A systematic review of survival following anti-cancer treatment for small cell lung cancer
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 7th 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.
At
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.
References (195)
- et al.
Small-cell lung cancer (SCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†
Ann. Oncol.
(2013) - 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) - et al.
30-day mortality after systemic anticancer treatment for breast and lung cancer in England: a population-based, observational study
Lancet Oncol.
(2016) - et al.
Meta-analysis in clinical trials
Control. Clin. Trials
(1986) - et al.
Prospective randomized phase III trial of etoposide/cisplatin versus high-dose epirubicin/cisplatin in small-cell lung cancer
Clin. Lung Cancer
(2004) - et al.
Long-term follow-up of a randomised trial of combined chemoradiotherapy induction treatment, with and without maintenance chemotherapy in patients with small cell carcinoma of the lung
Eur. J. Cancer
(1996) - et al.
Cisplatin/etoposide chemotherapy combined with twice daily thoracic radiotherapy for limited small-cell lung cancer: a clinical phase II trial
Int. J. Radiat. Oncol. Biol. Phys.
(2005) - et al.
Characteristics and outcomes of small cell lung cancer patients diagnosed during two lung cancer computed tomographic screening programs in heavy smokers
J. Thoracic Oncol.
(2011) - et al.
Omission of elective node irradiation on basis of CT-scans in patients with limited disease small cell lung cancer: a phase II trial
Radiother. Oncol.
(2006) - et al.
Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial
Lancet Oncol.
(2017)
Long-term toxicity report from a Phase II study of accelerated twice-daily (BD) versus high dose once-daily (OD) thoracic radiotherapy (RT) with concurrent chemotherapy for limited-stage small cell lung cancer (LS-SCLC)
Int. J. Radiat. Oncol. Biol. Phys.
Topotecan/cisplatin compared with cisplatin/etoposide as first-line treatment for patients with extensive disease small-cell lung cancer: final results of a randomized phase III trial
J. Thoracic Oncol.
Locoregional failures following thoracic irradiation in patients with limited-stage small cell lung carcinoma
Radiother. Oncol.
Randomized phase II study of maintenance irinotecan therapy versus observation following induction chemotherapy with irinotecan and cisplatin in extensive disease small cell lung cancer
J. Thoracic Oncol.
A phase II study of biweekly irinotecan and cisplatin for patients with extensive stage disease small cell lung cancer
Lung Cancer
Phase II study of irinotecan plus cisplatin with concurrent radiotherapy for the patients with limited-disease small-cell lung cancer
Lung Cancer.
P-773 Cisplatin or carboplatin-based regimens for small-cell lungcancer — a randomized phase III study
Lung Cancer
Phase II study of induction cisplatin and irinotecan followed by concurrent carboplatin, etoposide, and thoracic radiotherapy for limited-stage small-cell lung cancer, CALGB 30206
J. Thoracic Oncol.
Combination chemotherapy with irinotecan and cisplatin in elderly patients (&65 years) with extensive-disease small-cell lung cancer
Lung Cancer
Etoposide and cisplatin versus irinotecan and cisplatin in patients with limited-stage small-cell lung cancer treated with etoposide and cisplatin plus concurrent accelerated hyperfractionated thoracic radiotherapy (JCOG0202): a randomised phase 3 study
Lancet Oncol.
Randomized phase II study of carboplatin and etoposide with or without obatoclax mesylate in extensive-stage small cell lung cancer
Lung Cancer
Carboplatin-etoposide combination in small cell lung cancer patients older than 70 years: a phase II trial
Lung Cancer
Effects of chemotherapy on survival of elderly patients with small-cell lung cancer: analysis of the SEER-medicare database
J. Thoracic Oncol.
Improving outcomes for limited stage small cell lung cancer patients in Scotland with concomitant chemoradiation
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.
Systematic review and network meta-analysis of overall survival comparing 3 mg/kg ipilimumab with alternative therapies in the management of pretreated patients with unresectable stage III or IV melanoma
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.
Prognostic factors in patients with small cell lung carcinoma
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
A retrospective analysis of survival outcomes for two different radiotherapy fractionation schedules given in the same overall time for limited stage small cell lung cancer
J. Med. Imaging Radiat. Oncol.
Carboplatin (CBDCA, JM-8) and VP-16-213 in previously untreated patients with small-cell lung cancer
J. Clin. Oncol.
Cisplatin and etoposide (VP-16) as a single regimen for small cell lung cancer. A phase II trial
Cancer
Phase III comparison of twice-daily split-course irradiation versus once-daily irradiation for patients with limited stage small-cell lung carcinoma
J. Clin. Oncol.
Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the Southwest Oncology Group
J. Clin. Oncol.
Preliminary study of efficacy of intravenous cisplatin plus oral etoposide in small cell lung cancer
J. Med. Assoc. Thai.
Modified one-day etoposide and cisplatin combination for previously untreated extensive-disease small-cell lung cancer: a retrospective evaluation of 36 cases
Mol. Clin. Oncol.
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