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J Thorac Cardiovasc Surg 1995;110:119-129
© 1995 Mosby, Inc.
GENERAL THORACIC SURGERY |
Santa, Monica, Calif.
Supported by grants CA 12582 and CA 29605 from the National Cancer Institute and by the Joyce and Ben Eisenberg Foundation, Los Angeles, Calif.
Address for reprints: Donald L. Morton, MD, John Wayne Cancer Institute, 2200 Santa Monica Blvd., Santa Monica, CA 90404.
Abstract
Although melanoma that metastasizes to distant sites is generally associated with a median survival of only 6 to 8 months, certain metastatic sites including the lung may carry a better prognosis than others. Surgical therapy for pulmonary metastases remains controversial because of the variable survival rates reported for previous small series. To determine the prognosis and optimal management of patients with melanoma with pulmonary metastases, we reviewed our 22-year melanoma database of over 6100 patients. Of 984 patients with metastatic melanoma involving the lung or thorax, 106 underwent resection by posterior lateral thoracotomy or median sternotomy. There were no operative deaths, and the median follow-up period for surgical patients was 55 months. The remaining 878 patients were treated without operation with immunotherapy, chemotherapy, radiation therapy, or a combination. In both treatment groups the male/female ratio was approximately 2:1. The primary lesion's Clark level of invasion and Breslow thickness and the patient's age at diagnosis of metastatic disease were not significantly different between the two groups. The 1-year, 3-year, and 5-year survival rates for surgical patients were 77%, 37%, and 27%, respectively, compared with 32%, 7%, and 3% for nonsurgical patients; these differences were highly significant (p = 0.0001). The highest 5-year survival rate (39%) occurred in those patients with a single metastatic lesion. Sixty-three percent of the surgical patients received some form of immunotherapy, compared with 34% of the nonsurgical patients. Multivariate analysis showed that resection and immunotherapy with a melanoma cell vaccine were both independent predictors of survival (p < 0.0001). These results indicate that the prognosis associated with metastatic melanoma may be less dismal than previously thought when distant metastases involve thoracic sites. We believe that surgical resection is the treatment of choice for patients with melanoma with pulmonary metastases; when combined with immunotherapy, this regimen offers the best chance for long-term survival. (J THORACCARDIOVASCSURG1995;110:119-29)
Patients with melanoma metastatic to distant sites usually have a poor prognosis. It is commonly assumed that melanoma follows the pattern of other carcinomas such as breast cancer, in which signs of distant spread usually indicate disseminated disease that requires systemic therapy rather than local treatment. However, a number of reports have shown that metastatic melanoma can be unpredictable and that some patients can survive for extended periods after resection of distant metastases.
1-6
These findings point toward reevaluation of the role of surgical resection in the management of patients with melanoma with advanced disease.
Thoracotomy for resection of metastatic disease is credited to Sedilott in 1885, 7 but the procedure was first performed withcurative intent by Barney and Churchill 8 in 1939. In the early 1940s, Alexander and Haight 9 described their results in 24 patients undergoing surgical resection of pulmonary metastases; their short-term survival data generated enthusiasm for surgical intervention in these patients. However subsequent studies reported that although thoracotomy improved the survival of some patients with carcinomas and sarcomas, patients with melanoma fared the worst. 10-17 More recent studies examining the role of thoracotomy specifically in patients with metastatic melanoma report variable survival rates. 1, 2, 10, 15, 16, 18-22 Like preceding studies, however, these studies have relatively few patients. The Duke experience reported by Harpole and colleagues 22 is the largest study to date, and its overall 5-year survival rate of 20% provides some optimism for the surgical management of patients with melanoma metastatic to the lung.
In 1988 we reported a 25% 5-year survival rate for 47 patients undergoing resection of melanoma metastatic to the lung. 1 This rate, the highest yet reported in this group of patients with melanoma, reflected strict selection criteria: tumor doubling time (TDT) more than 40 days, limited number of pulmonary metastatic sites, documented absence of extrapulmonary intrathoracic disease, and long disease-free interval. Because survival was excellent, we subsequently relaxed these selection criteria to study the results for a less rigidly selected operative group. We undertook the present study to determine the survival rate associated with less stringent selection criteria and to identify selection criteria associated with improved survival after aggressive surgical resection of pulmonary and thoracic metastases. Thus our first objective was to define more clearly the role of thoracotomy in the treatment of patients with melanoma with pulmonary metastases.
In 1985 we began clinical trials of our new polyvalent melanoma cell vaccine (MCV), 23 a highly immunogenic preparation consisting of irradiated cells from three human melanoma lines. The success of MCV in a phase II trial of patients with melanoma with regional and distant metastases prompted its routine application as a postoperative adjuvant therapy. Thus our second objective was to determine the impact of MCV adjuvant immunotherapy on the long-term prognosis of patients with melanoma undergoing surgical resection of pulmonary metastases.
PATIENTS AND METHODS
We reviewed the clinical records of 6129 patients with melanoma treated by the staff of the John Wayne Cancer Institute (JWCI) during the 22-year period from 1971 through 1993. These records were coded and entered into JWCI's computerized database developed to follow up patients with melanoma.
Of 2167 patients with melanoma with distant metastases, 984 patients had pulmonary involvement; 106 of 984 (11%) underwent surgical resection of pulmonary metastases, and 117 operations were performed. The median follow-up period from diagnosis of the primary disease was 55 months for surgically treated patients and 33 months for nonsurgically treated patients. The period of follow-up observation after development of pulmonary metastases was shorter: 17 and 7 months for nonsurviving surgical and nonsurgical patients, respectively, and 27 and 11 months for surviving surgical and nonsurgical patients, respectively. Mean age at diagnosis of pulmonary metastases was 52 and 51 years for surgical and nonsurgical patients, respectively. There were 66 male patients (62%) and 40 female patients (38%) in the surgical group, and 584 male patients (67%) and 294 female patients (33%) in the nonsurgical group.
The characteristics of the primary tumor (location, histologic type, thickness, level of invasion) and the type of operative/nonoperative treatment for metastatic disease were recorded in detail for each case. Thoracotomies were classified as wedge resection, lobectomy, pneumonectomy, or other (i.e., thoracoscopic resection, mediastinal dissection/resection, and resection of an unspecified amount of pulmonary or mediastinal tissue). The presence of extrapulmonary intrathoracic disease was determined, as well as the number of pulmonary lesions and whether all sites of metastatic disease were resected. TDT was calculated before operation, according to a previously described technique, 24 or determined retrospectively by review of radiographs and tumor measurements.
Many of these patients participated in adjuvant immunotherapy protocols, receiving nonspecific immunotherapy with bacille Calmette-Guerin vaccine, immunization with a tumor cell vaccine, or active specific immunotherapy with the new polyvalent MCV. 25 Administration of these immunotherapies is described elsewhere. 26, 27 We examined the impact of postoperative adjuvant immunotherapy on the survival of patients with melanoma.
Statistical analyses
Survival time was defined as the months a patient remained alive after documented lung metastases. Estimated survival rates were obtained with the nonparametric Kaplan-Meier method. The log-rank test was used to determine the difference in survival curves among subgroups of patients, and statistical significance was defined as an alpha level of 0.05. Multivariate analysis was modeled under the Cox proportional hazards technique. Any variable not statistically significant according to univariate analysis was excluded from the multivariate model. The statistical package of SAS procedures LIFETEST and PHREG software (SAS Institute, Inc., Cary, N.C.) was used for univariate and multivariate analyses. The standard 
2 statistic compared prognostic variables in surgical and nonsurgical groups, and a standard t test compared disease-free survival in the treatment groups. (Disease-free survival was defined as the disease-free interval between treatment of primary lesion/nodal metastases to diagnosis of pulmonary metastases.) SAS procedures FREQ and TTEST software (SAS Institute) were used to calculate the 2 and t test statistics, respectively.
RESULTS
Risk of pulmonary metastases
Table I shows the 3-, 5-, 10-, 15-, and 20-year risk of developing pulmonary metastases in all 6129 melanoma database patients and in a subgroup used to examine the natural history of melanoma metastatic to the lungs. This subgroup included all patients treated at JWCI within 4 months of diagnosis; it excluded patients presenting to JWCI staff with metastatic disease and those with unknown primary disease. Thus, the 5-year risk of pulmonary metastases developing is 10%; after 5 years the risk is about 13% per year. Cox multivariate regression analysis showed that the following factors increased the risk of pulmonary metastases (Table II): male gender, increasing thickness and invasion of the primary tumor, increasing age of the patient, nodular histologic status of the tumor, and nodal metastases.
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The majority of patients had pulmonary involvement: 68 patients (68%) had isolated pulmonary metastases, and 26 (26%) had pulmonary metastases plus nonpulmonary intrathoracic metastases. Only four patients had disease confined to extrapulmonary intrathoracic sites. The mean number of lung metastases was two (range 1 to >10); 56 patients (52%) had one metastasis, 23 (22%) had two to three, and 28 (26%) had more than 3. The most common technique of resection was posterior lateral thoracotomy (108 procedures); in addition, eight median sternotomies and one thoracoscopic resection were performed.
Of the 106 patients, 65 underwent removal of all visible tumor; the remaining 41 had an incomplete or unknown amount of tumor removed during the first surgical procedure.
Surgical mortality and morbidity
Surgical mortality for the 117 procedures was zero. The most common postoperative complications were pulmonary edema requiring reintubation (three patients) and cardiac arrhythmia (three patients). Other problems included bleeding requiring reoperation (two patients) and massive tissue emphysema requiring replacement of chest tubes (one patient).
Survival with surgical therapy
Univariate analysis identified the number of lung metastases, the presence of extrapulmonary metastases, and the TDT as significant variables affecting the prognosis of patients with melanoma undergoing resection of pulmonary metastases (Table III). Only TDT and the presence of extrapulmonary intrathoracic disease were significant by multivariate analysis, with the number of pulmonary metastases becoming less important. Figs. 1 through 6 show survival curves according to various prognostic factors. Those patients undergoing complete resection had a higher 5-year and median survival than those undergoing incomplete resection. (Patients undergoing an unknown degree of resection were not included.) The difference between their respective survival curves approached but did not reach significance because of the small number of patients undergoing incomplete resection (Fig. 1). A significant survival advantage was present for patients with less than five pulmonary lesions (Fig. 2). In addition, the 5-year survival rate tended to decrease as the number of pulmonary metastases increased from one (39%; Fig. 3) to between one and four (29%).
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The median survival for the nine patients undergoing multiple procedures was 33 months. Of those patients with extrapulmonary intrathoracic metastases, two died 5 and 14 months after resection, and two were alive at 18 and 149 months of follow-up.
Survival of patients with pulmonary metastases
Univariate analysis showed that surgical treatment plus MCV immunotherapy, location of the primary on an extremity, and extended disease-free interval were associated with improved survival. In the multivariate analysis, only surgical treatment and MCV immunotherapy remained significant (Table IV). The median survival time and the 5-year survival rate for the entire group of patients with pulmonary metastases were 9 months and 6%, respectively. Kaplan-Meier survival analysis showed improved survival in patients treated with resection (Fig. 7). Median survival time and 5-year survival rate were 8 months and 3%, respectively, for nonsurgical patients versus 23 months and 27% for surgical patients. This difference in survival between surgical and nonsurgical groups could not be explained by the location, histologic status, thickness, or level of invasion of the primary melanoma (data not shown). These factors were not significantly different between surgical and nonsurgical groups.
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Table IV): 63% of surgical patients received some form of immunotherapy, compared with only 34% of nonsurgical patients. Median survival was longer in patients treated with MCV (13 months) than in those treated with other nonsurgical therapies (8 months). DISCUSSION
Analysis of these data, which represent the largest series of surgically treated patients with melanoma metastatic to the lung and thorax, showed that the rate of 5-year survival can be as high as 39% in selected patients. This is a striking contrast to the median survival of 8 months generally ascribed to patients with melanoma metastatic to distant sites. 10-13, 28, 29 The implication is that certain patients with thoracic metastases should be considered for possible operative management. The fact that operative mortality was zero and operative morbidity was low also offers support for surgical intervention in selected patients.
Previous studies have reported surgical treatment of patients with melanoma metastatic to the lung or other sites, 1, 14-16, 19, 20-22 but few have had enough patients for detailed analysis. The variables associated with increased risk of pulmonary metastases in our multivariate analysis were similar to those reported by Harpole and colleagues. 22 Our study group's higher overall risk of the development of pulmonary metastases (Table I) reflects the fact that JWCI is a tertiary referral center for patients with melanoma. The risk for our subgroup (i.e., those treated at JWCI within 4 months of primary diagnosis), which better represents patients with melanoma, most probably approximates the true risk of pulmonary metastases in melanoma.
Our study group was large enough to determine the best candidates for resection (ie., patients with a solitary pulmonary lesion, no evidence of extrapulmonary intrathoracic metastases, and a TDT > 60 days). However, patients with multiple metastases and no extrapulmonary intrathoracic disease can still have a 5-year survival rate of 19% and therefore should be considered for resection.
Because of the small number of patients undergoing incomplete resection, no statistical difference was seen for complete versus incomplete resection; however, the respective survival curves were separate and would doubtless become statistically different as the number of patients increased TDT was frequently described as greater or less than 40 days, but its specific value was recorded for only 26 patients. This is unfortunate because TDT is a valuable selection criterion for surgical candidates. 29,30 Traditionally, patients with a TDT less than 40 days have not been considered for resection, and there were no 5-year survivors among patients whose TDT was less than 60 days. However, surgical intervention may still be considered if the patient has a solitary pulmonary lesion, no extrapulmonary intrathoracic metastases, or other favorable prognostic factors.
Although no statistically significant difference was found between treatment with lobectomy versus wedge resection, 5-year survival increased in those patients undergoing the latter procedure. This noteworthy trend may reflect use of lobectomy for patients with a single large metastatic lesion.
No previous series has reported survival data for patients with melanoma undergoing resection of extrapulmonary intrathoracic metastases. Although our study had only four such patients, three survived for more than 1 year. This acceptable rate of survival offers support for aggressive surgical management in selected patients. It has been suggested that median sternotomy is too aggressive for resection of bilateral metastases. However, Regal and colleagues 31 preferred this approach in their series of 131 patients. Of the eight patients in our study who underwent median sternotomy, one required reintubation because of pulmonary edema and one required treatment of cardiac arrhythmia; however, both recovered well.
In our study, administration of immunotherapy was associated with improved outcome. A prospective randomized study is needed to identify patients most likely to benefit from this intervention. However, both clinical studies 23 and experimental work with the use of animal models 32 point to improved survival after use of immunotherapy. Although the various regimens of adjuvant immunotherapy used during the 22-year study period complicate a comparative analysis, the data indicate that MCV immunotherapy improved the survival of patients with pulmonary metastases.
Even though our selection criteria have been relaxed, these patients continue to have a much better survival rate than do patients with melanoma whose thoracic metastases are not treated surgically. Although our study is limited by the selection bias of any retrospective analysis, we believe that if thorough evaluation fails to show sites of extrathoracic metastasis, if the patient is in overall good health, and all tumor can be resected during the surgical procedure, then thoracotomy and resection of metastases, followed by immunotherapy with our new MCV, offers the best chance for long-term survival.
In summary, these data offer support for a more optimistic and aggressive approach to patients with malignant melanoma that metastasizes to the thorax and lungs. We conclude that the treatment of choice for this stage of melanoma is surgical intervention plus immunotherapy in selected patients.
Appendix: DISCUSSION
Dr. Joel D. Cooper (St. Louis, Mo.).
Your paper actually casts a somewhat different point of view than what I have always had. I have always been rather discouraged when melanoma has shown up in the lung compared with other metastatic tumors. I congratulate you on the series.
I have one question I believe you showed us that the difference in the interval between the primary tumor and the treatment was significantly different for those having and those not having surgical treatment; and, having shown the importance of tumor doubling time, how much do you think this factor contributes to your ultimate conclusion?
Dr. Tafra.
Just to clarify your question, how much does the interval affect . . . ?
Dr. Cooper.
The selection of patients. Your conclusion was that surgery plays a role, and yet when you analyzed the results of the surgical versus the nonsurgical group of patients, if I understand it correctly, there was a much greater disease-free interval from the time of primary disease to the time of treatment in those undergoing surgical treatment than in those who did not have surgical treatment. In other words, were they preselected?
Dr. Tafra.
Certainly there was a selection bias. Without a prospective, randomized comparison of patients having a similar number of lesions and a similar tumor burden, we cannot prove that surgically treated patients fare better than those treated without operation. However, there is some evidence showing that surgical patients have improved survival. First, since we relaxed our selection criteria for operation 5 years ago, the tumor burden of our surgical patients has increased, yet their survival rate has remained the same. Second, although disease-free interval was significantly different between surgical and nonsurgical groups, this significance was not maintained in the multivariate analysis of patients with pulmonary metastases.
Dr. David J. Sugarbaker (Boston, Mass.).
I would just like to preface my remarks by saying that I think most of us approach patients with metastatic melanoma to the lung with a certain amount of trepidation, knowing that in a vast majority, after surgical resection, the other shoe will drop and the patient will turn up with an unresectable brain metastasis or something similar to that.
You showed us a 42% survival in patients having one to four lesions. Can you give us a little further breakdown as to how many of those patients had only one lesion and how many actually had anywhere from two to four, because I think most of the series suggest that when you get more than one—when you get to two, three, and four lesions—survival really begins to fall off.
Dr. Tafra.
The 5-year survival of these patients is related to the number and location of metastases. The majority of our patients had only one lesion and a 5-year survival rate of 39%, whereas patients with 1 to 4 lesions had a 5-year survival rate of 29%. The survival decreases further with an increasing number of lesions, and we had no 5-year survivors with 5 or more metastatic lesions. In general, we do not offer surgical treatment to patients with more than five metastatic lesions.
Undetected metastatic disease is a serious concern in these patients and we therefore perform a thorough metastatic workup that includes positron emission tomographic scans, which are sensitive for detecting metastatic disease. If this workup shows metastatic foci in extrathoracic sites, then the patient is generally not considered a candidate for resection. Other relative contraindications for surgical intervention include a rapid TDT and the presence of extrapulmonary intrathoracic disease.
Dr. George B. Haasler (Milwaukee, Wis.).
My question is really a corollary to Dr. Cooper's comment. Because the disease-free interval in the surgical patients was so much greater than that in the nonsurgical patients, I wondered whether you looked at those patients in the surgical group who had shorter disease-free intervals and compared them with the group in the medical, nonsurgical group that perhaps had disease-free intervals that were on the longer end of that spectrum to try and get a little closer comparison of the surgical versus nonsurgical patients.
Dr. Tafra.
We initially did not examine the survival of surgically versus nonsurgically treated patients grouped according to disease-free interval. Our data do suggest a close correlation between postoperative disease-free interval and TDT; however, this analysis was limited because TDT was usually recorded as above/below a cut-off value rather than as a specific number. In our multivariate analysis, disease-free interval did not influence survival, and I therefore would suspect that surgically treated patients survived longer than nonsurgically treated patients having a similar disease-free interval. In fact, we subsequently compared surgically treated patients whose disease-free interval exceeded 30 days with nonsurgical patients having the same disease-free interval: the surgical group continued to have improved survival.
Footnotes
Read at the Seventy-fourth Annual Meeting of The American Association for Thoracic Surgery, New York, N.Y., April 24-27, 1994. 
References
This article has been cited by other articles:
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