Results of Surgical Treatment for Patients with Small Cell Lung Cancer

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Results of Surgical Treatment for Patients with Small Cell

Lung Cancer

Takeshi Hanagiri, MD, PhD, Kenji Sugio, MD, PhD, Tetsuro Baba, MD, PhD,

Yoshinobu Ichiki, MD, PhD, Manabu Yasuda, MD, PhD, Hidetaka Uramoto, MD, PhD,

Takefumi Ohga, MD, PhD, Mitsuhiro Takenoyama, MD, PhD, and Kosei Yasumoto, MD, PhD

Objective: This study investigated the clinical features and the

postoperative prognosis in patients with small cell lung cancer (SCLC).

Subjects: In this study, 1373 patients underwent a resection of lung

cancer between 1980 and 2006. There were 53 patients (3.8%) with SCLC among them. They were divided into two groups, including the early (1980 –1993) and late (1994 –2004) period groups. The clin-icopathologic features and the results of surgery were investigated.

Results: The early and late period groups consisted of 22 and 31

patients, respectively. The pathologic stage of early group was stage IA in five, IB in three, II in five, IIIA in five, and IIIB in four patients and of late group was stage 0 in two, IA in three, IB in three, II in seven, IIIA in nine, and IIIB in seven patients. The survival rates 5 years after surgery were 8.7 and 38.3%, respectively. Preoperative chemotherapy with CAV (cyclophosphamide, doxorubicin, vincris-tine) or PE (cis-diamminedichloroplatinum⫹ VP16) regimens was performed in 11 patients in the early period group. The treatment response was evaluated as a partial response in eight patients and stable disease in three. In the late period group, cis-diamminedichlo-roplatinum/carboplatin⫹ VP16 therapies were administered to eight patients. The treatment response was evaluated as a complete re-sponse in two patients and partial rere-sponse in six.

Conclusion: Surgery could be performed with a curative intent in

only a small number of patients with limited disease of SCLC or significant nodal response after chemotherapy. The prognosis after surgery was not satisfactory, especially in the early period. It was considered to be partly because of differences in the regimens and dose intensity of chemotherapy between the early and late period.

Key Words: Small cell lung cancer, Pulmonary resection, Surgical

outcome, Chemotherapy.

(J Thorac Oncol. 2009;4: 964–968)

L

ung cancer is still a leading cause of cancer-related mor-tality in many industrialized countries.1,2 It remains a

considerable public health problem and reducing the mortal-ity of lung cancer remains an important issue. Small cell lung cancer (SCLC) represents 10 to 20% of all lung cancer in the United States and Europe.3,4The incidence of SCLC has been

decreasing over the last several years and the incident rate declined among males, but it is continuing to increase among females.5 SCLC is more aggressive lung cancer than

non-small lung cancer, because of its rapid growth and early tendency to spread to distant organs. SCLC is one of the most sensitive tumors to chemotherapy and radiotherapy, which can give patients a chance to prolong their survival.6 More

than 80% of patients with SCLC can respond to chemother-apy alone, but the 2-year overall survival rate is less than 20%.7,8 This may be associated with frequent local relapse

and distant metastases.

Previously, surgery is not thought to be indicated for SCLC, and surgical treatment is limited as an option for very early stage disease and its clinical significance was still uncertain for small cell carcinoma. Generally, surgery plays little role in the management of small-cell lung cancer, but the exceptions are a small number of patients those who are diagnosed at stage I (when the cancer is confined to the lung without any spread to the lymph nodes). Recent studies have reported that multimodality treatment involving surgery achieved a good prognosis in SCLC patients with limited-stage disease, thus suggesting the importance of surgery with a curative intent.9,10 Nevertheless, surgery alone is not

con-sidered to be sufficient to achieve a complete cure. The present study investigated the results of surgical treatment for patients with SCLC.

PATIENTS AND METHODS

The hospital records of 1373 consecutive patients who underwent a resection of lung cancer between 1980 and 2006 were reviewed. Among them, 53 patients (3.8%) had SCLC. Those patients were divided into two groups, early (n⫽ 22) (1980 –1993) and late (n ⫽ 31) (1994–2004) period groups and their clinicopathologic features and the results of surgery were investigated. Because granulocyte-colony stimulating factor (G-CSF) and serotonin-antagonizing antiemetic agent has become available since 1994, the chemotherapeutic

reg-Second Department of Surgery, School of Medicine, University of Occupa-tional and Environmental Health, Kitakyushu, Japan.

Disclosure: The authors declare no conflicts of interest.

Address for correspondence: Takeshi Hanagiri, MD, Second Department of Surgery, School of Medicine, University of Occupational and Environmental Health, Yahatanishi, Kitakyushu 807, Japan. E-mail: hanagiri@med.uoeh-u.ac.jp

Copyright © 2009 by the International Association for the Study of Lung Cancer

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imens were thus changed. Therefore, the patient groups were divided into those before and after 1994.

The preoperative assessments included chest roentgen-ography, computed tomography of the chest and upper abdo-men, bronchoscopy, and bone scintigraphy. Magnetic reso-nance imaging of the brain was used only in the late period. The patients’ records including the clinical data, preoperative examination results, details of the surgical operation, his-topathologic findings, and tumor, node, metastasis stages of all patients were also reviewed. Induction chemotherapy was planned for the patients if small cell carcinoma was diag-nosed preoperatively, but except for patients at stage I. The regimen of induction chemotherapy was mitomycin, CAV (cyclophosphamide, doxorubicin, vincristine), and PE (cis-diamminedichloroplatinum [CDDP] ⫹ VP16 [etoposide]) in the early period. In the late period, induction chemotherapy was performed with the PE regimen. CDDP was administered with 40 mg/m2on day 1 and VP16 (100 mg/body) was given on days 1, 2, and 3 in the early period. Nevertheless, CDDP was administered with 80 mg/m2on day 1 and the combined use of VP16 (100 mg/m2) on days 1, 2, and 3 in the late

period. In the both periods, two to three cycles of induction chemotherapy was performed. The candidates for surgical resection in both periods were (1) patients at stages IA and IB, or (2) patients with completely resectable tumor after induction chemotherapy.

All resected specimens including the primary tumor and systematically resected hilar and mediastinal lymph nodes were examined for tumor histology and the extent of lymph node metastases. The histopathologic findings were classified according to the World Health Organization crite-ria, and the UICC tumor, node, metastasis staging system was employed.11,12 The postoperative chemotherapy was

per-formed in the same manner as induction chemotherapy if the patient condition after surgery was well tolerable against the treatment, or unless patients refused additional chemother-apy. Follow-up information was obtained from all patients through office visits or telephone interviews with the patient, a relative, or their primary physicians. The patients were eval-uated every 3 months by chest roentgenography, and chest computed tomography scan and bone scintigraphy were ob-tained every 6 months for the first 2 years after surgery, and annually thereafter. The mean observation time was 3.2 years.

The survival curve was calculated by the Kaplan-Meier method and compared by using the log-rank test for the univariate analysis. Categorical variables were compared by Fisher’s exact test. The differences were considered to be significant, if the p value was less than 0.05. The Statview V software program (Abacus Concept, Berkeley, CA) was used for all statistical analyses.

RESULTS

In this study, 1373 patients underwent a resection of lung cancer between 1980 and 2006. Among them, 53 pa-tients (3.8%) were with SCLC, who were divided into two groups, the early (1980 –1993) and late (1994 –2004) period groups and their clinicopathologic features and the results of surgery were investigated. The early and late period groups

consisted of 22 and 31 patients, respectively (Table 1). A preoperative diagnosis of small cell carcinoma was obtained in 12 patients (54.5%) in the early period and 13 patients (41.9%) in the late period. The clinical stage of early group was IA in six, IB in five, II in one, IIIA in eight, and IIIB in two patients and that of late group was IA in seven, IB in three, II in three, IIIA in 12, and IIIB in six patients. Induction chemother-apy with CAV or PE regimens was performed in 11 patients in the early period group (Table 2). The treatment response was evaluated as a partial response in eight patients and stable disease in three. In the late period group, PE or CBDCA ⫹ VP16 therapies were administered to eight patients before sur-gery. The treatment response was evaluated as a complete response in two patients and partial response in six. Five pa-tients underwent neither induction nor adjuvant chemother-apy because of their refusal to undergo chemotherchemother-apy in two, renal failure in two, and interstitial pneumonia in one patient. The operative procedures included 7 pneumonectomies (31.8%), 12 lobectomies (54.5%), 2 segmentectomies (9.1%), and 1 partial resection in the early period (4.5%), and 8 pneumonectomies (25.8%), 20 lobectomies (64.5%), 1 seg-mentectomy (3.2%), and 2 partial resections in the late period (6.5%). The limited resections (partial resection and segmen-tectomy) with mediastinal lymph nodes sampling were

per-TABLE 1. Characteristics of Small Cell Lung Cancer Patients in the Early Period and the Late Period

Characteristics

Early Period (nⴝ 22) Late Period (n ⴝ 31)

No. of Patients (%) No. of Patients (%)

Age (mean yr) 65.5 67.6 Male 19 (86.4) 24 (77.4) Preoperative diagnosis of

small cell lung cancer

12 (54.5) 13 (41.9) Preoperative chemotherapy 11 (50.0) 8 (25.8) Postoperative chemotherapy 14 (63.6) 23 (74.2) Preoperative radiotherapy 0 3 (9.7) Postoperative radiotherapy 3 (13.6) 4 (12.9) Clinical stage IA 6 (27.3) 7 (22.6) IB 5 (22.7) 3 (9.7) II 1 (4.5) 3 (9.7) IIIA 8 (36.4) 12 (38.7) IIIB 2 (9.5) 6 (19.4) Operative procedure Pneumonectomy 7 (31.8) 8 (25.8) Lobectomy and bilobectomy 12 (54.5) 20 (64.5) Segmentectomy 2 (9.1) 1 (3.2) Partial resection 1 (4.5) 2 (6.5) Pathologic stage 0 0 2 (6.5) IA 5 (22.7) 3 (9.7) IB 3 (13.6) 3 (9.7) II 5 (22.7) 7 (22.6) IIIA 5 (22.7) 9 (29.0) IIIB 4 (18.9) 7 (22.5)

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formed as part of multimodality therapy. There were no signif-icant differences in operative procedures between the early and late period. The pathologic stage of the early group was stage IA in five, IB in three, II in five, IIIA in five, and IIIB in four patients, and of late group was stage 0 in two, IA in three, IB in three, II in seven, IIIA in nine, and IIIB in seven patient. The postoperative 5-year survival rates of early and late groups were 8.7 and 38.3%, respectively. The prognosis was significantly poorer in the early group than the late group (Figure 1). Accord-ing to the stage, the 5-year survival rates were 55.0 and 38.8% in stages I and III, respectively. In comparison with other histologies, the 5-year survival rates were 63.8, 47.3, 56.3, and 34.3% in adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and small cell carcinoma, respectively (Figure 2). Adenocarcinoma showed a significantly better prognosis than small cell carcinoma (p⬍ 0.01). No significant differences in the survival curves were observed between small cell carcinoma and large cell carcinoma or between small cell carcinoma and squamous cell carcinoma.

DISCUSSION

SCLC is the most aggressive subtype of lung cancer with a rapid tumor doubling time and early development of widespread metastases. Combination chemotherapy remains the mainstay of treatment for both limited-stage and exten-sive-stage SCLC. In general, the administration of etoposide and cisplatin plus chest radiotherapy for patients with good performance status and limited-stage disease provides a com-plete-response rate of approximately 80%, a median survival of 17 to 23 months and a 5-year survival of 12 to 25%.13,14

Therefore, a surgical resection was not indicated for SCLC at diagnosis, because radiotherapy was reported to superior to surgery as a local therapy previously.15,16However, Shields

et al.17 reported that 5-year survival rates of stages IA, IB,

IIA, IIB, and III after curative resection were 59.9, 27.9, 31.3, 9.0, and 3.6%, respectively, thus, suggesting that the initial surgical resection may play a role in the curative treatment for stage I disease.

Previously Lad et al.18 reported that the addition of

pulmonary resection after induction chemotherapy as multimo-darity treatment did not improve the survival for chemotherapy responders with SCLC in prospective randomized trial. Never-theless, the chemotherapy regimen was CAV in their study, and chemotherapy was thereafter replaced by CDDP⫹ VP16 as a front line chemotherapy. Recently a small population (5–10%) of SCLC patients was diagnosed at stages IA and IB and their 5-year survival was 20 to 40% after a surgical resection.9,10 These studies have also reported that

multidis-ciplinary treatment involving chemotherapy and surgery achieved a favorable prognosis in the SCLC patients without mediastinal lymph node metastasis, thus suggesting the im-portance of surgery.19,20The theoretical advantages of

surgi-cal treatment are to obtain an immediate complete response

1994-2006 0 20 40 60 80 100 % 0 1 2 3 4 5 1980-1993

Years after surgery

Cumulative survival

FIGURE 1. Comparison of the overall survival curves of pa-tients between the early period and the late period. The 5-year survival rates were 8.7 and 38.8% in the early period and the late period, respectively. The prognosis was significantly better in the late period than the early period (p⬍ 0.01).

Sm Large Sq Ad

0 1 2 3 4 5

Years after surgery 0 20 40 60 80 100 % Cumulative survival

FIGURE 2. Overall survival curves of patients with lung cancer according to the histology in the late period. The 5-year survival rates were 63.8, 47.3, 56.3, and 34.3% in adenocarcinoma, squamous cell carcinoma, large cell carci-noma, and small cell carcicarci-noma, respectively. The prognosis was significantly better in adenocarcinoma than small cell carcinoma (p⬍ 0.01). There were no significant differences between small cell carcinoma and large cell carcinoma or between small cell carcinoma and squamous cell carcinoma. Ad, adenocarcinoma; Sq, squamous cell carcinoma; large, large cell carcinoma; Sm, small cell carcinoma.

TABLE 2. Response to Preoperative Chemotherapy

Characteristics n CR PR SD Early period (n⫽ 11) MMC 1 1 CAV 2 2 CDDP⫹ VP16 6 4 2 CBDCA⫹ VP16 2 2 Late period (n⫽ 8) CDDP⫹ VP16 6 2 4 CBDCA⫹ VP16 2 2

CDDP was administered with 40 mg/m2

on day 1 and VP16 (100 mg/body) was given on days 1, 2, and 3 in the early period. In contrast, CDDP was administered with 80 mg/m2

on day 1 and the combined use of VP16 (100 mg/m2

) on days 1, 2, and 3 in the late period.

MMC, mitomycin; CAV, cyclophosphamide, doxorubicin, vincristine; CDDP, cisplatine; CBDCA, carboplatin; VP16, etoposide; CR, complete response; PR, partial response.

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without harmful effect to the bone marrow and to allow accurate disease staging. In stages II and III patients, chemo-therapy and radiochemo-therapy are mainly recommended; however, some studies indicate that surgery combined with adjuvant chemotherapy improves the prognosis.19,20

In the present study, the 5-year survival rates were 55.0% at stage I, thus suggesting the efficacy of surgery in combination of chemotherapy for patients without lymph node metastasis. When the postoperative survival of SCLC was compared with the other histologies of lung cancer, the patients with adenocarcinoma had a better prognosis than SCLC but no significant differences were observed among the other histologic types (Figure 3). The candidates for a surgical resection with stages II-III disease in the late period included those who were chemotherapy responders with a completely resectable tumor. The overall survival at 3 and 5 years after surgery in SCLC were 57.2 and 38.3%, respec-tively, and the median survival time was 46 months in the late period (Figure 1). However, the 3-year survival and the median survival time of patients, who underwent CDDP ⫹ VP16 with concurrent radiotherapy, were reported to be 30 to 40% and 20 to 23 months in the limited-disease SCLC.21,22

Therefore, this study suggested that surgery could play a potential role in the multimodality therapy for patients with the limited-disease SCLC.

In the present study, the results of induction chemo-therapy were better in the late period than the early period. The postoperative results in the late period group were also significantly better than those in the early period group. In the early period study, 21 (95.5%) of 22 patients underwent induction chemotherapy or adjuvant chemotherapy. In the late period group, 26 (83.9%) of 31 patients were adminis-tered induction chemotherapy or adjuvant chemotherapy. There were no significant differences in patient characteris-tics and operative procedures between the early and the late period. Therefore, the difference in the prognosis after surgery might be because of the difference in the chemotherapeutic regimen. In the late period group, more potent chemotherapy was performed, because G-CSF and serotonin-antagonizing an-tiemetic agents could be available in the late period. Myelo-suppression is the major toxicity in platinum-based chemo-therapy and leukocytopenia is preventable in most cases. Nevertheless, it is possible to recover rapidly after the ad-ministration of G-CSF in most patients. G-CSF plays an important role in dose intensification of the chemotherapy for in SCLC.23CDDP is well known to be one of highly

eme-togenic chemotherapeutic agents. Emesis is one of dose limiting factors and a major obstacle for continuous chemo-therapy. The administration of serotonin receptor antagonists for preventive therapy improves the management of chemo-therapy-induced nausea and vomiting significantly.24 The

intensive chemotherapy combined with surgery may contrib-ute to a better prognosis. This retrospective study covered a period of longer than 20 years, during which time the image diagnostic technology and perioperative management for lung cancer both dramatically improved. As a result, a time bias should also be considered to be another factor which

influenced their prognosis, because the medical eras remark-ably differed between the two periods of the cohort.

The preoperative diagnosis of the histology is impor-tant, because the treatment strategy for SCLC is different from that for non-small lung cancer. Nevertheless, a periph-eral lung tumor is not easy to diagnose precisely. In the present study, approximately half of the patients yielded a histologic diagnosis before surgery. The evaluation of medi-astinal lymph node metastasis is also necessary to determine the treatment strategy and decide the indication for surgery. A recent study demonstrated the useful role of positron emis-sion tomography to eliminate node positive disease, because lymph node metastasis is a strong prognostic factor.25

Endo-bronchial ultrasound guided needle and mediastinoscopy also provides histologic proof of mediastinal downstaging after induction chemotherapy with high diagnostic accuracy.26,27

Therefore, patients with SCLC at stage I can receive a benefit from a surgical resection combine with platinum-based chemotherapy. The patients with resectable SCLC at stages II and IIIA who respond to induction chemotherapy may have a chance of achieving a cure by surgery, but further prospective clinical trials are necessary.

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