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Gynecologic Cancers: Factors Affecting Survival After Pulmonary Metastasectomy Jose M. Clavero, MD, Claude Deschamps, MD, Stephen D. Cassivi, MD, Mark S. Allen, MD, Francis C. Nichols III, MD, Brigitte A. Barrette, MD, Dirk R. Larson, MS, and Peter C. Pairolero, MD Division of General Thoracic Surgery, Department of Obstetrics and Gynecology, and Division of Biostatistics, Mayo Clinic College of Medicine, Rochester, Minnesota

Background. Little information is available regarding long-term survival after pulmonary metastasectomy for gynecologic malignancies. Methods. All patients who underwent pulmonary resection for gynecologic malignancies at our institution between January 1985 and June 2001 were reviewed. Factors affecting long-term survival were analyzed. Results. There were 103 patients, 70 of whom had metastatic disease limited to the lungs. Median age of these 70 patients was 59.4 years (range, 31 to 80 years). The primary tumor originated in the uterine corpus in 37 patients, endometrium in 23, cervix in 7, ovaries in 2, and vagina in 1. Histopathology was leiomyosarcoma in 29 patients, adenocarcinoma in 23, other sarcoma in 11, squamous cell carcinoma in 5, and choriocarcinoma and endolymphatic stromal myosis in 1 each. The median time interval between the first gynecologic procedure and pulmonary resection was 24 months (range, 0 to 237 months). A wedge excision was performed in 44 patients, lobectomy in 14, bilobectomy in 2, pneumonectomy in 1,

and a combination in 9. Five patients (7%) had an incomplete resection. Eighteen patients (25.7%) developed at least one complication and 1 died (operative mortality, 1.4%). At last follow-up, 35 had died, and the median follow-up among those who were still alive was 36 months (range, 6 months to 13 years). Five-year and 10-year survival was 46.8% (95% confidence interval, 34.2% to 63.0%) and 34.3% (95% confidence interval, 19.7% to 52.5%), respectively. Factors that adversely affected survival include a disease-free interval between the first gynecologic procedure and pulmonary resection of less than 24 months (p ⴝ 0.004) and a primary site located in the cervix (p < 0.001). Conclusions. Pulmonary resection for metastatic gynecologic cancer in selected patients is safe and effective. Both a short disease-free interval between the primary gynecologic procedure and pulmonary metastasectomy, and a primary cervical tumor had an adverse effect on survival. (Ann Thorac Surg 2006;81:2004 –7) © 2006 by The Society of Thoracic Surgeons

T

Material and Methods

he first pulmonary resections for lung metastases were attributed to Weinlechner and Kronlein in 1882 and 1883, respectively. In 1939, Barney and Churchill [1] reported the first lobectomy for lung metastasis in a patient with renal cell carcinoma. They performed this procedure on a 55-year-old woman who subsequently survived 23 years and died from an unrelated cause. Since then many patients have undergone pulmonary resection for metastatic disease from a variety of primary sites with 5-year survivals ranking from 20% to 40% [2–12]. Unlike other solid tumors, however, little information is available regarding long-term survival after pulmonary resection for metastatic gynecologic cancers. Therefore we reviewed our experience with patients who had undergone pulmonary resection for metastatic gynecologic malignancies and analyzed the factors affecting survival. Accepted for publication Jan 4, 2006. Presented at the Poster Session of the Fifty-second Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 10 –12, 2005. Address correspondence to Dr Deschamps, Division of General Thoracic Surgery, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905; e-mail: [email protected].

© 2006 by The Society of Thoracic Surgeons Published by Elsevier Inc

All patients, who underwent pulmonary resection for metastatic gynecologic cancers between January 1985 and June 2001 at the Mayo Clinic in Rochester, Minnesota, were reviewed. There were a total of 103 patients. Eighteen of these patients also had metastases to other locations, and 15 had pulmonary excision for diagnostic purposes only. These 33 patients were excluded from further analysis. The medical records of the remaining 70 patients were analyzed for patient demographics, location of primary tumor, type of gynecologic resection, tumor histology, lymph node involvement, neoadjuvant and adjuvant chemotherapy, disease-free interval (DFI), type of pulmonary metastases (synchronous vs metachronous), type of pulmonary resections, number of pulmonary metastases excised, clinical outcome, and survival. The DFI was calculated as the time interval between the initial gynecologic procedure and the detection of pulmonary metastases. Pulmonary metastases were classified accordingly to the International Registry of Lung Metastasis Classification System [13]. The disease was classified as type 1 when the metastasis was solitary and the DFI was greater than 36 months; as type 0003-4975/06/$32.00 doi:10.1016/j.athoracsur.2006.01.068

CLAVERO ET AL PULMONARY METASTASECTOMY FOR GYNECOLOGIC CANCER

2 when either multiple metastases were present or the DFI was less than 36 months; as type 3 when both multiple metastases were present and the DFI was less than 36 months; and as type 4 when the metastases were unresectable. The metastases were considered to be synchronous if they were identified within 3 months of the diagnosis of the primary tumor, and metachronous if they were identified after 3 months. Operative mortality included all deaths occurring within 30 days of the pulmonary resection and those who died later but during the same hospitalization. Survival was estimated using the Kaplan–Meier method [14], and the date of the first pulmonary metastasectomy was considered the starting point. The effects of potential risk factors on survival were evaluated using log-rank tests and the Cox proportional hazards regression model [15]. Risk factors that were significant with univariate analysis were also evaluated simultaneously in a multivariable model. All statistical tests were two-sided and p values less than 0.05 were considered significant. All analyses were conducted with the SAS, version 8.2 (SAS Institute Inc, Cary, NC) and Splus, version 6.2 (Insightful Corp, Seattle, WA). The Mayo Clinic College of Medicine Institutional Review Board granted approval for this study on January 6, 2003, and individual consent was waived.

Results The median age of the 70 patients was 59.4 years (range, 31 to 80 years). The primary tumor originated in the uterine corpus in 37 patients (52.9%), endometrium in 23 (32.9%), cervix in 7 (10.0%), ovaries in 2 (2.8%), and vagina in 1 (1.4%). Histopathology was leiomyosarcoma in 29 patients (41.4%), adenocarcinoma in 23 (32.9%), other sarcoma in 11 (15.8%), squamous cell carcinoma in 5 (7.1%), and choriocarcinoma and endolymphatic stromal myosis in 1 each (1.4%). The initial gynecologic procedure was a total hysterectomy and bilateral salpingooophorectomy in 26 patients (37.2%), total hysterectomy and bilateral salpingo-oophorectomy combined with an associated procedure in 33 (47.1%), and other in 11 (15.7%). Sixteen patients (22.9%) underwent a second gynecologic procedure. Forty patients (57.1%) had adjuvant therapy, 24 (34.3%) had radiation therapy, 12 (17.1%) had chemotherapy, and 4 (5.7%) had both. The median DFI between the first gynecologic procedure and pulmonary resection was 24 months (range, 0 to 237 months). Metachronous metastases were present in 61 patients (87.1%) and synchronous in 9 (12.9%). Sixtyone patients (87.1%) were asymptomatic. Symptoms in the remaining 9 patients (12.9%) included cough in 5, chest pain in 2, abdominal pain in 1, and clubbing in 1. Eighteen patients had chemotherapy before metastasectomy (25.7%). Five patients had an International Registry of Lung Metastasis Classification System type 1 metastases (7.2%), 36 had type 2 (51.4%), and 29 had type 3 (41.4%). A total of 125 pulmonary procedures were performed in these 70 patients: 40 patients had 1 pulmonary operation; 18 patients had 2; 5 patients had 3; 3 patients had 4; 2 patients had 5; and 2 patients had 6. The initial surgical approach was a thoracotomy in 40 patients, staged bilat-

2005

Table 1. Morbidity Associated With 70 Patients Who Had Pulmonary Resection for Gynecologic Cancer Complication Respiratory Atrial fibrillation Prolonged air leak Pericarditis Postoperative anemia Others

Number

Percent

5 4 1 1 1 6

7.1 5.7 1.4 1.4 1.4 8.6

eral thoracotomies in 10, sternotomy in 18, and videoassisted thoracoscopy in 2. The initial pulmonary resection was a wedge excision in 44 patients, lobectomy in 14, bilobectomy in 2, pneumonectomy in 1, and a combination of resections in 9. The median number of pulmonary metastases resected was 2 (range, 1 to 19). Mediastinal lymphadenectomy was performed in 31 patients (44.3%). Complete pulmonary resection was achieved in 65 patients (93%). Complications occurred in 18 patients (25.7%) (Table 1). One patient died from respiratory failure and sepsis (operative mortality, 1.4%). Postoperatively, 17 patients had adjuvant treatment, 7 had chemotherapy, and 10 had hormonal therapy. Follow-up was complete in 64 patients (91.4%). At last follow-up 35 patients have died; among the 35 still alive at last follow-up, median follow-up was 36 months (range, 6 months to 13 years). Fifty-five patients (78.6%) had recurrence develop, 8 are cancer free, 1 had persistent disease, and 6 were lost to follow-up. The lung was the site of recurrence in 28 patients, pelvis in 4, brain in 7, and others in 16. Recurrent tumors were treated with surgical resection in 27 patients; twenty-four of these patients had a repeat pulmonary resection. In addition, other treatments for recurrent tumor included chemotherapy in 11 patients, radiotherapy in 9, hormonal therapy in 2, and supportive care only in 4. Overall 5-year and 10-year survival after pulmonary metastasectomy was 46.8% (95% confidence interval, 34.2% to 63.0%) and 34.3% (95% confidence interval, 19.7% to 52.5%), respectively (Fig 1). Median disease-free survival in patients with a complete pulmonary resection was 8 months. Overall 3-year disease-free survival was 14.7%. Ovarian carcinoma, endometrial carcinoma and corpus carcinoma 3-year survival were 100%, 27.8% and 5.7%, respectively. Factors that adversely affected survival with univariate analysis included a primary cancer located in the cervix (Fig 2) (p ⬍ 0.001), a DFI of less than 24 months (Fig 3) (p ⫽ 0.004), and adjuvant chemotherapy after the initial gynecologic cancer operation (Fig 4) (p ⫽ 0.03). Factors that adversely affected survival with multivariate analysis included a primary cancer located in the cervix (p ⫽ 0.008) and a DFI of less than 24 months (p ⫽ 0.022). Factors that did not significantly influence survival included age, type of gynecologic resection, tumor histology, lymph node involvement, type of pulmonary metastases (ie, synchronous vs metachronous according to the International Registry of Lung Metastasis Classification System), type of pulmonary resections, and the number of pulmonary metastases excised.

GENERAL THORACIC

Ann Thorac Surg 2006;81:2004 –7

GENERAL THORACIC

2006


Fig 1. Survival (death from any cause) in 70 patients who underwent resection of metastatic pulmonary carcinoma of gynecologic origin compared with expected survival in a matched population. Zero time on abscissa represents date of first lung resection. Numbers of patients at risks are shown above the abscissa.


Fig 3. Survival (death from any cause) in patients who underwent resection of metastatic pulmonary carcinoma of gynecologic origin with a disease-free interval of 24 months or greater compared with those who had a disease free-interval less than 24 months. Zero time on abscissa represents date of first lung resection. Numbers of patients at risks are shown above the abscissa.

Comment Approximately 80,000 women in 2006 in the United States will develop gynecologic cancers, 36% of whom will eventually die from their disease [16]. Lung metastases are present in approximately 30% of these patients, and the lung is the only site of metastases in 20% [12]. Although pulmonary metastases from gynecologic cancers are not uncommon and occur in 2% to 28% of patients, little information is available regarding the efficacy of pulmonary metastasectomy. Torek [17] in 1930 is believed to be the first to resect a pulmonary metastasis from a uterine adenocarcinoma. Since then reports available have suggested a 5-year survival ranging from 24% to 53% [12, 13, 18 –27]. Our overall 5-year survival of 47% compares favorably. We have identified predictors of decreased survival using both univariate and multivariate models. Gynecologic

cancers arising in sites other than the cervix were associated with increased survival. This is in contrast with others reports [10, 25, 27, 28]. A DFI of less than 24 months and chemotherapy at the time of the gynecologic procedure were associated with decreased survival. Although others have reported similar findings [28], the adverse effect on survival attributed to the administration of chemotherapy for the primary tumor likely reflects selection bias (ie, patients with more aggressive tumors were more likely to receive adjuvant therapy). Five-year and 10-year survival in our patients was similar to that observed when pulmonary metastasectomy are performed for other types of cancers [2–13]. The majority of our patients after pulmonary metastasectomy experienced systemic recurrence, with most being located in the lungs. This may reflect the systemic nature of

Fig 2. Survival (death from any cause) in patients who underwent resection of metastatic pulmonary carcinoma from cervical origin compared with patients who had resection of metastatic pulmonary carcinoma originating from other gynecologic locations. Zero time on abscissa represents date of first lung resection. Numbers of patients at risks are shown above the abscissa.

Fig 4. Survival (death from any cause) in patients who underwent resection of metastatic pulmonary carcinoma of gynecologic origin who had chemotherapy for the primary tumor compared with patients who did not have chemotherapy. Zero time on abscissa represents date of first lung resection. Numbers of patients at risks are shown above the abscissa.


the disease at the time of the initial pulmonary metastasectomy and suggest that postoperative chemotherapy and or hormonal therapy should be strongly considered. Lymphadenectomy was performed in approximately half of our patients; however, only 3 had lymph node metastases. Although no association was observed between lymphadenectomy and survival, the number of patients was too small to reach any significant conclusion regarding its effect on prognosis. We have previously shown that positive mediastinal lymph nodes from extrapulmonary carcinoma metastatic to the lung adversely affect prognosis [29]. In addition, some investigators have suggested that if mediastinal lymphadenopathy is observed preoperatively in a patient with suspected lung metastases, mediastinal exploration should be considered as a histologic confirmation would constitute a relative contraindication to metastasectomy [30]. Finally, the International Registry of Lung Metastasis Classification System, when applied to our cohort of patients, did not prove useful in predicting survival; this may also be due to the relatively small number of patients. In general, pulmonary metastasectomy for cancer of gynecologic origin should be considered in patients (1) with no evidence of recurrent disease at the primary site, (2) with pulmonary metastases that are limited in number, (3) with the patient who has adequate pulmonary reserve, and (4) when no evidence of extrathoracic metastatic disease exists. The procedure of choice for treatment of pulmonary metastatic disease is pulmonary wedge excision. Extensive pulmonary resection, such as pneumonectomy, should be discouraged in these patients with adverse prognostic factors. The possibility of a primary lung cancer should always be considered when an isolated pulmonary nodule is found in a patient with a history of primary gynecologic cancer. All patients should also be evaluated for recurrence at the primary cancer site. Evaluation for metastatic disease must include chest, abdomen, and pelvis computed tomography. A positron emission tomography scan should also be considered. In conclusion, pulmonary resection for metastatic gynecologic cancer in selected patients is safe and effective. Both a short DFI between the primary gynecologic procedure and pulmonary metastasectomy and a primary cervical tumor had adverse effects on survival.

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