PULMONARY RESECTION IN SMALL CELL LUNG CANCER

ORIGINAL ARTICLE

The Role of Pulmonary Resection in Small Cell Lung Cancer

VIDHAN CHANDRA, MD; MARK S. ALLEN, MD; FRANCIS C. NICHOLS III, MD; CLAUDE DESCHAMPS, MD; STEPHEN D. CASSIVI, MD; AND PETER C. PAIROLERO, MD
OBJECTIVE: To analyze the outcome of surgical resection for patients with small cell lung cancer (SCLC). PATIENTS AND METHODS: We identified all patients who underwent thoracotomy for SCLC at our institution from January 1985 to July 2002. All patients were staged using the American Joint Committee on Cancer TNM system. RESULTS: The median age of the 77 patients (44 men and 33 women) was 65 years (range, 35-85 years). Operations performed included thoracotomy with biopsy of hilar mass in 10 patients, wedge excision in 30 (6 with talc pleurodesis), segmentectomy in 4, lobectomy in 28, bilobectomy in 3, and pneumonectomy in 2. Mediastinal lymphadenectomy was performed in 50 patients and lymph node sampling in 19. Postoperative therapy included chemotherapy alone in 20 patients, radiation therapy in 3, and combined chemotherapy and radiation therapy in 40. Median tumor diameter was 4 cm (range, 1.0-10.0 cm). Postsurgical tumor stage was IA in 7 patients, IB in 11, IIA in 8, IIB in 7, IIIA in 30, IIIB in 10, and IV in 4. A total of 19 patients (25%) had complications: atrial arrhythmia in 7 patients, pneumonia in 6, prolonged air leak in 3, and myocardial infarction, postoperative bleeding, and cerebrovascular accident in 1 each. Operative mortality was 3% (2/ 77). Follow-up ranged from 4 days to 170 months (median, 19 months). At last follow-up, 20 patients were alive. The estimated overall 5-year survival was 27% when excluding the 10 patients who underwent a biopsy without additional surgery. Five-year survival for stage I and II combined (n=33) was 38% compared with only 16% for stage III and IV combined (n=34) (P=.02). Overall median survival was 24 months; median survival for patients who underwent curative surgery was 25 months compared with 16 months for those who had a palliative procedure (P=.34). CONCLUSION: Pulmonary resection in patients with stage I or stage II SCLC is safe with low mortality and morbidity. Curative resection is associated with long-term survival in early stage SCLC in some patients and should be considered in selected patients.

of tumor relapse is local recurrence.1 This has led to a renewed interest in the role of surgical resection to obtain better local control. The purpose of this study was to evaluate postoperative outcome in a group of patients with SCLC who underwent surgery. PATIENTS AND METHODS All patients who underwent thoracotomy with or without pulmonary resection for SCLC at Mayo Clinic in Rochester, Minn, from January 1985 to July 2002 were retrospectively reviewed. Preoperatively, histories were taken; all patients underwent physical examination, electrocardiography, chest radiography, and computed tomography of the chest and upper abdomen; and a complete blood cell count, liver chemistries, and serum creatinine levels were obtained. Diagnosis was established by histologic examination of the resected specimen. Patients were classified using the TNM staging system according to the criteria established by the American Joint Committee for Cancer Staging and End-Results Reporting for non-SCLC.2 Operative mortality was defined as death within 30 days of operation or during the same hospitalization. The time of thoracotomy was used as the starting date. Survival for all living patients was recorded up to June 31, 2003. The length of survival was determined for all patients who died. Survival was estimated using the Kaplan-Meier method.3 The effects of potential risk factors including age, sex, symptoms, smoking more than 40-pack-years, preoperative therapy, postoperative therapy, stage, extent of surgical procedure, lymphadenectomy, tumor location, and postoperative complications on survival were evaluated using log-rank tests.4 To evaluate the joint effects of potential risk factors on survival, Cox5 proportional hazards regression was used. Stepwise variable selection was used to identify risk factors for inclusion in the model. All statistical tests were 2-sided, and the threshold of significance was 0.05. The analysis was conducted using SAS version 8.2 (SAS Institute Inc, Cary, NC). The Mayo Foundation Institutional Review Board approved this study. RESULTS The study group consisted of 77 patients (44 men and 33 women). The median age at the time of thoracotomy was
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mall cell lung cancer (SCLC) is a virulent disease with a high metastatic potential. It is usually considered a systemic disease at presentation and therefore treated with chemotherapy, either alone or in combination with radiation therapy. Although the combination of chemotherapy and radiation therapy is associated with a good clinical response, long-term survival is poor. The most frequent site
From the Department of Surgery (V.C.) and Division of General Thoracic Surgery (M.S.A., F.C.N., C.D., S.D.C., P.C.P.), Mayo Clinic College of Medicine, Rochester, Minn. Dr Chandra is now with the University of Alabama, Birmingham. Presented at the American College of Chest Physicians 70th Annual International Scientific Assembly, Seattle, Wash, October 26, 2004. Individual reprints of this article are not available. Address correspondence to Mark S. Allen, MD, Department of Surgery, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: allen.mark@mayo.edu). 2006 Mayo Foundation for Medical Education and Research

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PULMONARY RESECTION IN SMALL CELL LUNG CANCER

TABLE 1. Postoperative Adjuvant Therapy at Various Stages No. of patients 7 11 8 7 30 10 4 77 Stage IA IB IIA IIB IIIA IIIB IV Total Chemotherapy 3 3 2 3 5 1 3 20 Radiotherapy Chemotherapy/ radiation 2 6 5 3 19 4 1 40 No adjuvant treatment 2 2 1 1 4 4 0 14

2 1 3

65 years (range, 35-85 years). Seventy-four patients were active smokers or had a history of smoking at the time of diagnosis; the remaining 3 patients were nonsmokers. Seventy-six patients were white, and 1 was African American. At initial presentation, cough was the most common symptom; 26 patients (34%) were asymptomatic. In addition, 13 patients (17%) presented with neurological symptoms, including gait disturbances in 5, neuralgic pain in 3, paraneoplastic syndrome in 2, and visual disturbance, myasthenia, and seizure disorder in 1 each. Two patients had nonspecific symptoms, including dysphagia and chest pain. Only 5 patients had combined chemotherapy and radiation therapy before thoracotomy; 2 patients had stage IIB, and 1 each had stage IIIA, IIIB, and IV disease. All showed clinical and radiological response after neoadjuvant therapy except for the patient with stage IIIB disease, and all had evidence of residual disease in the resected specimen. Mediastinoscopy was performed in 30 patients. Surgical procedures included wedge excision in 30 patients (6 with concomitant talc pleurodesis), segmentectomy in 4, lobectomy in 28, bilobectomy in 3, pneumonectomy in 2,

100 (67) 80 60 40 20 0 0 2 4 6 8 10 12 (29) (13) (8) (8) (6) (5) (0) 14

Years from surgery

and thoracotomy with biopsy of the hilar mass in 10. Mediastinal lymphadenectomy was performed in 50 patients, mediastinal lymph node sampling was done in 19 patients, and no mediastinal lymph nodes underwent biopsy in 8 patients. Median tumor diameter was 4 cm (range, 1.0-10.0 cm). A curative resection (R0 resection) was done in 46 patients (60%). Postsurgical stage was IA in 7 patients, IB in 11, IIA in 8, IIB in 7, IIIA in 30, IIIB in 10, and IV in 4. There were 2 perioperative deaths (operative mortality, 2.6%). The cause of death was pulmonary embolism in a patient with stage IV disease and unknown in another patient with stage IV disease. Postoperative complications occurred in 19 patients (24.4%) and included atrial arrhythmias in 7, pneumonia in 6, prolonged air leak in 3, and myocardial infarction, postoperative bleeding, and cerebrovascular accident in 1 each. Adjuvant therapy included chemotherapy in 20 patients, radiation therapy in 3, and both in 40 (Table 1). Median follow-up was 19 months (range, 4 days to 170 months). At last follow-up, 20 patients were alive and 57 had died. Excluding the 10 patients who just underwent biopsy, the overall 5-year survival was 27% (Figure 1) and varied according to stage (Table 2) (Figure 2). Five-year survival for patients with stage I disease was 36%; for stage II, 40%; for stage III, 17%; and for stage IV, 0% (P=.06). Five-year survival for patients with stage I and II disease combined was 38% compared with 16% for patients with stage III and IV disease (Figure 3) (P=.02). Median survival for patients who underwent curative surgery was 25 months compared with 16 months for those who had a palliative procedure (Figure 4) (P=.34). After multivariable analysis, surgical stage (III/IV vs I/II) was the only significant predictor identified, implying that after accounting for this risk factor, no other variable contributed significantly to the survival model. DISCUSSION Small cell lung cancer accounts for 10% to 15% of all bronchogenic carcinomas in the United States. It is a dis www.mayoclinicproceedings.com

FIGURE 1. Overall survival of patients. Probability of survival (death from any cause) in 67 patients who underwent resection of small cell lung cancer. Zero time on abscissa represents date of lung resection. Patients who had surgical biopsy only are excluded. Numbers in parenthesis are the number of patients at risk. Overall median survival was 24 months.

Percentage alive

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PULMONARY RESECTION IN SMALL CELL LUNG CANCER

TABLE 2. Survival Rates at Various Stages Percentage of patients who survived No. of patients 18 15 31 3 67* Stage I II III IV All patients Median survival (mo) 29 23 22 16 24 1y 78 79 69 67 73 2y 67 40 38 50 49 3y 49 40 23 0 33 5y 36 40 17 0 27

*The 10 patients who had only a biopsy are excluded.

tinct pathological entity with the unique clinical behavior of a short doubling time and thus rapid tumor growth.6 This behavior explains the aggressive clinical nature of SCLC and its high sensitivity to cytotoxic chemotherapy.7 Usually, SCLC is considered a systemic disease at the time of diagnosis and generally carries a poor prognosis because of both its rapid growth rate and its propensity to metastasize.7,8 Two thirds of patients with seemingly localized disease (disease limited to 1 hemithorax, the mediastinum, and supraclavicular nodes, provided all disease can be included in 1 radiotherapy field) at initial diagnosis have distant occult metastasis, precluding curative radiotherapy or surgery.9 Untreated, patients with limited stage SCLC rarely survive more than 35 weeks, and when extensive disease (ie,

disease beyond the domain of limited disease)10 is present, the median survival is only 20 weeks.11 Historically, only 10% of patients with SCLC present with disease confined to the ipsilateral hemithorax without evidence of distant spread.12 Most patients who undergo surgery for SCLC represent a select subgroup with limited disease; therefore, it is not surprising that a large proportion of our patients (34%) were asymptomatic at presentation. Before 1970, patients with SCLC were treated with surgical resection, often pneumonectomy. However, the poor survival of surgically treated patients in randomized clinical trials13-16 led most clinicians to abandon surgery as the initial treatment, and chemotherapy, either alone or in combination with radiation therapy, became the standard

100 Stage I Stage II Stage III Stage IV

80

Percentage alive

60

40

20

0 0 Stage I Stage II Stage III Stage IV 18 15 31 3 2 12 5 12 1 4 6 4 3 6 4 3 1 8 4 3 1 10 3 3 12 2 3 14 0 0

Years from surgery

FIGURE 2. Survival of patients by stage. Probability of survival (death from any cause) in patients who underwent resection of small cell lung cancer. Zero time on abscissa represents date of lung resection. Patients who had surgical biopsy only are excluded. Numbers under the graph represent the number of patients at risk. Log-rank, P=.13.

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PULMONARY RESECTION IN SMALL CELL LUNG CANCER

100

80

Stage I/II Stage III/IV

Percentage alive

60

40

20

0 0 Stage I/II Stage III/IV 33 34 2 17 12 4 10 3 6 7 1 8 7 1 10 6 12 5 14 0

Years from surgery

FIGURE 3. Survival of patients in stage I and II vs those in stage III and IV. Probability of survival (death from any cause) in patients who underwent resection of small cell lung cancer. Zero time on abscissa represents date of lung resection. Patients who had surgical biopsy only are excluded. Numbers under the graph represent the number of patients at risk. Log-rank, P=.02.

treatment.17,18 Although the initial results with combined chemotherapy and radiation therapy were encouraging,19 long-term survival is poor,20-22 with less than 15% of pa-

tients surviving more than 2 years.23 Even in patients with limited stage disease treated with chemotherapy and radiotherapy, the median survival is 15 to 20 months with 2- and

100

80

Palliative Curative

Percentage alive

60

40

20

10

12

14

Years from surgery

Curative 46 Palliative 31 22 9 10 4 6 2 6 2 6 5 0

FIGURE 4. Survival of patients who had curative surgery vs those who had noncurative procedures. Zero time on abscissa represents date of lung resection. Patients who had surgical biopsy only are included. Numbers under the graph represent the number of patients at risk. Log-rank, P=.34.

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PULMONARY RESECTION IN SMALL CELL LUNG CANCER

5-year survival rates of 40% to 50% and 10% to 20%, respectively.24 The most frequent localized relapse is at the site of the tumor. Even with the addition of thoracic radiation, relapse continues to occur at the primary site in up to one third of patients.1,25,26 This suggests that if survival is to improve, more aggressive local tumor control is necessary. This has led to renewed interest in the role of surgical resection of the primary tumor and regional lymph nodes. Although our retrospective study is not randomized, our results suggest that long-term survival can be achieved with surgical resection in selected patients with SCLC. Others have found similar results.12,19,27-36 Shields et al12 reported a 5-year survival rate of 23% in patients who had curative pulmonary resection and adjuvant chemotherapy. Our own survival results at 2 and 5 years of 49% and 27%, respectively, are also similar to other series. We analyzed several clinical variables in an attempt to identify factors predicting cumulative probability of survival. The pathological TNM stage was the only factor affecting survival. Long-term survival was greatest in patients with stage I and II disease. This finding has also been reported by others.12 Although we were unable to demonstrate that pulmonary resection significantly influenced survival, as suggested by Davis et al,35 our patients survived longer when curative pulmonary resection was performed. Our inability to show a statistically significantly difference is likely because of the limited number of patients. Surgical resection alone, however, is inadequate therapy for limited SCLC. The objective of surgical resection in the treatment of these patients is to achieve better control of the primary site when combined with postoperative chemotherapy and local radiotherapy.23 Patients with stage II and stage III disease with hilar and mediastinal lymph nodes are candidates for postoperative thoracic radiotherapy. Management of SCLC should utilize principles similar to those used in the management of non-SCLC. When the diagnosis of SCLC is established preoperatively, the stage of disease should be clinically determined by obtaining the history of the patient and performing a physical examination, computed tomography, and positron emission tomography. When clinically indicated, mediastinal exploration either by mediastinoscopy or mediastinotomy should be performed before thoracotomy. If occult mediastinal lymph node metastasis is found, pulmonary resection is unlikely to benefit the patient, and combined chemotherapy and radiation therapy should be offered. Patients with advanced local disease (any T3 or N2 lesions) have an extremely poor prognosis after resection.12 In our series, only 17% patients with N2 disease survived more than 5 years. The difference in survival for patients with N2 disease
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compared to those without it was statistically significant (P=.03). Patients with stage I tumors, even when proved to be SCLC on needle biopsy, should be offered a surgical approach since many of these tumors may prove not to be SCLC, and the results of surgical resection for stage I disease are excellent.37 Although a 20% five-year survival was reported for patients with limited SCLC in a recent radiotherapy intergroup trial,38 the disease in the patients in that study was not staged using the TNM staging system. In almost all instances, the surgical pathological staging is more advanced than the preoperative clinical staging even when mediastinoscopy is used.39 For this reason, a true estimation cannot be made of the cure rate of patients with clinical stage T1 N0 or T2 N0 disease who receive combined chemotherapy and radiation as the primary treatment. As long as a complete surgical resection can be performed, surgery must be considered as the first step of the multi-modality treatment in these patients. Future trials should be encouraged to use the TNM staging system since it provides better details of the stage of the disease compared to the terms limited and extensive disease so that a more valid comparison can be made in the future.37 The timing of surgical intervention is also controversial. Whether adjuvant or neoadjuvant chemotherapy and radiotherapy are more effective is often debated. The survival rates of preoperative chemotherapy followed by surgery are inferior to those obtained by treating patients with surgery first, followed by adjuvant chemotherapy.19 The 5year survival rate for patients who underwent surgery followed by postoperative chemotherapy for pathological stage I disease was as high as 48% in a study by Shepherd et al.23 The authors concluded that surgery followed by chemotherapy was the best treatment for stage I disease. Since only 5 of our patients had preoperative therapy, we cannot make a conclusive recommendation that differs from the current literature. CONCLUSION Pulmonary resection in patients with stage I or stage II SCLC is safe with low mortality and morbidity. Curative resection is associated with long-term survival in early stage SCLC and should be considered in selected patients.
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