J Thorac Cardiovasc Surg 2004;127:1107-1112
© 2004 The American Association for Thoracic Surgery
Pulmonary metastases from uterine malignancies: Results of surgical resection in 133 patients
Masaki Anraku, MDa,
Kohei Yokoi, MDa,*,
Ken Nakagawa, MDb,
Takehiko Fujisawa, MDc,
Jun Nakajima, MDd,
Hirohiko Akiyama, MDe,
Yoshihiro Nishimura, MDf,
Koichi Kobayashi, MDg for The Metastatic Lung Tumor Study Group of Japan
a Division of Thoracic Surgery, Tochigi Cancer Center, Tochigi, Japan
b Department of Chest Surgery, Cancer Institute Hospital, Tokyo, Japan
c Department of Thoracic Surgery, Chiba University, Chiba, Japan
d Department of Cardiothoracic Surgery, University of Tokyo, Tokyo, Japan
e Department of Thoracic Surgery, Saitama Cancer Center, Saitama, Japan
f Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan
g Department of Thoracic Surgery, Keio University School of Medicine, Tokyo, Japan
Received for publication May 20, 2003; revisions received September 28, 2003; accepted for publication October 6, 2003.
* Address for reprints: Kohei Yokoi, MD, Tochigi Cancer Center, Division of Thoracic Surgery, 4-9-13 Yohnan, Utsunomiya, Tochigi 320-0834, Japan
kyokoi{at}tcc.pref.tochigi.jp
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Abstract
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OBJECTIVE: The long-term results of the surgical treatment for patients with pulmonary metastases from uterine malignancies were clarified.
METHODS: A total of 133 patients who underwent pulmonary metastasectomy for uterine malignancies were enrolled in the Metastatic Lung Tumor Study Group of Japan between March 1984 and February 2002. These patients constituted the study population, and their clinical, pathologic, and prognostic data were retrospectively analyzed.
RESULTS: The morbidity and mortality rates related to the operation were minimal (1% and 1%, respectively). The 5- and 10-year survivals after the surgical resection in all cases were 54.6% and 44.9%, respectively. The 5-year survivals for each histologic type were estimated to be 46.8% for squamous cell carcinoma (n = 58), 40.3% for cervical adenocarcinoma (n = 13), 75.7% for endometrial adenocarcinoma (n = 23), 86.5% for choriocarcinoma (n = 16), and 37.9% for leiomyosarcoma (n = 11). In the univariate analysis, the following were shown to be associated with poor survival: primary tumor in the cervix, short disease-free interval (<12 months), large number of resected metastases (
4), and large tumor size (3 cm). After mutual adjustment, short disease-free interval (<12 months) alone was related to risk of death (hazard ratio = 2.26, 95% confidence interval = 1.06-4.78) for 105 patients, excluding patients with choriocarcinoma and miscellaneous histologic types.
CONCLUSION: Pulmonary metastasectomy for uterine malignancies is a safe and acceptable treatment to improve survival. Patients with a disease-free interval of 12 months or more are good candidates for this treatment if there is adequate control of the primary tumor without extrapulmonary metastasis.
Pulmonary metastasectomy has been widely adopted for treatment in properly selected patients with metastases isolated to the lung. Survival after pulmonary resections varies among different primary tumor types.1 Trek2 first reported a patient who underwent pulmonary resection for metastatic uterine adenocarcinoma in 1930. After that report, some investigators reported patients with uterine cancer with pulmonary metastases, treated with or without resection.3-6 However, the surgical results of pulmonary metastasectomy for uterine malignancies have been inadequate in large series of patients. This study analyzes the clinical and pathologic information and prognostic variables of a large number of patients undergoing pulmonary resection for metastatic uterine malignancies.
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Patients and methods
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Between March 1984 and February 2002, 133 female patients who underwent pulmonary resection for metastatic uterine malignancies were registered in the Metastatic Lung Tumor Study Group of Japan. The clinical, pathologic, and prognostic data were obtained from the registry in a retrospective fashion. The selection of patients for surgical treatment or the operative procedure depended on each institution. There was no unified guideline for the operative approach. Follow-up was performed at each institution. Operative mortality was defined as death within the first 30 days postoperatively or during hospitalization.
Survival was measured from the initial pulmonary metastasectomy until death or the last date of the follow-up (October 11, 2002), and the data were reported as mean and 95% confidence intervals (CIs). The survival curves according to selected clinical and pathologic characteristics were calculated with the Kaplan-Meier method,7 and comparisons among the curves were made with the log-rank test. Subsequently, we performed a multivariable analysis to clarify an independent effect of each characteristic on survival using a Cox proportional hazards model.8
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Results
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The mean age of the patients at thoracotomy was 56.4 years (range 26-80 years). The patients' characteristics are shown in Table 1. A total of 77 of the 133 patients (58%) underwent surgery for a single metastasis, and 23 patients (17%) underwent surgery for 4 or more metastases. The disease-free interval (DFI), defined as the time between treatment of the primary site and detection of lung metastases, ranged from 0 to 243 months. Pulmonary metastases were detected simultaneously with the primary tumor (DFI = 0) in 8 patients (6%). The DFI was less than 12 months in 23 patients (17%), whereas it was more than 36 months in 60 patients (45%). Thirty-eight patients (29%) underwent bilateral thoracotomy for complete tumor removal, 18 of whom underwent staged operations. Repeated metastasectomy was distinguished from a staged operation. Of 12 patients undergoing repeated metastasectomy for recurrent disease after the initial pulmonary resection, 2 patients underwent 3 metastasectomies and 1 patient underwent 4 metastasectomies. Forty-five patients (34%) underwent mediastinal or hilar lymphadenectomy, or both. Among them, 16 patients had pathologically positive lymph nodes. Eight patients (6%) had extrapulmonary metastases at the time of lung metastasectomy.
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TABLE 1. Characteristics of 133 patients who underwent surgical resection for pulmonary metastases from uterine malignancies
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There was 1 postoperative death as the result of cardiac infarction (mortality rate 1%). In the total of 166 operations in the 133 patients, there were 2 postoperative major complications (morbidity rate 1%): wound infection and liver dysfunction.
Median follow-up time was 40 months with a range of 0 to 220 months, and overall cumulative 5-year and 10-year survivals in the 133 patients were 54.6% (95% CI, 45.9%-63.9%) and 44.9% (95% CI, 34.3%-55.5%), respectively. The patients with a primary tumor in the cervix had a 5-year survival of 45.7% (95% CI, 33.2%-58.2%), and the patients with a tumor in the body had a 5-year survival of 66.3% (95% CI, 53.0%-79.5%) (P = .01). The 5-year survivals in different histologic types were calculated as 46.8% (95% CI, 32.3%-61.2%) in squamous cell carcinoma, 40.3% (95% CI, 11.6%-69.0%) in cervical adenocarcinoma, 75.7% (95% CI, 56.7%-94.6%) in endometrial adenocarcinoma, 86.5% (95% CI, 69.1%-100%) in choriocarcinoma, and 37.9% (95% CI, 6.3%-69.5%) in leiomyosarcoma (Figure 1). Among patients with pulmonary metastases from cervical cancers, there was no significant difference in survival between the 2 histologic types of adenocarcinoma and squamous cell carcinoma (P = .92). On the contrary, among patients with body tumors, leiomyosarcoma was associated with worse outcome in comparison with adenocarcinoma (P = .02).
Patients with a DFI of 12 months or more achieved a 5-year survival of 59.8% (95% CI, 49.3%-70.3%), whereas patients with a DFI of less than 12 months achieved a 5-year survival of 36.8% (95% CI, 17.3%-56.3%) (P = .02) (Figure 2). Excluding 8 patients with pulmonary metastases detected simultaneously with the primary tumor, those survivals were still significantly different (59.8% and 17.1%, respectively) (P < .0001). Patients with a DFI of more than 36 months demonstrated no additional survival advantage compared with those with a DFI between 12 and 36 months (5-year survivals, 56.9% and 52.8%, respectively) (P = .37).
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Figure 2. Survival curves from the time at initial metastasectomy: influence of DFI. Log-rank test: P = .022.
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A significant difference in survival according to the number of resected metastases is shown in Figure 3. The 5-year survivals of patients with 3 or less metastases and 4 or more metastases were 58.5% (95% CI, 48.4%-68.5%) and 32.1% (95% CI, 9.1%-55.1%), respectively (P = .03). Patients with a single metastasis (n = 77) achieved a 5-year survival of 60.5% (95% CI, 48.9%-72.0%). However, among the patients with a DFI of more than 12 months, the 13 patients with more than 4 metastases achieved a 5-year survival of 49.2%, and the survival was not significantly different from that of the other 85 patients with 3 or less lesions (P = .88).
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Figure 3. Survival curves from the time at initial metastasectomy: influence of the number of resected tumors. Log-rank test: P = .028.
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In regard to the resected tumor size, there was a significant difference between patients whose tumors had a maximum diameter of less than 3 cm and patients whose tumors had a maximum diameter of 3 cm or more (P = .01) (Figure 4).
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Figure 4. Survival curves from the time at initial metastasectomy: influence of resected tumor size. Log-rank test: P = .014.
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Lymph node dissection itself did not statistically affect prolonged survival (P = .76). Among the 45 patients who underwent lymphadenectomy, those with positive lymph nodes (n = 16) had poorer survival than those with negative lymph nodes (5-year survival, 30.3% vs 60.2%). However, there was no significant difference in the survival between these 2 groups (P = .25).
Eight patients (6%) with extrapulmonary metastasis had a poorer prognosis than the patients with no extrapulmonary metastasis (5-year survival, 43.8% vs 57.4%), but the survival between the 2 groups was not statistically different (P = .88).
Multivariable analysis was performed for patients with cervical squamous cell carcinoma, cervical adenocarcinoma, endometrial adenocarcinoma, or leiomyosarcoma (Table 2). In addition to the 12 cases of miscellaneous histologic types, the 16 cases of choriocarcinoma were excluded from the analysis because effective chemotherapy was available for the latter cases. Variables for the multivariable analysis were as follows: combination of site and histology, age, DFI, multiplicity of metastases, and tumor size. After mutual adjustment, a short DFI of less than 12 months alone was related to risk of death.
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TABLE 2. Relation between clinicopathologic characteristics and survival: Multivariable analysis with Cox proportional hazards model
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Discussion
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The concept of metastasectomy is surgical tumor eradication that may contribute to prolonged survival. In general, the indication for pulmonary metastasectomy includes the following: the primary tumor is controlled or controllable; there is no extrapulmonary disease; the medical status is adequate to tolerate lung resection; complete resection is possible; and no better treatment is available.9 A surgical approach for selected patients has been regarded as beneficial treatment, although almost all studies in the past were retrospective and without a control group. The surgical results after pulmonary metastasectomy of gynecologic cancers have also been published.3,10 Nevertheless, because those reports contained a relatively small number of cases, their data were inadequate to analyze the evidence of the thoracic surgical procedure. Therefore, to analyze the clinical, pathologic, and prognostic information of a large number of patients with pulmonary resection for metastatic uterine malignancies, we conducted a retrospective study of the patients enrolled in the Metastatic Lung Tumor Study Group of Japan.
In cervical cancers, the most common site of extrapelvic spread is the lung,11 and 80% to 90% of cervical cancers are squamous cell carcinomas. Seki and colleagues12 reported a 5-year survival of 52% in 32 patients with cervical squamous cell carcinoma who underwent pulmonary resection. The survival data were similar to the present findings. The survival of patients with cervical adenocarcinoma was comparable to the survival of patients with squamous cell carcinoma, although the number of patients was small. The present results encourage surgery to improve survival for highly selected patients with pulmonary metastases from cervical adenocarcinoma.
In endometrial malignancies, Anderson and colleagues10 reported a median survival of 46 months in 6 patients with endometrial adenocarcinoma who underwent pulmonary resection, and Otsuka and colleagues13 described a median survival of 50 months in 5 patients. Survival of our 23 patients with endometrial adenocarcinoma was more favorable (5-year survival of 75.7%). However, these results may be attributable to the patients' backgrounds, that is, 18 of the patients (78%) had less than 3 metastases, and 21 patients (91%) underwent complete resection. Levenback and associates14 documented a 5-year survival of 43% in 45 patients with leiomyosarcoma, which was similar to the present survival findings of patients with leiomyosarcoma and cervical cancer.
Prognostic indicators to select patients who will benefit from pulmonary metastasectomy have been analyzed for various tumor types.15 The number of metastases, bilaterality of lesions, DFI, and tumor doubling time are factors generally associated with survival after surgical resection. Shorter DFI or tumor doubling time may reflect tumor aggressiveness and indicate poor postresection survival.16,17 The present analysis confirmed that a longer DFI (12 months) strongly influenced good postthoracotomy survival. However, limited to the patients with a single metastasis, the group with a DFI of less than 12 months (n = 16) showed a 5-year survival of 48.6%. Therefore, a short DFI should not preclude patients from pulmonary resection.
The optimum number of metastases in candidates for surgery with curative intent was not clear. In the present series, the patients with 3 or less metastases showed better survival than those with more than 3 metastases, but this was not significantly different in the multivariable analysis. Limited to patients with a DFI of more than 12 months, the present findings indicate that metastasectomy for multiple lesions is effective to improve survival. Girard and associates18 investigated the surgical results of 44 patients with a large number of pulmonary metastases and concluded that the prognostic value depends on the resectability rather than the number of metastases. They reported a 5-year survival of 28% after metastasectomy for patients with 8 or more lesions, which was not significantly different from the survival of patients with less than 8 lesions. After thorough case-by-case selection of patients with a long DFI, pulmonary metastasectomy may enable prolonged survival irrespective of the number of metastases.
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Conclusion
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It is recommended that patients with resectable lung metastases from uterine malignancies undergo metastasectomy. Carefully selected patients, especially those with a DFI of more than 12 months, would have potential survival benefits.
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Appendix
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The following institutions participated in this study: Cancer Institute Hospital, Chiba Cancer Center, Chiba University, Hamamatsu University, International Medical Center of Japan, Keio University, National Cancer Center, National Defense Medical College, National Fuji Hospital, National Tokyo Medical Center, Nihon University, Saitama Cancer Center, Saitama Medical School, Tochigi Cancer Center, Toho University, Tokyo Medical University, Tokyo Metropolitan Komagome Hospital, and University of Tokyo.
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Acknowledgments
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We thank Satoshi Honjo, MD, Epidemiology Unit, Tochigi Cancer Center, for statistical review.
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Footnotes
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For a listing of participating institutions, see appendix.
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References
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Abstract
Patients and methods
