Use of Adjuvant Chemotherapy in Resected Non-small Cell Lung Cancer in Real-life Practice

A Systematic Review of Literature

Anne-Laure Desage; Wafa Bouleftour; Olivier Tiffet; Pierre Fournel; Claire Tissot

Transl Lung Cancer Res. 2021;10(12):4643-4665.

Abstract and Introduction

Abstract

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.

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).

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Next Section

Abstract and Introduction
Materials and Methods
Results
Discussion
References

Table 1. Dose intensity, toxicity and OS of main AC randomized clinical trials
Clinical trial	Number of patients included	Stage eligibility	Chemotherapy regimen	Cisplatin-dose intensity	Number of patients completed ≥3 cycles of AC	Neutropenia (grade 3–4)*	AC* related death	OS at 5 years (chemotherapy group)	OS at 5 years (control group)	P value (OS)
IALT (2)	1,867; 932 patients assigned to AC group	I–III	Cisplatin-based (with vindesine, vinorelbine, vinblastine or etoposide)	73.8% received ≥240 mg/m²	–	17.5%	0.8%	44.5%	40.4%	<0.03
ANITA (4)	840; 348 patients received AC	I–IIIA	Cisplatin-vinorelbine	63% received ≥66% of the total planned dose of cisplatin (i.e., 400 mg/m²)	61%	76%	2%	51.2%	42.6%	0.017
JBR.10. (3)	482; 242 patients assigned to AC group	IB–II	Cisplatin-vinorelbine	–	58%	73%	0.8%	69%	54%	0.03
LACE meta-analysis (5)	4,584	I–III	–	59% received at least 240 mg/m² of cisplatin	–	9% grade 3; 28% grade 4	0.9%	48.8%	43.5%	0.004

*, according to CTCAE classification. CTCAE, Common Terminology Criteria for Adverse Events; OS, overall survival; AC, adjuvant chemotherapy.

Table 2. Eligibility criteria for study selection process according to PICOS guidelines
PICOS guidelines	Eligibility criteria	Exclusion criteria
Patients	Patients that underwent curative-intent lung surgery for NSCLC. Patients with theoretical indication of AC or patients who received AC	Patients with advanced or metastatic NSCLC were excluded
		Articles that enrolled only patients with stage I NSCLC disease were excluded
		Patients with other histologic sub-types (i.e., small-cell lung cancer, large cell neuroendocrine lung carcinoma, carcinoid tumours, malignant pleural mesothelioma and other cancers) were excluded
Intervention	AC in real-life practice	Neoadjuvant strategies and other adjuvant strategies (i.e., targeted therapies, immunotherapy, other chemotherapy regimens) were excluded
Intervention	AC in real-life practice	Other studies dealing with treatments part of the multimodal strategy (i.e., surgery, radiotherapy, concomitant or sequential chemotherapy) were excluded
Comparison	No control group defined for intervention	–
Outcomes	No primary or secondary endpoints were defined	–
Study design	Prospective or retrospective observational studies on AC use in real-life practice for resected NSCLC. As the first randomized clinical trial on AC was published in 2004, study eligibility criteria also included period of publications from 2004 to 2021	Randomized clinical trials and sub-group analysis on AC out of the context of real-life practice were excluded
		Reviews and meta-analysis about lung cancer and AC out of the context of real-life practice were excluded
		Articles dealing with predictive and prognostic markers in lung cancer, pre-clinical studies, guidelines and case report on lung cancer were excluded

NSCLC, non-small cell lung cancer; AC, adjuvant chemotherapy.

Table 3. Median length of stay in hospital after curative-intent lung surgery in non-trial setting
Study	Number of patients included	Period of recruitment	Length of stay in hospital after surgery
Wright et al., 2008, (30)	4,979	Retrospective (2002 → 2006)	Median length of stay: 6 days
Wright et al., 2008, (30)	4,979	Retrospective (2002 → 2006)	Prolonged length of stay (i.e., exceeding 14 days) for 351 patients (i.e., 7% of patients) with a mean prolonged length of stay of 25.7 days
Massard et al., 2009, (18)	219	Retrospective (2004 → 2005)	Median length of stay: 8 days (range from 2 to 85 days)
Salazar et al., 2017, (32)	12,473	Retrospective (2004 → 2012)	Length of stay ≤14 days: 11,965 patients
Salazar et al., 2017, (32)	12,473	Retrospective (2004 → 2012)	Length of stay exceeding 14 days: 508 patients
Rodriguez et al., 2012, (33)	99	Retrospective (2006 → 2010)	Median length of stay significantly prolonged for patients ≥70 years old (4 vs. 6 days for respectively patients <70 and ≥70 years old); P=0.03
Rodriguez et al., 2012, (33)	99	Retrospective (2006 → 2010)	Median length of stay in intensive care unit significantly prolonged for patients ≥70 years old (2.5 vs. 1 day for respectively patients <70 and ≥70 years old); P=0.01
Lee et al., 2011, (34)	148	Retrospective (2000 → 2009)	Median length of stay in hospital: 7.05±2.69 days in thoracoscopic lobectomy group vs. 8.04±3.39 days in thoracotomy group
Lee et al., 2011, (34)	148	Retrospective (2000 → 2009)	Median stay in intensive care unit: 0.74±0.57 days in thoracoscopic lobectomy group vs. 0.97±0.37 days in thoracotomy group (P=0.004)
Jiang et al., 2011, (35)	110	Retrospective (2004 → 2010)	Median length of stay 10.8±3.7 days in VATS group vs. 12.5±4.8 days in thoracotomy group (P=0.043)
Bouchard et al., 2008, (31)	60	Retrospective (2004 → 2006)	Median length of stay in hospital 9.3±5.4 days
Bouchard et al., 2008, (31)	60	Retrospective (2004 → 2006)	Median length of stay was significantly shorter compared to patients who did not receive AC (P=0.0008)

VATS, video-assisted thoracic surgery; AC, adjuvant chemotherapy.

Table 4. Time from surgery to AC administration and impact on survival in real-life practice
Study	Number of patients received AC	Period of recruitment	Median time from surgery to AC administration	Impact of delayed AC on survival
Salazar et al., 2017, (32)	12,473	Retrospective (2004 → 2012)	48 (range, 18–127) days	Lower mortality risk when AC initiated in the 50 days after lung surgery (95% CI: 39–56)
Salazar et al., 2017, (32)	12,473	Retrospective (2004 → 2012)	48 (range, 18–127) days	No increased of mortality risk for patients who received AC later (i.e., between 57 to 127 days after resection): HR (95% CI): 1.037 (0.972–1.105); P=0.27
Booth et al., 2013, (36)	1,032	Retrospective (2004 → 2006)	8 (range, 1–16) weeks	No difference observed in 4-year OS between patients who started AC from 1 to 10 weeks after lung resection with those who received delayed AC from 11 to 16 weeks after surgery (64% vs. 61%; P=0.758)
Booth et al., 2013, (36)	1,032	Retrospective (2004 → 2006)	35% cases initiated AC more than 10 weeks after surgery
Ramsden et al., 2015, (37)	158	Retrospective (2005 → 2010)	8 (range, 3.7–20.3) weeks	–
Ramsden et al., 2015, (37)	158	Retrospective (2005 → 2010)	24% cases initiated AC more than 10 weeks after surgery	–
Zhu et al., 2016, (38)	409	Retrospective (2003 → 2013)	81.9% patients underwent postoperative AC within 46 days: median 34 (range, 25–45) days	No significant difference in terms of DFS between patients receiving AC either within 46 days after surgery {median DFS [95% CI]: 467 [450–552] days} or after 46 days from surgery {median DFS [95% CI]: 474 [400–623] days}; P=0.775
Zhu et al., 2016, (38)	409	Retrospective (2003 → 2013)	18.1% patients underwent postoperative AC in more than46 days: median 53.5 (range, 46–228) days
Zhai et al., 2016, (39)	865	Retrospective (2001 → 2013)	62% of patients received AC between 4 to 6 weeks after surgery	–
Velcheti et al., 2007, (40)	40	Retrospective (2003 → 2005)	49 (range, 16–188) days	–
Lee et al., 2011, (34)	148	Retrospective (2000 → 2009)	28.1±10.7 days in thoracotomy group	–
Lee et al., 2011, (34)	148	Retrospective (2000 → 2009)	26.9±7.5 days in thoracoscopic lobectomy group	–
Jiang et al., 2011, (35)	110	Retrospective (2004 → 2010)	33.7±10.9 days in VATS group	–
Jiang et al., 2011, (35)	110	Retrospective (2004 → 2010)	34±13.3 days in thoracotomy group	–
Sorensen et al., 2015, (41)	126	Retrospective (2005 → 2012)	Mean time: 41 days	–
Teh et al., 2014, (42)	44	Retrospective (2008 → 2013)	55.7±3.1 days in VATS resection group vs. 68.2±4.3 days in thoracotomy group (P=0.046)	–
Shukuya et al., 2009, (43)	25	Retrospective (2005 → 2008)	Median time from surgery to AC: 41 (range, 29–79) days	–
Wang et al., 2016, (44)	1,522	Retrospective (2004 → 2010)	10% patients received AC <30 days after surgery	Patients who received AC >60 days after surgery have a shorter OS compared to other patients who received AC <60 days after surgery (P=0.0034)
			17.1% received AC between 0–45 days after surgery
			19.05% received AC between 45–60 days after surgery
			53.7% received AC >60 days after surgery

AC, adjuvant chemotherapy; OS, overall survival; DFS, disease-free survival; VATS, video-assisted thoracic surgery.

Table 5. Use of AC in elderly patients
Study	Number of patients who underwent surgical resection; stage disease	Number of patients received AC	Period of recruitment	AC use in elderly patients	Chemotherapy regimen prescribed	Dose modification or omission	Survival analysis elderly patients
Booth et al., 2010, (47)	3,354; 43% older ≥70 years old; I–IV	1,224	Retrospective (2001 → 2006)	16% of patients >70 years old received AC	Cisplatin or carboplatin-based regimen	–	–
Cuffe et al., 2012, (48)	6,304; 43.8% older ≥70 years old; I–IV	1,224	Retrospective (2001 → 2006)	70–74 years old: 191 patients received AC among 1,317 who underwent lung resection	Cisplatin-based regimen (with vinorelbine or etoposide); carboplatin-based regimen (with vinorelbine or paclitaxel); other	584 chemotherapy data available:	–
				75–79 years old: 81 patients received AC among 980 who underwent lung resection	584 chemotherapy data available:	Cisplatin changed for carboplatin: 5% among 75–79 years old patients
				≥80 years old: 13 patients received AC among 466 patients who underwent lung resection	Cisplatin-based: 71% (70–74 years old), 67% (75–79 years old), 71% (≥80 years old)	Dose reduction: 30% (70–74 years old), 32% (75–79 years old)
					Carboplatin-based: 26% (70–74 years old), 33% (75–79 years old), 29% (≥80 years old)	Dose omission: 21% (70–74 years old), 32% (75–79 years old), 25% (≥80 years old)
Ganti et al.,2015, (49)	7,593; 38% older ≥70 years old; IB–III	1,928	Retrospective (2001 → 2011)	Percentage of older patients (i.e., ≥70 years old) who received AC: approximately one half of younger patients (15.3% vs. 31.6%; P<0.0001)	Cisplatin or carboplatin-based regimen	–	As for younger patients, AC significantly improved OS among patients ≥70 years old [adjusted HR (95% CI): 0.81 (0.71–0.92)]
Ganti et al.,2015, (49)	7,593; 38% older ≥70 years old; IB–III	1,928	Retrospective (2001 → 2011)		Compared with younger patients, patients ≥70 years old received significantly more frequently carboplatin-based regimen (72% vs. 62.3%; P<0.0001)	–
Kankesan et al., 2013, (52)	3,354; 45% older ≥70 years old; I–IV	1,032	Retrospective (2004 → 2006)	Patients older than 70 years old significantly less referred to medical oncologist (45% of patients; P<0.001)	–	–	–
Kankesan et al., 2013, (52)	3,354; 45% older ≥70 years old; I–IV	1,032	Retrospective (2004 → 2006)	Patients older than 70 years old significantly less treated with AC (35% of patients older than 70 years old referred to medical oncologist treated with AC; P<0.001)	–	–	–
Rajaram et al., 2016, (28)	112,049; 20% older ≥75 years old; IB–IIIA	31,709	Retrospective (2002 → 2011)	Compared to patients younger than 55 years old, patients older than 56 years old have significantly less likelihood to receive AC [adjusted OR (95% CI); especially among patients >75 years old: 0.15 (0.12–0.18); P<0.001]	–	–	–
Berry et al., 2015, (50)	2,781 patients >65 years old; stage II	784	Retrospective (1992 → 2006)	Patients aged 70–74, 75–79, 80–84 and ≥85 years old received significantly less AC	Platinum-based regimen administered to 76% of patients	61% received four or more cycles (no information about dose reduction)	AC remained an independent prognostic factor associated with survival among all patients aged ≥66 years old (P=0.0002)
Wisnivesky et al., 2011, (53)	3,324 patients >65 years old; IIA–IIIA	684	Retrospective (1992 → 2005)	–	–	–	AC associated with improved OS for patients 70–79 years old [adjusted HR (95% CI): 0.82 (0.71–0.94)]
Wisnivesky et al., 2011, (53)	3,324 patients >65 years old; IIA–IIIA	684	Retrospective (1992 → 2005)	–	–	–	No survival benefit for patients older than 80 years old [adjusted HR (95% CI): 1.33 (0.86–2.06)]
Rodriguez et al., 2012, (33)	99; 30% ≥70 years old; IB, II and higher	53	Retrospective (2006 → 2011)	Patients ≥70 years old received significantly less AC compared to youngers; (25% vs. 66.7%; P<0.01)	–	Significantly less cycles of chemotherapy received for patients aged ≥70 years old (median number of cycles received 2 {range, [1–2]} compared to younger (median number of cycles received 4 {range, [2–4]}; P=0.04	–
Batum et al., 2018, (54)	–; IA–IIIB	91	Retrospective (2012 → 2016)	–	Platinum-based regimen with vinorelbine, pemetrexed, gemcitabine, etoposide, docetaxel	No significant differences between number of cycles of AC received	No significant differences between younger and older patients in terms of OS (P=0.119) and DFS (P=0.407)
					>65 years old patients treated with: platinum + vinorelbine (70%); carboplatin-based regimen (5%)	90% of patients >65 years old completed four cycles of AC
					No significant differences in chemotherapy regimen administered between younger and older patients	90% of patients >65 years old completed four cycles of AC
Zhai et al., 2016, (39)	–; IB–IIIA	865	Retrospective (2001 → 2013)	–	Platinum-based regimen with vinorelbine, pemetrexed, gemcitabine, docetaxel, paclitaxel	No significant differences between number of cycles of AC received	No significant differences in DFS between younger and older patients (P=0.328)
					No significant differences in chemotherapy regimen received between younger (i.e., <65 years old) and older patients (i.e., ≥65 years old)	79.1% of patients ≥65 years old completed four cycles of AC
						No significant differences in mean time to receive AC after surgery between younger and older patients
Park et al., 2013, (55)	–; IB–IIIA	139	Retrospective (2008 → 2011)	–	Chemotherapy regimen: cisplatin-vinorelbine or carboplatin-paclitaxel	No significant differences in mean dose intensity and relative dose intensity between younger and older patients for both AC regimen	No significant differences between aged groups (i.e., <65 years old and ≥65 years old) in terms of OS (P=0.4274) and relapse-free survival (P=0.4512)
					Elderly patients (66 patients ≥65 years old) most frequently treated with carboplatin-paclitaxel (54.5%) and less frequently with cisplatin-vinorelbine (45.5%) although not significant	92.4% of elderly patients completed 4 cycles of AC
						40.9% of elderly patients has a dose reduction, no significant difference compared to youngers
Lin et al., 2012, (51)	2,231; 764 patients ≥70 years old; IA–IIIA	428	Retrospective (2004 → 2007)	Among patients ≥70 years old with stage II disease: 16% received AC	Platinum-based regimen	–	Among patients >70 years old with stage II and IIIA disease: AC use associated with a significant improvement of OS compared to surgery alone
Lin et al., 2012, (51)	2,231; 764 patients ≥70 years old; IA–IIIA	428	Retrospective (2004 → 2007)	Among patients ≥70 years old with stage IIIA disease: 42% received AC	Platinum-based regimen	–

AC, adjuvant chemotherapy; OS, overall survival; DFS, disease-free survival.

Table 6. AC regimen used and dose intensity, AC toxicity in real-life practice
Study	Period of recruitment	Number of patients treated with AC	Chemotherapy regimen prescribed	Dose reduction or omission	All grade 3–4* toxicity reported (% of patients)
Booth et al., 2012, (62)	Retrospective (2004 → 2006)	584	Cisplatin-based regimen (with vinorelbine or etoposide): 82% carboplatin-based regimen (with vinorelbine or paclitaxel): 17%; other (no platinum): 1%	Initial chemotherapy regimen changed: 6% (mainly cisplatin for carboplatin)	–
			Most frequent regimen: cisplatin-vinorelbine (72%)	Among 520 drug dosages available: 56% dose reduction or omission
			Most frequent regimen: cisplatin-vinorelbine (72%)	Cisplatin-vinorelbine sub-group: 64% dose reduction or omission
Ramsden et al., 2015, (37)	Retrospective (2005 → 2010)	158	Cisplatin-vinorelbine: 80%; carboplatin-paclitaxel: 15%; other: 5%	Median number of AC cycles received: 4	–
Ramsden et al., 2015, (37)	Retrospective (2005 → 2010)	158		72% of patients received >80% of planned dose of cisplatin or carboplatin	–
Aljubran et al., 2009, (63)	Retrospective (2003 → 2005)	50	Cisplatin-based regimen (with vinorelbine, gemcitabine or etoposide): 88%; carboplatin-based regimen (with vinorelbine, gemcitabine or paclitaxel): 12%	Initial chemotherapy regimen changed: 8% (cisplatin for carboplatin)	Grade 3–4 neutropenia: 28%; febrile neutropenia: 10%
			Most frequent regimen: cisplatin-vinorelbine (82%)	80% of patients completed 4 cycles of AC	Grade 3–4 anemia (4%) and thrombocytopenia (2%)
				Dose reduction: 40%	Grade 3–4 asthenia: 10%
				Mean dose of cisplatin received: 240.1 mg/m²	Grade 3–4 anorexia, nausea: 4% respectively
				Mean dose of vinorelbine received: 165.3 mg/m²	Grade 3–4 vomiting, diarrhea, constipation: 2% respectively
Kenmotsu et al., 2012 and 2017, (64,65)	Retrospective (2006 → 2011)	100	Cisplatin-vinorelbine	83% of patients completed 4 AC cycles	–
				59% of patients received the planned dose (i.e., cisplatin 320 mg/m² and vinorelbine 200 mg/m²)
				65% of patients received >300 mg/m² of cisplatin
Massard et al., 2009, (18)	Retrospective (2004 → 2005)	87	Cisplatin-based regimen (with vinorelbine, gemcitabine, paclitaxel or etoposide): 58%	40% of patients completed 4 AC cycles	29% patients experienced grade 3–4 toxicities; among them 12% of hematological toxicities and 16% of non-hematological toxicities (nausea/vomiting, acute renal failure and central venous infection)
			Carboplatin-based regimen (with vinorelbine, gemcitabine, paclitaxel or etoposide): 31%
			Most frequent regimen: cisplatin-gemcitabine (27%)
Williams et al., 2014, (66)	Retrospective (2001 → 2008)	1,084	Cisplatin-based regimen (with vinorelbine, docetaxel, etoposide or other): 29%; carboplatin-based regimen (with docetaxel, gemcitabine, paclitaxel or other): 71%; other (no platinum): 3%	–	–
Williams et al., 2014, (66)	Retrospective (2001 → 2008)	1,084	Most frequent regimen: carboplatin-paclitaxel (52%)	–	–
Moth et al., 2016, (23)	Prospective (2010 → 2012)	98	Cisplatin-vinorelbine most frequent regimen: 74%	71% of patients completed 4 AC cycles	–
Paull et al., 2006, (67)	Prospective (2004 → 2006)	10	Carboplatin-paclitaxel	Average dose of 1,074±212 mg/m² carboplatin and 708±50 mg/m² of paclitaxel	3 cases of grade 1–3 neutropenia or thrombocytopenia reported
				Average number of AC cycles received 4±0.5	2 cases of grade 1–3 gastrointestinal disturbance reported
				Average number of AC cycles received 4±0.5	No grade 4 toxicity reported
Park et al., 2013, (55)	Retrospective (2008 → 2011)	139	Cisplatin-vinorelbine: 53.2%; carboplatin-paclitaxel: 46.8%	Dose reduction in the global cohort: 58.3%	In the global cohort:
					Leukopenia grade ≥3: 9.3%
					Neutropenia grade ≥3: 40.3%
					Anemia grade ≥3: 2.9%
Kolek et al., 2018, (19)	Retrospective (2006 → 2013)	115	Platinum-based regimen with vinorelbine or other	82% completed cycles with platinum-based regimen and oral vinorelbine	Grade 3–4 neutropenia: 34.4% of patients. Febrile neutropenia: 2.2%
Kolek et al., 2018, (19)	Retrospective (2006 → 2013)	115	Platinum-based regimen with vinorelbine or other	Average number of cycles received: 3.87	Grade 3–4 nausea: 33.3%
Velcheti et al., 2007, (40)	Retrospective (2003 → 2005)	40	Cisplatin-docetaxel most frequent regimen: 43%	40% of patients received the planned dose	42% experienced grade 3–4 toxicities with 25% grade 3–4 neutropenia
			Other AC regimen: carboplatin-paclitaxel (17%), carboplatin-docetaxel (17%); carboplatin-gemcitabine (15%)	53% had AC dose reduction
				8% had AC dose delay
Kassam et al., 2007, (16)	Retrospective (2003 → 2005)	42	Cisplatin-vinorelbine most frequent regimen: 67%	–	–
Kassam et al., 2007, (16)	Retrospective (2003 → 2005)	42	Other regimen: cisplatin-etoposide, carboplatin-paclitaxel (9.5%), cisplatin-gemcitabine	–	–
Blinman et al., 2015, (22)	Prospective	106	Cisplatin-vinorelbine most frequent regimen: 73%	68% completed 4 AC cycles	–
Blinman et al., 2015, (22)	Prospective	106	Other regimen: platinum + gemcitabine	68% completed 4 AC cycles	–
Younis et al., 2008, (24)	retrospective (2005)	29	Carboplatin-paclitaxel most frequent regimen: 79.3%	–	–
Younis et al., 2008, (24)	retrospective (2005)	29	Cisplatin-vinorelbine (17.2%), carboplatin-vinorelbine (3.4%)	–	–
Chouaid et al., 2018, (20)	Retrospective (2009 → 2011)	402	Cisplatin-vinorelbine most frequent regimen: 64.2%	Median number of AC cycles received: 4	–
			Other regimen: carboplatin-vinorelbine, cisplatin-gemcitabine	62.1% completed the total planned dose of cisplatin
				66% completed the total planned dose of vinorelbine
Couillard-Montminy et al., 2017, (68)	Retrospective (2004 → 2013)	127	Cisplatin-vinorelbine most frequent regimen: 52%; carboplatin-vinorelbine	47% patients completed 4 cycles of cisplatin-vinorelbine	In cisplatin-vinorelbine group:
					Grade 3–4 neutropenia: 62.1%. Febrile neutropenia: 4.6%
					Grade 3–4 anemia: 15.2%
					Blood transfusion support for 25.8% patients
Lee et al., 2011, (34)	Retrospective (2000 → 2009)	148	Cisplatin-based regimen most frequent (no other precision)	89% patients completed 4 cycles of AC	–
Lee et al., 2011, (34)	Retrospective (2000 → 2009)	148	Cisplatin-based regimen most frequent (no other precision)	78.4% patients received the total planned dose	–
Jiang et al., 2011, (35)	Retrospective (2004 → 2010)	110	Carboplatin-paclitaxel (40.9%); cisplatin-gemcitabine (49%) and cisplatin-vinorelbine (0.1%)	45.5% patients received the total planned dose	28.2% experienced grade 3–4 toxicity
					Grade 3–4 neutropenia: 19%
					Grade 3–4 nausea: 18.2%
Sorensen et al., 2015, (41)	Retrospective (2005 → 2008)	126	Cisplatin-vinorelbine	59% completed 4 cycles of AC	–
Sorensen et al., 2015, (41)	Retrospective (2005 → 2008)	126	Cisplatin-vinorelbine	10% patients received one cycle with dose reduction, 6% patients received two cycles with dose reduction, 2% patients received 3 cycles with dose reduction, 6 % patients received four cycles with dose reduction	–
Custodio carretero et al., 2008, (69)	Retrospective (2003 → 2006)	41	Carboplatin associated with docetaxel or paclitaxel; cisplatin associated with docetaxel or paclitaxel	56.1% received 4 AC cycles	Grade 3–4 haematological toxicities: 9.75%. 2 patients with febrile neutropenia
Custodio carretero et al., 2008, (69)	Retrospective (2003 → 2006)	41		12.2 % patients had a dose reduction and 9.75% had a dose delay	Grade 3–4 non-haematological toxicities: 7.31%
Chang et al., 2014, (70)	Retrospective (2004 → 2011)	438	Carboplatin-paclitaxel (47.3%) and cisplatin-vinorelbine (52.7%)	Median number of AC cycles received: 4 in both groups	Grade 3–4 anemia (P=0.008) and neutropenia (P<0.001) were significantly more frequent in cisplatin-vinorelbine group
				55.1% completed 4 cycles in carboplatin-paclitaxel group	Grade 3–4 neutropenia: 38.1% in cisplatin-vinorelbine group vs. 7.2% in carboplatin-paclitaxel group
				50.6% completed 4 cycles in cisplatin-vinorelbine group	Most frequent grade 3–4 AC related toxicities in cisplatin-vinorelbine group: nausea (2.2%), vomiting (2.2%) and constipation (1.7%)
				19.8% in carboplatin-paclitaxel group vs. 56.3% in cisplatin-vinorelbine group required a dose delay (P<0.001)	Most frequent grade 3–4 AC related toxicities in carboplatin-paclitaxel group: peripheral neuropathy (2.9%), myalgia (1.9%), alanine aminotransferase and infection (1.0% respectively)
				16.4% of patients in carboplatin-paclitaxel group had a dose reduction vs. 35.1% in cisplatin-vinorelbine group (P<0.001)
				Cumulative dose received: 83% for carboplatin and paclitaxel respectively; 83% and 82% for cisplatin and vinorelbine respectively
Teh et al., 2014, (42)	Retrospective (2008 → 2013)	44	Platinum with vinorelbine	45% patients completed 4 cycles at 100% of planned dose of platinum-based and vinorelbine	29.5% presented grade 3–4 haematological toxicities
Shukuya et al., 2009, (43)	Retrospective (2005 → 2008)	25	Cisplatin-vinorelbine	92% patients completed 4 AC cycles	76% patients presented grade 3–4 neutropenia. Febrile neutropenia =4%
				Mean cumulative dose of cisplatin was 312 mg/m² and 195 mg/m² for vinorelbine	20% patients presented grade 3–4 leukopenia
				20% patients had a dose reduction	12% patients presented anemia, anorexia and nausea respectively
Bouchard et al., 2008, (31)	Retrospective (2004 2006)	60	Cisplatin-vinorelbine most frequent regimen: 46.9%	–	Grade 3–4 cytopenia reported in 47.8% patients treated with cisplatin-vinorelbine regimen
Bouchard et al., 2008, (31)	Retrospective (2004 2006)	60	Other regimen: carboplatin based regimen with paclitaxel, gemcitabine, vinorelbine; cisplatin based regimen with etoposide or gemcitabine	–