Magnitude of benefit of adjuvant chemotherapy for non-small cell lung cancer: Meta-analysis of randomized clinical trials
Introduction
Lung cancer is the leading cause of cancer death for both men and women in the US. Non-small cell lung cancer (NSCLC) accounts for about 80% of all lung cancers [1], [2]. Despite progress in imaging and diagnostic procedures, patients with NSCLC usually present as advanced (locally or more frequently disseminated), and a small proportion (around 30%) as early stage [2]. Even for patients presenting with early stage disease and are completely surgically resected, about half will die due to lung cancer.
In order to improve survival and to delay recurrence, randomized phase III trials have been conducted to examine whether adjuvant radiotherapy and/or chemotherapy add any benefit over surgery alone. A recently updated meta-analysis of more than 2000 patients showed that radiotherapy does not add any benefit over surgery alone, and should not be considered as standard treatment [3], [4], [5]. The adoption of older techniques and the extra-thoracic relapse can explain this effect and suggests a role for adjuvant chemotherapy [2].
The landmark meta-analysis published by the NSCLC Collaborative Group (NSCLC-CG-MA) showed a significant benefit of chemotherapy over supportive care in advanced NSCLC; a further part of the meta-analysis demonstrated no statistically significant survival benefit for chemotherapy over surgery alone, although a positive trend was seen [6].
Eleven randomized clinical trials (RCTs) addressing the adjuvant chemotherapy question have recently been completed and published with conflicting results [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. One further phase III trial has been presented, without providing any significant benefit for platinum-based chemotherapy over surgery alone in stage IB patients [19]. Since more than 7000 patients have been enrolled in these trials without unanimity about the role of adjuvant chemotherapy for early NSCLC, a meta-analysis, seems appropriate to define the role and quantify any benefit.
In the field of evidence-based medicine, common standard of medical practice is built on levels of evidence [20]; the strongest contribution to care changes is provided by level-one-recommendations, arising from large RCTs or meta-analyses. A meta-analysis is particularly needed in those clinical situations in which RCTs produce conflicting results or have small sample sizes [21].
Although a consensus regarding adjuvant chemotherapy after surgical treatment has been reached nowadays [22], we performed a meta-analysis to quantify the survival outcome benefit, by comparing death and recurrence events in adjuvant cisplatin-based chemotherapy treated and untreated population.
Section snippets
Methods
Our comprehensive literature-based meta-analysis was conducted following four steps: the definition of the outcomes (definition of the question which the analysis was designed to answer), the definition of the criteria applied for the selection of the eligible trials, the definition of the search strategy, and the detailed description of the used statistical method [21], [23].
Selected trials
Trials selected for the analysis are summarized in Table 1. Twelve phase III prospective randomized trials published as original papers in peer-review journals or presented at major meetings from 2000 to 2007 and one individual patient meta-analysis published in 1995 addressing our pre-specified question were collected. At the time of our examination, all trials were closed for final analyses. The primary end-point of all trials was OS. All arms within each of the RCTs were well balanced for
Discussion
Although a consensus has been recently reached, there are still several controversies about the magnitude of the benefit of adjuvant chemotherapy in early NSCLC, due to different results provided by the large RCTs available in the literature [22], [32]. These RCTs were designed to confirm the trend in favor of chemotherapy after surgery that has been demonstrated by the NSCLC Collaborative Group Meta-analysis published in 1995 [6].
In general, a quantitative combined analysis should always be
Conclusions
This literature-based meta-analysis of all randomized phase III adjuvant cisplatin-based chemotherapy trials indicates that a significant benefit on both overall and disease-free survival is consistent across all subgroups examined at the sensitivity analysis, performed to decrease heterogeneity and biases. While a consistent benefit was observed, the magnitude of the benefit was not large. Overall, about a 3–4% absolute benefit in survival is found. The data indicate that approximately 24–39
Conflict of interest
None.
Acknowledgement
Supported by Italian Ministry of Health grant.
References (50)
- et al.
Postoperative radiotherapy in non-small-cell lung cancer: update of an individual patient data meta-analysis
Lung Cancer
(2005) - et al.
Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial
Lancet Oncol
(2006) Postoperative adjuvant cisplatin, vindesine, plus uracil-tegafur chemotherapy increased survival of patients with completely resected p-stage I non-small cell lung cancer
Lung Cancer
(2005)- et al.
A randomized trial comparing adjuvant chemotherapy versus surgery alone for completely resected pN2 non-small cell lung cancer (JCOG9304)
Lung Cancer
(2004) - et al.
Meta-analyses of randomised clinical trials in oncology
Lancet Oncol
(2001) - et al.
Combination of chemotherapy without platinum compounds in the treatment of advanced non-small cell lung cancer: a systematic review of phase III trials
Lung Cancer
(2005) - et al.
Survival improvement in resectable non-small cell lung cancer with (neo)adjuvant chemotherapy: results of a meta-analysis of the literature
Lung Cancer
(2005) - et al.
Postoperative chemotherapy for non-small cell lung cancer: a systematic review and meta-analysis
J Thorac Cardiovasc Surg
(2004) - et al.
Evidence profiles for breast cancer: benefit/harms data based on the totality of randomized evidence
Cancer Treat Rev
(2007) - et al.
Cancer statistics
CA Cancer J Clin
(2008)
Multidisciplinary management of lung cancer
N Engl J Med
Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer
N Engl J Med
A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. Eastern Cooperative Oncology Group
N Engl J Med
Postoperative adjuvant therapy for stage IB non-small-cell lung cancer
Eur J Cardiothorac Surg
Randomised study of adjuvant chemotherapy for completely resected p-stage I–IIIA non-small cell lung cancer
Br J Cancer
Postsurgical chemotherapy in stage IB nonsmall cell lung cancer: long-term survival in a randomized study
Int J Cancer
Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer
J Natl Cancer Inst
Chemotherapy for patients with non-small cell lung cancer: the surgical setting of the Big Lung Trial
Eur J Cardiothorac Surg
Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer
N Engl J Med
Adjuvant chemotherapy following radical surgery for non-small-cell lung cancer: a randomized study on 70 patients
Chin Med J (Engl)
Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): update of Cancer and Leukemia Group B (CALGB) protocol 9633 [meeting abstracts]
J Clin Oncol
Levels of evidence for adult cancer treatment studies, health professional version
Cited by (43)
Perioperative treatment for resected non-small cell lung cancer: Which option in 2020?
2021, Revue des Maladies RespiratoiresPre- and postoperative care for stage I–III NSCLC: Which quality of care indicators are evidence-based?
2016, Lung CancerCitation Excerpt :Sub-analysis showed a detrimental effect of postoperative chemotherapy in patients with stage IA NSCLC (HR 1.40; 95% CI, 0.95–2.06) [101]. Three out of five meta-analyses showed a survival benefit of postoperative chemotherapy in patients with early stage NSCLC (i.e. a combination of stage I and II NSCLC; OR 0.78, 95% CI 0.64–0.94; HR 0.88, 95% CI 0.83–0.94; RR 0.85, 95% CI 0.79–0.91) [96,97,100]. For patients with stage III NSCLC two meta-analyses showed a survival benefit for patients receiving postoperative chemotherapy (HR = 0.91, 95% CI 0.85–0.96; HR 0.83, 95% CI 0.72–0.94) [100,101].
Temporal trends in the incidence and relative survival of non-small cell lung cancer in Canada: A population-based study
2015, Lung CancerCitation Excerpt :This is consistent with clinical studies on surgery, chemotherapy and radiation [34] which show a return to near baseline mortality 2–3 years after curative intent therapy as well as in palliative cases where almost all patients will have expired by 2 years. Chemotherapy was added to operable lung cancer in the late 90’s [35,36] which represents 20% of all cases but only adds 6–10% survival to that subgroup [37]. Staging has improved with PET scan but this came on board in early 2000’s [38].
Balancing activity and tolerability of neoadjuvant paclitaxel- and docetaxel-based chemotherapy for HER2-positive early stage breast cancer: Sensitivity analysis of randomized trials
2015, Cancer Treatment ReviewsCitation Excerpt :Data for primary and secondary outcomes were extracted: the last available update of each trial was considered as the original sources. All data were reviewed and separately computed by 3 investigators (L.C., I.S. and E.B.) [36]. Events for pCR (breast and axilla), grade 3–4 neutropenia, pCR according to HoR status, FN, and grade 3–4 neurotoxicity were extracted from papers and/or presentations; the cumulative Event Rate was determined and 95% confidence intervals (CIs) were derived [37–39].