Prolonged low-dose infusion for gemcitabine: a systematic review

Figures & data

Table 1 Characteristics of eligible trials

Trial	Study design	Patients	Male/female	Age	Tumor type	Chemotherapy regimens	Endpoints assessed	MINORS Score
Beniwal SK, 2012^Citation10	RCT	30	26/4	53.3 (35~65)	NSCLC	GEM (1,000 mg/m^2 in 30 min d1, d8)+ CBP(AUC 5 d1)	ORR SDR PDR PFS OS 1-YSR	N/A
		30	28/2	54.5 (40~70)		GEM (350 mg/m^2 in 6 h d1, d8) +CBP (AUC 5 d1)
Vrankar M 2014^Citation11	RCT	52	39/13	58 (42~72)	NSCLC	GEM (1250 mg/m^2 in 30 min d1, d8)+ DDP (75 mg/m^2 d2)	PFS OS 1-YSR ORR	N/A
		54	44/10	57 (30~77)		GEM (250 mg/m^2 in 6 h d1, d8) + DDP (75 mg/m^2 d2)
Zwitter M 2009^Citation12	RCT	125	95/30	58 (41~77)	NSCLC	GEM (1250 mg/m^2 in 30 min d1, d8) + DDP (75 mg/m^2 d2)	CRR PRR SDR PDR 1-YSR OS ORR PFS	N/A
		124	93/31	59 (40~79)		GEM (250 mg/m^2 in 6 h d1, d8) + DDP (75 mg/m^2 d2)
Zwitter M, 2010^Citation13	RCT	57	46/11	66 (41–8)	NSCLC	GEM (1250 mg/m^2 in 30 min d1, d8) +DDP (60 mg/m^2 d2)	PFS CRR PRR OS ORR 1-YSR	N/A
		55	37/18	65 (49–80)		GEM (200 mg/m^2 in 6 h d1, d8) +DDP (60 mg/m^2 d2)
Wu ZY 2014^Citation14	Non-RCT	37	28/9	58 (40–79)	NSCLC	Gem (250 mg/m^2 in 6 h d1, d8) + CBP (AUC 5 d1)	PFS ORR OS SDR	10
Narayanan P 2009^Citation15	Non-RCT	75	60/15	65(60–79)	NSCLC	Gem (350 mg/m^2 in 4 h d1, d8) + CBP (AUC 5 d1)	OS 1-YSR CRR PRR PDR ORR	8
Xiong J P 2008^Citation16	Non-RCT	58	39/19	61 (28–73)	NSCLC	Gem (250 mg/m^2 in 6 h d1, d8) + DDP (75 mg/m^2 d2)	ORR CRR PFS OS 1-YSR	11
Zwitter M 2005^Citation17	Non-RCT	32	22/10	58 (31–76)	NSCLC	Gem (250 mg/m^2 in 6 h d1, d8) + DDP (75 mg/m^2 d2)	ORR CRR PRR PFS OS 1-YSR	9
Kovac V 2012^Citation18	Non-RCT	78	58/20	58 (33–82)	MPM	Gem (250 mg/m^2 in 6 h d1, d8) + DDP (75 mg/m^2 d2)	CRR PRR SDR PDR PFS OS 1/2/3-YSR	11
Arrieta O 2014^Citation19	Non-RCT	39	26/13	59.7 (33–84)	MPM	Gem (250 mg/m^2 in 6 h d1, d8) + DDP (35 mg/m^2 d1, d8)	CRR PRR SDR PDR PFS OS	9
Khaled H 2008^Citation20	Non-RCT	57	41/16	55 (37–77)	Bladder cancer	Gem (250 mg/m^2 in 6 h d1, d8) + DDP (70 mg/m^2 d2)	CRR PRR PDR ORR PFS OS 1-YSR	10
Khaled H 2014^Citation21	RCT	60	48/12	62 (40–80)	Bladder cancer	Gem (1250 mg/m^2 in 30 min d1, d8)+DDP (70 mg/m^2 d2)	CRR PRR SDR PDR ORR PFS OS 1-YSR	N/A
		60	44/16	60 (40–85)		Gem (250 mg/m^2 in 6 h d1, d8) + DDP (70 mg/m^2 d2)
Guan HH 2014^Citation22	Non-RCT	26	12/14	55 (46–71)	NPC	Gem (250 mg/m^2 in 6 h d1, d8) + NDP (80 mg/m^2 d1)	CRR PRR SDR PDR ORR PFS 1-YSR	8
Eckel F 2003^Citation23	Non-RCT	18	9/9	68 (51–81)	PC	Gem (100 mg/m^2 in 24 h d1, d8, d15)	PRR ORR PFS	6
Von DS 2005^Citation24	Non-RCT	19	8/11	63 (30–83)	GBC	Gem (100 mg/m^2 in 24 h d1, d8, d15)	PRR SDR PFS OS 1-YSR	7
Schmid P 2005^Citation25	Non-RCT	44	0/44	45 (24–64)	Breast cancer	NPLD (60 mg/m^2 d1)+ DXT(60 mg/m^2 d1)+Gem (350 mg/m^2 in 4 h d4).	pCRR	9
Schmid P 1999^Citation26	Non-RCT	20	0/20	50.4 (35–63)	Breast cancer	Gem (250 mg/m^2 in 6 h d1, d8, d15)	CRR PRR ORR SDR PFS OS	8
Schmid P 2005^Citation27	Non-RCT	26	0/26	58.3 (32–75)	Breast cancer	Gem (350 mg/m^2 in 4 h d1, d8)+NVB (25 mg/m^2 d1, d8)	PRR ORR PFS OS	7
Spath SE 2000^Citation28	Non-RCT	18	10/8	58 (20–70)	STS	Gem (200 or 250 mg/m^2 in 6 h d1, d8, d15)	PRR SDR PFS 1-YSR	8

Abbreviations: ORR, overall response rate; SDR, stable disease rate; PDR, progressive disease rate; PRR, partial remission rate; CRR, complete remission rate; pCRR, pathologic complete response rate; CBP, carboplatin; DDP, cisplatin; NDP, nedaplatin; NPLD, non-pegylated; liposomal doxorubicin; DXT, docetaxel; MPM, malignant pleural mesothelioma; NPC, nasopharyngeal carcinoma; PC, pancreatic carcinoma; GBC, gallbladder and biliary tract carcinoma; STS, soft tissue sarcomas; RCT, randomized controlled trials.

Figure 1 Flowchart of included and excluded trials.

Table 2 Quality evaluation of included RCTs

Included trials	Sequence generation	Allocation concealment	Blinding	Incomplete data	Selective reporting	Other sources of bias
Beniwal SK, 2012^Citation10	Unclear	Unclear	Unclear	No	Unclear	Unclear
Vrankar M, 2014^Citation11	Unclear	Unclear	Unclear	Yes	Unclear	Unclear
Zwitter M, 2009^Citation12	Computer-generated sequence of random numbers	Unclear	Single- blind	Yes	Unclear	Unclear
Zwitter M, 2010^Citation13	Computer-generated sequence of random numbers	Unclear	Single- blind	Yes	Unclear	Unclear
Khaled H 2014^Citation21	Unclear	Unclear	Unclear	No	Unclear	Unclear

Abbreviation: RCTs, randomized controlled trials.

Table 3 Clinical application of Gem given in P-LDI

Trials	Tumor types	patients	Administration of GEM P-LDI or 30-min SDI	outcomes				Conclusions
				PFS month	OS month	ORR %	1-YSR %
Beniwal SK 2012^Citation10	NSCLC	30	30-min SDI	5.5	9.7	40	33.7	P-LDI has an equal activity and low toxicity compared with 30-min SDI.
		30	P-LDI	5.4	10.7	36.6	36.6
Vrankar M 2014^Citation11	NSCLC	52	30-min SDI	15.7	24.8	61.5	73.1	A trend towards better efficacy of treatment with P-LDI, but no statistical significance difference. Both schedules had a comparable toxicity profile.
		54	P-LDI	18.9	28.6	61.1	81.5
Zwitter M 2009^Citation12	NSCLC	125	30-min SDI	5.5	10.1	32.8	46.6	P-LDI has an equal activity and low toxicity compared with 30-min SDI.
		124	P-LDI	6.0	10.0	46.8	41.1
Zwitter M 2010^Citation13	NSCLC	57	30-min SDI	3.8	4.3	8.8	8.8	P-LDI has very low toxicity and better efficacy compared with 30-min SDI.
		55	P-LDI	5.6	6.8	25.5	25.5
Wu ZY 2014^Citation14	NSCLC	37	P-LDI	7.0	14.0	62.2	N/A	Gem in P-LDI combined with CBP was efficacious in patients with well tolerated toxicity profiles.
Narayanan P 2009^Citation15	NSCLC	75	P-LDI	N/A	11	25.3	40	Gem in P-LDI combined with CBP was effective in advanced NSCLC, and its toxicity was very favorable.
Xiong J P 2008^Citation16	NSCLC	58	P-LDI	5.5	10.5	39.3	41.4	Gem in P-LDI plus DDP was effective in NSCLC treatment. Toxicity, especially myelosuppression, was remarkably mild.
Zwitter M 2005^Citation17	NSCLC	32	P-LDI	6	9.5	43.8	40	treatment with Gem in P-LDI plus DDP was feasible.
Kovac V 2012^Citation18	MPM	78	P-LDI	8	17	50	67.3	Gem in P-LDI plus DDP may be considered for the primary treatment of MPM, especially in economically deprived populations.
Arrieta O 2014^Citation19	MPM	39	P-LDI	6.9	20.7	53.8	N/A	Gem in P-LDI plus DDP showed acceptable toxicity and high efficacy with improvement in the quality of life, representing an affordable regimen for the low-income population.
Khaled H 2008^Citation20	Bladder cancer	57	P-LDI	7.2	11.5	59.4	28	Gem in P-LDI plus DDP was an effective treatment for advanced bladder cancer.Toxicity, especially myelosuppression, was surprisingly mild.
Khaled H 2014^Citation21	Bladder cancer	60	30-min SDI	24	16	33.3	54.7	Gem in P-LDI plus DDP was not inferior to the standard GC regimen with a favorable toxicity profile and less financial costs.
		60	P-LDI	26	12	41.7	49.9
Guan HH 2014^Citation22	NPC	26	P-LDI	7	N/A	80.8	58	Gem in P-LDI plus nedaplatin was effective for nasopharyngeal carcinoma and yielded relatively mild toxicities.
Eckel F 2003^Citation23	PC	18	P-LDI	4.4	N/A	16.7	N/A	Gem in P-LDI seems to be as active as the 30 min-SDI. Relatively long PFS and improvement of symptom and quality of life scores.
Von DS 2005^Citation24	GBC	19	P-LDI	3.6	7.5	6	34	24 hr Gem at a dose of 100 mg/m^2 was well tolerated, relatively high rate of disease control.
Schmid P 2005^Citation25	Breast cancer	44	P-LDI	N/A	N/A	80	N/A	The evaluated schedule provides a safe and highly effective combination treatment for patients with early breast cancer.
Schmid P 1999^Citation26	Breast cancer	20	P-LDI	6.3	51.9	25	N/A	Gem in P-LDI plus vinorelbine was an effective treatment in metastatic breast cancer.
Schmid P 2005^Citation27	Breast cancer	26	P-LDI	4.6	14.5	30.4	N/A	Gem in P-LDI plus vinorelbine was a safe and effective treatment in anthracycline and/or taxane pretreated patients.
Späth SE 2000^Citation28	STS	18	P-LDI	N/A	8	11	28	Gem in P-LDI has a favorable toxicity profile and displays antitumor activity in patients with pretreated advanced soft tissue sarcomas.

Abbreviations: N/A, unknown or not measured; MPM, malignant pleural mesothelioma; NPC, nasopharyngeal carcinoma; PC, Pancreatic carcinoma; GBC, gallbladder and biliary tract carcinoma; STS, Soft tissue sarcomas.

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