2 6 5
6
recurrent disease, and nodes, contralateral chest, abdomen, and other were considered distant disease. Patients were then categorized according to whether disease developed locally, in distant sites,or in both localand distant sites. The number of patients who had recurrent or progressive disease in each area, both initiallyand at the time of last follow-up, is listed in Tables III and IV. Relapse occurred predominantly in distant sites in the EPP group, whereas initiallythe LO group and especiallythe NST group,had mainlyprogression oflocaldisease. Ultimately, though, distant disease developed in a large proportion of the LO and NST groups as well. Discussion
The role of surgical resection, and especially of extrapleural pneumonectomy, in the management of pleural mesothelioma is controversial. Most of the previously published series make it difficult to assess the impact of extrapleural pneumonectomy becausethey are retrospective,involve small numbers of patients treated overmany years, have unclear eligibility criteria for extrapleural pneumonectomy, and use highlyindividualized regimens of radiation or chemotherapy (or both) postoperatively.I- II The LCSG believed that extrapleural pneumonectomyshould be evaluated prospectively in a multiinstitutional setting where a large number of patients could be accrued over a short period of time. Thorough pathologic evaluation with immunohistochemistry or electron microscopy (or both) was required to exclude patients who had metastatic adenocarcinoma. Specific eligibility criteria for extrapleural pneumonectomy were set and included the routine use of CT scans for preoperativestaging.This provided an assessment of the applicabilityof extrapleural pneumonectomy to the overallpopulation of patients with malignant mesothelioma. Most important, the outcome of complete surgical resection alone was determined in the absence of adjuvant postoperative treatment. The patientsentered on this trial weremiddleaged and predominantly male. The majority of them had known asbestos exposure. This reflects the fact that several
Table IV. Number ofpatients who had local only, distant only, or local plus distant disease at time of last follow-up Biopsy only Local only Distant only Local plus distant
8 4
16
LO
EPP
9 I 12
0
5 8
LCSG-participating institutions are located in areas where there are asbestos mines or industries using large amounts of asbestos. Thus patients included in this study are similar to those in other series, and to patients with mesothelioma in general.I Becausemost other seriesare retrospective, it has been hard to determinewhat proportionof the total numberof patients with mesothelioma might truly be candidatesfor an extrapleural pneumonectomy. This proportion seems to vary strikinglyfrom one seriesto the next. In a 20-year review of patients with mesothelioma treated at the Dana Farber Cancer Institute, only 16 of 136 (11.7%) underwent extrapleural pneumonectomy.I? Likewise, in a 19yearcombinedexperience fromOntario and Quebec,only 23 of 332 (6.9%) patients underwent extrapleural pneumonectomy.P In contrast, 29 of 46 (63%) patients reported on by Butchart and colleagues 14, 15 and 33 of 56 (59%) patients reported on by DaValle and colleagues" qualified for extrapleural pneumonectomy. In our series only 20 of 83 (24%) patients underwent extrapleural pneumonectomy. The remainder did not meet the eligibility criteria becauseof either inadequate cardiopulmonary reserveor locally advanced disease. This is not surprising given the average age of these patients and their potential for underlying pulmonary disease related to smokingand asbestosexposure. Becauseall patients with mesothelioma seen at LCSG-participating institutions wereevaluatedprospectively and placedon thisstudy,the proportion of patients who are truly suitable for extrapleuralpneumonectomy ismorelikely to beaccurate than in retrospective series. Our data suggest that only a minority of patients with mesothelioma qualify for this operation at the time of diagnosis. The operativemortality of extrapleural pneumonectomy has alsovariedwidely. In the firstmajor seriesofthese operationsreported by Butchart and colleagues 14 in 1976, the operativemortality rate was 30%. Operative mortality rates have been lowerin more recent studies but have ranged from 10%to 20%in severalseries.i' 15 The lowest mortality rate to date has been 9% (3/33 patients) reported by DaValle and coworkers." Thus the mortal-
Volume 102 Number 1 July 1991
ity in this series is consistent with what has been described previously. The LCSG has previously reported a mortality rate of less than 7% for patients undergoing pneumonectomy for lung cancer.!? Thus our operative mortality for extra pleural pneumonectomy probably reflects the greater magnitude of the operation compared with a standard pneumonectomy rather than just the multiinstitutional nature of the study. Lower mortality rates may be achievable in a single institution if very stringent patient selection is used. To assess the impact of any treatment for mesothelioma, one must understand the natural history of the disease and the outcome after supportive care alone. Unfortunately such information is sparse. Assessment of treatment results is made even more difficult by the lack of a reproducible TNM-based staging system and by the highly individualized approach to treatment of mesothelioma. Law and coworkers" compared the outcome of64 patients treated with supportive care alone with that of 52 patients with clinically similar stage disease who received a variety of active treatments. There was no difference in survival between the two groups. The median survival from the onset of symptoms was 18 months, and seven patients survived more than 4 years." More recently Hulks, Thomas, and Waclawski'? reviewed the outcome of 68 patients managed with supportive care alone. The overall median survival was 30 weeks from the time of diagnosis. Patients who presented with pain had a median survivalof 22 weeks, whereas those who presented with dyspnea had a median survival of 44 weeks, probably reflecting the extent of disease at the time of diagnosis. The longer median survival reported by Law and coworkers" may represent the difference between measuring survival from the time of onset of symptoms compared with the time of diagnosis, since diagnosis is frequently delayed 3 months or more in patients with mesothelioma.13 Histologic findings did not affect survival in either of these two studies. Enthusiasm for any type of treatment must be tempered, therefore, with the knowledge that patients with mesothelioma can occasionally survive a year or more with supportive care alone. The operative morbidity and mortalityof extra pleural pneumonectomy is acceptable if it leads to prolonged survival. In the original reports by Butchart and associates.lv 15 only 9% (3/33 patients) survived 2 years or longer after extrapleural pneumonectomy. In the experience of Da Valle and coworkers," the 2-yearsurvival rate was 24% and the 3-year survival rate, 15% (5/33 patients). Half of the patients received adjuvant radiation or chemotherapy. Worn-? has also reported a series of 62 patients whose 2-year survival rate was 37% and 5-year survival rate was 10% after extrapleural
Malignant pleural mesothelioma 7
pneumonectomy. At the Dana Farber Cancer Institute, the 136 patients treated from 1965 to 1985 had a median survival of 16 months. The 14 patients who underwent extrapleural pneumonectomy and received postoperative chemotherapy appeared to have a significantly better survival.12 In the combined Ontario and Quebec review of 332 patients, the 23 patients who underwent extrapleural pneumonectomy did not have a better survival than the remainder of the group. Their 2-year survival rate was 17%.13 Thus the 2-year survival rate of 33% and median survival of 10 months seen after extrapleural pneumonectomy alone in our study are similar to what has been reported previously, even with adjuvant postoperative therapy. Comparison of the EPP group with the remainder of the study group is hazardous because this was not a randomized study. Nonetheless, the EPP group did not have a better overall survival even though they may have had more limited disease and may have been better-risk patients initially. The experience with extra pleural pneumonectomy can be contrasted with the experience with pleurectomyI decortication. Although the LO group in our trial includes mostly patients who had a pleurectomy/decortication, the study was not designed to evaluate this surgical procedure. We have not attempted to analyze this group in detail because it comprises a heterogeneous group of patients who underwent different surgical procedures and received various forms of treatment postoperatively. The largest and most uniform experience with pleurectomyI decortication, albeit retrospective, comes from the Memorial Sloan-Kettering Cancer Center. In a series of 64 patients operated on from 1972 to 1981, the operative mortality rate was 1.8%.6 All of the patients who had pleurectomy /decortication received postoperative external-beam radiation to the involved hemithorax. Radioactive implants were used to areas of gross residual disease that could not be resected by pleurectomy/decortication. From 1976 to 1988, 105 patients were treated in this manner. Forty-one patients received only external-beam radiation and 54 patients required both an implant and external-beam radiation. For the entire group, the median survival was 12.6 months, and the 2-year survival rate was 35%. Patients who required an implant of three or more sites had a median survival of 9,9 months and a 0% 2-year survival rate. A select group of 27 patients, however, who had pure epithelial histologic findings and who did not require an implant had a median survival of 22.5 months and a 2-year survival rate of 41%.21 Thus pleurectomy /decortication seems to be a safer operation than extra pleural pneumonectomy. At this point it is unclear what treatment might lead to a better survival rate.
The Journal of Thoracic and Cardiovascular Surgery
8 Rusch, Piantadosi, Holmes
The conflicting information with respect to the impact of a wide variety of treatments on survival underscores our ignorance of the prognostic factors in this disease and the lack of a uniform TNM-based staging system. Cell type, sex, age, performance status, weight loss, duration and type of symptoms, ability to resect all gross disease, and platelet count have all been variously cited as prognostic factors. Among published series, the correlation of these factors with survival has been variable, but epithelial cell type and good performance status seem the most consistently predictive of a better outcome.v 7,12,22,23 Factors such as the type of symptoms or the ability to resect all gross disease may simply reflect the local extent of disease (i.e., the "T status" of the primary tumor) rather than be true prognostic factors. Although univariate analysis showed that cell type, platelet count, and performance status had a significant effect on survival or recurrence in our trial, none of these factors emerged as significant in a multivariate analysis. Our ability to design clinical trials and to evaluate the outcome of therapy will probably not improve until we are able to select a more homogeneous group of patients to study. In turn, this requires continued evaluation of possible prognostic factors and a better staging system than the one proposed by Butchart and associates'? in 1976 and still in use today. Of note are the patterns of recurrence and disease progression in this trial. Patients who underwent extrapleural pneumonectomy had the greatest tendency toward the development of distant disease. In the past mesothelioma was thought to be primarily a problem oflocally recurrent disease.i" More recently, though, several autopsy series have demonstrated that pleural mesothelioma is widely disseminated at the time of death. I 3, 25, 26 The patterns of progression and relapse in this trial underscore the fact that mesothelioma rapidly becomes a systemic disease, especially when control of local disease has been possible initially. Eventually, effective treatment regimens for malignant mesothelioma must address the problem of systemic disease as well. In summary, extrapleural pneumonectomy appears to be a treatment option for a minority of patients with malignant pleural mesothelioma. It retains a substantial morbidity and mortality. As the sole initial treatment for mesothelioma, it confers an overall survival similar to that reported previously even with adjuvant therapy, and it is no better than lesser operations such as pleurectomy. Although local recurrence can in patients who undergo extrapleural pneumonectomy, the disease tends to relapse mainly in distant sites. Extrapleural pneumonectomy may still be an appropriate treatment option for a very select group of patients with mesothelioma, but it does not
offer optimal treatment for the majority of patients with this disease. REFERENCES I, McDonald AD, McDonald rc. Epidemiology of malignant mesothelioma. In: Antman K, Aisner J, eds. Asbestosrelated malignancy. Orlando: Grune & Stratton, 1987:3155. 2. Shemin RJ. Surgical treatment of pleural mesothelioma. In: Antman K, Aisner J, eds. Asbestos-related malignancy. Orlando: Grune & Stratton, 1987:323-37. 3. Antman KH, Li FP, Osteen R, et al. Mesothelioma. Cancer Updates 1989;3:1-16. 4. Alberts AS, Falkson G, Goedhals L, Vorobiof DA, Van Der Merwe CA. Malignant pleural mesothelioma: a disease unaffected by current therapeutic maneuvers. J Clin Oncol 1988;6:527-34. 5. Brady LW. Mesothelioma-the role for radiation therapy. Semin OncoI1981;8:329-34. 6. McCormack PM, Nagasaki F, Hilaris BS, Martini N. Surgical treatment of pleural mesothelioma. J THoRAc CARDIOVASC SURG 1982;84:834-42. 7. Martini N, McCormack PM, Bains MS, Kaiser LR, Burt ME, Hilaris BS. Pleural mesothelioma. Ann Thorac Surg 1987;43:113-20. 8. Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81. 9. Mantel N, Haentzel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Nat! Cancer Inst 1958;22:719-48. 10. Cox DR. Regression models and life tables [With discussion]. J R Stat Soc B 1972;34:187-220. II. Martini N, Rusch VW. Comprehensive approach to diagnosis and management of pleural mesothelioma. In: Deslauriers J, ed. International trends in general thoracic surgery; vol 6. St. Louis: CV Mosby-Year Book [In press]. 12. Antman K, Shemin R, Ryan L, et al. Malignant mesothelioma: prognostic variables in a registry of 180 patients, the Dana Farber Cancer Institute and Brigham and Women's Hospital experience over two decades, 1965-1985. J Clin OncoI1988;6:147-53. 13. Ruffie P, Feld R, Minkin S, et al. Diffuse malignant mesothelioma of the pleura in Ontario and Quebec: a retrospective study of 332 patients. J Clin OncoI1989;7:115768. 14. Butchart EG, Ashcroft T, Barnsley WC, Holden MP. Pleuropneurrionectomy in the management of diffuse malignant mesothelioma of the pleura. Thorax 1976;31:1524. 15. Butchart EG, Surgery of mesothelioma of the pleura. In: Roth JA, Ruckdeschel JC, Weisenburger TH, eds. Thoracic oncology. Philadelphia: WB Saunders 1989;566-83. 16. DaValle MJ, Faber LP, Kittle CF, Jensik RJ. Extrapleural pneumonectomy for diffuse malignant mesothelioma. Ann Thorac Surg 1986;42:612-8.
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17. Ginsberg RJ, Hill LD, Eagan RT, et al. Modern thirty-day mortality for surgical resections in lung cancer. J THORAC CARDIOVASC SURG 1983;86:654-8. 18. Law MR, Gregor A, Hodson ME, Bloom HJG, TurnerWarwick M. Malignant mesothelioma of the pleura: a study of 52 treated and 64 untreated patients. Thorax 1984;39:255-9. 19. Hulks G, Thomas JS, Waclawski E. Malignant pleural mesothelioma in western Glasgow 1980-1986. Thorax 1989;44:496-500. 20. Worn H. Moglichkeiten und Ergebnisse der chirurgischen Behandlung des malignen Pleuramesothelioms. Thoraxchirurgie 1974;22:391-3. 21. Mychalczak BR, Nori 0, Armstrong JG, Martini N, Harrison LB. Results of treatment of malignant pleural mesothelioma with surgery, brachytherapy, and external beam irradiation. Proceedings of the Twelfth Mid-Winter Meeting of the American Endocurietherapy Society, Dec. 6-9, 1989. 22. Chahinian AP, Pajak TF, Holland JF, Norton L, Ambinder RM, Mandel EM. Diffuse malignant mesothelioma. Ann Intern Med 1982;96:746-55. 23. Adams VI, Krishnan KU, Muhm JR, Jett JR, Ilstrup OM, Bernatz PE. Diffuse malignant mesothelioma of pleura: diagnosis and survival in 92 cases. Cancer 1986;58: 154051. 24. Nauta RJ, Osteen RT, Antman KH, Koster JK. Clinical staging and the tendency of malignant pleural mesotheliomas to remain localized. Ann Thorac Surg 1982;34:6670. 25. Roberts HG. Distant visceral metastases in pleural mesothelioma. Br J Dis Chest 1976;70:246-50. 26. Adams VI, Unni KK. Diffuse malignant mesothelioma of pleura: diagnostic criteria based on autopsy study. Am J Clin Pat hoi 1984;82: 15-23.
Lung Cancer Study Group This study was conducted by the Lung Cancer Study Group (LCSG). The institutions and principal and co-principal investigators participating in this study included the following:Albany Medical College, Albany, N.Y.: John C. Ruckdeschel, MD, and Martin McKneally, MD, PhD. Fred Hutchinson Cancer Center, Seattle, Wash.: Lucius Hill, MD, Nevin Murray, MD, BillNelems, MD, and Valerie W. Rusch, MD. Hopital Laval, Quebec, Quebec, Canada: Jean Deslauriers, MD. Illinois Cancer Council, Chicago, Ill.: Paul Thomas, MD. Johns Hopkins Oncology Center, Baltimore, Md.: Steven Piantadosi, MD, PhD, (group statistician). UCLA, Los Angeles, Calif.: E. Carmack Holmes, MD, (group chairman), and Robert Figlin, MD. Universityof Colorado, Denver, Colo.: Michael Johnston, MD, and Paul Bunn, MD. University of Texas, San Antonio, Tex.: Frederick L. Grover, MD. University of Toronto, Toronto, Ontario, Canada: Ronald Feld, MD, and Robert Ginsberg, MD. Data management for this study was performed by Infor-
mation Management Services, Inc., Rockville, Md.: William H. Lake, Jr., Sherrill Long, and Barbara Harrington.
Discussion Dr. Haney Pass (Bethesda. Md.). Dr. Rusch has presented a carefully designed study to look at the natural history and surgical options in patients for mesothelioma, and the manuscript is going to serve as a reference for this disease in the future. The implications of the study are that extrapleural pneumonectomy will provide a longer disease-free survival but possibly not overall survival. The real differences between the two groups that had surgical options needs to be carefully examined. We have tried to increase total control after radical resection of pleural malignancies by using intraoperative photodynamic therapy along with radical surgical resection. Photodynamic therapy involvesthe use of a photosensitizer that is given to the patient before the operation. The activation of this sensitizer by light then causes cell death in order to try to increase local control after resection. We use a 0.02% intralipid base solution, after resection and debulking of disease to 5 mm thickness, to fill the chest and to use for light delivery. The light isdelivered from an argon pump dye laser by way of specially modified endotracheal tubes. Intralipid is also put into the ends of the endotracheal tubes, and then these actually serve as light bulbs. (Slide) The light is delivered to all aspects of the chest after radical resection of the tumor. We then treat to 1500 J /cm 2, a dose that is cytotoxic to lung cancer cells. We are now performing a phase I trial to define the maximum tolerated dose of light that we can deliver to the pleura after radical resection, leaving only 5 mm of debulked disease. I have two questions, Dr. Rusch. You have had considerable experience in managing these patients with this operation; you have mentioned the high mortality. Because you have completed your learning curve, are there certain ideas or techniques that you can impart to us that may be useful in the performance of this operation? Second, you mention that systemic disease is more prevalent in the patients with extra pleural pneumonectomy. Do you imply that the performance of the operation may in some way contribute to systemic disease, or is it that debulking is never achieved in your control group and the patients die of their local disease before the progressive systemic disease develops? Dr. Rusch. Dr. Pass, the work that you are doing currently is very exciting and may provide some new therapeutic leads in this disease. It may be applicable both after pleurectomy/decortication and after extrapleural pneumonectomy, and, therefore, may be useful in the majority of patients who have this disease. This is not a common operation, there is something of a learning curve to doing it, and lower mortality rates may be achievable with more stringent patient selection and perhaps in a single-institution setting. A close examination of the patterns of systemic disease will show that relapse occurs first in the patients treated by extrapleural pneumonectomy, predominantly in distant sites, but that relapse ultimately occurs in the other groups of patients as well. It is a matter of difference in timing, and I think it simply underscores that effective systemic treatment is needed as well in mesothelioma.