Abstract
Background
The role of surgery in limited small cell lung cancer (SCLC) is still controversial. To assess the role of surgery in SCLC we performed a retrospective analysis of survival in a group of limited stage patients, who were managed with trimodal therapy including surgery, or with chemotherapy and radiotherapy.
Methods
We performed a retrospective survival analysis in a series of 153 limited stage SCLC patients treated between 1995 and 2013. Kaplan-Meier survival analysis and Cox regression analysis were used to calculate the overall survival of the surgical and non-surgical groups.
Results
Median survival in all patients was 21.5 months. Median survival for surgical and non-surgical patients was 30.5 months and 16.9 months, respectively. The survival curves for the two arms are significantly different (P < 0.01). In multivariate analysis, the benefit of surgical treatment and thoracic radiotherapy varied in a time-dependent fashion.
Conclusions
Our results suggest that surgery added to chemotherapy and radiotherapy may be associated with a therapeutic benefit in limited SCLC.
Keywords: Limited disease, small cell lung cancer, surgery
Background
Small cell lung cancer (SCLC) is a systemic disease. Chemotherapy produces high response rates in patients with more advanced disease, but the long-term survival is poor; a median survival of only 12–14 months for limited disease and relapse in the chest is common, despite the incorporation of thoracic irradiation to the treatment program. Recurrence or persistence of tumor in the chest is a problem, despite the use of radiotherapy, and removal of the lobe of origin plus mediastinal lymph nodes might be helpful in this regard. The role of surgery in the management of this tumor has been a subject of controversy. If surgical treatment is effective, one should expect a favorable impact on survival to justify the added morbidity of thoracotomy. The objectives of this study are to evaluate the role of surgery in SCLC treatment, to compare the survival of patients treated by adjuvant surgical resection with that of those who do not receive surgical treatment, and to determine whether clinical or surgical tumor node metastasis (TNM) staging is of clinical use in identifying candidates for resection or making more accurate prognoses.
Materials and methods
Patient selection
A review was undertaken for limited disease SCLC surgical and non-surgical patients, excluding clinical IIIB patients, who were treated at our Department of Thoracic Oncology Group, Peking University Cancer Hospital from 1995 to 2013. Fifty patients were treated by resection, 103 patients were managed with a conservative approach only. All 50 surgical patients received a neoadjuvant or adjuvant procedure, such as chemotherapy, radiotherapy, or prophylactic cranial irradiation (PCI).
Initial workup
Pretreatment evaluation in both groups included patient history, physical examination, complete blood count, serum chemistry, bronchoscopy, chest computed tomography (CT), ultrasound or CT of the abdomen, bone scan, and brain magnetic resonance imaging (MRI). The histological diagnosis in the non-surgical group was established based on an examination of specimens obtained in bronchoscopy, mediastinoscopy, or CT-guided percutaneous lung biopsy. Patients treated with surgery were additionally staged based on pathological examination of the resected specimen. Disease stage was evaluated according to the TNM Classification of Malignant Tumors, 7th Edition.
Treatment
Neoadjuvant chemotherapy was administered every 21 days for two cycles. Adjuvant chemotherapy was administered every 21 days for two to six cycles. In the early period, the regimen of induction or adjuvant chemotherapy was CAV (cyclophosphamide, doxorubicin, vincristine), and EP (cisplatin, etoposide). In the late period, chemotherapy was performed with the EP regimen. Treatment consisted of surgery with neoadjuvant therapy in 22.0% (11/50), and surgery with adjuvant therapy in 78.0% (39/50).
Fifty patients in the surgical group underwent radical pulmonary resection, including two pneumonectomies (4.0%), 35 lobectomies (70.0%), and 13 wedge resections (26.0%). Eighty-five of the 153 (55.6%) patients received thoracic radiotherapy while 50 of the 153 (32.7%) received PCI. The details are shown in Table 1. PCI included doses of 30 Gy in 10 fractions. Thoracic radiotherapy included doses of 40 Gy in 20 fractions or 50 Gy in 25 fractions.
Table 1.
Patient characteristic
| Variable | Non-surgical group | Surgical group | Total |
|---|---|---|---|
| Patients (%) | 103 (67.3) | 50 (32.7) | 153 (100.0) |
| Gender | |||
| Male (%) | 74 (71.8) | 38 (76.0) | 112 (73.2) |
| Female (%) | 29 (28.2) | 12 (24.0) | 41 (26.8%) |
| Mean age, years (range) | 56 (23–84) | 57 (32–75) | 56 (23–84) |
| Thoracic irradiation (%) | 76 (73.8) | 10 (20.0) | 86 (56.2) |
| PCI (%) | 39 (37.9) | 11 (22.0) | 50 (32.7) |
| T category | |||
| T1 (%) | 9 (8.7) | 14 (28.0) | 23 (15.0) |
| T2 (%) | 43 (41.7) | 25 (50.0) | 68 (44.4) |
| T3 (%) | 10 (9.7) | 4 (8.0) | 14 (9.2) |
| T4 (%) | 41 (39.8) | 7 (14.0) | 48 (31.4) |
| N category | |||
| N0 (%) | 15 (14.6) | 17 (34.0) | 32 (20.9) |
| N1 (%) | 5 (4.9) | 5 (10.0) | 10 (6.5) |
| N2 (%) | 83 (80.6) | 28 (56.0) | 111 (72.5) |
| Stage | |||
| I | 9 (8.7) | 11 (22.0) | 20 (13.1) |
| II | 7 (6.8) | 5 (10.0) | 12 (7.9) |
| III | 87 (84.5) | 34 (68.0) | 121 (79.1) |
PCI, prophylactic cranial irradiation.
Statistical methods
Survival times were calculated from the time of treatment until the date of death or last follow up. The cut-off date for follow up was January 2013. All statistical calculations were performed using the SPSS Statistics 17.0 software package (SPSS Inc.). Actuarial survival curves were computed using the Kaplan-Meier method. Cox proportional hazards regression models were used to ascertain the association between individual factors and survival. In this study, a P-value of 0.05 or less was considered statistically significant.
Results
Statistical analysis included all 153 patients, of whom 50 underwent surgical resection and 103 were treated with non-surgical approaches. The median age was 56 years (range 23 to 84). The demographic characteristics are shown in Table 1. Median follow-up for all patients was 15.8 months (range 0–148.0). The median survival was 21.5 months (95% confidence interval [CI]: 15.8–27.3) for all enrolled patients. By the time of the final analysis, 108 patients (70.6%) were deceased. One and five-year survival probabilities in all patients were 72.9% and 19.2%, respectively. Median survival for patients treated surgically and non-surgically was 30.5 months and 16.9 months, respectively ( Fig 1). The survival curves for the two arms are significantly different (P = 0.001).
Figure 1.
Overall survival in patients treated with or without surgery. 
, no surgery; 
surgery.
A subgroup analysis was performed to assess surgical outcomes based on lymph node status. A survival advantage related to surgery was observed in patients with stage III disease (Table 2). The difference reached a level of significance (Figs 2, 3).
Table 2.
Survival in particular T and N categories
| Median survival (months) | ||||
|---|---|---|---|---|
| Category | All patients | Surgical group | Non-surgical group | P |
| Total | 21.5 | 30.5 | 16.9 | 0.001 |
| Stage I | 25.8 | 25.8 | 22.5 | 0.470 |
| Stage II | 11.9 | 11.5 | 17.4 | 0.783 |
| Stage III | 21.1 | 34.5 | 16.5 | 0.002 |
| N0 | 24.7 | 25.8 | 20.0 | 0.069 |
| N1 | 17.4 | 11.9 | 17.4 | 0.786 |
Figure 2.
Survival in a subset of patients with N0 disease treated with or without surgery. 
, no surgery; 
surgery.
Figure 3.
Survival in a subset of patients with stage III disease treated with or without surgery. 
, no surgery; 
surgery.
Cox regression analyses were used to examine possible confounding and interactive effects of the entire group, with the following predictors: surgical treatment, gender, age, thoracic radiotherapy, PCI, T category, and N category. Two independent, significant factors reducing the risk of death were identified: surgical treatment and thoracic radiotherapy. The hazard ratios, CIs, and P-values from multivariate analysis are shown in Table 3. No impact on prognosis was found in relation to T stage, established either clinically or pathologically.
Table 3.
Prognostic value of selected variables (multivariate analysis)
| Variable | Hazard ratio | 95% confidence interval | P |
|---|---|---|---|
| Surgical treatment | 0.371 | 0.219–0.629 | <0.001 |
| Gender | 0.945 | 0.609–1.467 | 0.801 |
| Age | 1.014 | 0.997–1.032 | 0.109 |
| Radiotherapy | 0.590 | 0.358–0.973 | 0.039 |
| PCI | 0.619 | 0.378–1.015 | 0.057 |
| T category | 0.934 | 0.769–1.134 | 0.491 |
| N category | 1.071 | 0. 820–1.401 | 0.614 |
PCI, prophylactic cranial irradiation.
Discussion
SCLC accounts for 15–20% of all lung cancers and is recognized as a high-grade malignancy with rapid growth of the primary lesion and a propensity for spreading to mediastinal lymph nodes or distant organs. Treatment for limited disease typically comprises four to six courses of systemic chemotherapy with concurrent thoracic irradiation.1 PCI is also recommended in complete responders. The standard chemotherapy regimen for limited disease small cell lung cancer (LD-SCLC) is cisplatin/etoposide, as mentioned in the 2014 National Comprehensive Cancer Network (NCCN) guideline.2
The efficacy of surgical intervention for SCLC remains controversial. Patients with disease in excess of T1-2, N0 do not benefit from surgery.2 The aims of this study were to ascertain the results of surgical treatment and to evaluate the impact of stage on survival in patients with a completely resected limited stage sub-group of patients with SCLC. The conclusion of this study is that pulmonary resection could improve the survival for stage I-III SCLC.
Some studies have reported that the addition of pulmonary resection after induction chemotherapy as multimodality treatment does not improve the survival for chemotherapy responders with SCLC in prospective randomized trials.
Lad et al.3 reported a prospective randomized trial that did not support the addition of pulmonary resection to the multimodality treatment of SCLC. The median survival times were 15.4 months for the surgery group and 18.6 months for the non-surgery group, with no significant difference observed in survival. The study concluded that additional pulmonary resection had no benefit in treatment for SCLC. Furthermore, in this study, surgical resection and staging did not identify any subsets that appeared to benefit from its addition to multimodality therapy.
A retrospective review was undertaken of patients who underwent surgery between 1980 and 2006. There were no clear differences in the survival of patients in clinical T categories (P = 0.366), however, there were good overall results in patients across the spectrum of nodal disease from N0 to N2 (P = 0.498).4
The Japan Lung Cancer Registry Study (JLCRS) enrolled surgical and non-surgical cases in 2002, and showed a five-year survival rate of 14.7% for SCLC, worse than the 46.8% for NSCLC.5 Surgery is still practically performed in patients with early LD without node involvement, although some of these cases are postoperatively diagnosed with SCLC.
Several small series have reported favorable survival outcomes in patients who underwent surgical resection.6 There are some recently published studies demonstrating that a high local control rate can be achieved in early stage SCLC patients (stage I-IIIA), and this might, subsequently, result in favourable long-term results.7 In stage II and III patients, chemotherapy and radiotherapy are mainly recommended; however, some studies indicate that surgery combined with adjuvant chemotherapy improves the prognosis.8 The finding that first relapses often occur at the locoregional site suggests that an enhancement of locoregional control is necessary to increase the proportion of long-term survivors. Surgery used for local control, unlike radiotherapy, would not limit the intensity of chemotherapy that could be delivered. By rendering the patient free of disease in the chest without affecting the bone marrow reserves, surgery could possibly make the chemotherapy more effective.
Analyses from the National Cancer Institute Surveillance Epidemiology and End Results database of 205 patients who underwent radical lobectomy showed a five-year survival rate of 50.3% in c-stage I SCLC and better outcomes than non-surgical c-stage IA from the International Association for the Study of Lung Cancer (IASLC) report.9 The Japan Clinical Oncology Group (JCOG) 9101 reported three-year survival rates of 68%, 56%, and 13% in patients with c-stage I, II, and IIIA, respectively.10 Based on these historical studies, we posit that the indication for limited surgery should be limited to LD-SCLC cases without lymph node involvement at present. Among the 14 179 patients who were included in an American study, 2251 patients had N0 disease, 802 patients had N1 disease, and 7974 patients had N2 disease. For N2 disease, 187 patients underwent surgery, 7787 patients did not, and the median survival was 19 months versus 112 months in favor of the surgery group (P < 0.001).11
One study reported that 1373 patients underwent a resection of lung cancer between 1980 and 2006. There were 53 patients with SCLC among them. They divided into two groups, including the early and late period group. The survival rates five years after surgery were 8.7% and 38.3%, respectively.12 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.
These studies have also reported that multidisciplinary treatment involving chemotherapy and surgery achieved a favorable prognosis in the SCLC patients without mediastinal lymph node metastasis, thus suggesting the importance of surgery. In the majority of published studies, survival benefit related to surgery was limited to stage I and II disease.13,14 These data suggest that improved local control may be translated into prolonged survival in selected limited stage SCLC patients. The N2 designation has traditionally been considered as a contraindication to surgery. It has become clear that precise staging is very important in selecting patients with limited disease.15,16
Median survival in our study for patients treated with and without surgery was 16.9 and 30.5 months, respectively. The survival curves for the two arms are different (P = 0.001). A survival advantage related to surgery was observed in patients with III stage disease (P < 0.05). Our results suggest that surgery added to chemotherapy may be associated with therapeutic benefit in limited SCLC. The numbers of patients in each of the various TNM subsets are quite small, which makes survival comparisons of these subsets difficult. In our study, there were 111 patients with N2 disease. Prior to surgery, there were no mediastinal lymph nodes viewed in the CT scan, but after surgery, more accurate diagnoses were attainable. It is possible that it was not the surgery itself, but rather the selection factors enabling surgery, that played a critical role in producing favorable outcomes. It is debatable, though, whether this favorable survival was related to surgery added to systemic treatment or to the patient selection. SCLC patients eligible for resection represent a special subset characterized by early clinical stage and good performance. The favourable preselection may considerably influence the results of the published studies.
The patients were treated over a period of 18 years, and within this time treatment standards have been the subject of various modifications. For example, chemotherapy regimens used in both groups were different, and some combinations are no longer in routine clinical use. As a result, time bias should be considered as another factor influencing their prognosis. In an attempt to account the for lack of central pathology review, neuroendocrine and mixed non-SCLC tumors were not included in the current study.
One study has shown that age, gender, the stage in which surgery was performed, and the type of surgical resection were all strong independent predictors of long-term survival (P < 0.05).17
Multivariate analysis of overall survival in our series demonstrated two independent prognostic factors: surgical treatment and thoracic radiotherapy.
Surgery could be performed with a curative intent in only a small number of patients with limited disease SCLC or significant nodal response after chemotherapy. Based on the results of this study, surgical excision of the primary tumor with pre- and postoperative chemotherapy, with or without radiotherapy, may be necessary to achieve long term survival in patients with stage I-III SCLC; however, the optimal management of patients with stage III disease has yet to be determined by future randomized clinical trials. Nevertheless, surgery alone is not considered to be sufficient to achieve a complete cure. Platinum and etoposide based regimens of chemotherapy with concurrent chest radiation followed by PCI is the treatment for limited disease. Future prospective studies should consider the role of surgery as part of the multimodality management of this disease.
Conclusions
In summary, the major conclusion of this study is that pulmonary resection could improve the survival for I-IIIA stage SCLC. Systemic therapy is recommended for all patients with SCLC.
Disclosure
No authors report any conflict of interest.
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