Combination chemotherapy of gemcitabine and vinorelbine for pretreated non-small-cell lung cancer: a retrospective study

Figures & data

Table 1 Patient characteristics (N=85)

Age, years
Mean ± SD	65.5±9.7
Sex
Male/female	56/29
Histology
Ad/Sq/others	54/23/8
Staging
III/IV/post-surgical recurrence	20/58/7
Distant metastases
Brain metastasis	25
Bone metastasis	15
Liver metastasis	13
Intra-pulmonary or pleural metastasis	38
ECOG performance status
0–1/2/3	53/24/8
EGFR mutation status
Positive/wild-type/not evaluated	9/42/34
Number of prior regimens
1/2/≥3	13/35/37
Median (range)	2 (1–6)
Prior anti-tumor drugs
Carboplatin	82a
Cisplatin	5a
Docetaxel	38
EGFR-TKI	38
Pemetrexed	26

Note:

a Two patients previously received both carboplatin- and cisplatin-containing regimens.

Abbreviations: Ad, adenocarcinoma; ECOG, European Clinical Oncology Group; SD, standard deviation; Sq, squamous cell carcinoma; TKI, tyrosine-kinase inhibitor.

Table 2 Treatment (N=85)

Number of delivered courses
1/2/3/4/≥5	20/20/12/16/17
Mean ± SD	3.1±1.9
Discontinuation reasons (N)
Progressive disease	56
Deteriorated conditions	13
Completion of 4–8 courses	9
Complicated diseases	3
Adverse effects	3
Lost to follow-up	1
Initial dose intensity (%), mean ± SD
Gemcitabine (1,000 mg/m^2)	80.9±14.0
Vinorelbine (25 mg/m^2)	80.7±15.2
Total dose intensity (%), mean ± SD
Gemcitabine	66.8±16.8
Vinorelbine	67.3±18.0

Abbreviation: SD, standard deviation.

Table 3 Post-protocol chemotherapy

Number of regimens
0/1/2/≥3	32/27/14/12
Median (range)	1 (0–10)
Anti-tumor drugs
EGFR-TKI	25
S-1	21
Docetaxel	13
CPT-11	13
Pemetrexed	7
Gemcitabine	4

Abbreviations: CPT-11, irinotecan; S-1, oral 5-fluorouracil derivative consisting tegafur, gimeracil and oteracil potassium; TKI, tyrosine-kinase inhibitor.

Figure 1 Kaplan–Meier curves (solid line) of all participants (N=85).

Notes: (A) Progression-free survival (PFS); and (B) overall survival (OS) of gemcitabine and vinorelbine treatment with 95% confidence band (dashed lines).
Abbreviation: CI, confidence interval.

Figure 2 Kaplan–Meier curves (solid line) of third- and further-line chemotherapy (N=72).

Notes: (A) Progression-free survival (PFS); and (B) overall survival (OS) of gemcitabine and vinorelbine treatment with 95% confidence band (dashed lines).
Abbreviation: CI, confidence interval.

Table 4 Efficacy (N=85)

Efficacy	All (N=85)	Third- or further-line (N=72)
Complete response (N)	0	0
Partial response (N)	4	4
Stable disease (N)	22	20
Progressive disease (N)	48	41
Not evaluated (N)	11	7
Overall response rate (95% CI) (%)	4.7 (1.3–11.6)	5.6 (1.5–13.6)
Disease control rate (95% CI) (%)	30.6 (21.0–41.5)	33.3 (22.7–45.4)

Abbreviation: CI, confidence interval.

Table 5 Adverse effects (N=85)

	Grade
	1	2	3	4
Hematological (N)
Leukopenia	13	20	23	8
Neutropenia	11	4	25	21
Hemoglobin decrease	22	41	17	0
Thrombocytopenia	21	24	11	0
Non-hematological (N)
Aminotransferase increase	40	5	2	0
Serum creatinine increase	6	0	0	0
Febrile neutropenia	0	0	6	0
Anorexia	38	13	11	0
Nausea or vomiting	16	7	0	0
Fatigue	20	11	1	0
Constipation	21	23	4	0
Diarrhea	12	1	0	0
Oral mucositis	6	4	0	0
Vasculitis	4	5	0	0
Rash	10	6	0	0
Fever	18	2	0	0

Table 6 Univariate and multivariate Cox proportional hazard analysis of factors influencing progression-free survival (N=85)

Risk factors	Univariate			Multivariate
	HR	95% CI	P	HR	95% CI	P
Age
≥70 years vs <70 years	0.76	0.47–1.21	0.24	0.70	0.43–1.13	0.15
Sex
Male vs female	1.19	0.75–1.89	0.47	0.90	0.52–1.54	0.69
ECOG PS
2–3 vs 0–1	1.63	1.28–2.08	<0.001	1.65	1.27–2.14	<0.001
Histology
A denocarcinoma vs others	0.66	0.42–1.04	0.07	0.74	0.42–1.30	0.29
Distant metastases
Yes vs no or not evaluated	1.07	0.66–1.73	0.80	1.34	0.76–2.38	0.31
Number of prior regimens
≥3 vs 1–2	0.74	0.48–1.16	0.19	0.76	0.46–1.27	0.30
Gemcitabine initial dose reduction rate (%)
≥80% vs <80%	1.07	0.69–1.67	0.76	0.95	0.60–1.50	0.81

Notes: Coded as 1 (≥70 years, male, ECOG PS 2–3, adenocarcinoma histology, positive distant metastases, ≥3 prior regimens, and initial gemcitabine dose of more than 80%) and as 0 (<70 years, female, ECOG PS 0–1, non-adenocarcinoma histology, 1–2 prior regimens and initial gemcitabine dose of less than 80%).

Abbreviations: CI, confidence interval; ECOG PS, European Clinical Oncology Group performance status; HR, hazard ratio.

Table 7 Review of prospective studies of combination chemotherapy of gemcitabine and vinorelbine for pretreated patients

Authors (year)	N	Phase	Line	Dose and schedule	RR DCR	PFS	OS
Camps et al (2000)^Citation15	16	Pilot	2nd	G 1,200 mg/m^2 (Day 1, 8, 15) V 25 mg/m^2 (Day 1, 8) Every 28 days, until PD	6.25% 37.5%	ND	25 W
Hainsworth et al (2000)^Citation18	55	II	2nd	G 1,000 mg/m^2 (Day 1, 8, 15) V 20 mg/m^2 (Day 1, 8) Every 28 days	18% 66%	5.0 Ma	6.5 M
Kosmas et al (2001)^Citation22	40	II	2nd	G 1,000 mg/m^2 (Day 1, 8) V 25 mg/m^2 (Day 1, 8) Every 21 days	22.5% 55%	4.5 M	7 M
Pectasides et al (2001)^Citation24	39	II	2nd	G 800 mg/m^2 (Day 1, 8) V 25 mg/m^2 (Day 1, 8) Every 21 days	2.6% 64.1%	4.7 M	7.3 M
Herbst et al (2002)^Citation20	36	II	2nd or 3rd	G 900–1,000 mg/m^2 (Day 1, 8) V 25–30 mg/m^2 (Day 1, 8) Every 21 days	17% 67%	4.6 M	8.5 M
Chen et al (2003)^Citation17	17	II	2nd	G 800 mg/m^2 (Day 1, 8, 15) V 20 mg/m^2 (Day 1, 8, 15) Every 28 days	31.3% 93.8%	4.6 M	8.3 M
Park et al (2004)^Citation23	38	II	2nd	G 1,000 mg/m^2 (Day 1, 8) V 30 mg/m^2 (Day 1, 8) Every 21 days	21% 76%	3.9 M	8.1 M
Ando et al (2005)^Citation14	20	I	3rd	G 600–1,000 mg/m^2 (Day 1, 8) V 20–25 mg/m^2 (Day 1, 8) Every 21 days	0% 74%	3.9 M	6.8 M
Juergens et al (2007)^Citation21	15	II	2nd	G 1,000 mg/m^2 (Day 1, 15) V 30 mg/m^2 (Day 1, 15) Every 28 days, 6 cycles	0% 73%	4.2 M	9.2 M
Han et al (2008)^Citation19	40	Ran II	2nd	G 900 mg/m^2 (Day 1, 8) V 25 mg/m^2 (Day 1, 8) Every 21 days, until PD	13% 45%	2.6 M	ND
Chelis et al (2010)^Citation16	14	II	2nd or further-line setting	G 1,200 mg/m^2 (Day 1, 15) V 30 mg/m^2 (Day 1, 15) Every 28 days, 6 cycles	0% 27%	3 M	4 M
Our study	85	Retro	2nd or further-line setting	G 1,000 mg/m^2 (Day 1, 8) V 25 mg/m^2 (Day 1, 8) Every 21 days	4.7% 30.6%	2.1 M	6.9 M

Note:

a PFS of patients with stable disease ∼ complete remission.

Abbreviations: DCR, disease control rate; G, gemcitabine; M, months; ND, not described; OS, overall survival; PD, progressive disease; PFS, progression-free survival; Ran, randomized; Retro, retrospective; RR, response rate; V, vinorelbine; W, weeks.

Table 8 Review of prospective studies comparing combination chemotherapy of gemcitabine and vinorelbine with platinum-based regimens

Authors (year)	Phase	Line	N	Regimens	RR	PFS	OS
Gridelli et al (2003)^Citation10	III	1st	251	GV	25%	17 W	32 W
			250	CDDP + G or V	30%	23 W	38 W
				(Age <70 years)	P=0.30	P=0.004	P=0.08
Laack et al (2004)^Citation28	III	1st	143	GV	13.0%	19.3 W	35.9 W
			144	CDDP + GV	28.3%	22.3 W	32.4 W
					P=0.004	P=0.35	P=0.73
Chen et al (2005)^Citation25	Ran II	1st	43	GV	23.3%	4.1 M	9.5 M
			43	CDDP + GV	46.5%	7.8 M	13.1 M
					P=0.022	P=0.206	P=0.375
Esteban et al (2006)^Citation26	Ran II	1st	57	GV	37%	5.0 M	9 M
			57	CDDP + GV	47%	5.8 M	10 M
					P=0.5	P=0.6	P=0.9
Yamamoto et al (2006)^Citation30	Ran II	1st	64	GV	21.0%	137 D	385 D
			64	CBDCA + G	20.3%	165 D	432 D
					P=0.60	P=0.676	P=0.298
Greco et al (2007)^Citation27	II/III	1st	170	GV	24%	3.9 M	10.7 M
			167	CBDCA + G + PTX	25%	6.0 M	10.3 M
					P=ND	P=0.324	P=0.269
Han et al (2008)^Citation19	Ran II	1st	70	GV	26%	4.6 M	13.1 M
			75	CDDP + CPT-11	38%	3.8 M	15.9 M
					P=0.144	P=0.415	P=0.285
Flotten et al (2012)^Citation9	III	1st	215	GV	ND	ND	6.3 M
			222	CBDCA + V			7.0 M
							P=0.802
Saito et al (2012)^Citation29	Ran II	1st	43	GV	20.9%	2.7 M	6.0 M
			41	CBDCA + PTX	29.3%	2.9 M	5.9 M
				(ECOG PS 2)	P=ND	P=ND	P=ND

Abbreviations: CBDCA, carboplatin; CDDP, cisplatin; CPT-11, irinotecan; D, days; ECOG PS, European Clinical Oncology Group performance status; G, gemcitabine; M, months; ND, not described; OS, overall survival; PFS, progression-free survival; PTX, paclitaxel; Ran, randomized; RR, response rate; V, vinorelbine; W, weeks.

CampsCMartinezENJaimeABSecond-line treatment with gemcitabine and vinorelbine in non-small-cell lung cancer (NSCLC) cisplatin failures: a pilot studyLung Cancer2000271475310672783

 PubMed Web of Science ®Google Scholar

HainsworthJDBurrisHA3rdLitchySGemcitabine and vinorelbine in the second-line treatment of nonsmall cell lung carcinoma patients: a minnie pearl cancer research network phase II trialCancer20008861353135810717616

 PubMed Web of Science ®Google Scholar

KosmasCTsavarisNPanopoulosCGemcitabine and vinorelbine as second-line therapy in non-small-cell lung cancer after prior treatment with taxane+platinum-based regimensEur J Cancer200137897297811334721

 PubMed Web of Science ®Google Scholar

PectasidesDKalofonosHPSamantasEAn out-patient second-line chemotherapy with gemcitabine and vinorelbine in patients with non-small cell lung cancer previously treated with cisplatin-based chemotherapy. A phase II study of the Hellenic co-operative Oncology GroupAnticancer Res2001214B3005301011712802

 PubMed Web of Science ®Google Scholar

HerbstRSKhuriFRLuCThe novel and effective nonplatinum, nontaxane combination of gemcitabine and vinorelbine in advanced nonsmall cell lung carcinoma: potential for decreased toxicity and combination with biological therapyCancer200295234035312124835

 PubMed Web of Science ®Google Scholar

ChenYMPerngRPLeeCSLinWCTsaiCMWhang-PengJPhase II study of gemcitabine and vinorelbine combination chemotherapy in patients with non-small-cell lung cancer not responding to previous chemotherapyAm J Clin Oncol200326656757014663373

 PubMed Web of Science ®Google Scholar

ParkYHLeeJCKimCHRyooBYKimHTGemcitabine and vinorelbine as second-line therapy for non-small cell lung cancer after treatment with paclitaxel plus platinumJpn J Clin Oncol200434524524915231858

 PubMed Web of Science ®Google Scholar

AndoSSuzukiMIidaTNakajimaTKimuraHPhase I study of vinorelbine plus gemcitabine as third-line chemotherapy for refractory non-small cell lung cancerOncol Rep200514368969416077976

 PubMed Web of Science ®Google Scholar

JuergensRBrahmerJEttingerDGemcitabine and vinorelbine in recurrent advanced non-small cell lung cancer: sequence does matterCancer Chemother Pharmacol200759562162916937106

 PubMed Web of Science ®Google Scholar

HanJYLeeDHSongJERandomized phase 2 study of irinotecan plus cisplatin versus gemcitabine plus vinorelbine as first-line chemotherapy with second-line crossover in patients with advanced nonsmall cell lung cancerCancer2008113238839518484595

 PubMed Web of Science ®Google Scholar

ChelisLXenidisNAmarantidisKBiweekly vinorelbine and gemcitabine as second-line treatment and beyond in non-small cell lung cancerChemotherapy201056535335820926858

 PubMed Web of Science ®Google Scholar

GridelliCGalloCShepherdFAGemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials GroupJ Clin Oncol200321163025303412837810

 PubMed Web of Science ®Google Scholar

LaackEDickgreberNMullerTRandomized phase III study of gemcitabine and vinorelbine versus gemcitabine, vinorelbine, and cisplatin in the treatment of advanced non-small-cell lung cancer: from the German and Swiss Lung Cancer Study GroupJ Clin Oncol200422122348235615197195

 PubMed Web of Science ®Google Scholar

ChenYMPerngRPShihJFTsaiCMWhang-PengJA randomized phase II study of vinorelbine plus gemcitabine with/without cisplatin against inoperable non-small-cell lung cancer previously untreatedLung Cancer200547337338015713520

 PubMed Web of Science ®Google Scholar

EstebanEFraJFernandezYGemcitabine and vinorelbine (GV) versus cisplatin, gemcitabine and vinorelbine (CGV) as first-line treatment in advanced non small cell lung cancer: results of a prospective randomized phase II studyInvest New Drugs200624324124816096704

 PubMed Web of Science ®Google Scholar

YamamotoNNakagawaKUejimaHRandomized phase II study of carboplatin/gemcitabine versus vinorelbine/gemcitabine in patients with advanced nonsmall cell lung cancer: West Japan Thoracic Oncology Group (WJTOG) 0104Cancer2006107359960516804877

 PubMed Web of Science ®Google Scholar

GrecoFASpigelDRKuzurMEPaclitaxel/Carboplatin/gemcitabine versus gemcitabine/vinorelbine in advanced non-small-cell lung cancer: a phase II/III study of the Minnie Pearl Cancer Research NetworkClin Lung Cancer20078848348717922972

 PubMed Web of Science ®Google Scholar

FlottenOGronbergBHBremnesRVinorelbine and gemcitabine vs vinorelbine and carboplatin as first-line treatment of advanced NSCLC. A phase III randomised controlled trial by the Norwegian Lung Cancer Study GroupBr J Cancer2012107344244722759880

 PubMed Web of Science ®Google Scholar

SaitoHNakagawaKTakedaKRandomized phase II study of carboplatin-paclitaxel or gemcitabine-vinorelbine in patients with advanced nonsmall cell lung cancer and a performance status of 2: West Japan Thoracic Oncology Group 0004Am J Clin Oncol2012351586321293243

 PubMed Web of Science ®Google Scholar