A systematic review of survival following anti-cancer treatment for small cell lung cancer

doi:10.1016/j.lungcan.2019.12.015

Lung Cancer

Volume 141, March 2020, Pages 44-55

https://doi.org/10.1016/j.lungcan.2019.12.015 Get rights and content

Highlights

•
Systematic review of early and late survival in SCLC.
•
Causes of 30-day mortality following chemotherapy are explored.
•
Better survival following chemotherapy for Asian individuals with SCLC.
•
Early thoracic radiotherapy and PCI augment survival for LD-SCLC but not ED-SCLC.

Abstract

Objectives

We conducted a systematic review and meta-analysis of survival following treatment recommended by the European Society of Medical Oncology for SCLC in order to determine a benchmark for novel therapies to be compared with.

Materials and methods

Randomized controlled trials and observational studies reporting overall survival following chemotherapy for SCLC were included. We calculated survival at 30 and 90-days along with 1-year, 2-year and median.

Results

We identified 160 for inclusion. There were minimal 30-day deaths. Survival was 99 % (95 %CI 98.0–99.0 %, I²33.9 %, n = 77) and 90 % (95 %CI 89.0–92.0 %, I²79.5 %, n = 73) at 90 days for limited (LD-SCLC) and extensive stage (ED-SCLC) respectively. The median survival for LD-SCLC was 18.1 months (95 %CI 17.0–19.1 %, I²77.3 %, n = 110) and early thoracic radiotherapy (thoracic radiotherapy 18.4 months (95 %CI 17.3–19.5, I²78.4 %, n = 100)) vs no radiotherapy 11.7 months (95 %CI 9.1–14.3, n = 10), prophylactic cranial irradiation (PCI 19.7 months vs No PCI 13.0 months (95 %CI 18.5–21.0, I²75.7 %, n = 78 and 95 %CI 10.5–16.6, I²81.1 %, n = 15 respectively)) and better performance status (PS0–1 22.5 months vs PS0–4 15.3 months (95 %CI 18.7–26.1, I²72.4 %, n = 11 and 95 %CI 11.5–19.1 I²77.9 %, n = 13)) augmented this. For ED-SCLC the median survival was 9.6 months (95 %CI 8.9–10.3 %, I²95.2 %, n = 103) and this improved when irinotecan + cisplatin was used, however studies that used this combination were mostly conducted in Asian populations where survival was better. Survival was not improved with the addition of thoracic radiotherapy or PCI. Survival for both stages of cancer was better in modern studies and Asian cohorts. It was poorer for studies administering carboplatin + etoposide but this regimen was used in studies that had fewer patient selection criteria.

Conclusion

Early thoracic radiotherapy and PCI should be offered to people with LD-SCLC in accordance with guideline recommendations. The benefit of the aforementioned therapies to treat ED-SCLC and the use of chemotherapy in people with poor PS is less clear.

Introduction

The European Society of Medical Oncology (ESMO) recommend 4–6 cycles of cisplatin or carboplatin doublet chemotherapy as first-line treatment for all stages of SCLC [1]. Thoracic radiotherapy can be given concurrently, in fitter individuals with limited stage (LD-SCLC), or sequentially to people who have responded to initial chemotherapy. Prophylactic cranial irradiation (PCI) is generally reserved for people who have responded to chemotherapy. These treatments have remained unchanged for 30 years but novel therapies are emerging. Immunotherapies such as atezolizumab (IMPOWER-133 trial) and durvalumab (CASPIAN), in combination with chemotherapy, have shown increases in the median survival of approximately 2 and 3 months respectively when compared to chemotherapy alone [2,3]. Both these treatments have been given approval for use in extensive stage SCLC (ED-SCLC) by the US Food and Drug Administration. However, these new treatments are expensive and the U.K. list price for one vial of atezolizumab is approximately £3,800 [4]. Hence, in order to assess whether these novel treatments are economically viable a comprehensive survival assessment of the existing therapies is needed. This will ensure that the claimed survival advantages of immunotherapy are accurate.

Similarly, in order to maximise the efficacy of current treatments patients must be selected appropriately. Deaths occurring early after chemotherapy (within 30-days) are a measure of poor selection, but the evidence base for this in SCLC is limited [5]. Hence, the objectives of this study are to examine early and late survival by ESMO recommended treatments for SCLC in order to increase this evidence base and inform the appraisal process of novel treatments.

Section snippets

Search strategy

We searched EMBASE, MEDLINE and electronic search engines for English language randomized controlled trials (RCTs) or observational cohort studies which reported overall survival following receipt of cisplatin or carboplatin in combination with etoposide, irinotecan or topotecan for SCLC. The search strategy can be found in Supplement 1. Our search was conducted on 7^th June 2016. After the initial search we examined the archives of the European Society of Medical Oncology, American Society of

Search process

We identified 10,487 titles and after screening 130 remained. Another 30 studies were identified from references of included manuscripts giving a total of 160 studies. Fig. 1 is a flowchart of this process.

Summary of studies

In total, we examined survival data from 22,528 people. Supplement 4 summarises the included manuscripts, 11 of which were abstracts [[14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40]

Main findings

There were few deaths within the 30 days of the first chemotherapy dose and these were predominantly due to neutropenic sepsis. Early survival was similar across all ages but this changed at 1-year for LD-SCLC, where the elderly were less likely to survive, most likely a result of attrition bias. Long term survival varied considerably by stage and was better in Asian cohorts and recent studies that included people with good PS. Thoracic radiotherapy and PCI augmented median survival in LD-SCLC.

Strengths

Conclusions

We have conducted the largest systematic review and meta-analysis of survival in SCLC. Our findings support ESMO recommendations, in particular, early thoracic radiotherapy and PCI for LD-SCLC with the cautious use of chemotherapy for people with worse PS. Cisplatin and carboplatin are preferred, however, we found significant disparities in their long-term survival by ethnicity. This may relate to altered drug metabolism and the differing aetiological exposures for SCLC across ethnic groups.

Summary message

This is a comprehensive analysis of early and late survival following treatments recommended by the European Society of Medical Oncology for small cell lung cancer. Our survival benchmarks can inform the treatment selection process for patients undergoing chemotherapy in the future.

Funding

Roy Castle Lung cancer foundation (2015 14 Hubbard) and University of Nottingham John Turland fund

CRediT authorship contribution statement

Gavin S. Jones: Conceptualization, Methodology, Investigation, Formal analysis, Resources, Data curation. Kelly Elimian: Data curation, Investigation, Writing - review & editing. David R. Baldwin: Conceptualization, Methodology, Writing - review & editing, Supervision. Richard B Hubbard: Conceptualization, Methodology, Writing - review & editing, Supervision. Tricia M. McKeever: Conceptualization, Methodology, Data curation, Investigation, Writing - review & editing, Supervision.

Declaration of Competing Interest

None.

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A systematic review of survival following anti-cancer treatment for small cell lung cancer

Highlights

Abstract

Objectives

Materials and methods

Results

Conclusion

Introduction

Section snippets

Search strategy

Search process

Summary of studies

Main findings

Strengths

Conclusions

Summary message

Funding

CRediT authorship contribution statement

Declaration of Competing Interest

Ann. Oncol.

Lancet

Lancet Oncol.

Control. Clin. Trials

Clin. Lung Cancer

Eur. J. Cancer

Int. J. Radiat. Oncol. Biol. Phys.

J. Thoracic Oncol.

Radiother. Oncol.

Lancet Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

J. Thoracic Oncol.

Radiother. Oncol.

J. Thoracic Oncol.

Lung Cancer

Lung Cancer.

Lung Cancer

J. Thoracic Oncol.

Lung Cancer

Lancet Oncol.

Lung Cancer

Lung Cancer

J. Thoracic Oncol.

Clin. Oncol. R. Coll. Radiol. (R Coll Radiol)

First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung Cancer

N. Engl. J. Med.

British national formulary- Atezolizumab

On behalf of the EGWG. Hematopoietic growth factors: ESMO Clinical Practice Guidelines for the applications

Ann. Oncol.

Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves

BMC Med. Res. Methodol.

Systematic review and meta-analysis: techniques and a guide for the academic surgeon

Ann. Cardiothorac. Surg.

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Oncologist

Transformations related to the angular and the square root

Ann. Math. Stat.

Measuring inconsistency in meta-analyses

BMJ

Systematic review and meta-analysis of follow-up after hepatectomy for colorectal liver metastases

Br. J. Surg.

Integration of irinotecan and cisplatin with early concurrent conventional radiotherapy for limited-disease SCLC (LD-SCLC)

Int. J. Clin. Oncol.

Accelerated hypofractionated radiotherapy and concurrent etoposide/ cisplatin in patients with limited disease SCLC

J. Thorac. Oncol.

Mid-course thoracic radiotherapy with cisplatin-etoposide chemotherapy in limited-stage small-cell lung cancer

Med. Oncol.

The effect of small-molecular-weight heparin added to chemotherapy on survival in small-cell lung cancer - a retrospective analysis

Indian J. Cancer

Phase II study of celecoxib with cisplatin plus etoposide in extensive-stage small cell lung cancer

Cancer Invest.

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Med. Oncol. (Northwood, London, England)

Concurrent cisplatin-etoposide chemotherapy plus thoracic radiotherapy for limited-stage small cell lung Cancer

Jpn. J. Clin. Oncol.

Cisplatin plus oral etoposide in the treatment of patients with advanced small cell lung cancer. Japan Clinical Oncology Group

Japn. J. Clin. Oncol.

Phase III randomised trial of doxorubicin-based chemotherapy compared with platinum-based chemotherapy in small-cell lung cancer

Br. J. Cancer

Palliative care in poor-performance status small cell lung cancer patients: is there a mandatory role for chemotherapy?

Support. Care Cancer