Use of adjuvant chemotherapy in resected non-small cell lung cancer in real-life practice: a systematic review of literature

Introduction

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 (1). 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) (2). 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) (5). 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] (5). 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) (6). 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 (7). Similarly, the Big Lung Trial showed no benefit of cisplatin-based AC probably due to a lack of patients (8). 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 (9). The mortality rate due to AC was estimated at 0.8% of the patients in the IALT (2) and JBR.10. (3) trials whereas it was about 2% in the ANITA trial (4). In the LACE meta-analysis, there were 19 chemotherapy-related deaths reported, corresponding to a 0.9% mortality rate (5) (Table 1).

Consequently, since these randomized clinical trials were published, AC is recommended in resected NSCLC for stage IIA to IIIA, according to the 8^th 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) (5).

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 (5), 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).

Materials and methods

A systematic assessment of literature articles and reviews was performed by searching in several relevant database including Medline, Google Scholar and Cochrane Library, following PRISMA guidelines and PICOS (i.e., Population, Intervention, Comparison, Outcomes, Study design) eligibility criteria.

The request formulated in MEDLINE was built in the following way (“Carcinoma, non- small cell lung [MeSH Terms]” OR “resected non-small cell lung cancer [Other Terms]” OR “lung cancer [MeSH Terms]” and “adjuvant chemotherapy [MeSH Terms]” OR “delayed adjuvant chemotherapy [Other Terms]” OR “initiation of adjuvant chemotherapy [Other Terms]”). Applying this request formulation in Medline on 8^th March 2021 resulted in 3,137 results. Additional filters were applied (“years of publication from 2004 to 2021”; “language: English”; “abstracts available”; “subject: cancer”; “species: humans”) which led to 1692 results. The request formulated in Cochrane Library on 29^th September 2021 was built in the following way (“non-small cell lung cancer” [Title, abstract, keyword] AND “adjuvant chemotherapy” [Title, abstract, keyword] AND “observational” [Abstract]) which led to 244 results. Applying this request formulation with additional filters on years of publication (i.e., 2004 to 2021) led to 210 results. The request formulated in Google Scholar on 30^th September 2021 was built in the following way (“adjuvant chemotherapy” AND “lung cancer” AND “real-life practice”) and allowed to identify 65 results. Additional filter applied based on years of publication (i.e., 2004 to 2021) led to 55 results.

Relevant articles were selected after reading titles and abstracts by one author based on PICOS eligibility criteria (Table 2). After screening, eligible articles were either included or excluded through full-text reading by one author. The formulation request, the selection process and the eligibility of articles were critically peer-reviewed by all authors. This research allowed to select 56 relevant articles included in the results section (Figure 1).

Figure 1 PRISMA 2020 flow diagram presenting the selection process for relevant articles on use of AC in real-life practice. AC, adjuvant chemotherapy.

Results

A total of 1957 titles/abstracts were screened given the search and restriction filters applied on Medline, Cochrane Library and Google Scholar database (Figure 1). This preliminary screening restricted our search to 112 potentially eligible papers that were either included or excluded through full-text reading. Overall, 56 relevant articles were selected and included in this systematic literature review (Figure 1).

Adherence to guidelines regarding AC administration was estimated at 59% among 99 eligible patients who underwent curative-intent lung surgery for stage II–III NSCLC disease (13) while it was reported at 54.1% among a cohort of 14,892 patients who underwent surgical resection for pN1 disease (14). Barni et al. reported the main reasons for no respect to guidelines: patient’s refusal (10%), patient’s clinical conditions (43%); negative lymph node disease (17%) and clinician’s choices (13%) (13). In particular, concerns for AC toxicity was involved in 31% of patient’s refusal (15). Consistently with previous observations, advanced age and disease progression were associated with a lower likelihood to receive AC, in 6% cases respectively (16,17). Postoperative complications (18-20) and prolonged length of stay after surgery (21) were also identified as main factors to not receive AC although recommended. In this context, AC use in non-trial setting will be described in the following sections according to the 56 relevant articles selected (Figure 1) through the selection process.

Delay of initiation of AC in real-life practice and impact on survival

Several barriers may impact the use of AC in non-trial setting such as patient’s decision, physician and patient opinions regarding the ability to tolerate AC and the potential benefits outweigh the risks. As well, recovery from lung surgery and post-operative complications or prolonged length of stay in hospital might contribute to the decision and to delayed AC administration. Notably, referral to medical oncologist is also important to consider in real-life practice.

An observational study reporting patient’s and physician’s preferences regarding AC, using the time trade-off method, highlighted that most patients and physicians judged moderate survival benefits sufficient to make AC worthwhile after curative-intent lung surgery for a NSCLC (22). As well, the authors described patients’ opinions at baseline regarding AC tolerance. Interestingly, the main symptoms expected at baseline by patients were asthenia, nausea, trouble sleeping or lack of appetite whereas main symptoms experienced at 6 months by patients were asthenia, altered sense of taste, constipation or lack of appetite (22). In clinical setting, such symptoms related to AC need to be clearly explained as they might contribute to patient’s refusal to underwent AC. In line with these observations, referral to medical oncologist is of particular interest. Of note, preferred and perceived decision making roles on AC were reported as collaborative for both physicians and patients (23). Younis et al. reported that 73% patients with stage II–III NSCLC were referred to a medical oncologist (24). Consistently, referral to medical oncologist was reported as 72% among 352 patients with stage IB–IIB NSCLC (15). In another retrospective study, 44% of patients who underwent curative-intent surgery for stage I–III NSCLC were referred to medical oncologist, with a median of 29 days between surgery to medical oncologist referral (25). As well, timeline was estimated at 16 days between medical oncologist referral and consultation and 7 days between medical oncologist’s consultation and AC administration (25). A shorter timeline for medical oncologist referral was significantly associated with surgeon requesting for medical oncologist referral (P=0.008) and presence of comorbidities (P=0.036) (25). In multivariate analysis, higher likelihood of referral to medical oncologist was associated with higher stage disease (i.e., stage II/III vs. I), surgery (i.e., pneumonectomy) and age (i.e., younger) (24). Of note, patient’s refusal was involved in 5% cases of no referral to medical oncologist (24) while it was estimated at 18% (16) and 2% (26) in other retrospective studies. Apart from patient’s refusal (16,24,26), comorbidities, advanced age, postoperative complications and poor performance status (PS) were the main reason advanced by surgeons for judging patients as not fit to receive AC (16,27). Likewise, altered condition after surgery was involved in 7.2% of cases for not referred to medical oncologist (26). Consistently with predictive factors associated with referral to medical oncologist (27), intermediate or high grade tumour (i.e., vs. low grade tumour) and higher stage disease (i.e., IIIA vs. IIA and IIB) were associated with a higher likelihood to receive AC while advanced aged, pneumonectomy, squamous cell histologic sub-type, higher comorbidities according to Charlson index and academic hospital (i.e., vs. community hospital) were associated with a less likelihood to receive AC (14,28). Of note, histologic sub-type might be associated with a lower likelihood to receive AC as among a cohort of 94 patients who underwent curative-intent lung surgery for stage II–III squamous-cell carcinoma, only 25.5% of them received AC (29).

Prolonged length of stay in hospital after curative-intent lung surgery might contribute to a delayed administration of AC. The median length of stay in hospital was about 6 days in a retrospective study including 4,979 patients (30) while it was estimated at 8 (18) and 9.3 days (31) in two other retrospective cohorts of 219 and 60 patients respectively (18,31) (Table 3). In a large retrospective study which enrolled 12473 patients who underwent AC after curative-intent lung resection, length of stay exceeded 14 days for 508 patients (32) (Table 3). Moreover, Bouchard et al. found that patients who underwent AC had significant shorter length of stay in hospital compared to those who did not receive AC (P=0.0008) (31). In this setting, predictors for prolonged length of stay in hospital have been described. Wright et al. observed that patients with prolonged length of stay after lobectomy surgery have much more postoperative events (3.4 vs. 1.2 events, P<0.0001) associated with more comorbidities than the others (30). Similarly, postoperative complications were documented in 40% of patients, mainly postoperative infections (i.e., 35 patients among 87 patients who experienced postoperative complications) (18). Although no significant differences in postoperative complications, baseline comorbidities, surgical procedure and histologic sub-type, Rodriguez et al. identified age as a significant prognostic factor for prolonged length of stay after lung resection (33). Indeed, patients older than 70 years old had a significant prolonged length of stay in hospital and intensive care unit compared to younger patients (33) (Table 3). Finally, these retrospective studies highlighted that patients who underwent thoracotomy had prolonged length of stay in hospital compared to others (34,35) (Table 3).

Nowadays, according to guidelines, AC have to be initiated within 4 to 8 weeks after curative-intent lung surgery (10-12). The median time between surgery and AC was 40 days and 39 days in the IALT trial (2) and the LACE meta-analysis (5) respectively. For 7% of the patients, the delay to initiate AC exceeded 60 days in the IALT trial (2). In non-trial setting, several retrospective studies were interested in the median time from surgery to AC administration (32,34-43). In real-life practice, these retrospective studies showed that the delay of initiation of AC did not differ significantly compared to clinical trials (Table 4). Indeed, the median time between surgery and AC administration was approximately comprised between 5 to 8 weeks (32,34-43) (Table 4). Moreover, these studies showed that in real-life practice, AC administration might be delayed after 8 weeks following lung surgery (Table 4). In this context, predictors of delayed AC have been described (32,36-38). Squamous cell carcinoma, undetermined grade, pneumonectomy resection, extended length of stay in surgery and unplanned 30-day readmission have been identified as significant predictors of delayed initiation of AC (32,36). Zhu et al. also identified higher rate of smoking history as a predictor of delayed AC administration (38). On the contrary, increased comorbidity according to Charlson index (36) and advanced age (39) were not associated with delayed AC. Finally, postoperative complications including infections (16%), postoperative recovery of performance status (32%), patient’s decision (18%) and referral delay to medical oncologist (16%) were also described as main factors associated with a delayed AC (37). Interestingly, these retrospective studies outlined that delayed AC was not associated with an increased mortality risk (32,36,38) (Table 4). Notably, patients who received delayed AC (i.e., after 57 days) had a lower mortality risk [HR (95% CI): 0.664 (0.623–0.707); P<0.001] compared to patients treated with surgery alone (32). However, patients who received AC >8 weeks after lung surgery have significant shorter OS compared to those who received AC within 8 weeks after lung resection (44). Finally, in accordance with hospital length stay after surgery, thoracotomy surgery is associated with a longer delay of AC administration compared to video-assisted thoracoscopic surgery (VATS) (42) (Table 4).

Overall, these retrospective studies highlighted that decision of AC administration is influenced by several predictors including patient’s and physician’s decision, patient’s baseline characteristics, lung surgery and post-operative complications as well as referral to medical oncologist. Although no difference with main randomized clinical trials, all these predictive factors might also contribute with prolonged length of stay in hospital following surgery and thus, delayed AC administration. Otherwise, these retrospective studies outlined that although delayed; AC administration remains associated with a better prognosis compared to surgery alone.

Is age a limiting factor to receive AC in real-life practice?

Despite literature supporting AC use in completely resected IIA to IIIA NSCLC, there is actually a lack of literature data regarding AC use in elderly patients. Indeed, in main randomized clinical trials of AC in NSCLC, elderly patients did not meet the inclusion criteria. Of note, in IALT trial, there were only 4 patients older than 75 years old among 932 patients who received AC (2). In the ANITA trial, the median age in chemotherapy group was 59 years old, with no patients older than 75 years old included (4). Notably, sub-group analysis was conducted based on JBR.10. trial patients’ cohort as the age varies from 35 to 82 years old in the chemotherapy group (3,45). Pepe et al. analysed the population study of the JBR.10. trial by separating the population study into two groups according to the age (i.e., patients younger or older than 65 years old) (45). Although a potential bias of well selected aged patients, this sub-group analysis outlined that AC can be used safely in elderly patients. Indeed, no significant differences were reported between age groups in terms of chemotherapy toxicities, rate of hospitalization and treatment-related death (45). Moreover, this sub-group analysis highlighted that unless elderly patients received lower intensities of cisplatin-vinorelbine, AC use remained a significant prognostic factor of prolonged OS for patients older than 65 years old [adjusted HR (95% CI): 0.61 (0.38–0.98); P=0.04] compared to surgery alone (45). Likewise, the sub-group analysis of the LACE meta-analysis according to the age (i.e., <65, 65–70, and >70 years old) revealed no significant differences of AC related toxicities (46). As well, the oldest patients received lower doses of cisplatin and lower number of AC cycles. Indeed, only 42% of the elderly patients received a total cisplatin dose ≥275 mg/m² in comparison with 64% of young patients (P<0.0001) and; 58% of the elderly patients received more than two or three of the four planned chemotherapy cycles, compared with 77% of young patients (46).

In non-trial setting, several retrospective studies outlined that older patients received significantly less AC compared to their younger counterparts. Indeed, AC use for patients older than 70 years old ranged from 10% to 25% (33,47-51) (Table 5). This might be related to a less referral to medical oncologist (52). Otherwise, older patients have a higher likelihood to receive AC in case of higher stage disease, as 42% of patients older than 70 years old with stage IIIA disease were treated with AC (51). Moreover, most of these retrospective studies highlighted that there was no significant difference in chemotherapy regimen received (39,48,54,55) (Table 5). Among these, only two studies reported that elderly patients received more frequently Carboplatin-based (P<0.0001) (49) or Carboplatin-paclitaxel regimen compared to younger (without a statistical significance) (55) (Table 5).

In real-life practice, despite contradictory data (33), no significant differences in the number of chemotherapy cycles received was observed between younger and older patients (39,54). Of note, the percentage of patients older than 65 years old who completed four cycles of AC ranged from 61% (50) to 92.4% (39,54,55) (Table 5). Likewise, no significant differences in terms of dose intensity received was reported (55). A dose reduction was reported among 30% (48) to 40.9% (55) of older patients while a dose omission was observed between 21% to 32% of cases (48) (Table 5). As an assessment of well-tolerated AC in this specific population, no significant difference was reported between patients younger and older than 65 years old regarding hematologic toxicities, except for all grade anemia (55). Notably, grade 3–4 neutropenia was not significantly more frequent in older patients (i.e., 39.4%) compared to their younger counterparts (i.e., 41.1%) (55). Adverse events reported by elderly patients during AC treatment were sore mouth (P=0.0032), peripheral neuropathy (P<0.001) and alopecia (P<0.001) (55). Overall, quality of life (QOL) during AC treatment did not significantly deteriorate among elderly patients (55).

More interestingly, several studies outlined that AC is efficient in this sub-population (39,49-51,53-55) (Table 5). Indeed, AC significantly improved OS compared to surgery alone among patients older than 66 (49) or 70 years old (51,53). As well, no significant differences were reported between younger and older patients who received AC in terms of OS (49-51,53-55) and DFS (39,54,55) (Table 5). However, Wisnivesky et al. observed that AC use was not associated with a survival benefit for patients older than 80 years old (53).

Overall, these retrospective studies showed that unless AC is used less frequently among elderly patients, AC remains safe and efficient in non-trial setting. As for their younger counterparts, fit older patients should be treated with platinum based chemotherapy; cisplatin remained preferrable if patient suitable to receive it (56). As an exception, AC use might be carefully discussed for patients older than 80 years old as no survival benefit was observed (53,57). Otherwise, chronological age should not be considered as a limiting factor to receive AC as well as performance status (57). Indeed, several reviews on AC use in clinical practice among elderly patients, outlined that comprehensive geriatric assessment is of particular interest to limit both over and undertreatment in this specific population (56-61).

Which type of chemotherapy is used in real-life practice? Are patients received the planned dose of AC?

AC, and in particular cisplatin-based regimen, may have toxicity. Consequently, this arises the question of patients who subsequently received AC when recommended as well as the regimen and dose intensity received in non-trial setting.

According to main randomized clinical trials, among patients assigned to receive AC, the percentage of patients who never received chemotherapy ranged from 4.5% to 9.8% (2-4); mainly due to patient’s refusal. Among patients who received AC, 73.8% received at least 240 mg/m² of cisplatin in the IALT trial (2) while 38% and 63% patients received more than 66% of the total planned dose of vinorelbine and cisplatin respectively in ANITA trial (4) (Table 1). In the LACE meta-analysis, 59% of patients received at least 240 mg/m² of cisplatin (5) (Table 1). The median number of cycles delivered was three in the JBR.10. trial (3); 77% of patients had at least one dose reduction or omission and 55% required at least one dose delay (3). Main factors associated with incomplete chemotherapy planned in IALT trial were adverse events (51.5%), patient’s or physician’s decision (24.3%) and disease progression (5.1%) or early death (8.1%) (2). Similarly to the IALT trial, the main reasons for receiving less than the planned number of AC cycles were patient’s refusal (35%), toxicity (34%) and early death or progression (9%) in the LACE meta-analysis (5).

Firstly, these studies highlight that cisplatin-based regimen is the most frequently used in non-trial setting (Table 6). Of note, consistently with guidelines, cisplatin-vinorelbine is the most frequently AC regimen prescribed by physicians in real-life practice (Table 6). On the contrary, only two retrospective studies mentioned that carboplatin-paclitaxel regimen was the most frequently prescribed AC regimen (24,66). Otherwise, these studies either included patients previously main randomized clinical trials were published (66) or recently published (24) and; the median age of patients was older than 66 years old (66). In this setting, initial chemotherapy regimen was changed for 6% (62) to 8% (63) of patients (i.e., mainly cisplatin for carboplatin-based regimen). The main reasons involved for this chemotherapeutic change were nephrotoxicity, asthenia and vomiting (63). Although heterogeneity data (18,22,41,68,70), the number of patients who completed four cycles of AC ranged from 71% to 92% in non-trial setting (Table 6). In particular, the percentage of patients who received the total planned dose ranged from 40% (40) to 78.4% (34). Moreover, patients experience dose reduction or omission in a range of 40% (63) to 64% (62) (Table 6). In particular, dose reduction was significantly associated with cisplatin-used (P=0.004) and poorer ECOG (i.e., performance status 0–1 as reference, P=0.020) (37). In line with these observations, cisplatin-vinorelbine regimen was significantly associated with higher frequency of dose delay or dose reduction compared to patients treated with carboplatin-paclitaxel (70). Although dose modification was not found to be associated with inferior survival (62), Ramsden et al. showed that patients with a delivery of <80% of total planned platinum dose was a significant factor affecting OS (37). Likewise, the number of AC cycles received is important to consider as patients who received four AC cycles had a significant prolonged DFS compared to those who received less than four cycles of AC [HR (95% CI): 0.727 (0.552–0.958); P=0.0023] (39). On the contrary, Kenmotsu et al. found that the total dose of cisplatin received was not a prognostic factor (64). Finally, main reasons for discontinuation of AC were AC toxicities (i.e., 8%) and patient’s refusal (i.e., 8%) (64,65). Finally, thoracoscopy seems to be associated with higher compliance to AC compared to thoracotomy (34,35). Indeed, a significant higher rate of patients completed 4 AC cycles in case of thoracoscopy compared to thoracotomy (34,35).

Taken together, these studies showed that physicians prescribe mostly cisplatin-vinorelbine regimen. In a population of less-selected patients, literature data showed that the percentage of patients who received either 4 AC cycles or experienced dose reduction or omission is not different compared to randomized clinical trials.

AC related toxicities

Finally, a major point to take into account in real-life practice is the toxicity of AC, which can lead to either dose reduction or omission and incomplete planned dose received. In main randomized clinical trials, the rate of overall grade 3–4 toxicity was estimated at 66% (5). In particular, neutropenia was reported as the most frequent serious adverse event occurring in patients treated with AC: 9% grade 3 and 28% grade 4 neutropenia reported in the LACE meta-analysis while 73% and 76% of patients experienced grade 3 or 4 neutropenia in the JBR.10. and ANITA trials respectively (Table 1).

Similar to AC clinical trials, neutropenia remains the most frequent adverse event reported in real-life practice (Table 6). In contrast with Shukuya et al. (43) who reported 76% of patients experienced grade 3–4 neutropenia, other studies highlight that in non-trial setting neutropenia occurrence is not more frequent compared with randomized clinical trials (Table 6). Indeed, the rate of grade 3–4 neutropenia ranged from 19% (35) to 62.1% (68), with up to 10% of patients who experienced febrile neutropenia (63) (Table 6). In this setting, neutropenia was significantly more frequent in case of cisplatin-vinorelbine regimen (P<0.001) (70). In real-life practice, other AC adverse events frequently reported were asthenia, anorexia and nausea-vomiting (Table 6). Moreover, AC related toxic death was low in randomized clinical trials with a rate ranging from 0.8% to 2% (Table 1). Similar observations were reported according to retrospective studies in real-life practice (18,40,62,64,65,69). Indeed, 0.009% to 1.6% related AC toxicity death were reported by Massard et al. (18) and Booth et al. (62) respectively, while other retrospective studies reported no AC toxic death (40,64,65,69). In this context, predictors of early mortality (i.e., within 6 months following AC administration) have been identified (71). Prolonged length of stay in hospital (>6 days), 30-day readmission on hospital, higher stage disease, higher comorbidities according to Charlson index (i.e., ≥2) and pneumonectomy were significantly associated with higher risk of early mortality following AC administration (71). Notably, AC related toxic death seems to be more frequent in older patients. Indeed, AC related toxic death within 12 weeks following AC administration was estimated at 3.1% among a population of 684 patients with a mean age of 71.5 years old (53). Moreover, this retrospective study outlined the increased risk of dehydration in this specific population which occurred in 6.7% (53). In accordance with Wisnivesky et al., patients older than 80 years old or aged between 70 and 80 years old were also identified at higher risk of early mortality (i.e., within 6 months following AC administration) compared with younger patients (i.e., <50 years old) (71). The mortality rate at 6 months was 7.6% among patients older than 80 years old (71).

Finally, sub-group analysis of the JBR.10. trial showed that patients had transient worsening QOL scores following AC (72). Otherwise, these scores were found to return to baseline within 9 months following AC, except for sensory neuropathy (72). In non-trial setting, patients also experienced a transient worsening QOL partially associated with AC administration (67). Indeed, Paull et al. reported all three measures of global QOL (Trial Outcome Index, Functional Assessment of Cancer Therapy-Lung and Functional Assessment of Cancer Therapy-General) as well as the subscales of physical and functional well-being at baseline and after lung resection among 37 patients for a stage I–III NSCLC disease. These scores were significantly decreased at 0 to 3 months compared with baseline whereas these scores were not significantly different from baseline after 3 months (67).

Overall, consistently with clinical trials, literature data regarding AC toxicity in non-trial setting highlight that AC use is mostly associated with a risk of neutropenia. AC administration remains well-tolerated in most of patients and might be associated with a transient worsening QOL.

Discussion

At the beginning of 2000, AC has been implemented in NSCLC with the aim to reduce the risk of disease recurrence through eliminating residual disease. To our knowledge, this is the first systematic literature review reporting AC use for resected NSCLC patients in real-life practice as previous reviews on this topic focused on AC use in elderly patients. This systematic literature review highlights a lack of literature data regarding AC use in real-life practice, as most of these were retrospective studies. Although data from large registries such as National Cancer Database or SEER (Surveillance, Epidemiology and End Results program) database, most of the retrospective studies included were either monocentric or multicentric with a limited number of patients which might limit external validity of results. Similarly, retrospective studies are also subjected to potential bias, in particular selection bias and information or misclassification bias. As well, although broad search terms were applied in the request formulated on several research database in order not to miss relevant articles, only one author carried out the selection and peer-reviewed process which constitute a potential bias of selection. Otherwise, the eligibility and the relevance of articles selected was peer-reviewed by all authors.

Despite the absence of a control group and the quality of data sources and collection, RWE has gained increased interest recently as they could focus on a specific population underrepresented in randomized clinical trials or provide pharmaco-economic data. There is a lack of RWE regarding AC use in resected NSCLC patients. In this setting, RWE would be interesting to evaluate AC use in elderly patients or in stage IB disease as AC use remains controversial in these specific populations. Notably, in the context of adjuvant immunotherapy and targeted therapies development, RWE on AC would be valuable to define which patients would better benefit from these different therapeutic options in next future and provide pharmaco-economic data.

Consistently with randomized clinical trials, this systematic literature review shows that benefit outweigh the risk is in favour of AC use when recommended. Indeed, in a less-selected population, AC use remains safe and associated with a therapeutic efficacy. In particular, this systematic review highlights that AC could be used in fit elderly patients—especially for those younger than 80 years old—which is a frequent clinical situation in daily-life practice. Furthermore, delayed AC remains efficient compared to surgery alone.

Nowadays, guidelines for AC administration are mainly based on patient’s clinical characteristics (age, performance status) and NSCLC disease’s characteristics. In this context, there has been a great interest to identify prognostic and predictive biomarkers of AC treatment to better select patients. However, these interesting markers such as DNA methylation, miRNA or gene signatures have not proven their clinical value in prospective trials yet (73). In this context, other biomarkers currently used in metastatic context tend to be used as well in early-stage NSCLC disease. Thus, the specific place of standard AC has to be precised in the next future since targeted therapies and immunotherapy seem promising strategies in adjuvant setting. Indeed, although the therapeutic efficacy of PD-1 and PD-L1 antibodies remain currently unclear in adjuvant treatment strategies for NSCLC, preliminary results of phase III IMpower010 (NCT02486718) randomized clinical trial hopes for future. Primary results recently reported at ASCO (American Society of Clinical Oncology) meeting 2021 showed that patients who received atezolizumab following AC have significant increased DFS compared to best supportive care (P=0.0395 after a median follow-up of 32.2 months) (74). In the same way, other phase III randomized trials are currently ongoing to evaluate the impact of immune checkpoint inhibitors on DFS following AC treatment (ANVIL trial NCT02595944; PEARLS/Keynote091 trial NCT02504372; BR31 Canadian Cancer Trial Group NCT02273375). In case of oncogenic-driven mutations, ADAURA trial recently demonstrated that osimertinib significantly prolonged DFS after curative-intent lung surgery compared to placebo for patients harbouring EGFR-sensitizing mutations (i.e., del19 and L858R EGFR mutations), regardless patients received AC or not (75).

To conclude, despite a lack of literature regarding AC use in real-life practice, this systematic literature review reports that AC use is safe and efficient in non-trial setting. Several strategies are currently under development to better select patients that will benefit from AC and to implement other strategies depending on immune checkpoint inhibitors and targeted therapies.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://dx.doi.org/10.21037/tlcr-21-557

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-557). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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