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Original Articles: Thoracic

Treatment Timing in Small Cell Lung Cancer, a National Cancer Database Analysis

Bhandari, Shruti MD*; Kumar, Rohit MD*; Pham, Danh MD*,†; Gaskins, Jeremy PhD; Kloecker, Goetz MD, MSPH*

Author Information
American Journal of Clinical Oncology: May 2020 - Volume 43 - Issue 5 - p 362-365
doi: 10.1097/COC.0000000000000676
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Abstract

Small cell lung cancer (SCLC) accounts for 15% of all the lung cancers. The majority (75%) of this aggressive cancer is diagnosed as metastatic disease and associated with poor outcomes overall. Only 6% survive to 5 years.1 Given this cancer’s rapid doubling time, current recommendations and practices favor initiating treatment as soon as possible, usually within 1 week.2 However, evidence supporting this urgent treatment initiation is lacking. Some small retrospective studies have suggested worse survival with a shorter time to treatment initiation (TTI).3,4 We investigated the factors influencing time to chemotherapy initiation (TCI) and its effect on survival in SCLC.

MATERIALS AND METHODS

We queried the deidentified National Cancer Database (NCDB) to obtain our study cohort. The NCDB is a nationwide oncology database which prospectively collects from more than 1500 Commission on cancer-accredited programs. The database includes ∼70% of all new cancer diagnoses in the United States. This study was exempt from review by our institutional review board. For this study, adult patients diagnosed with SCLC between 2010 and 2014 were identified. Patients were excluded if they did not receive chemotherapy, if TCI exceeded 180 days or if information was missing for study variables (insurance, facility type, unknown stage, treatment regimen, treatment time, follow-up). TCI was calculated as the time from date of diagnosis to the start of chemotherapy. TCI was thought to be an appropriate surrogate for TTI to minimize skewing of results from an early local treatment like radiation for acute symptom relief. TCI was separated into 4 categories: 0 to 7, 8 to 14, 15 to 28, and >28 days.

Multivariate analysis for the factors influencing TCI was considered using multiple linear regression with the outcome as the logarithm of TCI; regression coefficients were exponentiated to represent multiplicative changes in TCI. Overall survival (OS) was measured as the length of time between the start of chemotherapy and death or loss to follow-up. Kaplan-Meier curves for OS by TCI category were generated, and OS was compared with log-rank test. Multivariate analysis of OS was performed using the Cox proportional hazards regression for each stage (I and II combined), controlling for all variables in Table 1. All analysis was performed using R statistical software, version 3.5.1.5

TABLE 1
TABLE 1:
Demographic and Clinical Characteristics of SCLC Patients, Stratified by Time to Chemotherapy Initiation

RESULTS

A total of 64,491 patients were included with median age of 66 years (IQR 59 to 73). Demographic and clinical characteristics of the study cohort are summarized in Table 1, stratified by TCI. The majority of patients were females (52%), white (90%), insured by government programs (67%), treated in community practice (62%), and had stage IV disease (64%). Median TCI was 18 days (IQR 9 to 31). TCI was ≤7 days in 21%, 8 to 14 days in 21%, 15 to 28 days in 30%, and >28 days in 28%. Several factors were identified to be associated with TCI and are summarized in Table 2. With median follow-up of 9.2 months, survival was compared between TCI categories (Fig. 1). Significantly improved OS was found with increasing TCI (P<0.001) after controlling for confounders (age, sex, race, Hispanic ethnicity, insurance, facility type, distance to facility, comorbidities, diagnosis year, zip-code, income level, histology, treatment order). Among stage IV patients, compared with TCI≤7 days, the relative hazard ratio (HR)=0.92 (95% confidence interval [CI], 0.89 to 0.95, P<0.001) for 8 to 14 days, HR=0.82 (95% CI, 0.80 to 0.85, P<0.001) for 15 to 28 days, and HR=0.77 (95% CI, 0.74 to 0.79, P<0.001) for >28 days of TCI. Results were similar for stage III and for stage I+II (Fig. 2).

TABLE 2
TABLE 2:
Multiple Linear Regression Model for Time to Chemotherapy Initiation*
FIGURE 1
FIGURE 1:
Kaplan-Meier estimates of overall survival according to time to chemotherapy initiation (TCI).
FIGURE 2
FIGURE 2:
Adjusted hazard ratios for time to chemotherapy initiation (TCI) for each stage. Hazard ratios comes from multivariate Cox proportional hazard models for each stage, controlling for confounders in Table 1.

DISCUSSION

This study provides a large-scale analysis of real-world data, identifying factors influencing TCI and its effect on survival in SCLC. Treatment initiation was faster in SCLC (median TCI 18 d) as compared to other solid cancers (TTI in various cancer: breast cancer—24 d, non–small cell lung cancer—29 d, head and neck cancer—26 d).6,7 A major finding of our analysis is the association between TCI and OS indicating worse survival with shorter TCI. These findings are consistent with a prior analysis that also demonstrated worse survival with shorter TTI in SCLC, but was limited to Kentucky.3 Our study expands on prior work through the use of a national database with improved sample size and additional variables namely comorbidity index, distance traveled, facility type, and location. Known poor prognostic factors for SCLC include advanced age, male sex, extensive stage, poor performance status and low albumin level.8 Our analysis is adjusted for age, sex, and stage but performance status, and albumin level were not available in the NCDB. A possible explanation may be that patients who were more symptomatic and/or had worse performance status received treatment more rapidly. Also, some of these patients may not have been appropriately staged due to the urgency to treat.9 Our observations are consistent with those of Radzikowska et al4 regarding worsened prognosis with more rapid treatment.

Several predictors of increased TCI were identified. Many of the predictors were similar to previous studies in other cancers. For example, black race and treatment at an academic facility were associated with increased TTI.6 Interestingly, our analysis identified a shorter TCI among patients with higher comorbidity scores. This finding is in contrast to previous study on other solid cancers where higher comorbidity scores was associated with increased TTI.6 This may reflect the inclusion of only early stage disease where surgery is an important part of treatment and can cause delay in treatment in patients with higher comorbidities.

Providing timely treatment is vital, linked to survival and demands significant health care resources.6 The results of this study showed that delays in chemotherapy initiation (longer TCI) did not compromise survival, as many practicing oncologists believe currently. From this study we do not want to suggest delaying treatment in SCLC as timely treatment is central to quality cancer care. We believe oncologists should individualize treatment for each SCLC patient. Although early treatment should be considered in patients with early stage disease to prevent stage progression, optimizing symptoms and nutritional status should be considered in others in order to gain maximum treatment benefit.

The finding of potential harm associated with shorter TCI warrants further studies. Our study is limited by its retrospective nature. There were small proportion of patient with missing data or follow-up. In addition, the NCDB does not provide information on performance status that could potentially affect survival. Although most of the randomized trials on SCLC do not report timing of treatment or chemotherapy initiation, it is recorded and would be easy to calculate TTI or TCI. Further ad hoc analysis of these randomized trials can provide us with more data on TTI in clinical trial setting in patients with good performance status.

CONCLUSIONS

Early treatment was associated with poor survival in SCLC, contrary to current belief. Therefore, these results warrant reevaluating the urgency in initiating cytotoxic chemotherapy for SCLC. No current evidence supports the practice of treatment within 1 week of diagnosis. More prospective studies are needed to understand the appropriate timing of chemotherapy in SCLC.

REFERENCES

1. Noone AMHN, Krapcho M, Miller D, et al. SEER Cancer Statistics Review, 1975-2015, Small Cell Cancer of the Lung and Bronchus (Invasive), National Cancer Institute. 2018. Available at: https://seer.cancer.gov/archive/csr/1975_2015/browse_csr.php?sectionSEL=15&pageSEL=sect_15_table.13#f. Accessed September 12, 2019.
2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Small Cell Lung Cancer Version 2.2018. 2018. Available at: https://nccn.org/professionals/physician_gls/pdf/sclc.pdf. Accessed August 5, 2018.
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4. Radzikowska E, Roszkowski-Sliz K, Chabowski M, et al. Influence of delays in diagnosis and treatment on survival in small cell lung cancer patients. Adv Exp Med Biol. 2013;788:355–362.
5. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2018. Available at: https://R-project.org/. Accessed August 1, 2018.
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7. Murphy CT, Galloway TJ, Handorf EA, et al. Increasing time to treatment initiation for head and neck cancer: an analysis of the National Cancer Database. Cancer. 2015;121:1204–1213.
8. Sculier JP, Chansky K, Crowley JJ, et al. The impact of additional prognostic factors on survival and their relationship with the anatomical extent of disease expressed by the 6th Edition of the TNM Classification of Malignant Tumors and the proposals for the 7th Edition. J Thorac Oncol. 2008;3:457–466.
9. Xanthopoulos EP, Corradetti MN, Mitra N, et al. Impact of PET staging in limited-stage small-cell lung cancer. J Thorac Oncol. 2013;8:899–905.
Keywords:

small cell lung cancer; SCLC; timing of chemotherapy; survival; National Cancer Database

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