Small cell lung cancer (SCLC), which represents 20%

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1 ORIGINAL ARTICLES: GENERAL THORACIC Surgical Results for Small Cell Lung Cancer Based on the New TNM Staging System Masayoshi Inoue, MD, Shinichiro Miyoshi, MD, Tsutomu Yasumitsu, MD, Takashi Mori, MD, Keiji Iuchi, MD, Hajime Maeda, MD, and Hikaru Matsuda, MD, for the Thoracic Surgery Study Group of Osaka University, Osaka, Japan Department of Surgery, Osaka Prefectural Habikino Hospital, Department of Surgery, Course of Interventional Medicine (E1), Osaka University Graduate School of Medicine, Department of Surgery, National Kinki Central Hospital for Chest Diseases, and Department of Surgery, Toneyama National Hospital, Osaka, Japan Background. Operation with combined chemotherapy has been recently recommended for very early stage of small cell lung cancer without lymph node metastasis. Methods. A retrospective study was undertaken in 91 patients who had undergone pulmonary resection for small cell lung cancer according to the new international staging system. Results. The 5-year overall probability of survival was 37.1%. The 5-year survival rate was 100% for p-stage 0, 56.1% for p-stage IA, 30.0% for p-stage IB, 57.1% for p-stage IIA, and 42.9% for p-stage IIB. In the p-stage IA IIB patients who underwent a complete resection, the 5-year survival rate of the patients treated by operation with chemotherapy was better than that of patients treated by operation alone. In addition, the 5-year survival rate of the patients who had four or more courses of chemotherapy was 80.0%. Conclusions. These results suggest that operation should be considered for p-stage IA IIB patients and more than four courses of combined chemotherapy might be desirable in these resectable cases. (Ann Thorac Surg 2000;70:1615 9) 2000 by The Society of Thoracic Surgeons Small cell lung cancer (SCLC), which represents 20% to 25% of all lung cancer cases, shows a high grade malignancy with a rapid growth and early metastasis to other organs as compared with non-small cell lung cancer [1]. As for the treatment for SCLC, operation was once abandoned after the results reported by the British Medical Research Council and chemotherapy has played a great role [2]. Chemotherapy has been generally accepted as effective for SCLC and the response rate has been reported to be 80% to 90%. However, local recur- For editorial comment, see page rence has been frequently found even in those patients who show complete remission and the 5-year survival has been reported as 19% to 23% in limited disease (LD) [3 5]. Recently, a surgical treatment with combined chemotherapy has been recommended in LD patients without lymph node metastasis [6 11]. In this study, we retrospectively analyzed SCLC patients who had undergone pulmonary resection according to the new TNM staging system to clarify the operative indication and significance of the chemotherapy treatment in these resectable cases [12]. Accepted for publication Jan 5, Address reprint requests to Dr Miyoshi, Department of Surgery, Course of Interventional Medicine (E1), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka , Japan; miyoshi@surg1.med.osaka-u.ac.jp. Material and Methods Between January 1975 and December 1994, thoracotomies were performed in 3,497 lung cancer patients at Osaka University Hospital, Osaka Prefectural Habikino Hospital, National Kinki Central Hospital, and Toneyama National Hospital. Among them, there were 95 SCLC patients (2.7%) including four exploratory thoracotomies. Ninety-one SCLC patients treated by pulmonary resection were enrolled in this study. The patient characteristics are shown in Table 1. A histologic or cytologic diagnosis was performed using the specimens obtained by a transbronchial lung biopsy or percutaneous needle biopsy. Sixty-one patients were diagnosed as SCLC, 8 as squamous cell carcinoma, 5 as adenocarcinoma, whereas 17 could not be diagnosed preoperatively. Clinical staging was evaluated using a computed tomography of the chest, brain, and abdomen, as well as bone scintigraphy. There were 32 patients with c-stage IA, 30 with c-stage IB, 6 with c-stage IIA, 12 with c-stage IIB, and 11 with c-stage IIIA. An operative indication was considered for c-stage IA IIB in patients who had been preoperatively diagnosed as SCLC. The operative cases with c-n2 included 8 patients who had not been confirmed as SCLC preoperatively, and 1 patient who had been reduced to y-n0 by induction chemotherapy. Pathologically, there were 4 patients with p-stage 0, 30 with p-stage IA, 20 with p-stage IB, 7 with p-stage IIA, 7 with p-stage IIB, 19 with p-stage IIIA, and 4 with p-stage IIIB. A pneumonectomy was performed in 10 patients, lobectomy in 77 patients, and segmentectomy or 2000 by The Society of Thoracic Surgeons /00/$20.00 Published by Elsevier Science Inc PII S (00)

2 1616 INOUE ET AL Ann Thorac Surg OPERATION FOR SMALL CELL LUNG CANCER 2000;70: Table 1. Characteristics of SCLC Patients Treated by Pulmonary Resection Characteristics Data Age (yr) ( ) Sex male 75, female 16 Preoperative diagnosis SCLC 61, SQ 8, AD 5, not determined 17 c-stage IA 32, IB 30, IIA 6, IIB 12, IIIA 11 (T3N1 2, T1-2N2 7, T3N2 2) p-stage 0 4, IA 30, IB 20, IIA 7, IIB 7, IIIA 19 (T1-2N2 14, T3N2 5), IIIB 4 (T4N1 2, T4N2 1, T2N3 1) Operation Pneumonectomy 10, lobectomy 77, segmentectomy or partial resection 4 Chemotherapy 71 (pre- and postoperative 9, preoperative 20, postoperative 42) Radiation therapy 17 (PCI 5) AD adenocarcinoma; PCI prophylactic cranial irradiation; SQ squamous cell carcinoma. Table 3. Relationship Between c-n and p-n in SCLC Patients Who Did Not Receive Preoperative Chemotherapy p-n0 p-n1 p-n2 p-n3 Total c-n c-n c-n Total partial resection in 4 patients. As for the radicality, a curative resection was performed in 81 patients. Chemotherapy was performed in 71 patients, whereas 17 were irradiated, including 5 who had prophylactic cranial irradiation. Preoperative chemotherapy has been given to the good risk patients with histologic diagnosis of SCLC under the judgment of the attending physicians. The survival period was counted from either the operative date or the beginning date of induction chemotherapy. The mean follow-up period was months and the median was 136 months. Survival was estimated according to the method of Kaplan and Meier. The influence of variables on survival was analyzed using a log-rank test. The relative importance of various prognostic factors for postoperative survival as identified by multivariate analysis was performed with Cox s proportional hazards model with the forward stepwise method. Statistical analyses were performed with the commercially available personal computer program SPSS (SPSS Inc, Chicago, IL). A probability value of less than 0.05 was considered significant. Results Preoperative Evaluation We first compared the clinical stage with the pathologic stage in 62 patients who had not been treated by induction chemotherapy (Table 2). The accuracy was 61.3% (38 of 62 patients). We had underestimated the stage in 20 patients (32.3%). It was conspicuous that 6 patients had been underestimated out of 9 in c-stage IIB. On the other hand, we had overestimated the stage in only 4 patients (6.5%). As for the N-factor, the relationship between c-n and p-n is shown in Table 3. The accuracy by thoracic computed tomography was 67.7% (42 of 62 patients). We had underestimated the N-factor in 19 patients (30.6%), in which 6 were conspicuously included among the 10 c-n1 patients. We had overestimated only 1 patient (1.6%). Thus, our clinical stage underestimating was mainly due to the N-factor. Survival Rate by c-stage and p-stage The overall survival curve is shown in Figure 1. The 5-year probability of survival was 37.1% and the median survival time (MST) was 26 months. Figure 2 shows the survival curves by c-stage. The 5-year survival rate and MST were 49.4% and 53 months for c-stage IA, 46.7% and 25 months for c-stage IB, and 33.3% and 18 months for Table 2. Relationship Between c-stage and p-stage in SCLC Patients Who Did Not Receive Preoperative Chemotherapy p-stage IA IB IIA IIB IIIA IIIB Total c-stage IA IB IIA IIB IIIA Total Fig 1. Overall survival of small cell lung cancer patients who underwent pulmonary resection.

3 Ann Thorac Surg INOUE ET AL 2000;70: OPERATION FOR SMALL CELL LUNG CANCER 1617 Fig 2. Survival curves according to clinical stage. c-stage IIA, respectively. The MST was 14 months for c-stage IIB and 9 months for c-stage IIIA. The survival by p-stage is shown in Figure 3. The 5-year survival rate and MST were 56.1% and 67 months for p-stage IA, 30.0% and 23 months for p-stage IB, 57.1% and 106 months for p-stage IIA, and 42.9% and 14 months for p-stage IIB, respectively. The MST was 9 months for p-stage IIIA and 4 months for p-stage IIIB. Survival Rate by T-Factor and N-Factor We also analyzed the survival rate by pathologic T- and N-factor. As shown in Figure 4A, survival seemed to be determined by the T-factor and the 5-year survival rate was 100% for p-t0, 50.9% for p-t1, and 24.3% for p-t2. The survival rate for p-t1 patients was significantly better than that for p-t2 ( p ) and p-t2 was better than that for p-t3 ( p ). As for the p-n factor, the 5-year survival rate was 48.5% for p-n0 and 46.7% for p-n1 (Fig 4B). The survival rate for both p-n0 and p-n1 was significantly better than that of p-n2 ( p and p ). Fig 3. Survival curves according to pathologic stage. Chemotherapy for p-stage IA IIB Patients In the p-stage IA IIB patients who had undergone a complete resection, the survival rate for the 40 patients treated by operation and perioperative chemotherapy (preoperative 9, postoperative 27, both 4) was compared with that for the 9 patients treated by operation alone. The patients who received irradiation were excluded. As to chemotherapy regimens, vincristine (1.5 to 2.0 mg/ body) and cyclophosphamaide (600 to 1000 mg/m 2 ) had been mainly administered until Cisplatin (60 to 100 mg/m 2 ) and etoposide (240 to 360 mg/m 2 ) have been adopted at our facilities since As shown in Figure 5A, the 5-year probability of survival for patients with perioperative chemotherapy was 54.9%, as compared with 22.2% for patients without chemotherapy ( p , significant). However, there were several patients who did not have chemotherapy because of such complications such as heart disease, renal dysfunction, or liver dysfunction. Among those patients who had operation alone, 4 died of causes other than SCLC. When not considering patients whose cause of death was other than SCLC, a significant difference cannot be found in the 5-year probability of survival between patients with perioperative chemotherapy and those without chemotherapy. The 5-year survival rate for patients with four or more courses was 80.0%, as compared with 46.4% for patients treated with one to three courses ( p ; Fig 5B). By multivariate analysis with Cox s proportional hazards model, treatment with four or more courses of chemotherapy was shown to be an independent factor to determine postoperative survival. The p value and the relative risk were and , respectively. Survival did not depend on the T ( p ) or N (p ) factor. Comment The benefit of chemotherapy with irradiation for SCLC has been generally accepted. Five-year survival rate has been improved and reported as more than 20%, when chemoradiation therapy is given to LD patients [5]. On the other hand, operation has been recently adopted as a locoregional therapy in a combined modality therapy for SCLC [13]. As for the results of treatment with operation for LD, Shepherd and colleagues [7] reported that the 5-year survival rate was 51% for p-stage I, 28% for p-stage II, and 19% for p-stage IIIA. Karrer and Ulsperger [11] reported that the 4-year probability of survival was 56% for p-stage I and 29% for p-stage II, and Macchiarini and associates [8] reported a 5-year survival rate of 36% for p-n0 patients. For patients with T3 or N2 tumors, operation appears to offer little benefit other than as a salvage procedure [14]. Because it has been recommended to consider the value of the new TNM staging system for locoregional SCLC, we retrospectively reviewed the surgical results of 91 patients according to this new staging system [15]. According to the results in this study, we propose that operation should be indicated for c-stage

4 1618 INOUE ET AL Ann Thorac Surg OPERATION FOR SMALL CELL LUNG CANCER 2000;70: Fig 4. Survival curves by pathologic T-factor (A) and N-factor (B). p-t1 versus p-t2, p ; p-t2 versus p-t3, p p-n0 versus p-n2, p ; p-n1 versus p-n2, p IA IIA and p-stage IA IIB with accurate preoperative staging. Because the results of chemoradiation therapy for the very early LD (ie, stage I II) patients had not been clarified yet, at present we cannot compare the results of chemoradiation with those of operation. Clinical staging for lung cancer has become precise with an improvement in diagnostic imaging [16 18]. It was, however, reported that a lymph node metastasis is often underestimated in SCLC patients. Shepherd and colleagues [7] reported that 58 c-stage I patients included only 28 at p-stage I and most of the remaining 30 cases had been underestimated due to false-negative results concerning lymph node metastasis. In our study, although c-n0 comparatively corresponded with p-n0, c-n1 patients included 60% with p-n2 disease. A diagnosis of c-n1 may suggest the possibility of p-n2. Therefore, a mediastinal exploration using either mediastinoscopy or mediastinotomy, or both, is mandatory to rule out occult mediastinal lymph node metastasis as Shields and associates [14] suggested. However, it was pointed out that occult mediastinal involvement might be missed even by medistinoscopy in SCLC [7]. Fluoro-2-deoxy-Dglucose Positron Emission Tomography (FDG-PEG) may be useful for the evaluation of mediastinal lymph nodes [16, 17]. How N2 disease could be accurately diagnosed before a thoracotomy is still an important issue to be solved. Operation will be indicated for the patients with c-stage IIB if more accurate evaluation is possible. An analysis by the new TNM staging system revealed that the survival rate in p-stage IB was worse than that in p-stage IIA, although the number of patients was small. A detailed analysis interestingly showed that the T- factor, rather than the N-factor, determined the prognosis in these resectable cases. Shields and colleagues [14] also reported that large lesions more than 3 cm (T2), even without lymph node metastasis (N0), have a less favor- Fig 5. (A) Survival curves for p-stage IA IIB patients who underwent complete resection with or without adjuvant chemotherapy. (B) Survival curves for p-stage IA IIB patients who underwent complete resection with four or more chemotherapy courses versus one to three courses.

5 Ann Thorac Surg INOUE ET AL 2000;70: OPERATION FOR SMALL CELL LUNG CANCER 1619 able prognosis than either of the aforementioned categories (T1N0M0 or T1N1M0). On the contrary, Angeletti and associates [18] reported that the N-factor has a stronger negative effect on prognosis than the T factor. These contradictions may depend on a difference in patient population or perioperative chemotherapy. It is possible that perioperative chemotherapy improves the survival in p-stage IA IIB patients who undergo curative resection, as SCLC shows a high response rate for chemotherapy. Actually, the multivariate analysis demonstrated that four or more courses of chemotherapy is only one independent factor to determine the postoperative survival of the IA IIB patients. The patients in this study received 2.3 courses of chemotherapy on average, which seems to be insufficient. According to the results in this study, we suppose that four or more courses of perioperative chemotherapy are recommended, even for resectable patients with p-stage IA IIB, although it cannot be denied that the good risk patients who were unable to receive four or more courses of chemotherapy show the favorable prognosis [7, 8, 10, 11]. There is no significant difference in survival among the patients with preoperative chemotherapy, those with postoperative chemotherapy, and those with both in our study. As for the regimen, cisplatin and etoposide were administered in 8 of the 10 patients treated with four or more courses of chemotherapy. Thus, at present we can reconfirm the adequacy of this chemotherapy regimen, while the development of new carcinostatics is expected. Further prospective study is required to determine the regimen and timing of chemotherapy. As for postoperative irradiation, local recurrence was found in 4 patients among 12 treated by thoracic radiation. Brain metastasis was found in 1 patient among the 5 treated with prophylactic cranial irradiation. A distinct survival benefit could not be found in this study. Thus, complete control of SCLC by adjuvant radiation therapy could not be expected, although the progress of the disease was not the target of this study. It was previously reported that salvage operation might be considered for c-stage IIIA cases who remarkably respond to chemotherapy or local recurrent cases after chemotherapy [19, 20]. In our study, a c-stage IIIA patient underwent an operation after being restaged to y-stage IA by curative chemotherapy and survived for 38 months. This patient was initially considered as inoperable due to the metastatic mediastinal node. Any operative indication for c-stage IIIA patient who has good response to chemotherapy should be considered. In summary, a retrospective analysis of surgical results for SCLC based on the new TNM staging system suggested that operation should be indicated for c-stage IA IIA and p-stage IA IIB patients who have had four or more courses of perioperative chemotherapy. In this situation, an accurate preoperative diagnosis of the N- status is required. References 1. Ihde DC. Current status of therapy for small cell carcinoma of the lung. Cancer 1984;54: Fox W, Scadding JG. Medical Research Council comparative trial of surgery and radiotherapy for primary treatment of small-celled or oat-celled carcinoma of bronchus: ten-year follow-up. Lancet 1973;2: Wiatr E, Starzynska T, Danczak-Ginalska Z, Zych J, Rowinska-Zakrzewska E. Survival of patients with limited small cell lung cancer in whom complete remission was obtained (a non-randomised retrospective study of 124 consecutive patients). Lung Cancer 1995;13: Johnson BE, Bridges JD, Sobczeck M, et al. 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