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Results of surgical resection of patients with primary lung cancer: a retrospective analysis of 1,905 cases
Results of Surgical Resection of Patients With Primary Lung Cancer: A Retrospective Analysis of 1,905 Cases Dekang Fang, MD, Dawei Zhang, MD, Guojun Huang, MD, Rugang Zhang, MD, Liangjun Wang, MD, and Dechao Zhang, MD Department of Thoracic Surgery, Cancer Institute (Hospital), Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
Background. Surgical resection, combined therapies, and lymphadenectomy are extensively utilized in the treatment of patients with lung cancer. In the present study, we summarized the clinical data of patients with primary lung cancer after surgical resection alone or combined with adjuvant therapy, and evaluate the main factors influencing long-term survival. Methods. A retrospective review of 1,905 consecutive patients with primary lung cancer treated at the Cancer Institute of the Chinese Academy of Medical Sciences from March 1961 through December 1995 was performed. Statistical analysis was done using STATA software. The survival rate was estimated using the life-table method. Survival differences were performed using the log-rank test. The modified 1997 TNM staging system was used. Results. There was a 12.28% morbidity rate and a 1.31%
hospital mortality in our series. The 5-year survival rate for the complete resection was 49.5% and for the palliative resection 18.8% (p < 0.01). The 5-year survival rate was 72.0% in stage IA and 61.0% in stage IB (p < 0.05), 32.9% in stage IIA and 34.5% in stage IIB, 22.6% in stage IIIA and 15.9% in stage IIIB (p < 0.05), and 7.1% in stage IV. Conclusions. Multiple factors influence the long-term survival of patients with primary lung cancer after surgery. They include TNM staging, the extent of surgical resection (complete or palliative), resection margin (positive or negative), pathologic type of tumors, and type of resection.
D
over a period of 37 years in the Thoracic Department of our hospital (one of the largest cancer centers in mainland China).
ifferent therapeutic modalities have been used in the management of lung cancer depending on the tumor stage and the clinical status of the patients. Among them, surgical resection remains the mainstay procedure for treatment of lung cancer, particularly in patients with stages IA to IIIA of lung cancer. However, there is no standard recommendation on the extent of lymphadenectomy in the treatment of lung cancer. Some centers routinely perform mediastinal lymph node sampling with resection on suspicious lymph nodes, whereas others recommend radical systematic mediastinal lymphadenectomy for improvement of survival and better staging [1]. In addition, the beneficial effect of postoperative adjuvant chemotherapy or radiotherapy is a controversial issue. Some studies showed that postoperative radiotherapy significantly reduced local relapses but did not improve overall survival [2]. Other investigations demonstrated that patients did not benefit with adjuvant radiotherapy alone [3]. To address these issues, we retrospectively analyzed 1,905 consecutive patients with primary lung cancer who underwent surgical resection Accepted for publication May 29, 2001. Address reprint requests to Dr Fang, Department of Thoracic Surgery, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, People’s Republic of China; e-mail: [email protected].
© 2001 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
(Ann Thorac Surg 2001;72:1155–9) © 2001 by The Society of Thoracic Surgeons
Patients and Methods In the 37-year period between March 1961 and December 1995, a total of 1,905 patients underwent surgical resection for primary lung cancer at Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences. There were 1,516 men (79.58%) and 389 women (20.42%), between 20 and 83 years of age, with a mean age of 55.5 ⫾ 9.14 years. The median duration of illness was 4.36 months. There were 1,357 patients (70.94%) who had the illness less than 5 months. A central lung lesion was diagnosed in 36.04% and peripheral lesion in 63.96%. One thousand seven hundred fourteen patients (90%) had clinical symptoms and chief complaints before the diagnosis of lung cancer was made, which are summarized in Table 1. The remaining 10% of patients were asymptomatic and the disease was found during routine physical examination. Preoperatively, all patients underwent thorough diagnostic and staging procedures that included chest roentgenogram and abdominal ultrasound. Since 1985, computed tomography (CT) of chest and abdomen were 0003-4975/01/$20.00 PII S0003-4975(01)02932-0
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Table 1. Clinical Symptoms and Chief Complaints
Results
Symptom
Two hundred thirty-four patients had postoperative complications, for a resection-morbidity rate of 12.28%. Common complications included atelectasis in 25 patients (1.31%), arrhythmia in 21 patients (1.10%), intrathoracic hemorrhage in 20 patients (1.05%), bronchopleural fistula in 18 patients (0.94%), empyema in 18 patients (0.94%), respiratory failure in 17 patients (0.89%), and pneumonia in 13 patients (0.68%). Twenty-five patients died during the initial hospitalization, and the hospital mortality rate was 1.31% for the series. The major cause of postoperative death included respiratory failure (n ⫽ 7), pulmonary embolism (n ⫽ 4), cardiac infarction (n ⫽ 3), postoperative hemorrhage (n ⫽ 3), and bronchopleural fistula (n ⫽ 2). The overall 5-, 10-, 15-, and 20-year survival rates were 44.04%, 32.68%, 25.13%, and 19.17%, respectively. There were 1,382 patients (72.6%) who had the lobectomy procedure, 315 patients (16.5%) who had pneumonectomy, 166 patients (8.7%) who had sleeve lobectomy, and 42 patients (2.2%) who had partial lung resection for the series. The 5-year survival rate was 57.2% for sleeve lobectomy, 43.9% for lobectomy, 39.4% for pneumonectomy, and 33.2% for partial resection. Patients who underwent sleeve resection were found to have significantly higher 5-year survival rates compared with patients in other groups (p ⬍ 0.05), suggesting that choice of surgical resection procedure influences the long-term survival. There were 1,558 patients (81.8%) who underwent complete resection in the series. The 5-year survival rate for patients undergoing complete resection was 49.5% and for palliative resection 18.8% (p ⬍ 0.01). In the group undergoing palliative resection, 203 (61.70%) patients were diagnosed as non-small cell lung cancer (NSCLC). They received postoperative adjuvant therapies including radiation therapy (n ⫽ 158), chemotherapy (n ⫽ 32), and chemoradiotherapy (n ⫽ 13). Histopathological examination showed that 48.3% of the tumors were squamous cell carcinoma, 34.5% were adenocarcinoma, 7.9% were small cell lung cancer (SCLC), 4.8% were adeno-squamous cell carcinoma, 1.8% were alveolar cell carcinoma, and 1.1% were large cell carcinoma. Additionally, 1.7% of specimens were miscellaneous. The 5-year survival rate for patients who had alveolar cell carcinoma was 62.4%, for squamous cell carcinoma 51.0%, for SCLC 42.6%, for adenocarcinoma 36.6%, for adeno-squamous cell carcinoma 34.4%, and for large cell carcinoma 12.0%. In this series, patients with large cell carcinoma had the lowest 5-year survival rate (p ⬍ 0.01). Seventy-eight patients who did not have lymphadenectomy performed were excluded from p-TNM staging. Thus, 1,827 patients (95.90%) were staged pathologically according to the TNM classification of the UICC. As shown in Table 2, 5-year survival rates for patients with stage IA, IB, IIB, or IIIA were significantly different compared with those with stage IB, IIA, IIIA, or IIIB, respectively (p ⬍ 0.05). However, a significant difference was not found when comparing 5-year survival rate for patients with IIA with those with IIB or IIIB with IV. One thousand eight hundred three patients (94.7%) had negative resection margins in this series. A significant difference in 5-year survival rate was found between
Cough Sputum Bloody sputum Dyspnea Chest pain Fever Hypodynamia Arthralgia
Patients 1,473 (77.32%) 1,151 (60.41%) 958 (50.28%) 687 (36.06%) 681 (35.74%) 507 (26.61%) 296 (15.53%) 104 (5.45%)
performed for noninvasive preoperative staging. Some patients who had pain on bone received emission computed tomography (ECT) of bone. A mediastinoscopy was performed with histopathological examination of biopsy specimens in 33 patients for suspect N3 metastasis stage based on CT scan. Intraoperatively, upper lobe lobectomy was performed on left (n ⫽ 294) and right (n ⫽ 353) lungs of 647 patients. Middle lobe lobectomy was performed in 79 patients, lower lobe lobectomy on either lung in 454 patients (left lung, n ⫽ 232; right lung, n ⫽ 222), upper-middle lobe bilobectomy in 23 patients, middle-lower lobe bilobectomy in 177 patients, upper lobe sleeve lobectomy on either lung in 142 patients (left lung, n ⫽ 48; right lung n ⫽ 94), middle lobe sleeve lobectomy in 2 patients, lower lobe sleeve lobectomy on either lung in 13 patients (left lung, n ⫽ 9; right lung, n ⫽ 4), upper-middle lobe sleeve lobectomy in 6 patients, middle-lower lobe sleeve lobectomy in 11 patients, pneumonectomy on either lung in 315 patients (left lung, n ⫽ 212; right lung, n ⫽ 103), and partial resection on either lung in 42 patients (left lung, n ⫽ 24; right lung, n ⫽ 18). In addition, pulmonary resection was abandoned in 19 patients who were diagnosed as pathologic N3 stage IV disease. The resection was considered complete when surgeons were as certain as possible that all known disease and lymph nodes with metastasis were removed, and resection margins were free at histopathologic examination. Based on the operative specimens, all patients were staged pathologically according to UICC 1997 revised TNM classification [4]. Follow-up information was obtained from follow-up examinations or surveys. All patients were followed beyond 5 years. One hundred and thirty-seven patients lost to follow-up were presumed dead. The follow-up rate was 93.02%. One thousand and twelve patients have died. Among them, 766 patients died with extensive cancer metastases or recurrence, 27 with cardiac disease, 25 with postoperative complications, 25 with miscellaneous disease, 20 with pulmonary disease, and 17 with a secondary primary malignancy. In addition, 132 patients died of unknown causes. The data were statistically analyzed with the STATA 5.0 software. The survival rate was calculated by life-table method [5], the influence of variables on the survivors analyzed by the log-rank test, and the Cox proportional hazards model for continuous variables and for multivariate analysis [6⬃7].
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Table 2. Five-Year Survival Rate in Subgroups of TNM Staging
TNM stage IA IB IIA IIB IIIA IIIB IV
No.
5-Year Survival Rate
p
126 (6.6%) 702 (36.9%) 32 (1.7%) 499 (26.1%) 366 (19.2%) 49 (2.6%) 53 (2.8%)
72.0% 61.0% 32.9% 34.5% 22.6% 15.9% 7.1%
⬍ 0.05a ⬍ 0.05a ⬎ 0.05b ⬍ 0.05a ⬍ 0.05a ⬎ 0.05b
a
Comparison between the stage IA and IB; IB and IIA; IIB and IIIA; and b IIIA and IIIB. Comparison between stage IIA and IIB; and IIIB and IV.
patients having negative resection margins and those having positive resection margins (44.6% vs 28.9%, p ⬍ 0.01). There were 1,755 tumors that were histologically classified as NSCLC in this series. Combined therapy was applied to 34.39% of patients with NSCLC (n ⫽ 603). Among them, 106 patients received preoperative adjuvant treatments, including radiation therapy (n ⫽ 90), chemotherapy (n ⫽ 9), and bronchial artery infusion chemotherapy (n ⫽ 7). In addition, 497 patients with NSCLC received postoperative adjuvant therapies, including radiation therapy (n ⫽ 359), chemotherapy (n ⫽ 101), and chemo-radiotherapy (n ⫽ 37). Chemotherapy protocols for patients with NSCLC included Cyclophosphamide⫹Adriamycin⫹Cis-platinum (CTX⫹ADM⫹DDP), Navelbine (NVB)⫹DDP, and Vindesine⫹Mitomycin C⫹DDP (VDS⫹MMC⫹DDP). They were individualized for each patient with physicians from the Department of Chemotherapy at the hospital. The 5-year survival rates in surgery-only groups were higher than combined therapy groups in stage IA to IIA. However, the 5-year survival rates in combinedtherapy groups were higher than surgery-only groups in stage IIB-IV. However, a significant difference was only found between combined-therapy group and surgeryonly group in stage IIIA (Table 3). There were 150 patients with SCLC in the series. Combined therapy was used on 80.67% of these patients (n ⫽ 121). Among them, 14 patients received preoperative adjuvant treatments, including chemotherapy (n ⫽ 4), chemo-radiotherapy (n ⫽ 2), and radiation therapy (n ⫽ 8). In addition, 107 patients with SCLC received postoperative adjuvant treatments, including chemotherapy (n ⫽ 73), chemoradiotherapy (n ⫽ 28), and radiation therapy (n ⫽ 6). Protocols of chemotherapy for patients with SCLC included Carboplatin⫹Etoposide (CBP⫹VP16) or VDS⫹ADM⫹DDP, which were individualized with physicians from the Department of Chemotherapy. The 5-year survival rate of 44.5% in the combined group was higher than those in the surgery-only group (36.7%), although statistical significance was not observed. As shown in Table 4, there were increases in the patients’ mean age, lymphadenectomy rate, and 5-year survival rate in each decade. In contrast, the rate of postoperative complications declined over the 37 years.
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To identify factors influencing survival for patients in the series, multivariate analysis was performed. As shown in Table 5, the survival was affected by a variety of parameters, including the procedure of resections, TNM staging, and the positive rate of resection margin. However, pathologic type of tumors and type of resection did not significantly affect the final outcome.
Comment Previously, Wu and associates reviewed 8,382 cases operated with lung dissection between 1960 and 1985 in China. They found that that rate of pneumonectomy decreased from 22.0% to 49.2% to 13.0% to 17.5% in three decades. With reducing the rate of pneumonectomy and improving surgeons’ experience, the mortality 30 days after operation was not increased at their center [8]. In the present study, we found that the mean age of patients for lung cancer receiving surgical treatments was 46.5 years in the 1960s compared with 57.3 years in the 1990s. The postoperative complication rate has dropped from 23.0% in the 1960s to 9.7% in the 1990s. Moreover, the pulmonary complication rate was 8.11% in the 1960s and 2.49% in the 1990s (p ⬍ 0.05). In addition, the rate of miscellaneous complications was 10.81% in the 1960s and 2.37% in the 1990s (p ⬍ 0.05). Taken together, these observations suggest that: (a) the mean age of patients has steadily and markedly increased during the past decades; and (b) there has been a significant decrease in both pulmonary and miscellaneous complications during past decades. Reasons for the reduction in complication rate are not entirely clear in the present series. In recent decade, more patients were asked to go through a procedure for improving pulmonary function. In addition, preoperative care to patients was improved each year in the department. Furthermore, patients have routinely been transferred to the intensive care unit (ICU) postoperatively in our hospital since the 1980s. Surgeons in the department have become more experienced. Thus, we propose that these factors are the major causes for the reduction in complication. Table 3. Comparison of Survival Between CombinedTherapy Group and Surgery-Alone Group in Same Subgroup of TNM Stages for Non-Small Cell Lung Cancer Patients
IA IB IIA IIB IIIA IIIB IV
Combined Surgery alone Combined Surgery alone Combined Surgery alone Combined Surgery alone Combined Surgery alone Combined Surgery alone Combined Surgery alone
No.
5-Year Survival Rate
16 104 82 567 15 11 195 270 192 136 26 18 25 25
54.14% 74.29% 54.86% 62.29% 35.56% 42.42% 37.33% 31.86% 26.14% 11.95% 14.29% 11.76% 8.80% 5.49%
p ⬎ 0.05 ⬎ 0.05 ⬎ 0.05 ⬎ 0.05 ⬍ 0.05 ⬎ 0.05 ⬎ 0.05
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Table 4. Results During Different Decades
Cases of resection Median age (years) Rate of complication (%) Lymphadenectomy (%) N2 metastasis (%) 5-year survival rate (%) Total Stage IA to IB Stage IIA to IIB Stage IIIA to IIIB Stage IV
1960s
1970s
1980s
1990s
74 46.54 22.97 77.05 6.76
303 52.05 14.19 87.13 8.91
642 55.71 13.71 96.42 18.69
886 57.28 9.71 98.31 23.93
44.59 48.28 38.89 12.50 0
44.22 61.76 24.44 27.27 0
38.10 54.50 33.89 15.53 4.35
49.78 72.46 39.32 25.41 8.82
Another changing tendency is that lymphadenectomy has been emphasized in the treatment of lung tumors. In this series, the rate of lymphadenectomy has been increased from 77.05% in the 1960s to 98.31% in the 1990s. Meanwhile, the percentage of N2 lymph node metastasis increased from 6.76% in the 1960s to 23.93% in the 1990s. During the operation, surgeons have been asked to examine paratracheal, tracheobronchial angle, aortopulmonary window, para-aortic, anterior mediastinal, subcarinal, paraesophageal, and inferior pulmonary ligament lymph nodes. Enlarged lymph nodes in these areas are routinely removed from patients. Recently, several investigators showed that the increased incidence of N2 disease is because of the use of extensive lymphadenectomy [9, 10]. Thus, the extent of lymphadenectomy in the treatment of NSCLC is still a matter of controversy. Some centers perform mediastinal lymph node sampling with resection of only suspicious lymph nodes, while others recommend a radical systematic mediastinal lymphadenetomy to improve survival and to achieve better staging. Izbicki and associates reported that the radical systematic mediastinal lymphadenectomy does not influence disease-free or overall survival of patients with NSCLC without overt lymph node involvement [1]. However, a small subgroup of patients with limited mediastinal lymph node metastases might benefit from a systematic lymphadenectomy. Asamura and associates reported that subcarinal lymphadenectomy is not always necessary for tumors of the right upper lobe and left upper segment of lungs [11]. However, procedures of both superior mediastinal dissection and subcarinal dissection are beneficial to patients with tumors on other lobes. In addition, Okada and associates reported that patients having involvement of subcarinal nodes from upper-lobe lesions had a significantly worse prognosis than those with metastasis only to the upper mediastinal or aortic nodes [10]. Moreover, the overall survival of patients with nodal involvement of the upper mediastinum from lower-lobe tumors is significantly lower that those with metastasis limited to the lower mediastinum. During the last two decades, lymphadenectomy has been performed routinely in our department. We consider extensive lymphadenectomy to be the key factor influencing complete resection and correct staging. In the present series, we staged patients according to the 1997 UICC revised staging system for lung cancer. The data showed a significant difference in the 5-year
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survival rate between stage IA and stage IB, stage IB and IIA, stage IIB and IIIA, and stage IIIA and IIIB, respectively. But, there was no significant difference in the 5-year survival rates between stage IIA and IIB or stage IIIB and IV in the present series. Our results confirmed the justification for the recent revisions in the staging system of lung cancer. These same results were found in other studies [12, 13]. However, there are still some discrepancies that can not be explained. For example, the incidence of stage IIA is the lowest among the stage subgroups in the present series, which is similar to Mountain’s observation [14]. There was no significant difference between patients with stage IB disease and those with stage IIA disease [12]. Lam and associates reported that patients with primary lung cancer in stage I or II status are potentially curable with surgical treatment alone. The tumors in stage IIIA are also potentially operable in NSCLC [15]. The data in the present series demonstrated that survival in the surgery alone group was better than that in the combined-therapy group in stage I-IIA. Thus, we recommend use of surgical procedures for the treatment of patients with NSCLC in stages I, II, or IIIA. It is very important to stage lesions as accurately as possible before surgical therapies are planned. Here, we should emphasize the use of current modern diagnostic technologies such as CT, magnetic resonance imaging (MRI) scans, abdominal ultrasonography, and ECT during preoperative staging procedures. Mediastinoscopy should be performed if data from CT scanning indicate patients have suspicious N3 metastasis. Surgical resection is the best treatment procedure for patients with stage IA-IIIA lesions. The 5-year survival rate of the sleeve lobectomy group is the highest in the present series. Moreover, the incidence of stages I and II is 89.6% in the sleeve lobectomy group, 62.6% in the pneumonectomy group, and 74.6% in the lobectomy group. Comparing the survival of sleeve lobectomy group and pneumonectomy group in the same subgroup of the TNM stage, 5-year survival for the sleeve lobectomy group is significant higher than pneumonectomy only in stage I (p ⬍ 0.05). This may indicate that sleeve lobectomy does not improve survival. But for patients whose tumor involves the orifice of lobar bronchus or even part of the main bronchus, the sleeve lobectomy can be performed as an alternative to pneumonectomy. With improvement in the sleeve lobectomy surgical procedure, we expect that fewer patients will require pneumonectomy in the future. Hence, the quality of life in patients undergoing sleeve lobectomy will be much better than pneumonectomy because of the improved preservation of functional lung tissue. Particularly, this is very important for patients with low cardio-
Table 5. Factors Influencing Survival by Multivariate Analysis
Resection nature TNM stage Positive margin Type of resection Pathological type
Hazards Ratio
p
2.091 1.139 0.754 1.012 1.018
0.000 0.000 0.049 0.296 0.469
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respiratory reserve. Several studies have demonstrated that not only are the postoperative complication and mortality rates decreased in the sleeve lobectomy group, but the quality of life is better than after pneumonectomy [16, 17]. Recently, Suen and associates reported that the operative mortality and the long-term survival rate after sleeve lobectomy for NSCLC is similar to pneumonectomy [18]. In the present series, the rate of positive margin is 10.2% for sleeve lobectomy, which is the highest among all types of resection. It is significantly higher than that for regular lobectomy (10.2% vs 4.4%, p ⬍ 0.05). Thus, we emphasized that an adequate length of bronchus away from the tumor should be ensured. In addition, frozen section of the resection margin should be done routinely during the operation to guarantee a clean margin. In the present series, 80.67% patients with SCLC received combined-therapy. The 5-year survival rate in this group is better than the surgery alone group. Thus, we recommend having combined chemotherapy for patients with SCLC after operation. Within the subgroups of TNM staging for NSCLC, the patients with stage IIB to IV tumors in the combined-therapy group had better survival than surgery alone. But, a significant difference between the combined-therapy group and surgery alone group was only observed in stage IIIA. Based on this observation, we recommend that patients with stage II to IV should be given adjuvant treatment. Previously, Logan and associates analyzed 22 randomized-controlled trials (RCT) for patients with NSCLC after complete resection using the method of meta-analysis [3]. They found that postoperative radiotherapy reduced the rate of local recurrence although it did not improve the overall survival. Moreover, postoperative cisplatin-based chemotherapy reduced the relative risk of death and chemotherapy with alkylating agents increased the relative risk of death. Postoperative chemotherapy with or without radiotherapy resulted in a slightly reduced (statistically nonsignificant) risk of death among patients with surgically resected stage II or IIIA NSCLC. Furthermore, Lam and associates performed several metaanalyses on NSCLC and showed that postoperative chemotherapy is not suitable to apply to patients with diseases in stages I to IIIA [15]. However, their data indeed support using cisplatin-based postoperative chemotherapy on patients with stage IIIA N2 and stage IIIB diseases in improving survival. In the present series, we showed that patients with advanced-stage (ie, IIB to IV) diseases benefited from combination therapy. In contrast, applying postoperative combined chemotherapy to patients with early stage lesions (ie, stage I to IIA) has resulted in reducing overall survival. Together, these studies suggest that postoperative combined therapy should be used on patients with stage IIB to IV. However, further studies should be performed to determine which postoperative treatment protocols have the most beneficial effect for patients with NSCLC. As postoperative radiotherapy does not show any effect on improving overall survival on patients with lung cancer, it is very
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important to conduct studies with combined chemotherapy in the future. We thank Dr Ranna A. Rozenfeld for critical reading of the manuscript.
References 1. Izbicki JR, Passlick B, Pantel K, Pichlmeier U, Hosch SB. Effectiveness of radical systematic mediastinal lymphadenectomy in patients with resectable non-small cell lung cancer: results of a prospective randomized trial. Ann Surg 1998;227:138– 44. 2. Feng QF, Wang M, Wang LJ, et al. A study of postoperative radiotherapy in patients with non-small-cell lung cancer: a randomized trial. Int J Radiat Oncol Biol Phys 2000;47:925–9. 3. Logan MD, Lochrin CA, Darling G, Eady A, Newman TE, Ewans WK. Adjuvant radiotherapy and chemotherapy for stage II or IIIA non-small cell lung cancer after complete resection. Provincial lung cancer disease site group. Cancer Prev Control 1997;1:366–78. 4. Sobin LH, Wittekind Ch. TNM Classification of Malignant Tumors, 5th ed, 1st revision. New York: Wiley-Liss, 1997: 93–7. 5. Cox DR. Regression models and life-tasks. J R Stat Soc (series B) 1972;34:187–220. 6. Kaplan E, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457– 81. 7. Peto R, Peto J. Asymptotically efficient rank invariant procedures (with discussion). J R Statist Soc (series A) 1972;135: 185–207. 8. Wu YL, Huang ZF, Rong TH, Yang MT, Cao CG. Developing contrast study for surgery results in lung cancer. Chinese J Thorac Cardiovasc Surg 1992;8:250–2. 9. Que JQ, Ma FJ, Huang WH. Necessity for resection metastatic lymph nodes in mediastinum in lung cancer. Chinese J Thorac Cardiovasc Surg 1995;11:151–3. 10. Okada M, Tsubota N, Yoshimura M, Miyamoto Y, Matsuoka H. Prognosis of completely resected pN2 non-small cell lung carcinomas: what is the significant node that affects survival? J Thorac Cardiovasc Surg 1999;118:270–5. 11. Asamura H, Nakayama H, Kondo H, Tsuchiya R, Naruke T. Lobe-specific extent of systematic lymph node dissection for non-small cell lung carcinomas according to a retrospective study of metastasis and prognosis. J Thorac Cardiovasc Surg 1999;117:1102–11. 12. Inoue K, Sato M, Fujimura S, Sakurada A, Takahashi S, Usuda K, et al. Prognostic assessment of 1310 patients with non-small-cell lung cancer who underwent complete resection from 1980 to 1993. Jpn J Thorac Cardiovasc Surg 1998; 116:407–11. 13. Koike T, Terashima M, Takizawa T, Aoki T, Watanabe T, Akamatsu H. Results of surgery for primary lung cancer based on the new international staging system. Jpn J Thorac Cardiovasc Surg 1999;47:313–7. 14. Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997;111:1710–7. 15. Lam WK. Management of non-small cell lung cancer according to staging: an update. Respirology 1998;3:51– 4. 16. Yoshino I, Yokoyama H, Yano T, Ueda T, Takai E, Mizutani K, et al. Comparison of the surgical results of lobectomy with bronchoplasty and pneumonectomy for lung cancer. J Surg Oncol 1997;64:32–5. 17. Gaissert HA, Mathisen DJ, Moncure AC, Hilgenberg AD, Grillo HC, Wain JC. Survival and function after sleeve lobectomy for lung cancer. J Thorac Cardiovasc Surg 1996; 111:948–53. 18. Suen HC, Meyers BF, Guthrie T, Pohl MS, Sundaresan S. Favorable results after sleeve lobectomy or bronchoplasty for bronchial malignancies. Ann Thorac Surg 1999;67: 1557– 62.
Background. Surgical resection, combined therapies, and lymphadenectomy are extensively utilized in the treatment of patients with lung cancer. In the present study, we summarized the clinical data of patients with primary lung cancer after surgical resection alone or combined with adjuvant therapy, and evaluate the main factors influencing long-term survival. Methods. A retrospective review of 1,905 consecutive patients with primary lung cancer treated at the Cancer Institute of the Chinese Academy of Medical Sciences from March 1961 through December 1995 was performed. Statistical analysis was done using STATA software. The survival rate was estimated using the life-table method. Survival differences were performed using the log-rank test. The modified 1997 TNM staging system was used. Results. There was a 12.28% morbidity rate and a 1.31%
hospital mortality in our series. The 5-year survival rate for the complete resection was 49.5% and for the palliative resection 18.8% (p < 0.01). The 5-year survival rate was 72.0% in stage IA and 61.0% in stage IB (p < 0.05), 32.9% in stage IIA and 34.5% in stage IIB, 22.6% in stage IIIA and 15.9% in stage IIIB (p < 0.05), and 7.1% in stage IV. Conclusions. Multiple factors influence the long-term survival of patients with primary lung cancer after surgery. They include TNM staging, the extent of surgical resection (complete or palliative), resection margin (positive or negative), pathologic type of tumors, and type of resection.
D
over a period of 37 years in the Thoracic Department of our hospital (one of the largest cancer centers in mainland China).
ifferent therapeutic modalities have been used in the management of lung cancer depending on the tumor stage and the clinical status of the patients. Among them, surgical resection remains the mainstay procedure for treatment of lung cancer, particularly in patients with stages IA to IIIA of lung cancer. However, there is no standard recommendation on the extent of lymphadenectomy in the treatment of lung cancer. Some centers routinely perform mediastinal lymph node sampling with resection on suspicious lymph nodes, whereas others recommend radical systematic mediastinal lymphadenectomy for improvement of survival and better staging [1]. In addition, the beneficial effect of postoperative adjuvant chemotherapy or radiotherapy is a controversial issue. Some studies showed that postoperative radiotherapy significantly reduced local relapses but did not improve overall survival [2]. Other investigations demonstrated that patients did not benefit with adjuvant radiotherapy alone [3]. To address these issues, we retrospectively analyzed 1,905 consecutive patients with primary lung cancer who underwent surgical resection Accepted for publication May 29, 2001. Address reprint requests to Dr Fang, Department of Thoracic Surgery, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100021, People’s Republic of China; e-mail: [email protected].
© 2001 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
(Ann Thorac Surg 2001;72:1155–9) © 2001 by The Society of Thoracic Surgeons
Patients and Methods In the 37-year period between March 1961 and December 1995, a total of 1,905 patients underwent surgical resection for primary lung cancer at Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences. There were 1,516 men (79.58%) and 389 women (20.42%), between 20 and 83 years of age, with a mean age of 55.5 ⫾ 9.14 years. The median duration of illness was 4.36 months. There were 1,357 patients (70.94%) who had the illness less than 5 months. A central lung lesion was diagnosed in 36.04% and peripheral lesion in 63.96%. One thousand seven hundred fourteen patients (90%) had clinical symptoms and chief complaints before the diagnosis of lung cancer was made, which are summarized in Table 1. The remaining 10% of patients were asymptomatic and the disease was found during routine physical examination. Preoperatively, all patients underwent thorough diagnostic and staging procedures that included chest roentgenogram and abdominal ultrasound. Since 1985, computed tomography (CT) of chest and abdomen were 0003-4975/01/$20.00 PII S0003-4975(01)02932-0
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Table 1. Clinical Symptoms and Chief Complaints
Results
Symptom
Two hundred thirty-four patients had postoperative complications, for a resection-morbidity rate of 12.28%. Common complications included atelectasis in 25 patients (1.31%), arrhythmia in 21 patients (1.10%), intrathoracic hemorrhage in 20 patients (1.05%), bronchopleural fistula in 18 patients (0.94%), empyema in 18 patients (0.94%), respiratory failure in 17 patients (0.89%), and pneumonia in 13 patients (0.68%). Twenty-five patients died during the initial hospitalization, and the hospital mortality rate was 1.31% for the series. The major cause of postoperative death included respiratory failure (n ⫽ 7), pulmonary embolism (n ⫽ 4), cardiac infarction (n ⫽ 3), postoperative hemorrhage (n ⫽ 3), and bronchopleural fistula (n ⫽ 2). The overall 5-, 10-, 15-, and 20-year survival rates were 44.04%, 32.68%, 25.13%, and 19.17%, respectively. There were 1,382 patients (72.6%) who had the lobectomy procedure, 315 patients (16.5%) who had pneumonectomy, 166 patients (8.7%) who had sleeve lobectomy, and 42 patients (2.2%) who had partial lung resection for the series. The 5-year survival rate was 57.2% for sleeve lobectomy, 43.9% for lobectomy, 39.4% for pneumonectomy, and 33.2% for partial resection. Patients who underwent sleeve resection were found to have significantly higher 5-year survival rates compared with patients in other groups (p ⬍ 0.05), suggesting that choice of surgical resection procedure influences the long-term survival. There were 1,558 patients (81.8%) who underwent complete resection in the series. The 5-year survival rate for patients undergoing complete resection was 49.5% and for palliative resection 18.8% (p ⬍ 0.01). In the group undergoing palliative resection, 203 (61.70%) patients were diagnosed as non-small cell lung cancer (NSCLC). They received postoperative adjuvant therapies including radiation therapy (n ⫽ 158), chemotherapy (n ⫽ 32), and chemoradiotherapy (n ⫽ 13). Histopathological examination showed that 48.3% of the tumors were squamous cell carcinoma, 34.5% were adenocarcinoma, 7.9% were small cell lung cancer (SCLC), 4.8% were adeno-squamous cell carcinoma, 1.8% were alveolar cell carcinoma, and 1.1% were large cell carcinoma. Additionally, 1.7% of specimens were miscellaneous. The 5-year survival rate for patients who had alveolar cell carcinoma was 62.4%, for squamous cell carcinoma 51.0%, for SCLC 42.6%, for adenocarcinoma 36.6%, for adeno-squamous cell carcinoma 34.4%, and for large cell carcinoma 12.0%. In this series, patients with large cell carcinoma had the lowest 5-year survival rate (p ⬍ 0.01). Seventy-eight patients who did not have lymphadenectomy performed were excluded from p-TNM staging. Thus, 1,827 patients (95.90%) were staged pathologically according to the TNM classification of the UICC. As shown in Table 2, 5-year survival rates for patients with stage IA, IB, IIB, or IIIA were significantly different compared with those with stage IB, IIA, IIIA, or IIIB, respectively (p ⬍ 0.05). However, a significant difference was not found when comparing 5-year survival rate for patients with IIA with those with IIB or IIIB with IV. One thousand eight hundred three patients (94.7%) had negative resection margins in this series. A significant difference in 5-year survival rate was found between
Cough Sputum Bloody sputum Dyspnea Chest pain Fever Hypodynamia Arthralgia
Patients 1,473 (77.32%) 1,151 (60.41%) 958 (50.28%) 687 (36.06%) 681 (35.74%) 507 (26.61%) 296 (15.53%) 104 (5.45%)
performed for noninvasive preoperative staging. Some patients who had pain on bone received emission computed tomography (ECT) of bone. A mediastinoscopy was performed with histopathological examination of biopsy specimens in 33 patients for suspect N3 metastasis stage based on CT scan. Intraoperatively, upper lobe lobectomy was performed on left (n ⫽ 294) and right (n ⫽ 353) lungs of 647 patients. Middle lobe lobectomy was performed in 79 patients, lower lobe lobectomy on either lung in 454 patients (left lung, n ⫽ 232; right lung, n ⫽ 222), upper-middle lobe bilobectomy in 23 patients, middle-lower lobe bilobectomy in 177 patients, upper lobe sleeve lobectomy on either lung in 142 patients (left lung, n ⫽ 48; right lung n ⫽ 94), middle lobe sleeve lobectomy in 2 patients, lower lobe sleeve lobectomy on either lung in 13 patients (left lung, n ⫽ 9; right lung, n ⫽ 4), upper-middle lobe sleeve lobectomy in 6 patients, middle-lower lobe sleeve lobectomy in 11 patients, pneumonectomy on either lung in 315 patients (left lung, n ⫽ 212; right lung, n ⫽ 103), and partial resection on either lung in 42 patients (left lung, n ⫽ 24; right lung, n ⫽ 18). In addition, pulmonary resection was abandoned in 19 patients who were diagnosed as pathologic N3 stage IV disease. The resection was considered complete when surgeons were as certain as possible that all known disease and lymph nodes with metastasis were removed, and resection margins were free at histopathologic examination. Based on the operative specimens, all patients were staged pathologically according to UICC 1997 revised TNM classification [4]. Follow-up information was obtained from follow-up examinations or surveys. All patients were followed beyond 5 years. One hundred and thirty-seven patients lost to follow-up were presumed dead. The follow-up rate was 93.02%. One thousand and twelve patients have died. Among them, 766 patients died with extensive cancer metastases or recurrence, 27 with cardiac disease, 25 with postoperative complications, 25 with miscellaneous disease, 20 with pulmonary disease, and 17 with a secondary primary malignancy. In addition, 132 patients died of unknown causes. The data were statistically analyzed with the STATA 5.0 software. The survival rate was calculated by life-table method [5], the influence of variables on the survivors analyzed by the log-rank test, and the Cox proportional hazards model for continuous variables and for multivariate analysis [6⬃7].
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Table 2. Five-Year Survival Rate in Subgroups of TNM Staging
TNM stage IA IB IIA IIB IIIA IIIB IV
No.
5-Year Survival Rate
p
126 (6.6%) 702 (36.9%) 32 (1.7%) 499 (26.1%) 366 (19.2%) 49 (2.6%) 53 (2.8%)
72.0% 61.0% 32.9% 34.5% 22.6% 15.9% 7.1%
⬍ 0.05a ⬍ 0.05a ⬎ 0.05b ⬍ 0.05a ⬍ 0.05a ⬎ 0.05b
a
Comparison between the stage IA and IB; IB and IIA; IIB and IIIA; and b IIIA and IIIB. Comparison between stage IIA and IIB; and IIIB and IV.
patients having negative resection margins and those having positive resection margins (44.6% vs 28.9%, p ⬍ 0.01). There were 1,755 tumors that were histologically classified as NSCLC in this series. Combined therapy was applied to 34.39% of patients with NSCLC (n ⫽ 603). Among them, 106 patients received preoperative adjuvant treatments, including radiation therapy (n ⫽ 90), chemotherapy (n ⫽ 9), and bronchial artery infusion chemotherapy (n ⫽ 7). In addition, 497 patients with NSCLC received postoperative adjuvant therapies, including radiation therapy (n ⫽ 359), chemotherapy (n ⫽ 101), and chemo-radiotherapy (n ⫽ 37). Chemotherapy protocols for patients with NSCLC included Cyclophosphamide⫹Adriamycin⫹Cis-platinum (CTX⫹ADM⫹DDP), Navelbine (NVB)⫹DDP, and Vindesine⫹Mitomycin C⫹DDP (VDS⫹MMC⫹DDP). They were individualized for each patient with physicians from the Department of Chemotherapy at the hospital. The 5-year survival rates in surgery-only groups were higher than combined therapy groups in stage IA to IIA. However, the 5-year survival rates in combinedtherapy groups were higher than surgery-only groups in stage IIB-IV. However, a significant difference was only found between combined-therapy group and surgeryonly group in stage IIIA (Table 3). There were 150 patients with SCLC in the series. Combined therapy was used on 80.67% of these patients (n ⫽ 121). Among them, 14 patients received preoperative adjuvant treatments, including chemotherapy (n ⫽ 4), chemo-radiotherapy (n ⫽ 2), and radiation therapy (n ⫽ 8). In addition, 107 patients with SCLC received postoperative adjuvant treatments, including chemotherapy (n ⫽ 73), chemoradiotherapy (n ⫽ 28), and radiation therapy (n ⫽ 6). Protocols of chemotherapy for patients with SCLC included Carboplatin⫹Etoposide (CBP⫹VP16) or VDS⫹ADM⫹DDP, which were individualized with physicians from the Department of Chemotherapy. The 5-year survival rate of 44.5% in the combined group was higher than those in the surgery-only group (36.7%), although statistical significance was not observed. As shown in Table 4, there were increases in the patients’ mean age, lymphadenectomy rate, and 5-year survival rate in each decade. In contrast, the rate of postoperative complications declined over the 37 years.
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To identify factors influencing survival for patients in the series, multivariate analysis was performed. As shown in Table 5, the survival was affected by a variety of parameters, including the procedure of resections, TNM staging, and the positive rate of resection margin. However, pathologic type of tumors and type of resection did not significantly affect the final outcome.
Comment Previously, Wu and associates reviewed 8,382 cases operated with lung dissection between 1960 and 1985 in China. They found that that rate of pneumonectomy decreased from 22.0% to 49.2% to 13.0% to 17.5% in three decades. With reducing the rate of pneumonectomy and improving surgeons’ experience, the mortality 30 days after operation was not increased at their center [8]. In the present study, we found that the mean age of patients for lung cancer receiving surgical treatments was 46.5 years in the 1960s compared with 57.3 years in the 1990s. The postoperative complication rate has dropped from 23.0% in the 1960s to 9.7% in the 1990s. Moreover, the pulmonary complication rate was 8.11% in the 1960s and 2.49% in the 1990s (p ⬍ 0.05). In addition, the rate of miscellaneous complications was 10.81% in the 1960s and 2.37% in the 1990s (p ⬍ 0.05). Taken together, these observations suggest that: (a) the mean age of patients has steadily and markedly increased during the past decades; and (b) there has been a significant decrease in both pulmonary and miscellaneous complications during past decades. Reasons for the reduction in complication rate are not entirely clear in the present series. In recent decade, more patients were asked to go through a procedure for improving pulmonary function. In addition, preoperative care to patients was improved each year in the department. Furthermore, patients have routinely been transferred to the intensive care unit (ICU) postoperatively in our hospital since the 1980s. Surgeons in the department have become more experienced. Thus, we propose that these factors are the major causes for the reduction in complication. Table 3. Comparison of Survival Between CombinedTherapy Group and Surgery-Alone Group in Same Subgroup of TNM Stages for Non-Small Cell Lung Cancer Patients
IA IB IIA IIB IIIA IIIB IV
Combined Surgery alone Combined Surgery alone Combined Surgery alone Combined Surgery alone Combined Surgery alone Combined Surgery alone Combined Surgery alone
No.
5-Year Survival Rate
16 104 82 567 15 11 195 270 192 136 26 18 25 25
54.14% 74.29% 54.86% 62.29% 35.56% 42.42% 37.33% 31.86% 26.14% 11.95% 14.29% 11.76% 8.80% 5.49%
p ⬎ 0.05 ⬎ 0.05 ⬎ 0.05 ⬎ 0.05 ⬍ 0.05 ⬎ 0.05 ⬎ 0.05
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Table 4. Results During Different Decades
Cases of resection Median age (years) Rate of complication (%) Lymphadenectomy (%) N2 metastasis (%) 5-year survival rate (%) Total Stage IA to IB Stage IIA to IIB Stage IIIA to IIIB Stage IV
1960s
1970s
1980s
1990s
74 46.54 22.97 77.05 6.76
303 52.05 14.19 87.13 8.91
642 55.71 13.71 96.42 18.69
886 57.28 9.71 98.31 23.93
44.59 48.28 38.89 12.50 0
44.22 61.76 24.44 27.27 0
38.10 54.50 33.89 15.53 4.35
49.78 72.46 39.32 25.41 8.82
Another changing tendency is that lymphadenectomy has been emphasized in the treatment of lung tumors. In this series, the rate of lymphadenectomy has been increased from 77.05% in the 1960s to 98.31% in the 1990s. Meanwhile, the percentage of N2 lymph node metastasis increased from 6.76% in the 1960s to 23.93% in the 1990s. During the operation, surgeons have been asked to examine paratracheal, tracheobronchial angle, aortopulmonary window, para-aortic, anterior mediastinal, subcarinal, paraesophageal, and inferior pulmonary ligament lymph nodes. Enlarged lymph nodes in these areas are routinely removed from patients. Recently, several investigators showed that the increased incidence of N2 disease is because of the use of extensive lymphadenectomy [9, 10]. Thus, the extent of lymphadenectomy in the treatment of NSCLC is still a matter of controversy. Some centers perform mediastinal lymph node sampling with resection of only suspicious lymph nodes, while others recommend a radical systematic mediastinal lymphadenetomy to improve survival and to achieve better staging. Izbicki and associates reported that the radical systematic mediastinal lymphadenectomy does not influence disease-free or overall survival of patients with NSCLC without overt lymph node involvement [1]. However, a small subgroup of patients with limited mediastinal lymph node metastases might benefit from a systematic lymphadenectomy. Asamura and associates reported that subcarinal lymphadenectomy is not always necessary for tumors of the right upper lobe and left upper segment of lungs [11]. However, procedures of both superior mediastinal dissection and subcarinal dissection are beneficial to patients with tumors on other lobes. In addition, Okada and associates reported that patients having involvement of subcarinal nodes from upper-lobe lesions had a significantly worse prognosis than those with metastasis only to the upper mediastinal or aortic nodes [10]. Moreover, the overall survival of patients with nodal involvement of the upper mediastinum from lower-lobe tumors is significantly lower that those with metastasis limited to the lower mediastinum. During the last two decades, lymphadenectomy has been performed routinely in our department. We consider extensive lymphadenectomy to be the key factor influencing complete resection and correct staging. In the present series, we staged patients according to the 1997 UICC revised staging system for lung cancer. The data showed a significant difference in the 5-year
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survival rate between stage IA and stage IB, stage IB and IIA, stage IIB and IIIA, and stage IIIA and IIIB, respectively. But, there was no significant difference in the 5-year survival rates between stage IIA and IIB or stage IIIB and IV in the present series. Our results confirmed the justification for the recent revisions in the staging system of lung cancer. These same results were found in other studies [12, 13]. However, there are still some discrepancies that can not be explained. For example, the incidence of stage IIA is the lowest among the stage subgroups in the present series, which is similar to Mountain’s observation [14]. There was no significant difference between patients with stage IB disease and those with stage IIA disease [12]. Lam and associates reported that patients with primary lung cancer in stage I or II status are potentially curable with surgical treatment alone. The tumors in stage IIIA are also potentially operable in NSCLC [15]. The data in the present series demonstrated that survival in the surgery alone group was better than that in the combined-therapy group in stage I-IIA. Thus, we recommend use of surgical procedures for the treatment of patients with NSCLC in stages I, II, or IIIA. It is very important to stage lesions as accurately as possible before surgical therapies are planned. Here, we should emphasize the use of current modern diagnostic technologies such as CT, magnetic resonance imaging (MRI) scans, abdominal ultrasonography, and ECT during preoperative staging procedures. Mediastinoscopy should be performed if data from CT scanning indicate patients have suspicious N3 metastasis. Surgical resection is the best treatment procedure for patients with stage IA-IIIA lesions. The 5-year survival rate of the sleeve lobectomy group is the highest in the present series. Moreover, the incidence of stages I and II is 89.6% in the sleeve lobectomy group, 62.6% in the pneumonectomy group, and 74.6% in the lobectomy group. Comparing the survival of sleeve lobectomy group and pneumonectomy group in the same subgroup of the TNM stage, 5-year survival for the sleeve lobectomy group is significant higher than pneumonectomy only in stage I (p ⬍ 0.05). This may indicate that sleeve lobectomy does not improve survival. But for patients whose tumor involves the orifice of lobar bronchus or even part of the main bronchus, the sleeve lobectomy can be performed as an alternative to pneumonectomy. With improvement in the sleeve lobectomy surgical procedure, we expect that fewer patients will require pneumonectomy in the future. Hence, the quality of life in patients undergoing sleeve lobectomy will be much better than pneumonectomy because of the improved preservation of functional lung tissue. Particularly, this is very important for patients with low cardio-
Table 5. Factors Influencing Survival by Multivariate Analysis
Resection nature TNM stage Positive margin Type of resection Pathological type
Hazards Ratio
p
2.091 1.139 0.754 1.012 1.018
0.000 0.000 0.049 0.296 0.469
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respiratory reserve. Several studies have demonstrated that not only are the postoperative complication and mortality rates decreased in the sleeve lobectomy group, but the quality of life is better than after pneumonectomy [16, 17]. Recently, Suen and associates reported that the operative mortality and the long-term survival rate after sleeve lobectomy for NSCLC is similar to pneumonectomy [18]. In the present series, the rate of positive margin is 10.2% for sleeve lobectomy, which is the highest among all types of resection. It is significantly higher than that for regular lobectomy (10.2% vs 4.4%, p ⬍ 0.05). Thus, we emphasized that an adequate length of bronchus away from the tumor should be ensured. In addition, frozen section of the resection margin should be done routinely during the operation to guarantee a clean margin. In the present series, 80.67% patients with SCLC received combined-therapy. The 5-year survival rate in this group is better than the surgery alone group. Thus, we recommend having combined chemotherapy for patients with SCLC after operation. Within the subgroups of TNM staging for NSCLC, the patients with stage IIB to IV tumors in the combined-therapy group had better survival than surgery alone. But, a significant difference between the combined-therapy group and surgery alone group was only observed in stage IIIA. Based on this observation, we recommend that patients with stage II to IV should be given adjuvant treatment. Previously, Logan and associates analyzed 22 randomized-controlled trials (RCT) for patients with NSCLC after complete resection using the method of meta-analysis [3]. They found that postoperative radiotherapy reduced the rate of local recurrence although it did not improve the overall survival. Moreover, postoperative cisplatin-based chemotherapy reduced the relative risk of death and chemotherapy with alkylating agents increased the relative risk of death. Postoperative chemotherapy with or without radiotherapy resulted in a slightly reduced (statistically nonsignificant) risk of death among patients with surgically resected stage II or IIIA NSCLC. Furthermore, Lam and associates performed several metaanalyses on NSCLC and showed that postoperative chemotherapy is not suitable to apply to patients with diseases in stages I to IIIA [15]. However, their data indeed support using cisplatin-based postoperative chemotherapy on patients with stage IIIA N2 and stage IIIB diseases in improving survival. In the present series, we showed that patients with advanced-stage (ie, IIB to IV) diseases benefited from combination therapy. In contrast, applying postoperative combined chemotherapy to patients with early stage lesions (ie, stage I to IIA) has resulted in reducing overall survival. Together, these studies suggest that postoperative combined therapy should be used on patients with stage IIB to IV. However, further studies should be performed to determine which postoperative treatment protocols have the most beneficial effect for patients with NSCLC. As postoperative radiotherapy does not show any effect on improving overall survival on patients with lung cancer, it is very
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important to conduct studies with combined chemotherapy in the future. We thank Dr Ranna A. Rozenfeld for critical reading of the manuscript.
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