Abstract and Introduction
Background: Adjuvant chemotherapy (AC) is recommended since 2004 for patients with a completely resected non-small cell lung cancer (NSCLC). Indeed, several randomized clinical trials have demonstrated an improved survival for patients treated with adjuvant cisplatin-based regimen than surgery alone. In these large clinical trials, patients were well selected and fit to receive AC. As the benefit of AC was estimated at 5.4% of 5-year overall survival (OS), it seems important to evaluate AC use in a less selected population. In particular, elderly patients were underrepresented in large randomized clinical trials. Furthermore, other confounding factors might limit AC efficacy in real-life practice such as the delay of chemotherapy initiation following lung surgery or the number of AC cycles received. Therefore, the aim of this systematic review is to summarize the state of the literature on AC use in current clinical practice.
Methods: A systematic assessment of literature articles and reviews on AC use in real-life practice was performed by searching in several relevant database including Medline, Google Scholar and Cochrane Library following PICOS (i.e., Population, Intervention, Comparison, Outcomes, Study design) eligibility criteria and PRISMA guidelines. Among the 1,957 results obtained with the request formulated on these research database, 56 relevant articles on AC use in non-trial setting were selected and included in the results section.
Results: This systematic literature review highlights the lack of literature on AC use in real-life practice as most of these studies were retrospective. Interestingly, a delayed AC—mostly due to postoperative complications—was better than surgery alone. Furthermore, AC was less purposed to elderly patients, despite retrospective studies outlined that this therapeutic option could be benefit in this specific population as for younger patients. In real-life practice, AC was also often incomplete due to adverse events, but dose reduction or omission was not always associated with an inferior survival. In non-trial setting, number of AC cycles delivered, dose reduction or omission is quite similar to randomized clinical trials.
Discussion: Nowadays, AC is part of the therapeutic strategy used in completely resected NSCLC. In a population of less selected patients, this systematic literature review shows that AC can be used safely and efficiently, especially in elderly patients. As well, delayed AC seems effective. Finally, the place of immunotherapy and targeted therapies have to be precised in the future as well as biomarkers to better select patients that would response to chemotherapy.
According to 2018 Global Cancer Observatory (GLOBOCAN), lung cancer represents 11.6% of the number of new cases of cancer worldwide and is responsible of 18.4% number of deaths from cancer. Adjuvant chemotherapy (AC) for completely resected non-small cell lung cancer (NSCLC) has been implemented at the beginning of the 2000s.
Several randomized clinical trials conducted at the beginning of 2000 have demonstrated an improved survival for patients treated with cisplatin-based AC after complete surgical resection for stage IIA–IIIA NSCLC compared to surgery alone.[2–4] The IALT trial (The International Adjuvant Lung Cancer Trial Collaborative Group) was the first and the largest AC trial which demonstrated a statistically significant improvement in overall survival (OS) for patients treated with cisplatin-based AC. Indeed, in the IALT trial which compared cisplatin-based regimen (with etoposide, vinorelbine, vinblastine or vindesine) with surgery alone, the 5-year survival rates were 44.5% and 40.4% (P<0.03) in respectively AC and surgery alone group (Table 1). Likewise, JBR.10. (National Cancer Institute of Canada Clinical Trials Group and North American Intergroup Study JBR.10) and ANITA (Adjuvant Navelbine International Trialist Association) clinical trials which compared cisplatin-vinorelbine with surgery alone, demonstrated a significant benefit of AC use on OS (Table 1).[3,4] The LACE meta-analysis (Lung Adjuvant Cisplatin Evaluation) included a total of 4,584 patients from five cisplatin-based adjuvant trials (i.e., IALT, JBR.10., ANITA, ALPI-EORTC and Big Lung Trial). This meta-analysis confirmed the benefit of AC with a 5.4% improvement in survival at 5 years (P=0.0043) (Table 1). The disease-free survival (DFS) was also significantly improved with a hazard ratio of 0.8 [HR (95% CI): 0.8 (0.78–0.9); P<0.001]. Finally, a Cochrane review published in 2015, based on 8,447 individual data analyses showed a benefit of AC with an absolute increase in survival (4% at 5 years). Other clinical trials were conducted but failed to demonstrate a survival benefit of AC. This was the case of the ALPI trial (Adjuvant Lung Project Italy) in which patients received three cycles of mitomycin, vindesine and cisplatin. Similarly, the Big Lung Trial showed no benefit of cisplatin-based AC probably due to a lack of patients. Furthermore, the CALGB trial (Cancer and Leukemia Group B) which enrolled only patients with IB (i.e., T2N0M0) resected NSCLC failed to demonstrate a statistically significant benefit of Carboplatin-Paclitaxel AC. The mortality rate due to AC was estimated at 0.8% of the patients in the IALT and JBR.10. trials whereas it was about 2% in the ANITA trial. In the LACE meta-analysis, there were 19 chemotherapy-related deaths reported, corresponding to a 0.9% mortality rate (Table 1).
Consequently, since these randomized clinical trials were published, AC is recommended in resected NSCLC for stage IIA to IIIA, according to the 8th TNM classification.[10–12] Of note, four cycles of cisplatin-vinorelbine (cisplatin 80 mg/m2 J1 and vinorelbine 30 mg/m2 J1–J8) must be preferred. Indeed, in the LACE meta-analysis, the effect of cisplatin-vinorelbine was better in terms of OS and DFS compared to other drugs combination (P=0.11 for OS and P=0.07 for DFS).
In view of contradictory data, the aim of this systematic literature review is to summarize the state of literature regarding AC use in current clinical practice. Indeed, in randomized clinical trials, patients were well selected to fit chemotherapy. In the setting of real-life practice, elderly patients were not included in those clinical trials and chemotherapy was administered in a delay which did not exceed 60 days after surgery. Therefore, as AC provides a moderate benefit of 5.4% of 5-year OS in large randomized clinical trials, the assessment of AC efficacy and safety profile in a less selected and more heterogeneous population is valuable. In this context, real-world evidence (RWE) would be interesting to validate whether AC provides same efficacy and safety profile as reported in large randomized clinical trials. Thus, this systematic literature review will detail the use of AC for resected NSCLC in routine clinical practice. We present the following article in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 reporting checklist (available at https://dx.doi.org/10.21037/tlcr-21-557).
Transl Lung Cancer Res. 2021;10(12):4643-4665. © 2021 AME Publishing Company