Meta-analysis of postoperative adjuvant chemotherapy without radiotherapy in early stage non-small cell lung cancer

Figures & data

Figure 1 Flow chart of screening process.

Table 1 Baseline characteristics of the included RCTs in this meta-analysis

Researches	Stage	Number		Age (years)		Chemotherapy regimens	Compliance (%)	Median follow-up (months)
		Chemotherapy group	Control group	Chemotherapy group	Control group
Niiranen et al^Citation29	I–II	54	56	57	59	C (400 mg/m^2) + A (40 mg/m^2) + P (40 mg/m^2), 6 cycles	57.4	120
Feld et al^Citation28	I	136	133	NR	NR	C (400 mg/m^2) + A (40 mg/m^2) + P (60 mg/m^2), 4 cycles	53	45.6
Wada et al^Citation37	I–II	109	116	63	62.7	P (80 mg/m^2) d1 + V (2–3 mg/m^2) d1, 8+ M (8 mg/m^2) d1 → UFT (400 mg/day), 1 year	78.8	60
Mineo et al^Citation31	I	33	33	63.3±8.5	64.4±8.4	P (100 mg/m^2) d1 + E (120 mg/m^2) d1–3, 6 cycles	75.7	≥60
Endo et al^Citation11	I–II	109	110	63.9	62.2	UFT (260 mg/m^2/day or 400 mg/body/day), 2 years	63.3	63.5
Kato et al^Citation12	I	491	488	62	62	UFT (250 mg/m^2/day), 2 years	61	72/73
Imaizumi et al^Citation32	I	50	50	62.1±7.7	62.5±6.3	P (80 mg/m^2) d1 + V (3 mg/m^2) d1, 8+ UFT (400 mg/day), 2 years	86	NR
Imaizumi et al^Citation32	I	50	50	61.8±8.6	62.5±6.3	UFT (400 mg/day), 2 years	74	NR
Nakagawa et al^Citation13	I	163	169	62.5	63.1	UFT (400 mg/day), 1 years	50.9	75.8
Park et al^Citation33	I	59	59	58.7±6.5	57.9±7.02	M (10 mg/m^2) d1 + Vb (6 mg/m^2) d1 + P (100 mg/m^2) d1–5, 3 or 4 cycles	57.6	87.6
Nakagawa et al^Citation34	I	85	87	60.2	60.9	UFT (400 mg/day), ≥1 year	76.7	88.8
Roselli et al^Citation14	I	70	70	64.7±9.9	62.9±9.2	P (100 mg/m^2) d1 + E (120 mg/m^2) d1–3, 6 cycles	63	NR
Strauss et al^Citation35	I	173	171	61	62	Pa (200 mg/m^2) + Ca (6 mg/mL), 4 cycles	86	74
Felip et al^Citation36	I	163	154	64	64	Pa (200 mg/m^2) + Ca (6 mg/mL/min), 3 cycles	60.9	51
Butts et al^Citation15	I–II	242	240	60.5	61	Vi (25 mg/m^2), 16 course + P (50 mg/m^2) d1 and d8, 4 cycles	NR	111.6

Abbreviations: A, doxorubicin; C, cyclophosphamide; Ca, carboplatin; E, etoposide; M, mitomycin; NR, not reported; P, cisplatin; Pa, paclitaxel; RCTs, randomized control trials; UFT, tegafur–uracil; V, vindesine; Vb, vinblastine; Vi, vinorelbine; d, day.

Figure 2 Forest plots of pooled results on DFS (A) and OS (B) comparing chemotherapy and control groups.

Abbreviations: CI, confidence interval; DFS, disease-free survival; IV, inverse variance; OS, overall survival; SE, standard error.

Figure 3 Subgroup analysis of DFS comparing chemotherapy and control groups.

Notes: (A) Subgroup analysis of stage I. (B) Subgroup analysis of stage IB. (C) Subgroup analysis of cisplatin-based chemotherapy. (D) Subgroup analysis of single-agent UFT therapy.
Abbreviations: CI, confidence interval; DFS, disease-free survival; IV, inverse variance; SE, standard error; UFT, tegafur–uracil.

Figure 4 Subgroup analysis of OS comparing chemotherapy and control groups.

Notes: (A) Subgroup analysis of OS in stage I. (C) Subgroup analysis of OS in stage IA. (B) Subgroup analysis of OS in stage IB. (D) Subgroup analysis of OS in cisplatin-based chemotherapy. (E) Subgroup analysis of OS in a single-agent UFT therapy. *Used random effect models.
Abbreviations: CI, confidence interval; IV, inverse variance; OS, overall survival; SE, standard error; UFT, tegafur–uracil.

Table 2 Publication bias accessed by Begg’s and Egger’s tests

	Begg’s test	Egger’s test
DFS
Stage I–II	0.304	0.029
Stage I	0.251	0.065
Stage IB	1.000	0.336
Cisplatin-based chemotherapy	0.118	0.029
Single UFT chemotherapy	1.000	0.950
OS
Stage I–II	0.112	0.152
Stage I	0.087	0.152
Stage IA	1.000	0.771
Stage IB	0.548	0.187
Cisplatin-based chemotherapy	0.048	0.045
Single UFT therapy	0.462	0.402

Abbreviations: DFS, disease-free survival; OS, overall survival; UFT, tegafur–uracil.

Table 3 Main results of other related meta-analyses

Meta-analyses	Objects	Radiotherapy	Number		HR (95% CI)	P-value
			Studies	Patients
Hotta et al^Citation4	Stage I–IV patients	Yes	11	5,537	0.87 (0.81–0.94)	0.001
	Subgroup analyses
	S versus S + cis-based	Yes	8	3,786	0.89 (0.82–0.98)	0.012
	S versus S + UFT	No	5	1,751	0.80 (0.67–0.96)	0.015
Sedrakyan et al ^Citation41	Stage I–IIIA patients	Yes	19	7,200	0.87 (0.81–0.93)	<0.0001
	S versus S + cis-based	Yes	12	NR	0.89 (0.82–0.96)	0.004
	S versus S + UFT	No	7	NR	0.87 (0.81–0.93)	<0.0001
Berghmans et al ^Citation40	Stage I–III patients	Yes	19	7,644	0.84 (0.78–0.89)	NR
	Subgroup analysesa
	Stage I–II	Yes	10	4,602	0.88 (0.83–0.94)	NR
	Stage III	Yes	5	1,481	0.85 (0.69–1.04)	NR
	S versus S + cis-based	Yes	16	NR	0.86 (0.80–0.92)	NR
	S versus S + UFT	No	6	NR	0.72 (0.61–0.85)	NR
Hamada et al ^Citation38	Stage I patientsb	No	6	2,003	0.74 (0.61–0.88)	0.001
	Subgroup analysesa
	IA	No	NR	1,308	0.73 (0.56–0.93)	0.72
	IB	No	NR	674	0.78 (0.60–1.01)	0.72
Pignon et al^Citation10	Stage I–III patientsc	Yes	5	4,584	0.89 (0.82–0.96)	0.005
	Subgroup analyses
	Stage IA	Yes	NR	NR	1.40 (0.95–2.06)	NR
	Stage IB	Yes	NR	NR	0.93 (0.78–1.10)	NR
	Stage II	Yes	NR	NR	0.83 (0.73–0.95)	NR
	Stage III	Yes	NR	NR	0.83 (0.72–0.94)	NR
Bria et al ^Citation39	Stage I–III patientsc	Yes	20	7,408	0.91 (0.85–0.97)	0.011
	Subgroup analysesa
	Stage I–II	Yes	9	3,774	0.85 (0.79–0.91)	<0.0001
	Stage I	Yes	7	1,888	0.88 (0.79–0.98)	0.022
	Stage III	Yes	6	1,666	0.91 (0.85–0.96)	0.004
NSCLC	Stage I–IV patients	Yes	34	8,447	0.86 (0.81–0.92)	<0.0001
Meta-analyses	Subgroup analysesa
Collaborative	S versus S + cis-based	Yes	18	2,620	0.89 (0.82–0.97)	0.006
Group^Citation19	S versus S + UFT	No	8	3,848	0.80 (0.71–0.90)	0.001

Notes:

a Trials included more than one subgroup comparison;

b patients received single UFT chemotherapy only;

c patients received cisplatin-based chemotherapy only.

Abbreviations: HR, hazard ratio; OS, overall survival; CI, confidence interval; S, surgery; UFT, tegafur–uracil; NR, not reported; cis-based, cisplatin-based chemotherapy.

NiiranenANiitamo-KorhonenSKouriMAssendelftAMattsonKPyrhönenSAdjuvant chemotherapy after radical surgery for non-small-cell lung cancer: a randomized studyJ Clin Oncol19921012192719321333518

 PubMed Web of Science ®Google Scholar

FeldRRubinsteinLThomasPAAdjuvant chemotherapy with cyclophosphamide, doxorubicin, and cisplatin in patients with completely resected stage I non-small cell lung cancer. An LCSG TrialChest19941066 Suppl307S309S7988250

 PubMed Web of Science ®Google Scholar

WadaHMiyaharaRTanakaFHitomiSPostoperative adjuvant chemotherapy with PVM (Cisplatin + Vindesine + Mitomycin C) and UFT (Uracil + Tegaful) in resected stage I-II NSCLC (non-small cell lung cancer): a randomized clinical trial. West Japan Study Group for lung cancer surgery (WJSG)Eur J Cardiothorac Surg199915443844310371118

 PubMed Web of Science ®Google Scholar

MineoTCAmbrogiVCorsaroVRoselliMPostoperative adjuvant therapy for stage IB non-small-cell lung cancerEur J Cardiothorac Surg200120237838411463561

 PubMed Web of Science ®Google Scholar

EndoCSaitoYIwanamiHA randomized trial of postoperative UFT therapy in p stage I, II non-small cell lung cancer: North-east Japan Study Group for Lung Cancer SurgeryLung Cancer200340218118612711119

 PubMed Web of Science ®Google Scholar

KatoHIchinoseYOhtaMA randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lungN Engl J Med2004350171713172115102997

 PubMed Web of Science ®Google Scholar

ImaizumiMStudy Group of Adjuvant Chemotherapy for Lung Cancer (Chubu, Japan)Postoperative adjuvant cisplatin, vindesine, plus uracil-tegafur chemotherapy increased survival of patients with completely resected p-stage I non-small cell lung cancerLung Cancer2005491859415949594

 PubMed Web of Science ®Google Scholar

NakagawaMTanakaFTsubotaNA randomized phase III trial of adjuvant chemotherapy with UFT for completely resected pathological stage I non-small-cell lung cancer: the West Japan Study Group for Lung Cancer Surgery (WJSG) – the 4th studyAnn Oncol2005161758015598942

 PubMed Web of Science ®Google Scholar

ParkJHLeeCTLeeHWBaekHJZoJIShimYMPostoperative adjuvant chemotherapy for stage I non-small cell lung cancerEur J Cardiothorac Surg20052761086109115896623

 PubMed Web of Science ®Google Scholar

NakagawaKTadaHAkashiARandomised study of adjuvant chemotherapy for completely resected p-stage I-IIIA non-small cell lung cancerBr J Cancer200695781782116969350

 PubMed Web of Science ®Google Scholar

RoselliMMariottiSFerroniPPostsurgical chemotherapy in stage IB nonsmall cell lung cancer: Long-term survival in a randomized studyInt J Cancer2006119495596016550600

 PubMed Web of Science ®Google Scholar

StraussGMHerndonJE2ndMaddausMAAdjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study GroupsJ Clin Oncol200826315043505118809614

 PubMed Web of Science ®Google Scholar

FelipERosellRMaestreJAPreoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-small-cell lung cancerJ Clin Oncol201028193138314520516435

 PubMed Web of Science ®Google Scholar

ButtsCADingKSeymourLRandomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10J Clin Oncol2010281293419933915

 PubMed Web of Science ®Google Scholar

HottaKMatsuoKUeokaHKiuraKTabataMTanimotoMRole of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trialsJ Clin Oncol200422193860386715326194

 PubMed Web of Science ®Google Scholar

SedrakyanAVan Der MeulenJO’ByrneKPrendivilleJHillJTreasureTPostoperative chemotherapy for non-small cell lung cancer: a systematic review and meta-analysisJ Thorac Cardiovasc Surg2004128341441915354101

 PubMed Web of Science ®Google Scholar

BerghmansTPaesmansMMeertAPSurvival improvement in resectable non-small cell lung cancer with (neo)adjuvant chemotherapy: results of a meta-analysis of the literatureLung Cancer2005491132315949586

 PubMed Web of Science ®Google Scholar

HamadaCTanakaFOhtaMMeta-analysis of postoperative adjuvant chemotherapy with tegafur-uracil in non-small-cell lung cancerJ Clin Oncol200523224999500616051951

 PubMed Web of Science ®Google Scholar

PignonJPTribodetHScagliottiGVLung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative GroupJ Clin Oncol200826213552355918506026

 PubMed Web of Science ®Google Scholar

BriaEGrallaRJRaftopoulosHMagnitude of benefit of adjuvant chemotherapy for non-small cell lung cancer: meta-analysis of randomized clinical trialsLung Cancer2009631505718565615

 PubMed Web of Science ®Google Scholar

NSCLC Meta-analyses Collaborative GroupArriagadaRAuperinAAdjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient dataLancet201037597221267127720338627

 PubMed Web of Science ®Google Scholar