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Ann Thorac Surg 1997;63:334-338
© 1997 The Society of Thoracic Surgeons

Original Article: General Thoracic

Patterns of Failure After Trimodality Therapy for Malignant Pleural Mesothelioma

Elizabeth Healey Baldini, MD, Abram Recht, MD, Gary M. Strauss, MD, Malcolm M. DeCamp, Jr, MD, Scott J. Swanson, MD, Michael J. Liptay, MD, Steven J. Mentzer, MD, David J. Sugarbaker, MD

Joint Center for Radiation Therapy, Division of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, and Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

Accepted for publication September 3, 1996.


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
Background. Malignant pleural mesothelioma is uncommon, and presently, no standard treatment of this disease exists. The objective of our analysis was to study the patterns of failure for malignant pleural mesothelioma after trimodality treatment consisting of extrapleural pneumonectomy, chemotherapy, and radiation therapy.

Methods. Between 1987 and 1993, 49 patients with malignant pleural mesothelioma underwent extrapleural pneumonectomy. There were two perioperative deaths, and 1 patient died 5 weeks after extrapleural pneumonectomy. Thirty-five of the surviving patients received adjuvant chemotherapy (32/35 received cyclophosphamide, doxorubicin, and cisplatin) followed by hemithorax radiation therapy. Ten patients received chemotherapy but no radiation therapy, and 1 patient received no adjuvant therapy. Median follow-up time for the 23 living patients from the date of operation was 18 months.

Results. Of the 46 evaluable patients, 25 had recurrence (54%), with a median time to first failure of 19 months (range, 5 to 51 months). The sites of first recurrence were local in 35% of patients, abdominal in 26%, the contralateral thorax in 17%, and other distant sites in 8%. (Some patients had recurrence in multiple sites simultaneously.)

Conclusions. The most common site of failure after trimodality therapy was the ipsilateral hemithorax. Isolated distant failures were uncommon. Future strategies should investigate methods of enhancing local tumor control.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
The incidence of diffuse malignant pleural mesothelioma continues to increase [1–3]. At the present time, no standard approach to the treatment of this disease exists. Recommended approaches range from supportive care only, to single-modality therapy (eg, operation or radiation therapy), to aggressive combinations of operation, radiation therapy (RT), and chemotherapy ("trimodality therapy") [4–10]. In the absence of randomized trials, it is not possible to define optimal treatment. However, careful review of the patterns of failure in retrospective and nonrandomized, prospective studies may help guide future therapeutic strategies.

At our institutions, an aggressive treatment plan was developed using cytoreductive extrapleural pneumonectomy (EPP), adjuvant chemotherapy, and consolidative RT. The purpose of this analysis was to define the patterns of failure after this trimodality treatment for malignant pleural mesothelioma.


   Material and Methods
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
Patients referred to Brigham and Women's Hospital or the Dana-Farber Cancer Institute with malignant pleural mesothelioma were considered for trimodality treatment. Patients were eligible for this treatment strategy if (1) pathology review confirmed a diagnosis of mesothelioma, (2) disease was confined to the ipsilateral chest (Butchart stage I) on preoperative evaluation with chest computed tomography and, after 1988, magnetic resonance imaging, (3) the disease appeared potentially resectable based on these radiologic studies, and (4) there were no medical contraindications to EPP. The details of the preoperative evaluation have been previously described [11]. Only patients with predicted postoperative forced expiratory volume in 1 second greater than 1 L, room air arterial carbon dioxide tension less than 45 mm Hg, oxygen tension greater than 65 mm Hg, an ejection fraction of greater than 0.45, and no significant comorbid disease remained eligible for EPP. In situations of equivocal radiologic evidence of mediastinal or abdominal involvement, thoracoscopy or laparoscopy was planned before definitive resection. Between January 1987 and June 1993, 49 patients fulfilled these criteria and underwent EPP with curative intent at the Brigham and Women's Hospital; these patients constitute the study population. Informed consent was obtained for each of the treatment modalities from all patients.

Surgical resection included en bloc removal of the lung, parietal pleura, ipsilateral pericardium, and ipsilateral diaphragm. The pericardium was reconstructed with a prosthetic patch for all right-sided procedures, and the diaphragm was reconstructed with prosthetic mesh for all cases. In addition, a limited resection was performed for previous biopsy or chest tube sites or areas of limited local tumor invasion. A description of the surgical technique has been published elsewhere [11].

Adjuvant chemotherapy began 4 to 6 weeks postoperatively and, for the majority of patients, consisted of cyclophosphamide, 600 mg/m2, doxorubicin, 60 mg/m2, and cisplatin, 70 mg/m2 (CAP). Chemotherapy was given every 3 weeks for four to six cycles. Among the 39 patients who received adjuvant CAP, a median of four cycles was delivered (range, one to eight cycles).

After chemotherapy, external-beam radiation therapy was delivered to 35 patients using linear accelerators that ranged in energy from 4 MV to 10 MV. Treatment fields included the ipsilateral hemithorax and mediastinum with a boost delivered to localized areas of previous bulk disease when possible. Radiation therapy consisted of a median dose to the hemithorax of 30.6 Gy (range, 20 to 41.4 Gy) and a median total dose to the boost region of 50 Gy (range, 25 to 59.4 Gy). (Nine patients did not receive boost treatment.)

After completion of trimodality treatment, patients were seen in follow-up every 3 to 4 months. Data on initial treatment, survival, recurrence, and complications were abstracted from the clinical records and through contact with local physicians. Sites of recurrence were categorized as involving the ipsilateral hemithorax (local), the contralateral thorax, the abdomen, or other (distant) sites. Recurrence was scored as present when detected by computed tomography or magnetic resonance imaging or on physical examination. Confirmatory histologic or cytologic evidence of recurrence was available for the majority of patients, but this was not required to score a patient as having a recurrence.

Survival and freedom from disease progression were calculated from the date of operation and estimated by the Kaplan-Meier method [12]. Proportions were compared with Fisher's exact test [13].


   Results
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 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
The median age of the 49 patients was 55 years (range, 27 to 69 years). There were 37 men (76%) and 12 women (24%). The histology was epithelial for 35 (71%), sarcomatoid for 3 (6%), and mixed epithelial and sarcomatoid for 11 (22%). All but 3 patients underwent a gross total resection. Two patients were thought to have minimal residual disease involving the chest wall, and 1 patient was noted to have small tumor excrescences on the peritoneal surface. Resection margins were microscopically positive in 30 patients (61%) and negative in 19 (39%). Histologic lymph node status was positive for 14 (29%) and negative for 33 (67%). In 2 patients, no lymph nodes were present in the resection specimen.

There were two perioperative deaths (4%), both of which occurred on the ninth postoperative day. One patient died of multiple pulmonary emboli, and 1 of adult respiratory distress syndrome. An additional patient died at home 5 weeks postoperatively of an unknown cause. Thus, 46 of the 49 patients were eligible for adjuvant therapy. Thirty-five of the 46 patients (76%) received EPP, chemotherapy, and RT; 10 patients received EPP and chemotherapy; and 1 patient received no adjuvant therapy. Among the 45 patients who received chemotherapy, 39 (87%) received CAP. Eleven patients did not receive RT for the following reasons: progressive chest and abdominal disease developing during chemotherapy (3), respiratory compromise after chemotherapy (2), cardiomyopathy after chemotherapy (1), herniation of bowel into chest (2), history of prior RT for Wilms' tumor (1), and patient refusal (2). The median follow-up time for the living patients was 18 months (range, 7 to 64 months).

The median survival for all 49 patients was 22 months (range, 0 to 64 months), and the median length of freedom from disease progression was 19 months (range, 2 to 64 months). At 3 years, the actuarial survival rate was 34% ± 17%, and the rate of freedom from disease progression was 33% ± 18%. The median time to relapse for the 35 patients who received all three treatment modalities was 20 months, and for the 11 patients who did not receive all three modalities, it was 11 months. However, there was no difference in median survival between these groups.

There were 25 patients who recurred among the 46 evaluable patients (54%), with a median time to first recurrence of 19 months. Nineteen (76%) of the recurrences were confirmed by histologic or cytologic assessment. The remaining cases were determined by radiologic imaging studies and physical examination. The sites of first recurrence are listed in Table 1Go and included a local component for 16 patients, an abdominal component for 12, a component in the contralateral thorax for 8, and a distant component for 2. Six patients (25%) experienced local recurrence only. Local sites of recurrence included incision and skin (8), chest wall (4), reconstructed diaphragm (1), pericardium (1), neo-pleura and pericardium (1), and neo-pleura, pericardium, and diaphragm (1). The abdominal sites of recurrence included retroperitoneal adenopathy or mass (4), chest mass extending into the abdomen (3), ascites (2), chest mass extending into the abdomen plus ascites (2), and peritoneal nodules (1). The sites of recurrence in the contralateral hemithorax included malignant effusion (3), pleura (1), pericardium (1), mediastinum plus pleura (1), diaphragm, pleura, and effusion (1), and chest wall mass (1). The two sites of distant recurrence both involved the central nervous system: brain parenchyma and carcinomatous meningitis in 1 patient each. Survival after relapse was short. Twenty-one of the 25 patients who experienced a recurrence have died with a median time from relapse to death of 3 months (range, 0 to 24 months). Three patients are alive with disease at 0, 1, and 9 months from the time of relapse. One patient who experienced a local-only recurrence in the incision is alive without disease 6 months from the time of initial relapse after treatment with operation and RT.


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  		Table 1. . Sites of First Recurrence After Trimodality Therapy for Malignant Pleural Mesotheliomaa
 
Table 2Go describes the delivery of RT according to resection margin status. There was a somewhat greater proportion of patients with positive resection margins in the group that received RT than in the group that did not (23/35 [66%] versus 5/11, [45%]; p = not significant). Despite this, the local recurrence rate was somewhat lower among patients who received RT compared with those who did not (Table 3Go). Table 4Go presents an analysis of the risk of local recurrence according to both resection margin status and whether or not patients received RT. Among patients with positive resection margins, the local recurrence rate was lower for those who received RT than for those who did not. Among patients with negative resection margins, no consistent benefit of RT was found. Analysis of local failure according to dose of RT delivered (both first course and total dose) failed to show a dose-response effect. Furthermore, analyses of recurrence and specific patterns of recurrence according to histology and lymph node status showed no statistically significant differences among groups (data not shown).


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  		Table 2. . Delivery of Radiotherapy According to Resection Margin Status (n = 46)
 

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  		Table 3. . Local Recurrence as First Site of Failure According to Delivery of Radiation Therapy (n = 46)
 

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  		Table 4. . Local Recurrence as First Site of Failure According to Resection Margin Status and Delivery of Radiation Therapy (n = 46)a
 
In addition to the three deaths (two perioperative and one 5 weeks after EPP), treatment morbidities related to the operation included reversible atrial fibrillation (11 patients), herniation of abdominal contents into the chest (5), and a bronchopleural fistula (1). Grade 3 or 4 chemotherapy morbidity included fever and neutropenia (6 patients), nausea/vomiting (4), respiratory compromise (2), cardiomyopathy (1), and neurotoxicity (1). Radiotherapy morbidities that required a break in treatment included thrombocytopenia (3 patients) and esophagitis (1). Other morbidities not attributed to a single treatment modality included respiratory compromise (5 patients, with one fatal pneumonia), depression (3), cardiac toxicity (2), and gastrointestinal toxicity (2).


   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
In this series of 49 patients treated with EPP, CAP chemotherapy, and RT median survival was 22 months and 3-year survival was 34%. Although outcome comparisons of different series can be fraught with multiple biases, the survival observed in our population compares favorably with those of most other reported series. Rusch and associates [7] described a 3-year survival rate of about 30% among 20 patients treated with EPP alone. Rice and colleagues [8] reported a 3-year survival rate of 22% among 10 patients treated with EPP and 9 treated with pleurectomy followed by intrapleural chemotherapy and subsequent systemic chemotherapy. DaValle and associates [14] reported a 3-year survival rate of 15% for 33 patients treated with EPP with or without adjuvant chemotherapy or RT.

Moreover, the morbidity and mortality of these treatment modalities have diminished over time. For example, the low perioperative mortality rate of 6% in this series is comparable with the rates of 15%, 5%, and 9% in the Rusch, Rice, and DaValle series, respectively. All represent a significant improvement compared with rates as high as 31% described in earlier series [15].

About one half of the evaluable patients in this series had recurrence. The predominant site of first failure was within the ipsilateral hemithorax (67% of all recurrences). Abdominal failures, recurrences in the contralateral hemithorax, and recurrences at other sites occurred less frequently. Interestingly, both distant recurrences were in the central nervous system.

These specific categories of recurrence provide important insights into the mechanisms and routes of disease dissemination. Disease detected in the contralateral hemithorax or abdomen most likely results from contiguous spread or tumor seeding from the primary disease process. De novo or multifocal malignant mesothelioma arising in the opposite pleura or abdomen, or lymphatic/hematogenous spread to these neighboring sites, is also possible, but less likely. Conversely, disease recurrence in bone, brain, or other "distant" organs much more likely represents hematogenous or lymphatic spread of the primary disease.

Other investigators have reported patterns of failure among groups of patients treated with strategies other than EPP, chemotherapy, and RT. Rusch reported patterns of failure for a group of nonrandomized patients treated with EPP (n = 20), more limited operation (primarily pleurectomy, n = 26), or biopsy only (n = 37) in a Lung Cancer Study Group trial [7]. No adjuvant treatment was delivered to those patients who underwent EPP, and details of adjuvant treatment administered to the latter two treatment groups were not provided. In the EPP group, 13 of 17 evaluable patients (76%) experienced a recurrence. The high rates of recurrence seen in the ipsilateral hemithorax, abdomen, and contralateral thorax are similar to those seen in the current series (Table 5Go). However, failures in other distant sites were seen in 35% of patients, compared with 8% of patients in the current series. It is possible that the use of systemic chemotherapy in the current series accounts for the lower rate of distant recurrence that we observed.


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  		Table 5. . Comparison of Patterns of Failure After Extrapleural Pneumonectomy With or Without Adjuvant Therapy in Three Series
 
Rice and colleagues [8] reported a series of 19 patients treated at the Cleveland Clinic hospitals with either EPP (10) or pleurectomy and decortication (9) followed by intrapleural cisplatin with or without mitomycin C. Fifteen of the patients received subsequent cisplatin-based systemic chemotherapy. Twelve of the 18 evaluable patients had recurrence (67%). The patterns of failure were reported as local for 10 (56%) and distant for 5 (28%). Overall, 83% of recurrences were local, and 42% of recurrences were "distant" (see Table 5Go). However, the relative distribution of recurrences within the abdomen and contralateral thorax as opposed to other distant sites was not stated. The high local recurrence rate seen in this report may be related to the fact that half of the patients received pleurectomy rather than EPP and that no RT was delivered; alternatively, apparent differences in local recurrence rates between this series and others may be an artifact of small patient numbers and other patient differences.

In the current phase II trial, it was not possible to separate the relative contributions of any single treatment modality to outcome. Seventy-one percent of patients completed the planned treatment course and received RT. Subset analysis comparing the patients who did and did not receive RT is fraught with potential biases. Nonetheless, there was a suggestion of improved local control for those patients who received RT, especially in the situation of positive resection margins. There was also a suggestion of a prolonged time to relapse for patients who received all three treatment modalities.

Several retrospective studies have suggested a potential role for RT in the treatment of mesothelioma [16–18]. However, perhaps an equal number of reports have failed to demonstrate the utility of RT for the treatment of this disease [4, 19, 20]. The fact that trials varied greatly regarding indications for RT, RT doses, and RT treatment volumes makes it impossible to make a definitive assessment of the benefit of RT in malignant pleural mesothelioma based on the current literature. Furthermore, a significant obstacle to the delivery of effective RT doses is the fact that several radiosensitive normal organs lie within the target volume. Specifically, these normal structures include the remaining lung, heart, liver, spinal cord, and, in the absence of a reconstructed diaphragm, displaced intestines. If positive resection margins or residual gross disease overlie these critical organs, radiation doses must often be compromised to avoid undue risks of toxicity.

In conclusion, these data suggest that selected patients can obtain up to a 34% 3-year survival rate after trimodality treatment for malignant pleural mesothelioma confined to the hemithorax. The predominant pattern of failure after this treatment is local. Future treatment strategies should attempt to improve local control. Possible avenues to explore include the use of radiation modifiers, concurrent administration of RT and chemotherapy, intrapleural chemotherapy, and the delivery of RT at an earlier point in the treatment program.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 
Address reprint requests to Dr Baldini, Joint Center for Radiation Therapy, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.


   References
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

  1. McDonald AD, McDonald JC. Epidemiology of malignant mesothelioma, In: Antman K, Aisner J, eds. Asbestos-related malignancy. Orlando: Grune & Stratton, 1987:31-55.
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  7. Rusch VW, Piantadosi S, Holmes EC. The role of extrapleural pneumonectomy in malignant pleural mesothelioma. A Lung Cancer Study Group trial. J Thorac Cardiovasc Surg 1991;102:1–9.[Abstract]
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 Ann. Thorac. Surg.Home page
J. H. Schouwink, L. Schultze Kool, E. J. Rutgers, F. A. N. Zoetmulder, N. van Zandwijk, M. J. v.d. Vijver, and P. Baas
The value of chest computer tomography and cervical mediastinoscopy in the preoperative assessment of patients with malignant pleural mesothelioma
Ann. Thorac. Surg., June 1, 2003; 75(6): 1715 - 1718.
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 Ann. Surg. Oncol.Home page
W.R. Smythe and P.F. Mansfield
Hyperthermia: Has Its Time Come?
Ann. Surg. Oncol., April 1, 2003; 10(3): 210 - 212.
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 ChestHome page
S. van Ruth, P. Baas, and F. A. N. Zoetmulder
Surgical Treatment of Malignant Pleural Mesothelioma: A Review
Chest, February 1, 2003; 123(2): 551 - 561.
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 J. Thorac. Cardiovasc. Surg.Home page
H. I. Pass
Pleural mesothelioma in 2002: Going somewhere very slowly
J. Thorac. Cardiovasc. Surg., December 1, 2002; 124(6): 1074 - 1077.
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P. Bonnette, G. B. Heckly, S. Villette, A. Fragola, J. H. Schouwink, and P. Bass
Intraoperative Photodynamic Therapy After Pleuropneumonectomy for Malignant Pleural Mesothelioma
Chest, November 1, 2002; 122(5): 1866 - 1867.
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 Eur. J. Cardiothorac. Surg.Home page
T. Aziz, A. Jilaihawi, and D. Prakash
The management of malignant pleural mesothelioma; single centre experience in 10 years
Eur. J. Cardiothorac. Surg., August 1, 2002; 22(2): 298 - 305.
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 CarcinogenesisHome page
G. J. Gordon, K. Appasani, J. P. Parcells, N. K. Mukhopadhyay, M. T. Jaklitsch, W. G. Richards, D. J. Sugarbaker, and R. Bueno
Inhibitor of apoptosis protein-1 promotes tumor cell survival in mesothelioma
Carcinogenesis, June 1, 2002; 23(6): 1017 - 1024.
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 Am. J. Respir. Cell Mol. Bio.Home page
X. X. Cao, I. Mohuiddin, F. Ece, D. J. McConkey, and W. R. Smythe
Histone Deacetylase Inhibitor Downregulation of bcl-xl Gene Expression Leads to Apoptotic Cell Death in Mesothelioma
Am. J. Respir. Cell Mol. Biol., November 1, 2001; 25(5): 562 - 568.
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V. W. Rusch, K. Rosenzweig, E. Venkatraman, L. Leon, A. Raben, L. Harrison, M. S. Bains, R. J. Downey, and R. J. Ginsberg
A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma
J. Thorac. Cardiovasc. Surg., October 1, 2001; 122(4): 788 - 795.
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 ChestHome page
H. Schouwink, E. T. Rutgers, J. van der Sijp, H. Oppelaar, N. van Zandwijk, R. van Veen, S. Burgers, F. A. Stewart, F. Zoetmulder, and P. Baas
Intraoperative Photodynamic Therapy After Pleuropneumonectomy in Patients With Malignant Pleural Mesothelioma : Dose Finding and Toxicity Results
Chest, October 1, 2001; 120(4): 1167 - 1174.
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R. Bueno, K. Appasani, H. Mercer, S. Lester, and D. Sugarbaker
The {{alpha}} folate receptor is highly activated in malignant pleural mesothelioma
J. Thorac. Cardiovasc. Surg., February 1, 2001; 121(2): 0225 - 233.
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 Ann. Thorac. Surg.Home page
V. W. Rusch and E. S. Venkatraman
Important prognostic factors in patients with malignant pleural mesothelioma, managed surgically
Ann. Thorac. Surg., November 1, 1999; 68(5): 1799 - 1804.
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M. Metintas, N. Ozdemir, I. Ucgun, O. Elbek, M. Kolsuz, S. Mutlu, and S. Metintas
Cisplatin, Mitomycin, and Interferon-{alpha}2a Combination Chemoimmunotherapy in the Treatment of Diffuse Malignant Pleural Mesothelioma
Chest, August 1, 1999; 116(2): 391 - 398.
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D. H. Sterman, L. R. Kaiser, and S. M. Albelda
Advances in the Treatment of Malignant Pleural Mesothelioma
Chest, August 1, 1999; 116(2): 504 - 520.
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 J. Thorac. Cardiovasc. Surg.Home page
G. B. Ratto, D. Civalleri, M. Esposito, E. Spessa, A. Alloisio, F. D. Cian, and M. O. Vannozzi
PLEURAL SPACE PERFUSION WITH CISPLATIN IN THE MULTIMODALITY TREATMENT OF MALIGNANT MESOTHELIOMA: A FEASIBILITY AND PHARMACOKINETIC STUDY
J. Thorac. Cardiovasc. Surg., April 1, 1999; 117(4): 759 - 765.
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D. J. Sugarbaker, R. M. Flores, M. T. Jaklitsch, W. G. Richards, G. M. Strauss, J. M. Corson, M. M. DeCamp Jr, S. J. Swanson, R. Bueno, J. M. Lukanich, et al.
RESECTION MARGINS, EXTRAPLEURAL NODAL STATUS, AND CELL TYPE DETERMINE POSTOPERATIVE LONG-TERM SURVIVAL IN TRIMODALITY THERAPY OF MALIGNANT PLEURAL MESOTHELIOMA: RESULTS IN 183 PATIENTS
J. Thorac. Cardiovasc. Surg., January 1, 1999; 117(1): 54 - 65.
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