Resected small cell lung cancer—time for more?

The incidence of small cell lung cancer (SCLC) in the United States has been decreasing from a peak of 11 per 100,000 person years in the mid-1980s to 7 per 100,000 patient-years in 2010 (1). Although, approximately two thirds of patients with SCLC are diagnosed with advanced disease (2), the remaining patients are diagnosed at a stage where their disease may be curable. However, even in limited stage small cell lung cancer (LS-SCLC), where the goal of therapy is a cure, 5 years overall survival (OS) in clinical trials is only about 25% (3). Thus clearly more needs to be done in order to improve outcomes from this disease.

The mainstay of treatment of LS-SCLC is chemotherapy and radiation (4). However, now emerging data have suggested a role for surgical resection as part of multimodality therapy in LS-SCLC, especially in very early stage disease. A prospective study demonstrated a 5-year survival rates of >65% with resection, in patients without nodal involvement Approximately 4% of lung cancers present as a solitary pulmonary nodule are SCLC (5) and therefore could be candidates for surgical resection. However the benefit of adjuvant chemotherapy in this setting is unclear. Also, given the rarity of this presentation, it is unlikely that a randomized clinical trial will ever be performed to answer this question. In this context the retrospective analysis conducted by Yang et al. using the National Cancer Database is very significant (6).

Yang et al. reviewed the records of 954 patients in the National Cancer Database, with resected pT1–2, pN0, M0 SCLC between 2003 and 2011 (6). Of the 954 patients, 566 (59%) received some adjuvant therapy. The majority of patients (n=544; 96%) received chemotherapy, either alone (n=354) or with radiation (n=190); ninety-nine patients received cranial radiation. Patients treated with adjuvant chemotherapy with or without radiation had a median OS of 66.0 months and a 5-year OS of 52.7%. The corresponding figures for patients who did not receive adjuvant therapy were 42.1 months and 40.4% respectively. On multivariate analysis, the receipt of adjuvant chemotherapy alone [hazard ratio (HR), 0.78; 95% CI, 0.63–0.95] or with brain radiation (HR, 0.52; 95% CI, 0.36–0.75) was associated with significantly improved survival as compared to surgery alone. Increasing age, tumor size, and Charlson Deyo Comorbidity score of 2+ were associated with worse survival, while the performance of a lobectomy was associated with improved survival.

The nature of the database leads to significant limitations of this analysis. The exact nature of the chemotherapy and radiation performed cannot be ascertained. The authors assumed that additional therapy was given as adjuvant therapy and not for early relapses and defined adjuvant as chemotherapy and radiation therapy (whether to lung or brain) given within 5 and 8 months of surgery, respectively.

Although the NCCN guidelines recommend the use of adjuvant chemotherapy following resection, this based on extrapolation from the understanding of the biology of SCLC and limited data (7). The limitations of this retrospective analysis notwithstanding, these results are significant and should establish adjuvant chemotherapy as the standard of care in patients with resected, node negative SCLC.

Another interesting finding in this analysis is the 48% decreased risk of mortality with adjuvant chemotherapy and brain radiation. The brain is a common site of metastasis in SCLC and approximately 45% patients who obtain a complete response with initial therapy will present with brain metastases as the only site of relapse (8). Prophylactic cranial irradiation (PCI) is recommended for patients with LS-SCLC and a good performance status following completion of definitive chemoradiation (8,9). Given the biology of SCLC, it stands to reason that patients with extremely early stage SCLC, as in the Yang study would benefit too. Again, it is unlikely that a randomized trial evaluating the role of PCI in this population will be performed. Hence these results should establish PCI as the standard of care following resection and adjuvant chemotherapy for SCLC.

This study however does not clarify the role of chest radiation following surgery. There was no benefit to thoracic radiation, either with or without adjuvant chemotherapy. It is possible that the relatively small numbers precluded the identification of a significant clinical benefit, but there was a significant benefit with PCI in similar numbers of patients. Also, it is not clear due to the nature of the database whether thoracic radiation was given truly adjuvant or as a salvage option. In non-SCLC, the detrimental effect of post-operative radiation in N0 or N1 disease is well-known (10) and a similar phenomenon may be at play in SCLC as well.

The disappointing feature of this analysis is that despite aggressive treatment in an extremely good-risk patient population, the 5-year OS was only 53%. It is unlikely that we will make much meaningful progress in SCLC with the existing approaches. Immunotherapy approaches seem promising and these and other novel approaches must be evaluated rapidly in order to improve outcomes in this disease.

Acknowledgements

Funding: Research reported in this publication was supported by the Fred & Pamela Buffett Cancer Center Support Grant (P30CA036727).

Footnote

Provenance: This is an invited Perspective commissioned by the Section Editor Lei Deng (West China Hospital, Sichuan University, Chengdu, China).

Conflicts of Interest: The authors have no conflicts of interest to declare.

Comment on: Yang CF, Chan DY, Speicher PJ, et al. Role of Adjuvant Therapy in a Population-Based Cohort of Patients With Early-Stage Small-Cell Lung Cancer. J Clin Oncol 2016;34:1057-64.

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