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Ann Thorac Surg 1997;63:334-338
© 1997 The Society of Thoracic Surgeons
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.
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Abstract |
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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.
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Introduction |
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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.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentReferences |
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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].
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Results |
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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 1
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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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 3). Table 4 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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Comment |
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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 5). 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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). 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.
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T. L. Moskal, T. J. Dougherty, J. D. Urschel, J. G. Antkowiak, A.-M. Regal, D. L. Driscoll, and H. Takita Operation and photodynamic therapy for pleural mesothelioma: 6-year follow-up Ann. Thorac. Surg., October 1, 1998; 66(4): 1128 - 1133. [Abstract] [Full Text] [PDF]
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H. I. Pass, B. K. Temeck, K. Kranda, S. M. Steinberg, and I. R. Feuerstein Preoperative Tumor Volume Is Associated With Outcome In Malignant Pleural Mesothelioma J. Thorac. Cardiovasc. Surg., February 1, 1998; 115(2): 310 - 318. [Abstract] [Full Text]
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