Next Article in Journal
Impact of Oral Targeted Therapy on the Economic Burden of Chronic Lymphocytic Leukemia in Canada
Previous Article in Journal
The Impact of Radiotherapy on the Incidence of Secondary Malignancies: A Pan-Cancer Study in the US SEER Cancer Registries
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Current Oncology
Volume 28
Issue 1
10.3390/curroncol28010036
curroncol-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Real World Analysis of Small Cell Lung Cancer Patients: Prognostic Factors and Treatment Outcomes

by
Sarah Sharman Moser
1,*,†,
Jair Bar
2,3,†,
Inna Kan
4,
Keren Ofek
4,
Raanan Cohen
4,
Nikhil Khandelwal
5,
Varda Shalev
1,3,
Gabriel Chodick
1,3 and
Nava Siegelmann-Danieli
1
1
Maccabitech, Maccabi Institute for Research & Innovation, Maccabi Healthcare Services, Tel Aviv 6812509, Israel
2
Sheba Medical Center, Institute of Oncology, Tel Hashomer, Ramat Gan 5262000, Israel
3
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
4
Abbvie Biopharmaceuticals Ltd., Hod Hasharon 4524075, Israel
5
Abbvie Inc., Chicago, IL 60064, USA
*
Author to whom correspondence should be addressed.
†
First two authors had equal contribution.
Curr. Oncol. 2021, 28(1), 317-331; https://doi.org/10.3390/curroncol28010036
Submission received: 17 November 2020 / Revised: 2 December 2020 / Accepted: 3 December 2020 / Published: 8 January 2021
Browse Figures
Versions Notes

Abstract

:
In this observational study, we assessed treatment patterns and prognostic factors in patients with small cell lung cancer (SCLC) in a large state-mandated healthcare organization in Israel. Methods: All incident cases with histologically confirmed SCLC who initiated systemic anti-cancer treatment between 2011 and 2017 were identified. Treatment patterns and overall survival (OS) were evaluated for each line of therapy. Results: A total of 235 patients were identified (61% male, median age 64 years, 95% ever smokers, 64% had extensive stage). The first-line treatment was platinum–etoposide regimen for 98.7% of the cohort. The second and third-line regimen were given to 43% and 12% of patients, respectively. Mean OS for extensive and limited stage patients was 9.1 and 23.5 months respectively. In a multivariable model, increased risk for mortality was observed among patients with an ECOG performance status (PS) of 2 compared to a PS of 0–1 for the extensive stage patients (Hazard ratio (HR) = 1.63, 95% confidence ratios (CI): 1.00–2.65); and for males compared to females for the limited stage patients (HR = 2.17; 95% CI: 1.12–4.20). Regarding all 2nd line patients in a multivariable model incorporating relevant confounding factors, demonstrated a significantly better outcome with platinum–based regimens compared to topotecan. Median survival after initiation of 2nd line in platinum-sensitive patients was longer (p = 0.056) for those re-challenged with platinum–based regimen (n = 7): 6.8mo (6.1-not reported (NR)), compared with those switched to a different treatment (n = 27): 4.5 mo (2.6–6.6) for extensive stage patients, and a non-significant difference was also observed for limited stage patients. Conclusion: To our knowledge, this is one of the largest real-world studies of SCLC patients. OS for SCLC patients was similar to that reported in clinical trials. PS for extensive stage patients and sex for limited stage patients were significant correlates of prognosis. Re-challenge of the platinum–based doublet was associated with longer OS compared to switching treatment in extensive stage patients.

1. Introduction

Small cell lung cancer (SCLC) is an aggressive smoking-associated malignancy with rapid growth and early metastatic dissemination [1] that accounts for 10% to 15% of all diagnoses of lung cancers [2,3,4,5,6]. Almost two-thirds of SCLC patients have extensive stage disease at presentation, with a median survival of 7 to 11 months and only 1% being alive at 5 years [7,8,9].
Patients with limited stage disease are treated with concurrent chemotherapy and chest irradiation, whereas extensive stage patients are traditionally treated with chemotherapy alone. First-line (L1) chemotherapy with cisplatin or carboplatin with etoposide has been the standard of care for several decades [10], with no changes besides the recent incorporation of atezolizumab to platinum–based regimen in patients with extensive stage disease [11,12,13,14]. Prophylactic brain irradiation mostly for responding patients with limited disease was part of the standard of care [15,16] but has recently been challenged [17]. Consolidate radiotherapy for highly responding extensive disease is another controversial topic [18,19]. Despite high sensitivity to initial chemotherapy and radiotherapy, most patients with either limited or extensive tumors relapse relatively early [20,21] and cure rates remain low [22].
Recurrent disease has limited treatment options. Second-line (L2) systemic chemotherapy is the standard of care [23,24,25,26] for medically fit patients, with regimen choice partly determined by prior response to L1 platinum-based regimen [26,27,28]. Sensitive disease is defined in this tumor type by initial response to L1 platinum-based treatment and a post-treatment progression-free interval of at least 90 days [23]. Patients with sensitive tumors have a much greater likelihood of responding to any further systemic treatment than resistant patients [29,30,31] and are often candidates for re-challenge with platinum-based regimens; all relapsed patients are candidates for topotecan therapy [8,32,33,34]. Amrubicin is another L2 treatment option approved and utilized in Japan [20]. A small fraction of patients may benefit from immunotherapy treatment with the anti-PD-1 agent nivolumab, mostly in L3, as treatment benefit was not seen in a randomized trial of L2 patients [11,35,36,37]. Chemotherapy for L3 may be considered for a limited group of medically fit patients, and studies suggest survival of 3.8–4.7 months [38,39] Thus, treatment options for relapsing cases are limited, confer mostly short-term clinical benefit, and are mostly based on data from single-institution retrospective reviews or small, single-arm trials [40,41,42,43].
Considering the developments in the field of immune-oncology, updated, multi-institutional real-world data have a high value for guiding design of future studies and for critical evaluation of novel therapies. We are aware of only one cohort of real-world patients with extensive-stage disease treated with chemotherapy alone during the years 2009–2013 [44]. We describe here a retrospective cohort study of the characteristics, treatment patterns and overall survival (OS) of SCLC patients with both limited and extensive-stage, including immunotherapy-treated patients in recent years.

2. Materials and Methods

2.1. Data Source

This retrospective cohort study was conducted using the computerized databases of Maccabi Healthcare Services (MHS), the second largest of four nationwide healthcare insurer-provider organizations. Membership in MHS is free and every citizen is eligible to register as a member for whichever health fund he or she chooses, without limitations of preconditions or age. MHS has approximately 2.1 million members, representing a quarter of the population and shares similar sociodemographic characteristics with the general population [45]. The MHS database contains longitudinal clinical data that are automatically collected since 1993 for a stable population (with less than 1% of members moving out each year), including laboratory results from a single central laboratory, pharmacy prescription and purchase data, hospitalizations, procedures and consultations. MHS uses the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) coding systems, as well as self-developed coding systems to provide more granular diagnostic information. Procedures are coded using Current Procedural Terminology codes. MHS has developed several computerized registries of major chronic diseases, such as cardiovascular disease, oncologic diseases, diabetes mellitus, and osteoporosis, in order to improve the quality of chronic care delivery to its members. Such registries are continuously updated, and they identify patients via automatic search formulas, as opposed to being dependent upon active reporting by physicians [46,47,48].
In addition to the automatic data collection, data that were not available in the main database such as disease staging, imaging results, metastases and eastern cooperative oncology group performance status (PS), were manually extracted by trained data extractors from individual PDF files of patient data in the MHS medical health records.

2.2. Study Population

In this retrospective cohort study we identified MHS members aged 18 years or above with a SCLC diagnosis, based on the national cancer registry (which uses diagnosis data from the Israel Ministry of Health, linked to cancer medication approvals and pathology reports from MHS) [49] or with a SCLC diagnosis code in the MHS electronic medical records, and confirmed by manual review of pathology reports. To be included in the study patients had to have received at least one systemic chemotherapy regimen.
Patients were included if they received the first systemic treatment for SCLC between 1 January 2011 and 31 December 2017. Index date was set as the date of initiation of first systemic treatment. Patients with less than one year of healthcare registration in MHS before index date were excluded.
Data was collected up to June 2018 to allow for a minimum follow-up of 6 months.

2.3. Study Variables

Demographic and clinical data collected included age at index date, sex, socioeconomic status, district, comorbid conditions, weight and smoking. Socioeconomic status was categorized into quartiles based on the poverty index of the member’s enumeration area, as defined by 2008 Israeli National Census [50]. The poverty index is based on several parameters including household income, educational level, crowding and car ownership.
Co-morbidities at baseline were identified using MHS registries (for diabetes mellitus, hypertension, chronic obstructive pulmonary disease, cardiovascular disease, chronic kidney disease and osteoporosis).
Drug purchases and smoking data were cross-linked between the automatic extraction from the database and additional manually extracted data.

2.4. Treatment Patterns

Treatment lines were defined according to the sequence of dispensed medications, with information captured both from pharmacy database (for medications approved by MHS), and from hospital medical records (including information on medications provided by private insurance and clinical studies). Addition of a new drug to a current regimen was considered a new treatment line, and cessation of a medication from a combination regimen (likely due to tolerance issues) was considered the same line.

2.5. Statistical Analysis

Baseline descriptive characteristics were compared using t tests for continuous variables and chi-square tests for discrete variables.
OS was assessed using all-cause mortality data from the National Insurance Institute, with Kaplan–Meier and Cox proportional hazards regression methods, and plots of expected survival were generated from L1 and L2 treatment initiation. All analyses were performed for extensive and limited stage patients separately, and subdivided into platinum-resistant and platinum-sensitive patients. Platinum sensitivity was defined as an interval of ≥3 months from the end of L1 treatment to the beginning of L2 treatment. Relapse free interval was defined as the interval between last dose of L1 treatment and initiation of L2 therapy (split by 0–3 months, 3–6 months, 6–9 months and 9–12 months).
All analyses were conducted using IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp, and a p-value < 0.05 was considered statistically significant.
The study was approved by the local ethics review board of Bayit Balev Hospital in Israel.

3. Results

A total of 235 patients with histologically confirmed SCLC initiated L1 treatment between the years 2011–2017 (inclusive). Median age at start of treatment was 64 years (interquartile range (IQR) 58, 70), 61% were male, 95% ever smokers, and 60% had 0–1 PS at index date (Table 1).
L1 treatment was platinum (carboplatin/cisplatin)-etoposide regimen for 232 patients (98.7%) of the cohort, and three patients (1.3%) received another platinum-based regimen. Median OS for the study population was 11.8 months (95% confidence interval (CI) 9.9–13.7). A hundred and one (43%) patients continued to Line 2 therapy, and 29 (12%) to Line 3.

3.1. Extensive Stage Disease

A total of 150 (64%) patients with extensive stage disease were eligible for this analysis and consisted of 38% females, 94% ever smokers, 57% 0–1 PS and 17% brain metastases at index date (Table 1). Mean OS was 9.1 months (95% CI: 8.4–10.3). Additional factors that correlated with better OS in the univariate analysis included better PS (9.6 vs. 8.9 months, PS 0–1 vs. 2, p = 0.09, Table 2). In a multivariable model for all-cause mortality, patients with PS = 2 compared to PS = 0–1 had significant increase in mortality with a HR of 1.63 (95% CI: 1.00–2.65, Table 3).
OS from initiation of L2 treatment (n = 62) was 4.54 months (95% CI: 3.19–6.12, Table 2). When split by L2 treatment, OS was 6.81 (6.12-NR), 3.48 (2.63–5.13) and 10.55 (2.43-NR) for platinum-based regimen(n = 7), topotecan (n = 40) and PD-1/PD-L1 inhibitor treatment (n = 7) respectively (p = 0.04, Figure 1). Multivariate hazard ratios confirmed a significant difference between platinum-based regimen vs. topotecan L2 treatment (Table 4). Demographic and clinical characteristics were similar between patients that were re-challenged with platinum-based regimen (n = 7) or switched (n = 55) to a different L2 treatment (data not shown).
Extensive stage patients were further stratified by those that were platinum- resistant (n = 28) and platinum-sensitive (n = 34) to L1 therapy. Demographic and clinical characteristics were similar, however platinum-resistant patients were younger (median age = 61 vs. 65 years, p = 0.20), had a higher percentage of males (71% vs. 56%, p = 0.32) and were slightly less likely to be smokers (93% vs. 97%, p = 0.86) as compared to platinum-sensitive patients (all not significant, data not shown).
Among those that received L2 therapy and were resistant to L1 platinum-basedtherapy (initiated L2 therapy ≤3 months from the cessation of L1 therapy), all patients (n = 28) were switched to a different L2 treatment and did not receive re-challenge with L1 platinum-based regimen: 19 received topotecan (OS = 3.5, 2.1–6.3) and 4 received PD-1/PD-L1 inhibitor treatment (OS = 5.6, 0.66-NR, p = 0.43) for the difference between the treatment options (data not shown).
Median survival after initiation of 2nd line in platinum-sensitive patients was longer (p = 0.056) for those re-challenged with platinum-regimen (n = 7): 6.8mo (6.12-NR), compared with those switched to a different treatment (n = 27): 4.5 mo (2.6–6.6) for extensive stage patients (Figure 2). Of these, 22 received topotecan, 3 received PD-1/PD-L1 inhibitor therapy and 2 received other treatment. Demographic and clinical variables were similar for platinum-sensitive patients between those re-challenged and switched (data not shown).

3.2. Limited Stage Disease

A total of 85 (36%) patients with limited stage disease were eligible for this analysis and consisted of 40% females, 98% ever smokers, 66% 0–1 PS and 0% brain metastases at index date (Table 1). Mean OS was 23.5 months (95% CI: 19.4–27.9, Table 2). An additional factor that significantly correlated with better OS in the univariate analysis was female sex (29.6 vs. 21.5 months, p = 0.03, Table 2). In a multivariable model for all-cause mortality, males had significant increase in mortality with a HR of 2.17 (95% CI: 1.12–4.20, Table 3).
For patients with relapsed limited stage disease, OS from initiation of L2 treatment (n = 39) was 8.68 months (95% CI: 6.02–14.04, Table 2). When split by L2 treatment, OS was 9.11 (7.4–18.8), 5.06 (3.62-NR) and NR for platinum-based regimen (n = 20), topotecan (n = 13) and PD-1/PD-L1 inhibitor treatment (n = 3) respectively (p = 0.01, Figure 1). Multivariate hazard ratios confirmed a non-significant difference between platinum-based regimen vs. topotecan L2 treatment (Table 4). Demographic and clinical characteristics were similar between patients that were re-challenged with platinum-based regimen (n = 20) or switched (n = 19) to a different L2 treatment (data not shown).
Relapsed limited stage patients were further stratified by those that were platinum- resistant (n = 6) and platinum-sensitive (n = 33) to L1 therapy and demographic and clinical characteristics were similar between the groups.
Among those that received L2 therapy and were resistant to L1 platinum-basedtherapy (initiated L2 therapy ≤3 months from the cessation of L1 therapy), all patients (n = 6) were switched to a different L2 treatment and did not receive re-challenge with L1 platinum-based treatment (data not shown).
Median survival after initiation of L2 for platinum-sensitive patients was numerically longer though results were non-significant between those re-challenged with L1 platinum-based regimen (n = 20, OS = 9.1 mo (7.4–18.8)) and those switched to a different therapy (n = 13, OS = 6.4 mo (5.1-NR)), for the difference between the treatment options (Figure 2). Demographic and clinical variables were similar for platinum-sensitive patients between those re-challenged and switched (data not shown).

3.3. Sensitivity Analyses

As a sensitivity analysis, we analyzed all patients with sensitive disease together (n = 67). We found the patients re-challenged with platinum-based regimen (n = 27) to have a significantly longer median OS (9.1 mo, 95% CI: 6.1–12.1) than those switched to topotecan (n = 32, 4.6 mo, 95% CI: 2.9–6.2, p < 0.001). Four patients received PD-1/PD-L1 inhibitor therapy and had a median OS of 16.4 mo (95% CI: NR).
Additionally, a multivariable model considering of all L2 patients (focusing on OS from initiation of L2 therapy) incorporated age, sex, stage (at initial diagnosis), initial PS, brain metastasis, platinum sensitivity to L1 and treatment regimen at L2, found that extensive stage patients had a HR for death of 2.05 (95% CI: 1.19–3.53) as compared to limited stage, and patients that received treatment with topotecan had a HR of 2.67 (95% CI: 1.47–4.85) as compared to those re-treated with platinum based regimen (data not shown).
A further sensitivity analysis examined OS from initiation of L2 therapy stratified by the relapse free interval from end of L1 therapy to initiation of L2 therapy (split by 0–3 months, 3–6 months, 6–9 months and 9–12 months). No difference in OS was observed between the different relapse free intervals.
We further focused on 39 patients (16.6% of the study cohort) who survived for at least 24 months from initiation of L1 treatment. Of these, 80% were limited stage, 54% were female and 72% had 0–1 PS. Of the 8 patients with initial extensive stage disease who demonstrated long-term survival, 5 (63%) were female, 7 (88%) had 0–1 PS, 6 (75%) received radiation during L1 treatment (who had excellent response of mostly advanced localized disease), and 7 (88%) were brain metastases free.

4. Discussion

Our study reports patient characteristics and OS for a consecutive cohort of unselected SCLC patients. To the best of our knowledge, this is the first real-world study of SCLC patients with relatively recent data, including some patients that received immunotherapy as L2 therapy. In our study, only 43% of patients received L2 therapy and even fewer (12%) went on to receive L3 therapy.
Median OS from L1 treatment initiation was 11.8 months, similar to previous studies [51,52,53,54], a result that has not significantly changed over the past 20 years. OS for extensive stage patients was 9.1 months (95% CI: 8.4, 10.3), comparable to a recent study which reported 10.7 months (95% CI: 9.3, 11.8) [44] in a real-world setting, as well as the control arm of a clinical study which reported 10.3 mo (95% CI: 9.3, 11.3) [12]
Predictors of survival included better PS for extensive stage patients, and female sex for limited stage patients, and were mostly similar to those reported in previous studies [55,56,57,58]. Unlike studies which identified female sex as positive prognostic factors for all patients, in our cohort the benefit was seen only for the limited disease patients who dominated the long-term survivors. Other prognostic factors reported in the literature include PS at the time of disease recurrence for all patients [59] and sensitivity to L1 therapy [31,60].
Median OS for patients from L2 treatment was 4.5 months for extensive stage and 8.7 months for limited stage, similar to other studies [31,61] showing the important prognostic significance of stage at initial diagnosis. We found when limiting the analysis to platinum-sensitive patients, those re-treated with platinum–based chemotherapy had a longer numerical survival than those switched to treatment with topotecan single agent for both extensive and limited stage, but did not reach statistical significance, similar to a previously published study [31]. A randomized phase III prospective trial including 180 platinum sensitive patients were treated at relapse with platinum-based regimen or other chemotherapy. Those re-treated with platinum-based therapy had better outcomes than those that were switched [62]. The non-statistical significance in our study could be due to the small numbers in the sub-cohorts. L2 therapy is generally much less effective than initial treatment making it more challenging to draw conclusions on optimal treatment.
Finally, we compared OS from initiation of L2 treatment, by relapse free interval from end of L1 treatment to initiation of L2 treatment, however did not find any difference in OS between the groups, similar to another study [63].
OS for SCLC has not improved over the last few decades, and in recent years immunotherapy has become a potential new treatment for SCLC patients. In 2019 the US Food and Drug Administration approved atezolizumab in combination with L1 platinum doublet chemotherapy for extensive stage disease, and recently durvalumab was approved in a similar setting, based on improvement in OS and progression free survival [12,64]. Although the numbers were small, we found that those switched to immunotherapy had a longer numeric median OS than those that received platinum-basedor topotecan therapy for extensive stage. These results need to be interpreted with caution but may be seen as supportive for the role of immunotherapy in SCLC treatment.
Long-term survivors were more likely to be female, have limited stage and 0–1 PS, at baseline and [31] received up-front radiotherapy similar to reports in the literature [65,66].
This study has several strengths including high quality data obtained from the MHS digital database and comprehensive review of patient medical records, long follow up and relatively recent data. Limitations include the retrospective nature of this study with a lack of data as to treatment decisions and patient treatment preference in L2.

5. Conclusions

OS for SCLC patients in a real-world setting was found to be similar to those reported in clinical trials. Factors significantly associated with prognosis included PS for extensive stage patients and sex for limited stage patients. Re-challenge of the platinum-based doublet in relapsing patients who were platinum sensitive was associated with longer OS compared to switching to topotecan treatment in extensive stage patients. In this cohort, long term (24 months or more) survivors, were associated mostly with female limited stage patients, with low PS and upfront combined chemotherapy-irradiation approach.

Author Contributions

Conceptualization, V.S., G.C., I.K., K.O. and R.C.; methodology, G.C., J.B., S.S.M. and N.S.-D.; validation, S.S.M.; formal analysis, S.S.M., N.S.-D., J.B. and G.C.; data curation S.S.M.; writing—original draft preparation, S.S.M., G.C., N.S.-D. and J.B.; writing—review and editing, S.S.M., J.B., I.K., K.O., R.C., N.K., V.S., G.C. and N.S.-D. All authors have read and agreed to the published version of the manuscript.

Funding

The study was funded by Abbvie. The design and study conduct were performed in collaboration of AbbVie with Maccabi Healthcare Services as well as participation of the interpretation of data, review, and approval of the publication. Gabriel Chodick, Varda Shalev, Nava Siegelmann-Danieli, and Sarah Sharman Moser do not have any conflict of interest. Jair Bar has served as a consultant to AbbVie, and has received research funding and speaker fees from AbbVie. Keren Ofek, Inna Kan, Nikhil Khandelwal, and Raanan Cohen are employees of AbbVie and own AbbVie stock. The authors wish to acknowledge and thank Maccabi Healthcare Services and AbbVie for overall support and forming REAL WORLD research collaboration in order to generate and develop the data for this abstract.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Lally, B.E.; Urbanic, J.J.; Blackstock, A.W.; Miller, A.A.; Perry, M.C. Small Cell Lung Cancer: Have We Made Any Progress Over the Last 25 Years? Oncologist 2007, 12, 1096–1104. [Google Scholar] [CrossRef] [PubMed]
  2. Cheng, S.; Evans, W.K.; Stys-Norman, D.; Shepherd, F.A.; The Lung Cancer Disease Site Group of Cancer Care Ontario’s Program in Evidence-based Care. Chemotherapy for Relapsed Small Cell Lung Cancer: A Systematic Review and Practice Guideline. J. Thorac. Oncol. 2007, 2, 348–354. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Govindan, R.; Page, N.; Morgensztern, D.; Read, W.; Tierney, R.; Vlahiotis, A.; Spitznagel, E.L.; Piccirillo, J. Changing Epidemiology of Small-Cell Lung Cancer in the United States Over the Last 30 Years: Analysis of the Surveillance, Epidemiologic, and End Results Database. J. Clin. Oncol. 2006, 24, 4539–4544. [Google Scholar] [CrossRef] [PubMed]
  4. Brownson, R.C.; Chang, J.C.; Davis, J.R. Gender and Histologic Type Variations in Smoking-Related Risk of Lung Cancer. Epidemiology 1992, 3, 61–64. [Google Scholar] [CrossRef] [PubMed]
  5. Society AC. Cancer Facts & Figures 2019 Atlanta, GA. Available online: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdf (accessed on 4 March 2019).
  6. Varghese, A.M.; Zakowski, M.F.; Yu, H.A.; Won, H.H.; Riely, G.J.; Krug, L.M.; Kris, M.G.; Rekhtman, N.; Ladanyi, M.; Wang, L.; et al. Small-Cell Lung Cancers in Patients Who Never Smoked Cigarettes. J. Thorac. Oncol. 2014, 9, 892–896. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Rodriguez, E.; Lilenbaum, R.C. Small Cell Lung Cancer: Past, Present, and Future. Curr. Oncol. Rep. 2010, 12, 327–334. [Google Scholar] [CrossRef]
  8. Kalemkerian, G.P. Advances in pharmacotherapy of small cell lung cancer. Expert Opin. Pharmacother. 2014, 15, 2385–2396. [Google Scholar] [CrossRef]
  9. Clark, R.; Ihde, D.C. Small-cell lung cancer: Treatment progress and prospects. Oncology 1998, 12, 647–658. [Google Scholar]
  10. Oze, I.; Hotta, K.; Kiura, K.; Ochi, N.; Takigawa, N.; Fujiwara, Y.; Tabata, M.; Tanimoto, M. Twenty-Seven Years of Phase III Trials for Patients with Extensive Disease Small-Cell Lung Cancer: Disappointing Results. PLoS ONE 2009, 4, e7835. [Google Scholar] [CrossRef]
  11. Antonia, S.J.; López-Martin, J.A.; Bendell, J.; Ott, P.A.; Taylor, M.; Eder, J.P.; Jäger, D.; Pietanza, M.C.; Le, D.T.; De Braud, F.; et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): A multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016, 17, 883–895. [Google Scholar] [CrossRef] [Green Version]
  12. Horn, L.; Mansfield, A.S.; Szczęsna, A.; Havel, L.; Krzakowski, M.; Hochmair, M.J.; Huemer, F.; Losonczy, G.; Johnson, M.L.; Nishio, M.; et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N. Engl. J. Med. 2018, 379, 2220–2229. [Google Scholar] [CrossRef] [PubMed]
  13. Metro, G.; Cappuzzo, F. Emerging drugs for small-cell lung cancer. Expert Opin. Emerg. Drugs 2009, 14, 591–606. [Google Scholar] [CrossRef] [PubMed]
  14. Byers, L.A.; Rudin, C.M. Small cell lung cancer: Where do we go from here? Cancer 2015, 121, 664–672. [Google Scholar] [CrossRef]
  15. Auperin, A.; Arriagada, R.; Pignon, J.-P.; Le Péchoux, C.; Gregor, A.; Stephens, R.J.; Kristjansen, P.E.; Johnson, B.E.; Ueoka, H.; Wagner, H.; et al. Prophylactic Cranial Irradiation for Patients with Small-Cell Lung Cancer in Complete Remission. N. Engl. J. Med. 1999, 341, 476–484. [Google Scholar] [CrossRef] [PubMed]
  16. Slotman, B.; Faivre-Finn, C.; Kramer, G.; Rankin, E.; Snee, M.; Hatton, M.; Postmus, P.; Collette, L.; Musat, E.; Senan, S.; et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N. Engl. J. Med. 2007, 357, 664–672. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Takahashi, T.; Yamanaka, T.; Seto, T.; Harada, H.; Nokihara, H.; Saka, H.; Nishio, M.; Kaneda, H.; Takayama, K.; Ishimoto, O.; et al. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2017, 18, 663–671. [Google Scholar] [CrossRef]
  18. Slotman, B.J.; Van Tinteren, H.; Praag, J.O.; Knegjens, J.L.; El Sharouni, S.Y.; Hatton, M.; Keijser, A.; Faivre-Finn, C.; Senan, S. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: A phase 3 randomised controlled trial. Lancet 2015, 385, 36–42. [Google Scholar] [CrossRef]
  19. Gore, E.M.; Hu, C.; Sun, A.Y.; Grimm, D.F.; Ramalingam, S.S.; Dunlap, N.E.; Higgins, K.A.; Werner-Wasik, M.; Allen, A.M.; Iyengar, P.; et al. Randomized Phase II Study Comparing Prophylactic Cranial Irradiation Alone to Prophylactic Cranial Irradiation and Consolidative Extracranial Irradiation for Extensive-Disease Small Cell Lung Cancer (ED SCLC): NRG Oncology RTOG 0937. J. Thorac. Oncol. 2017, 12, 1561–1570. [Google Scholar] [CrossRef] [Green Version]
  20. Asai, N.; Ohkuni, Y.; Kaneko, N.; Yamaguchi, E.; Kubo, A. Relapsed small cell lung cancer: Treatment options and latest developments. Ther. Adv. Med Oncol. 2014, 6, 69–82. [Google Scholar] [CrossRef] [Green Version]
  21. Simon, M.; Argiris, A.; Murren, J.R. Progress in the therapy of small cell lung cancer. Crit. Rev. Oncol. 2004, 49, 119–133. [Google Scholar] [CrossRef]
  22. Shepherd, F.A.; Crowley, J.J.; Van Houtte, P.; Postmus, P.E.; Carney, D.; Chansky, K.; Shaikh, Z.; Goldstraw, P. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals Regarding the Clinical Staging of Small Cell Lung Cancer in the Forthcoming (Seventh) Edition of the Tumor, Node, Metastasis Classification for Lung Cancer. J. Thorac. Oncol. 2007, 2, 1067–1077. [Google Scholar] [CrossRef] [PubMed]
  23. Cancer Care Ontario. Members of the Lung Cancer Disease Site Group. Chemotherapy for Relapsed Small Cell Lung Cancer. Toronto Program in Evidence-Based Care Evidence-based Series No.: 7-17 Version 2. 2013. Available online: https://www.cancercareontario.ca/en/guidelines-advice/types-of-cancer/801 (accessed on 4 March 2019).
  24. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines). Small Cell Lung Cancer. Version 2.2014. 2014. Available online: http://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf (accessed on 4 March 2019).
  25. NICE. Topotecan for the Treatment of Relapsed Small-Cell Lung Cancer. Available online: https://www.nice.org.uk/guidance/ta184 (accessed on 4 March 2019).
  26. Vincent, M.; Evans, B.; Smith, I. First-line chemotherapy rechallenge after relapse in small cell lung cancer. Cancer Chemother. Pharmacol. 1988, 21, 45–48. [Google Scholar] [CrossRef] [PubMed]
  27. Hurwitz, J.L.; McCoy, F.; Scullin, P.; Fennell, D.A. New Advances in the Second-Line Treatment of Small Cell Lung Cancer. Oncologist 2009, 14, 986–994. [Google Scholar] [CrossRef] [PubMed]
  28. Arcaro, A.; Fischer, B. Current Status of Clinical Trials for Small Cell Lung Cancer. Rev. Recent Clin. Trials 2008, 3, 40–61. [Google Scholar] [CrossRef] [PubMed]
  29. Postmus, P.E.; Berendsen, H.H.; Van Zandwijk, N.; Splinter, T.A.; Burghouts, J.T.M.; Bakker, W. Retreatment with the induction regimen in small cell lung cancer relapsing after an initial response to short term chemotherapy. Eur. J. Cancer Clin. Oncol. 1987, 23, 1409–1411. [Google Scholar] [CrossRef]
  30. Huisman, C.; Postmus, P.; Giaccone, G.; Smit, E. Second-line chemotherapy and its evaluation in small cell lung cancer. Cancer Treat. Rev. 1999, 25, 199–206. [Google Scholar] [CrossRef] [PubMed]
  31. Garassino, M.C.; Torri, V.; Michetti, G.; Dico, M.L.; La Verde, N.; Aglione, S.; Mancuso, A.; Gallerani, E.; Galetta, D.; Martelli, O.; et al. Outcomes of small-cell lung cancer patients treated with second-line chemotherapy: A multi-institutional retrospective analysis. Lung Cancer 2011, 72, 378–383. [Google Scholar] [CrossRef]
  32. Giaccone, G. Second line chemotherapy in small cell lung cancer. Lung Cancer 1989, 5, 207–213. [Google Scholar] [CrossRef]
  33. Schiller, J.H.; Adak, S.; Cella, D.; Devore, R.F., III; Johnson, D.H. Topotecan Versus Observation After Cisplatin Plus Etoposide in Extensive-Stage Small-Cell Lung Cancer: E7593—A Phase III Trial of the Eastern Cooperative Oncology Group. J. Clin. Oncol. 2001, 19, 2114–2122. [Google Scholar] [CrossRef]
  34. Von Pawel, J.; Schiller, J.H.; Shepherd, F.A.; Fields, S.Z.; Kleisbauer, J.; Chrysson, N.G.; Stewart, D.J.; Clark, P.I.; Palmer, M.C.; Depierre, A.; et al. Topotecan Versus Cyclophosphamide, Doxorubicin, and Vincristine for the Treatment of Recurrent Small-Cell Lung Cancer. J. Clin. Oncol. 1999, 17, 658–667. [Google Scholar] [CrossRef]
  35. Hellmann, M.D.; Ott, P.A.; Zugazagoitia, J.; Ready, N.E.; Hann, C.L.; De Braud, F.G.; Antonia, S.J.; Ascierto, P.A.; Moreno, V.; Atmaca, A.; et al. Nivolumab (nivo) ± ipilimumab (ipi) in advanced small-cell lung cancer (SCLC): First report of a randomized expansion cohort from CheckMate 032. J. Clin. Oncol. 2017, 35, 8503. [Google Scholar] [CrossRef]
  36. Ready, N.E.; Farago, A.F.; De Braud, F.; Atmaca, A.; Hellmann, M.D.; Schneider, J.G.; Spigel, D.R.; Moreno, V.; Chau, I.; Hann, C.L.; et al. Third-Line Nivolumab Monotherapy in Recurrent SCLC: CheckMate 032. J. Thorac. Oncol. 2019, 14, 237–244. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Horn, L.; Reck, M.; Gettinger, S.N.; Spigel, D.R.; Antonia, S.J.; Rupnow, B.A.; Pieters, A.; Selvaggi, G.; Fairchild, J.P.; Peters, S. LBA5 Efficacy and safety of nivolumab (nivo) monotherapy versus chemotherapy (chemo) in recurrent small cell lung cancer (SCLC): Results from CheckMate 331. Ann. Oncol. 2018, 29, 511. [Google Scholar]
  38. Schwartzberg, L.; Korytowsky, B.; Penrod, J.; Yuan, Y.; Gu, T.; Le, T.; Abraham, P.; Selvaggi, G. P1.12-21 Developing a Real-World 3L Comparator to CheckMate 032: Overall Survival (OS) in Patients with Small Cell Lung Cancer (SCLC). J. Thorac. Oncol. 2018, 13, S581–S582. [Google Scholar] [CrossRef] [Green Version]
  39. Simos, D.; Sajjady, G.; Sergi, M.; Liew, M.S.; Califano, R.; Ho, C.; Leighl, N.; White, S.; Summers, Y.; Petrcich, W.; et al. Third-Line Chemotherapy in Small-Cell Lung Cancer: An International Analysis. Clin. Lung Cancer 2014, 15, 110–118. [Google Scholar] [CrossRef]
  40. De Jong, W.K.; Hacken, N.H.T.; Groen, H.J. Third-line chemotherapy for small cell lung cancer. Lung Cancer 2006, 52, 339–342. [Google Scholar] [CrossRef]
  41. Lebeau, B.; Chouaid, C.; Baud, M.; Masanes, M.-J.; Febvre, M. Oral second- and third-line lomustine–etoposide–cyclophosphamide chemotherapy for small cell lung cancer. Lung Cancer 2010, 67, 188–193. [Google Scholar] [CrossRef]
  42. Park, S.; Ahn, M.J.; Ahn, J.S.; Lee, J.; Hong, Y.S.; Park, B.-B.; Lee, S.C.; Hwang, I.G.; Park, J.O.; Lim, H.; et al. Combination chemotherapy with paclitaxel and ifosfamide as the third-line regimen in patients with heavily pretreated small cell lung cancer. Lung Cancer 2007, 58, 116–122. [Google Scholar] [CrossRef]
  43. Igawa, S.; Yamamoto, N.; Ueda, S.; Ono, A.; Nakamura, Y.; Tsuya, A.; Murakami, H.; Endo, M.; Takahashi, T. Evaluation of the Recommended Dose and Efficacy of Amrubicin as Second- and Third-Line Chemotherapy for Small Cell Lung Cancer. J. Thorac. Oncol. 2007, 2, 741–744. [Google Scholar] [CrossRef] [Green Version]
  44. Steffens, C.-C.; Elender, C.; Hutzschenreuter, U.; Dille, S.; Binninger, A.; Spring, L.; Jänicke, M.; Marschner, N. Treatment and outcome of 432 patients with extensive-stage small cell lung cancer in first, second and third line—Results from the prospective German TLK cohort study. Lung Cancer 2019, 130, 216–225. [Google Scholar] [CrossRef] [Green Version]
  45. Cohen, R. Membership in Sick Funds 2017. Available online: https://www.btl.gov.il/Publications/survey/Documents/seker_303.pdf (accessed on 4 March 2019).
  46. Shalev, V.; Chodick, G.; Goren, I.; Silber, H.; Kokia, E.; Heymann, A.D. The use of an automated patient registry to manage and monitor cardiovascular conditions and related outcomes in a large health organization. Int. J. Cardiol. 2011, 152, 345–349. [Google Scholar] [CrossRef] [PubMed]
  47. Chodick, G.; Heymann, A.D.; Shalev, V.; Kookia, E. The epidemiology of diabetes in a large Israeli HMO. Eur. J. Epidemiol. 2002, 18, 1143–1146. [Google Scholar] [CrossRef] [PubMed]
  48. Goldshtein, I.; Chandler, J.; Shalev, V.; Ish–Shalom, S.; Nguyen, A.; Rouach, V.; Chodick, G. Osteoporosis in the Community: Findings from a Novel Computerized Registry in a Large Health Organization in Israel. J. Aging Res. Clin. Pract. 2015, 4, 59–65. [Google Scholar]
  49. Israel Center for Disease Control MoH. Israel National Cancer Registry 2019. Available online: https://www.health.gov.il/English/MinistryUnits/HealthDivision/Icdc/Icr/Pages/default.aspx (accessed on 4 March 2019).
  50. Israel Central Bureau of Statistics. Characterization and Classification of Geographic Units by the Soci-Economic Level of the Population 2008; Publication No. 1530; Central Bureau of Statistics: Jerusalem, Israel, 2013.
  51. Crown, J.P.A.; Chahinian, A.P.; Jaffrey, I.S.; Glidewell, O.J.; Kaneko, M.; Holland, J.F. Predictors of 5-year survival and curability in small cell lung cancer. Cancer 1990, 66, 382–386. [Google Scholar] [CrossRef]
  52. Chute, J.P.; Venzon, D.J.; Hankins, L.; Okunieff, P.; Frame, J.N.; Ihde, D.C.; Johnson, B.E. Outcome of Patients With Small-Cell Lung Cancer During 20 Years of Clinical Research at the US National Cancer Institute. Mayo Clin. Proc. 1997, 72, 901–912. [Google Scholar] [CrossRef]
  53. Foster, N.R.; Qi, Y.; Shi, Q.; Krook, J.E.; Kugler, J.W.; Jett, J.R.; Molina, J.R.; Schild, S.E.; Adjei, A.A.; Mandrekar, S.J. Tumor response and progression-free survival as potential surrogate endpoints for overall survival in extensive stage small-cell lung cancer. Cancer 2011, 117, 1262–1271. [Google Scholar] [CrossRef] [Green Version]
  54. Tartarone, A.; Lerose, R.; Ardito, R.; Troiani, L.; Tedesco, B.; Bozza, G.; Cangiano, R.; Aieta, M. Long-term survival in small cell lung cancer: A case report and review of the literature. Futur. Oncol. 2014, 10, 523–528. [Google Scholar] [CrossRef]
  55. Li, J.; Dai, C.-H.; Chen, P.; Wu, J.-N.; Bao, Q.-L.; Qiu, H.; Li, X.-Q. Survival and prognostic factors in small cell lung cancer. Med Oncol. 2009, 27, 73–81. [Google Scholar] [CrossRef]
  56. Paesmans, M.; Sculier, J.P.; Lecomte, J.; Thiriaux, J.; Libert, P.; Sergysels, R.; Bureau, G.; Dabouis, G.; Cutsem, O.V.; Mommen, P.; et al. Prognostic factors for patients with small cell lung carcinoma: Analysis of a series of 763 patients included in 4 consecutive prospective trials with a minimum follow-up of 5 years. Cancer 2000, 89, 523–533. [Google Scholar] [CrossRef]
  57. Spiegelman, D.; Maurer, L.H.; Ware, J.H.; Perry, M.C.; Chahinian, A.P.; Comis, R.; Eaton, W.; Zimmer, B.; Green, M. Prognostic factors in small-cell carcinoma of the lung: An analysis of 1,521 patients. J. Clin. Oncol. 1989, 7, 344–354. [Google Scholar] [CrossRef]
  58. Singh, S.; Parulekar, W.; Murray, N.; Feld, R.; Evans, W.K.; Tu, D.; Shepherd, F.A. Influence of Sex on Toxicity and Treatment Outcome in Small-Cell Lung Cancer. J. Clin. Oncol. 2005, 23, 850–856. [Google Scholar] [CrossRef] [PubMed]
  59. Sundstrøm, S.; Bremnes, R.M.; Kaasa, S.; Aasebø, U.; Aamdal, S.; Norwegian Lung Cancer Study Group. Second-line chemotherapy in recurrent small cell lung cancer. Results from a crossover schedule after primary treatment with cisplatin and etoposide (EP-regimen) or cyclophosphamide, epirubicin, and vincristin (CEV-regimen). Lung Cancer 2005, 48, 251–261. [Google Scholar] [CrossRef] [PubMed]
  60. Kim, Y.H.; Goto, K.; Yoh, K.; Niho, S.; Ohmatsu, H.; Kubota, K.; Saijo, N.; Nishiwaki, Y. Performance status and sensitivity to first-line chemotherapy are significant prognostic factors in patients with recurrent small cell lung cancer receiving second-line chemotherapy. Cancer 2008, 113, 2518–2523. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  61. Korkmaz, T.; Seber, S.; Kefeli, U.; Sari, E.; Canhoroz, M.; Oven, B.; Yildirim, E.; Yasar, N.; Aydin, D.; Balvan, O.; et al. Comparison of second-line treatment outcomes between sensitive and refractory small cell lung cancer patients: A retrospective analysis. Clin. Transl. Oncol. 2012, 15, 535–540. [Google Scholar] [CrossRef]
  62. Niho, S.; Yoshida, T.; Akimoto, T.; Sakamaki, K.; Ono, A.; Seto, T.; Nishio, M.; Yamamoto, N.; Hida, T.; Okamoto, H.; et al. Randomized phase II study of chemoradiotherapy with cisplatin + S-1 versus cisplatin + pemetrexed for locally advanced non-squamous non-small cell lung cancer: SPECTRA study. Lung Cancer 2020, 141, 64–71. [Google Scholar] [CrossRef]
  63. Genestreti, G.; Tiseo, M.; Kenmotsu, H.; Kazushige, W.; Di Battista, M.; Cavallo, G.; Carloni, F.; Bongiovanni, A.; Burgio, M.A.; Casanova, C.; et al. Outcomes of Platinum-Sensitive Small-Cell Lung Cancer Patients Treated With Platinum/Etoposide Rechallenge: A Multi-Institutional Retrospective Analysis. Clin. Lung Cancer 2015, 16, e223–e228. [Google Scholar] [CrossRef]
  64. Paz-Ares, L.; Dvorkin, M.; Chen, Y.; Reinmuth, N.; Hotta, K.; Trukhin, D.; Statsenko, G.; Hochmair, M.J.; Özgüroğlu, M.; Ji, J.H.; et al. Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): A randomised, controlled, open-label, phase 3 trial. Lancet 2019, 394, 1929–1939. [Google Scholar] [CrossRef]
  65. Skarin, A.T. Analysis of Long-term Survivors With Small-Cell Lung Cancer. Chest 1993, 103, 440S–444S. [Google Scholar] [CrossRef] [Green Version]
  66. Jacoulet, P.; Depierre, A.; Moro, D.; Riviere, A.; Milleron, B.; Quoix, E.; Ranfaing, E.; Anthoine, D.; Lafitte, J.J.; Lebeau, B.; et al. Long-term survivors of small-cell lung cancer (SCLC): A French multicenter study. Ann. Oncol. 1997, 8, 1009–1014. [Google Scholar] [CrossRef]
Curroncol 28 00036 g001 550
Figure 1. Overall survival from L2 initiation for patients that initiated L2 by treatment, split by extensive (n = 62) and limited (n = 39) stage.
Figure 1. Overall survival from L2 initiation for patients that initiated L2 by treatment, split by extensive (n = 62) and limited (n = 39) stage.
Curroncol 28 00036 g001
Curroncol 28 00036 g002 550
Figure 2. Overall survival from L2 treatment initiation for patients sensitive to L1 therapy (initiated L2 ≥3 months after cessation of L1 therapy), for re-challenge of L1 therapy or switch, split by extensive (n = 34) and limited (n = 33) stage.
Figure 2. Overall survival from L2 treatment initiation for patients sensitive to L1 therapy (initiated L2 ≥3 months after cessation of L1 therapy), for re-challenge of L1 therapy or switch, split by extensive (n = 34) and limited (n = 33) stage.
Curroncol 28 00036 g002
Table
Table 1. Demographic and clinical characteristics of small cell lung cancer (SCLC) patients at index date (initiation of L1 treatment), n = 235. n(%) unless otherwise stated.
Table 1. Demographic and clinical characteristics of small cell lung cancer (SCLC) patients at index date (initiation of L1 treatment), n = 235. n(%) unless otherwise stated.
Total n = 235Extensive Stage
n = 150		Limited Stage
n = 85		p-Value
Demographic Variables
SexFemale91 (38.7)57 (38.0)34 (40.0)0.870
Agemedian (IQR **)64.0 (58.0,69.5)64.0 (58.0,69.0)63.0 (58.0,70.0)0.637
35–64124 (52.8)76 (50.7)48 (56.5)0.684
65–7486 (36.6)57 (38.0)29 (34.1)
≥7525 (10.6)17 (11.3)8 (9.4)
DistrictCentre155 (66.0)104 (69.3)51 (60.0)0.245
North50 (21.3) 27 (18.0)23 (27.1)
South30 (12.8)19 (12.7)11 (12.9)
Socio-economic status, groups *Low101 (43.0)65 (43.3)36 (42.4)0.933
Median49 (20.9)32 (21.3)17 (20.0)
High85 (36.2)53 (35.3)32 (37.6)
Clinical Variables
Co-morbiditiesDiabetes mellitus70 (29.8)45 (30.0)25 (29.4)1.000
Cardiovascular disease72 (30.6)48 (32.0)24 (28.2)0.650
Hypertension132 (56.2)83 (55.3)49 (57.6)0.836
Chronic kidney disease40 (17.0)27 (18.0)13 (15.3)0.727
COPD75 (31.9)50 (33.3)25 (29.4)0.635
Osteoporosis43 (18.3)29 (19.3)14 (16.5)0.712
SmokingEver224 (95.3)141 (94.0)83 (97.6)0.342
Never11 (4.7)9 (6.0) 2 (2.4)
ECOG PS0–1141 (60.0)85 (56.7) 56 (65.9)0.039
230 (12.8)25 (16.7) 5 (5.9)
3–44 (1.7)4 (2.7) 0 (0.0)
Unknown60 (25.5)36 (24.0) 24 (28.2)
Brain metastases 26 (11.1)26 (17.3) 0 (0.0)<0.001
* Socioeconomic status is based on the poverty index of the member’s enumeration area, as defined by the 2008 National Census. The poverty index is based on parameters including household income, educational level, crowding, physical conditions and car ownership. A higher score indicates higher level of socioeconomic status. ECOG, eastern cooperative oncology group; PS, performance status; COPD chronic obstructive pulmonary disease. ** IQR = interquartile range
Table
Table 2. Univariate analysis for prognostic parameters for overall survival (survival from initiation of L1 treatment, unless otherwise stated; log-rank test).
Table 2. Univariate analysis for prognostic parameters for overall survival (survival from initiation of L1 treatment, unless otherwise stated; log-rank test).
Prognostic ParametersNEvents n (%)Median OS (95% CI)Alive At 1 Year N (%)Alive at 2 Years N (%)p-Value
EXTENSIVE STAGE, N = 150
SexMale9384 (90.3%)8.91 (7.96,10.50)30.0% (21.8–41.4%)3.9% (1.3–11.8%)0.13
Female5751 (89.5%)9.63 (8.61,11.70)32.8% (22.6–47.8%)13.6% (6.7–27.7%)
ECOG PS0–18573 (85.9%)9.63 (8.65,13.80)41.0% (31.6–53.2%)11.2% (5.7–22.0%)0.09
22525 (100.0%)8.91 (4.9,11.30)20.0% (9.1–43.8%)-
3–444 (100.0%)8.43 (3.45, NR) --
Unknown3633 (91.7%)8.73 (6.94,9.90)19.7% (9.9–39.2%)6.6% (1.7–24.7%)
Brain metastasesNo124111 (89.5%)9.17 (8.38,10.30)32.1% (24.7–41.8%)7.6% (3.8–15.2%)0.89
Yes2624 (92.3%)8.81 (7.27,12.10)26.9% (14.3–50.7%)7.7% (2.0–29.1%)
Survival from line L1150135 (90.0%)9.14 (8.38, 10.30)31.08% (24.3–39.7%)7.70% (4.2–14.2%)
L26257 (91.9%)4.54 (3.19, 6.12)9.99% (4.4–22.5%)
Treatment pattern at L2 for those sensitive to L1 treatmentRetreatment77 (100.0%)6.81 (6.12, NR)14.30% (2.3–87.7%) 0.06
Treatment switch2723 (85.2%)4.5 (2.63, 6.61)7.06% (1.3%–39.7%)
LIMITED STAGE, N = 85
SexMale5139 (76.5%)21.50 (17.60,27.10)79.9% (69.4–91.9%)38.0% (26.1%55.3%)0.03
Female3416 (47.1%)29.60 (20.4, NR)75.8% (62.5–92.0%)57.9% (42.5–78.7%)
ECOG PS0–15633 (58.9%)24.50 (20.50,34.90)85.0% (75.9–95.2%)50.5% (38.0–67.2%)0.07
253 (60.0%)50.50 (22.10, NR)80.0% (51.6–100.0%)60.0% (29.3–100.0%)
Unknown2419 (79.2%)16.00 (11.70,32.30)62.5% (45.8–85.2%)31.4% (17.0–58.1%)
Survival from line L18555 (64.7%)23.54 (19.40,27.90)78.20% (69.8–87.7%)45.70% (35.6–58.5%)
L23933 (84.6%)8.68 (6.02, 14.04)34.37% (21.9–54.0%)7.50% (2.1–27.1%)
Treatment pattern at L2 for those sensitive to L1 treatmentRetreatment2017 (85.0%)9.11 (7.40, 18.80)36.94% (20.5–66.5%)12.31% (3.4–44.1%)0.14
Treatment switch1312 (92.3%)6.43 (5.06, NA)25.00% (9.4–66.6%)
ECOG, eastern cooperative oncology group; PS, performance status;NR, not reported
Table
Table 3. Multivariable model for factors associated with survival from L1 treatment initiation for the study cohort (N = 235).
Table 3. Multivariable model for factors associated with survival from L1 treatment initiation for the study cohort (N = 235).
Adjusted HR95% CIp-Value
LowerUpper
EXTENSIVE STAGE, N = 150
Ageyears1.010.991.040.191
SexMale vs. female1.320.921.920.136
Socio-economic status, groups *low (Ref.)
Medium0.770.471.250.283
High0.780.531.160.225
ECOG PS0–1 (Ref.)
21.631.002.650.048
3–42.450.837.240.104
Unknown1.530.992.350.054
Brain metastases 0.980.621.540.927
LIMITED STAGE, n = 85
Ageyears0.990.951.020.474
SexMale vs. female2.171.124.200.022
Socio-economic status, groups *low (Ref.)
Medium0.930.461.870.845
High0.710.361.420.337
ECOG PS 0–1 (Ref.)
20.750.212.630.650
Unknown2.421.314.470.005
* Socioeconomic status is based on the poverty index of the member’s enumeration area, as defined by the 2008 National Census. The poverty index is based on parameters including household income, educational level, crowding, physical conditions and car ownership. A higher score indicates higher level of Socioeconomic status. ECOG, eastern cooperative oncology group; COPD chronic obstructive pulmonary disease.
Table
Table 4. Multivariable model for factors associated with survival from L2 treatment initiation (n = 101).
Table 4. Multivariable model for factors associated with survival from L2 treatment initiation (n = 101).
Adjusted HR95% CIp-Value
LowerUpper
EXTENSIVE STAGE, N = 62
Age *years1.010.981.050.531
SexFemale vs. Male1.550.832.910.172
ECOG PS * 0–1 (Ref.)
22.221.034.790.043
3–43.450.3633.160.284
missing 1.330.622.850.462
Brain metastases * 0.760.361.600.471
L2 Drug TreatmentPlatinum-based regimen (Ref.)
Topotecan2.791.057.390.039
PD-1/PD-L1 inhibitor therapy0.960.273.400.950
Other1.270.354.660.715
Platinum sensitivity to L1 treatment 1.180.642.20.592
LIMITED STAGE, n = 39
Age *years1.010.951.070.762
SexFemale vs. Male1.080.412.840.870
ECOG PS * 0–1 (Ref.)
20.30.032.630.274
missing 2.280.895.860.087
L2 Drug TreatmentPlatinum-based regimen (Ref.)
Topotecan2.430.946.240.066
PD-1/PD-L1 inhibitor therapy0.190.022.240.186
Other0.230.041.170.076
Platinum sensitivity to L1 treatment 0.330.081.400.134
* At diagnosis. ECOG, eastern cooperative oncology group; PS, performance status.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Moser, S.S.; Bar, J.; Kan, I.; Ofek, K.; Cohen, R.; Khandelwal, N.; Shalev, V.; Chodick, G.; Siegelmann-Danieli, N. Real World Analysis of Small Cell Lung Cancer Patients: Prognostic Factors and Treatment Outcomes. Curr. Oncol. 2021, 28, 317-331. https://doi.org/10.3390/curroncol28010036

AMA Style

Moser SS, Bar J, Kan I, Ofek K, Cohen R, Khandelwal N, Shalev V, Chodick G, Siegelmann-Danieli N. Real World Analysis of Small Cell Lung Cancer Patients: Prognostic Factors and Treatment Outcomes. Current Oncology. 2021; 28(1):317-331. https://doi.org/10.3390/curroncol28010036

Chicago/Turabian Style

Moser, Sarah Sharman, Jair Bar, Inna Kan, Keren Ofek, Raanan Cohen, Nikhil Khandelwal, Varda Shalev, Gabriel Chodick, and Nava Siegelmann-Danieli. 2021. "Real World Analysis of Small Cell Lung Cancer Patients: Prognostic Factors and Treatment Outcomes" Current Oncology 28, no. 1: 317-331. https://doi.org/10.3390/curroncol28010036

Article Metrics

Back to TopTop