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Department of Medicine/Division of Hematology and Oncology, University of Missouri Kansas City, Kansas City, MissouriDivision of Oncology, Saint Luke's Cancer Institute, Kansas City, Missouri
Corresponding author. Address for correspondence: Janakiraman Subramanian, MD, MPH, Division of Oncology, Saint Luke's Cancer Institute, University of Missouri at Kansas City, 4321 Washington Street, Suite 4000, Kansas City, Missouri, 64111.
Department of Medicine/Division of Hematology and Oncology, University of Missouri Kansas City, Kansas City, MissouriDivision of Oncology, Saint Luke's Cancer Institute, Kansas City, Missouri
The optimal treatment strategy for resected stage I large cell neuroendocrine carcinoma of the lung (LCNEC) remains unknown. In this analysis, we evaluate the impact of systemic chemotherapy on patients with stage I LCNEC who have undergone surgical resection.
Methods
The study population included patients who underwent surgical resection for LCNEC and had pathologic stage I disease. We compared overall survival between patients who underwent surgical resection alone and those who underwent surgical resection plus chemotherapy. Overall survival was estimated by the Kaplan-Meier method, and comparisons were analyzed by using multivariable Cox models and propensity score–matched analyses.
Results
From 2004 to 2013, 1232 patients underwent surgical resection for stage I LCNEC in the National Cancer Database, including 957 patients (77.7%) who underwent surgical resection alone and 275 (22.3%) who received both surgery and systemic chemotherapy. Five-year survival was significantly improved in patients who received chemotherapy (64.5% versus 48.4% [hazard ratio =0.54, 95% confidence interval: 0.43–0.68, p < 0.001]). Multivariable Cox modeling confirmed the survival benefit from chemotherapy for patients with resected stage I LCNEC (hazard ratio = 0.54, 95% confidence interval: 0.43–0.68, p <0.0001). The survival benefit was further confirmed by propensity-matched analysis. In addition, older (age >70 years), comorbid white patients who underwent sublobar resections for tumors larger than 20 mm had worse survival outcomes.
Conclusion
In this largest-reported retrospective study of patients with resected stage I LCNEC, survival was improved in patients who received chemotherapy in both stage IA and stage IB LCNEC.
It was first classified in 1991 as part of the spectrum of pulmonary neuroendocrine tumors; previously, it was defined as a high-grade atypical carcinoid tumor.
LCNEC is defined by large cell morphology and neuroendocrine differentiation on either immunohistochemistry or electron microscopy, with a low nuclear-to-cytoplasm ratio, a high mitotic rate (>10/10 high-power fields), and frequent areas of necrosis. The 2015 World Health Organization Classification of Lung Tumors groups LCNEC, SCLC, and carcinoids together under lung neuroendocrine tumors.
Clinically, LCNEC is an aggressive malignancy, with a poor prognosis compared with that of large cell carcinomas without neuroendocrine differentiation, and patients are at significantly higher risk of recurrence.
The role for adjuvant chemotherapy for stage I LCNEC after surgical resection remains unknown, and small-scale studies have yielded conflicting results.
Most of the studies have investigated platinum-based regimens. To our knowledge, only a single prospective adjuvant chemotherapy trial has been completed exclusively in patients with resected LCNEC; the results were suggestive of benefit from adjuvant cisplatin and etoposide.
We analyzed the National Cancer Database (NCDB) to study the role of chemotherapy in the management of resected stage I LCNEC.
Materials and Methods
The NCDB is a joint project of the American Cancer Society and the Commission on Cancer of the American College of Surgeons. Established in 1989, the NCDB is a nationwide, facility-based, comprehensive clinical surveillance resource oncology data set that currently captures 70% of all newly diagnosed malignancies in the United States annually. The American College of Surgeons has executed a business associate agreement that includes a data use agreement with each of its Commission on Cancer–accredited hospitals. The NCDB contains information regarding demographics, comorbidities, tumor characteristics, staging, treatment including surgery, radiation and systemic therapy, and mortality.
The NCDB was used to identify patients who underwent surgical resection and received a diagnosis of pathologic stage I LCNEC. Pathologic staging is recorded in the NCDB according to the sixth and seventh editions of the American Joint Committee on Cancer classification. Patients with LCNEC were identified by using International Classification of Diseases for Oncology, Third Edition, histologic code 8013. Cases diagnosed between 2004 and 2013 were included to ensure adequate outcomes data. Patients without complete treatment data sets were excluded, as were cases with positive surgical margins. Patients who underwent radiation were excluded (Supplementary Fig. 1). The NCDB does not include data regarding the type of chemotherapy regimen administered.
We categorized our study population into patients undergoing surgical resection and those undergoing surgical resection plus chemotherapy. The primary end point was 5-year survival for surgical resection alone versus surgical resection with chemotherapy; 30-day landmark analysis was performed to reduce selection bias.
The Kaplan-Meier method was used for survival estimates, and the results were compared using unadjusted Cox proportional hazards regression models. Multivariable Cox models were adjusted for age (<70 years), sex, ethnicity, tumor grade, tumor size, number of lymph nodes excised, surgery type, income, education, Charlson-Deyo comorbidity score, facility type, and year of diagnosis. Propensity-matched score analysis was also performed for further confirmation. Propensity-matched score variables were identical to the variables in the Cox model. All analyses were performed with SAS software, version 9.4 (SAS Institute, Inc., Cary, NC).
Results
Between 2004 and 2013, 1984 patients underwent surgical resection for stage I LCNEC in the NCDB. After the exclusion criteria were applied, 1232 patients were included in the analysis (see Supplementary Fig. 1). Of these patients, 957 (77.7%) underwent surgical resection alone and 275 (22.3%) received systemic chemotherapy (Table 1). Most of the patients had stage IA disease and were treated in a comprehensive community cancer program or academic research program. Patients with larger tumors were also more likely to receive chemotherapy after surgery (median tumor size 30 mm versus 23 mm [p < 0.001]). Patients receiving chemotherapy after surgery were more likely to have private insurance than were patients treated with surgery alone (46.9% versus 28.3% [p < 0.001]). They also tended to have higher incomes and had more lymph nodes removed during resection, although these differences did not reach statistical significance.
Grade 1 includes well-differentiated tumors and tumors that are differentiated but not otherwise specified. Grade 2 includes moderately-differentiated tumors, moderately well-differentiated, and tumors with intermediate differentiation. Grade 3 includes poorly differentiated tumors. Grade 4 includes undifferentiated, anaplastic tumors. Other indicates that cell type was not determined, not stated, or not applicable; unknown primaries; or high-grade dysplasia.
0.762
1
8 (0.6%)
1 (0.4%)
7 (0.7%)
2
54 (4.4%)
10 (3.6%)
44 (4.6%)
3
712 (57.8%)
153 (55.6%)
559 (58.4%)
4
167 (13.6%)
40 (14.5%)
127 (13.3%)
Other
291 (23.6%)
71 (25.8%)
220 (23.0%)
Median tumor size (IQR), mm
24.0 (17.0–35.0)
30.0 (21.0–41.0)
23.0 (16.0–32.0)
<0.001
Lymph nodes
0.063
≥7 resected
697 (56.6%)
169 (61.5%)
528 (55.2%)
<7 resected
535 (43.4%)
106 (38.5%)
429 (44.8%)
Facility type
0.566
Community cancer program
94 (7.6%)
26 (9.5%)
68 (7.1%)
Comprehensive community cancer program
508 (41.3%)
112 (41.0%)
396 (41.4%)
Academic/research program
484 (39.3%)
102 (37.4%)
382 (39.9%)
Integrated network cancer program
144 (11.7%)
33 (12.1%)
111 (11.6%)
IQR, interquartile range.
a The percentage of people living in the patient’s zip code without a high school degree.
b Grade 1 includes well-differentiated tumors and tumors that are differentiated but not otherwise specified. Grade 2 includes moderately-differentiated tumors, moderately well-differentiated, and tumors with intermediate differentiation. Grade 3 includes poorly differentiated tumors. Grade 4 includes undifferentiated, anaplastic tumors. Other indicates that cell type was not determined, not stated, or not applicable; unknown primaries; or high-grade dysplasia.
Most patients underwent lobectomy (80.7%) followed by sublobar resection (17.7%) and pneumonectomy (1.6%). The NCDB does not provide information on the type of chemotherapy agents received. It does provide information regarding whether patients received single-agent or multiagent therapy. Of the 275 patients receiving chemotherapy treatment, 15 (5.5%) received single-agent chemotherapy and 229 (83.3%) received multiagent chemotherapy. The remaining 31 patients lacked information on the number of agents received.
Overall survival (OS) in a univariate 30-day landmark analysis was significantly improved in patients who received chemotherapy across the whole cohort (Fig. 1). The 5-year survival in a univariate 30-day landmark analysis (Table 2) was significantly improved in patients who received chemotherapy (64.5% versus 48.4%) across the whole cohort (hazard ratio [HR] = 0.54, 95% confidence interval [CI]: 0.43–0.68, p < 0.001). When further stratified by stage, 5-year survival remained significantly improved in both patients with stage IA LCNEC (59.4% versus 50.4% [HR = 0.64, 95% CI: 0.47–0.88, p = 0.006]) and patients with stage IB LCNEC (68.7% versus 44.7% [HR = 0.43, 95% CI: 0.32–0.59, p < 0.001]). Even after multivariable adjustment, chemotherapy was associated with improved 5-year survival in both patients with stage IA disease (HR = 0.64, 95% CI: 0.46–0.89, p = 0.008) and patients with stage IB disease (HR=0.46, 95% CI: 0.33–0.64, p < 0.001) (see Table 2). On propensity score–matched analysis, the 5-year survival benefit from chemotherapy remained statistically significant (64.5% versus 53.7% [HR = 0.58, 95% CI: 0.45–0.76, p < 0.001]). When further stratified by stage, 5-year survival remained significantly improved both in patients with stage IA disease and in patients with stage IB disease. Multivariable analysis also revealed older age (>70 years), white ethnicity, tumor size larger than 20 mm, Charlson-Deyo score of 2 or higher, and sublobar resection to be associated with worse survival (Table 3).
The role of adjuvant treatment in stage I LCNEC is not clearly defined, largely owing to its rarity and the lack of randomized control trials for this patient population. Histologic diagnosis is another obstacle, especially when differentiating between LCNEC and SCLC or poorly differentiated NSCLC.
Single-institution retrospective analyses have shown mixed results with regard to the benefit of neoadjuvant and adjuvant chemotherapy in stage I LCNEC.
In our analysis, we have reported the outcomes for more than 1200 patients with stage I LCNEC who underwent surgical resection with or without chemotherapy. The vast majority of patients who received chemotherapy received it in the adjuvant setting; a small proportion underwent neoadjuvant treatment. We found that patients with stage I disease who underwent chemotherapy had better overall survival. The survival benefit remained when further stratified by stage; both patients with stage IA disease and those with stage IB disease had improved survival with chemotherapy. The benefit remained significant after multivariable adjustment and was further supported by propensity score–matched analyses.
Randomized prospective trials have not identified survival benefit with the addition of adjuvant chemotherapy in patients with stage I NSCLC.
Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial.
In an NCDB analysis, patients with pT1-2N0M0 SCLC who underwent surgical resection alone without the addition of adjuvant chemotherapy had significantly poorer survival.
Because of the aggressive nature of LCNEC, it has been suggested that neoadjuvant and/or adjuvant chemotherapy improves survival, even for those with node-negative early-stage disease, similar to resected small cell carcinoma.
Adjuvant chemotherapy for large-cell neuroendocrine lung carcinoma: results from the European Society for Thoracic Surgeons Lung Neuroendocrine Tumours Retrospective Database.
A small prospective trial by Iyoda et al., in which 15 patients with LCNEC received adjuvant cisplatin and etoposide for two cycles after surgical resection, showed significantly improved survival compared with that in a control group that did not receive chemotherapy.
A recent single-institution retrospective study demonstrated significant improvement in survival in pathologic stages II or higher but not in stage I LCNEC with adjuvant treatment.
Another single-institution retrospective analysis noted that LCNEC histologic type predicted poorer OS and suggested that adjuvant treatment be used even in patients with stage IA LCNEC.
A histologic review of 766 resected lung cancer cases in 1998 identified 22 cases of LCNEC, 18 of which were initially classified as NSCLC, illustrating the difficulty with establishing an accurate histologic diagnosis in these cases.
Mutational analysis of pulmonary tumours with neuroendocrine features using targeted massive parallel sequencing: a comparison of a neglected tumour group.
Variation in genomic profiles may explain the differences in tumor behavior and treatment response seen among patients with LCNEC. One recent study of Japanese patients performed sequencing of all coding exons of 244 cancer-related genes in treatment-naive LCNEC and demonstrated that the genomic profiles of LCNEC were similar to those of SCLC.
Another recent study used targeted next-generation sequencing of 241 cancer-related genes in addition to histologic, immunohistochemical, and clinical information and was able to define specific subsets within LCNEC, including LCNEC tumors with genomic profiles similar to SCLC (co-mutated tumor protein p53 gene [TP53] and retinoblastoma 1 [RB1]), adenocarcinoma (hreonine kinase 11 gene [STK11] and kelch like ECH associated protein 1 gene [KEAP1] mutations), and highly proliferative carcinoid (Multiple Endocrine Neoplasia 1 gene mutation).
Next-generation sequencing of pulmonary large cell neuroendocrine carcinoma reveals small cell carcinoma-like and non-small cell carcinoma-like subsets.
Each subset had its own distinct clinical and pathologic features. Such discrete genomic subsets might explain the heterogeneous findings from previous attempts to classify these tumors based on morphology.
A recent retrospective cohort study in patients with stage IV LCNEC identified that STK11 mutated adenocarcinoma subtype had improved OS when treated with NSCLC like chemotherapy regimen (platinum plus either gemcitabine or taxanes) whereas the RB1 mutated or SCLC subtype fared similarly whether the regimen was NSCLC or SCLC type (platinum plus etoposide).
Our analysis is limited by its retrospective viewpoint, but prospective studies are difficult to conduct on account of the rarity of LCNEC. We also performed a 30-day landmark analysis, as well as a propensity score–matched analysis, to reduce the impact of confounding factors related to retrospective analysis, including the lack of randomization. Some T2b tumors may have been excluded from this analysis on account of staging definition change classifying T2bN0M0 tumors as stage IIA in the seventh edition of the American Joint Committee on Cancer classification, but this is unlikely to have significantly affected the overall results. Another limitation of this study is the lack of histologic review of the cases by experienced pathologists to confirm the diagnosis. It is possible that some patients with a non-LCNEC histologic type, including SCLC, could have been included in the cohorts. But we expect the overall numbers of cases of a non-LCNEC histologic type to be small. We have also done propensity matching to minimize any significant imbalance between the two cohorts. However, given the rarity of LCNEC, using the NCDB allows for study of a large sample. Another shortfall of the NCDB is the lack of information regarding the specific chemotherapy regimens that were administered to patients, including agents, doses, and number of cycles. The identification of survival benefit from the addition of chemotherapy despite the aforementioned limitations speaks to the need to develop treatment regimens that take into account the unique biology of LCNEC.
In this analysis, we have presented the largest reported study of patients with resected stage I LCNEC, comparing surgical resection alone to surgical resection with chemotherapy. Five-year survival was improved in patients who received chemotherapy, in both stage IA and stage IB LCNEC, although the optimal chemotherapy regimen is not defined. Data from our analysis and previous studies show that LCNEC is a unique subtype, and there is little information on the role of chemotherapy in the stage I setting. Our study shows that patients with stage I LCNEC may need a different treatment approach than patients with other NSCLC tumor types. It is important that we pay special attention to the LCNEC cohort in prospective adjuvant trials for patients with NSCLC to better understand the role of adjuvant chemotherapy in LCNEC. Landmark phase III trials on the role of adjuvant chemotherapy in resected NSCLC do not include data on the outcomes of patients with LCNEC.
Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the cancer and leukemia group B, radiation therapy oncology group, and North Central cancer treatment group study groups.
Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10.
Future adjuvant trials that incorporate genomic analysis could go a long way toward identifying the role for adjuvant chemotherapy in patients with stage I LCNEC; moreover, they could identify molecular markers that may be more effective in identifying patients who would benefit from adjuvant chemotherapy.
Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial.
Adjuvant chemotherapy for large-cell neuroendocrine lung carcinoma: results from the European Society for Thoracic Surgeons Lung Neuroendocrine Tumours Retrospective Database.
Mutational analysis of pulmonary tumours with neuroendocrine features using targeted massive parallel sequencing: a comparison of a neglected tumour group.
Next-generation sequencing of pulmonary large cell neuroendocrine carcinoma reveals small cell carcinoma-like and non-small cell carcinoma-like subsets.
Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the cancer and leukemia group B, radiation therapy oncology group, and North Central cancer treatment group study groups.
Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10.
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