Efficacy and safety of gemcitabine plus erlotinib for locally advanced or metastatic pancreatic cancer: a systematic review and meta-analysis

Figures & data

Table 1 Baseline characteristics of included studies for meta-analysis

Study	Study design	Patients, n	Male, n	Median age (range)	Performance status	Initially status, n	Line	Criteria for response	Criteria for AEs	Treatment regimen
Dragovich et al^Citation17	Phase IB trial	15	NA	63 (29–82)	KPS ≥80	Locally advanced, 5; metastatic, 10	NA	RECIST	NCI CTC	Gem 1,000 mg/m^2, weekly for 1st cycle (7 weeks), then weekly ×3 every 4 weeks + Erlo 100 or 150 mg/d
Moore et al^Citation16	Phase III RCT	285	136	63.7 (37.9–84.4)	ECOG 0–2	Locally advanced, 67; metastatic, 218	1st	RECIST	NCI CTC	Gem 1,000 mg/m^2, weekly ×7 weeks for 8 weeks, then weekly ×3 every 4 weeks + Erlo 100 or 150 mg/d
Ardavanis et al^Citation18	Single-arm, Phase II trial	27	16	63 (47–74)	ECOG 0–2	NA	NA	RECIST	NCI CTC	Gem 2,000 mg/m^2, in 2-week cycles + Erlo150 mg/d
Bengala et al^Citation19	Single-arm, Phase I/II trial	20	NA	64 (50–79)	NA	NA	NA	NA	NA	Gem 1,500–2,500 mg/m^2, 10 mg/m^2/min weekly ×2 every 4 weeks + Erlo 100 mg/d
Van Cutsem et al^Citation20	Phase III RCT	301	188	61 (33–85)	KPS ≥60	NA	1st	RECIST	NCI CTC	Gem 1,000 mg/m^2, weekly ×7 weeks for 8 weeks, then weekly ×3 every 4 weeks + Erlo 100 mg/d
Cheng et al^Citation21	Retrospective	20	12	65 (36–77)	KPS ≥60	Locally advanced, 5; metastatic, 15	1st	RECIST	NCI CTC	Gem 1,000 mg/m^2, weekly ×2 every 3 weeks; Erlo 100–150 mg/d
Milella et al^Citation22	Single-arm, Phase II trial	46	25	64 (35–81)	NA	NA	1st	RECIST	NA	Gem 1,000 mg/m^2, 10 mg/m^2/min weekly + Erlo 150 mg/d
Okusaka et al^Citation23	Single-arm, Phase II trial	106	56	62 (36–78)	ECOG 0–2	Locally advanced, 18; metastatic, 88	1st	RECIST	NCI CTC	Gem 1,000 mg/m^2, weekly ×3 every 4 weeks + Erlo 100 mg/d on days 3–28
Boeck et al^Citation24	Phase III RCT	67	38	63 (38–75)	KPS ≥60	Locally advanced, 12; metastatic, 55	1st	RECIST	NCI CTC	Gem 1,000 mg/m^2, weekly ×7 weeks for 8 weeks, then weekly ×3 every 4 weeks + Erlo 150 mg/d
Stuebs et al^Citation25	Retrospective	26	NA	NA	NA	NA	1st	NA	NCI CTC	Gem 1,000 mg/m^2 + Erlo 100 mg/d
Kim et al^Citation26	Phase II RCT	46	30	61	ECOG 0–1	NA	1st	NA	NA	Gem 1,000 mg/m^2, weekly ×4 every 4 weeks + Erlo 100 mg/d
Feliu et al^Citation27	Single-arm, Phase II trial	42	22	62 (47–79)	ECOG 0–2	Locally advanced, 6; metastatic, 38	1st	RECIST	NCI CTC	Gem 1,200 mg/m^2, 120 minutes, weekly ×3 every 4 weeks + Erlo 100 mg/d
Llarena et al^Citation28	Single-arm, Phase II trial	62	36	63 (37–78)	ECOG 0–2	Locally advanced, 16; metastatic, 46	1st	NA	NA	Gem 1,500 mg/m^2, weekly ×3 every 4 weeks + Erlo 100 mg/d
Aranda et al^Citation29	Single-arm, Phase II trial	153	82	64 (54–72)	KPS ≥60	Locally advanced, 28; metastatic, 125	1st	RECIST	NCI CTC	Gem 1,000 mg/m^2, weekly ×3 every 4 weeks + Erlo 100 mg/d
Jeon et al^Citation30	Retrospective	34	20	59.5 (35–73)	ECOG 0–2	Locally advanced, 3; metastatic, 27 Recurrent, 4	1st	RECIST	NCI CTC	Gem 1,000 mg/m^2, weekly ×3 every 4 weeks + Erlo 100 mg/d
Modiano et al^Citation31	Phase II RCT	39	NA	NA	NA	NA	NA	NA	NA	Gem 1,000 mg/m^2, weekly ×3 every 4 weeks + Erlo 100 mg/d
Park et al^Citation32	Single-arm, Phase II trial	69	50	62 (31–83)	ECOG 0–3	Locally advanced, 6; metastatic, 63	1st	RECIST	WHO	Gem 1,000 mg/m^2, weekly ×2 every 3 weeks + Erlo 100 mg/d
Van Cutsem et al^Citation33	Phase II RCT	75	34	63 (41–84)	ECOG 0–1	NA	1st	RECIST	NCI CTC	Gem 1,000 mg/m^2, weekly ×3 every 4 weeks + Erlo 100 mg/d
Lim et al^Citation34	Retrospective	44	25	63 (32–78)	ECOG 0–2	Locally advanced, 11; metastatic, 26; Recurrent, 7	1st	RECIST	NCI CTC	Gem 1,000 mg/m^2, weekly ×2 every 3 weeks + Erlo 100 mg/d
Wilmink et al^Citation35	Phase II RCT	61	27	63.9 (44.5–79.5)	WHO 0–2	Locally advanced, 16; metastatic, 45	1st and 2nd	NA	NA	Gem 1,000 mg/m^2, weekly ×3 every 4 weeks + Erlo 100 mg/d
Philip et al^Citation36	Phase II RCT	59	35	64	ECOG 0–2	NA	1st	NA	NCI CTC	Gem 1,000 mg/m^2, weekly ×3 every 4 weeks + Erlo 100 mg/d
Diaz Beveridge et al^Citation37	Retrospective	55	32	62 (43–80)	ECOG 0–2	Locally advanced, 22; metastatic, 33	1st	RECIST	NCI CTC	Gem 1,000 mg/m^2, weekly ×7 weeks for 8 weeks, then weekly ×3 every 4 weeks + Erlo 100 mg/d
Semrad et al^Citation38	Single-arm, Phase II trial	30	15	67 (46–84)	ECOG 0–2	Locally advanced, 4; metastatic, 26	1st	RECIST	NCI CTC	Gem 1,000 mg/m^2, weekly ×3 every 4 weeks + Erlo 150 mg/d on days 2–5, 9–12, and 16–26
Benavides et al^Citation39	Phase IIb RCT	60	34	64 (29–78)	ECOG 0–2	NA	1st	NA	NA	Gem 1,000 mg/m^2, weekly ×3 every 4 weeks + Erlo 100 mg/d

Abbreviations: RCT, randomized controlled trial; NA, not available; KPS, Karnofsky performance score; ECOG, Eastern Cooperative Oncology Group; WHO, World Health Organization; RECIST, Response Evaluation Criteria in Solid Tumors; NCI CTC, National Cancer Institute Common Terminology Criteria; Gem, gemcitabine; Erlo, erlotinib; AEs, adverse events; d, day.

Figure 1 Eligibility of studies for inclusion in the meta-analysis.

Table 2 Results of subgroup analysis for ORR and DCR

Subgroups	Studies (n)	Weighted estimates (95% CI)	Heterogeneity test
ORR
Dosage of gemcitabine
1,000 mg/m^2	17	13.3 (10.7–16.4)	I^2=32.6%, P=0.013
>1,000 mg/m^2	3	21.6 (12.8–34.0)	I^2=34.2%, P=0.111
Dosage of erlotinib
100 mg/d	14	15.3 (12.1–19.2)	I^2=35.8%, P=0.006
100–150 mg/d	3	8.2 (5.6–11.8)	I^2=0%, P=0.396
150 mg/d	3	15.1 (7.7–27.6)	I^2=30.6%, P=0.143
Sample size
Large studies	3	9.0 (7.1–11.3)	I^2=0%, P=0.363
Small studies	17	16.8 (13.8–20.2)	I^2=18.8%, P=0.157
DCR
Dosage of gemcitabine
1,000 mg/m^2	15	55.2 (52.2–58.2)	I^2=8.7%, P=0.257
>1,000 mg/m^2	4	53.7 (37.8–68.9)	I^2=41.3%, P=0.017
Dosage of erlotinib
100 mg/d	13	54.2 (49.8–58.6)	I^2=28.8%, P=0.060
100–150 mg/d	3	59.8 (48.0–70.5)	I^2=23.1%, P=0.193
150 mg/d	3	53.4 (43.7–62.9)	I^2=0%, P=0.294
Sample size
Large studies	3	57.0 (53.4–60.5)	I^2=0%, P=0.340
Small studies	7	53.9 (49.0–58.8)	I^2=26.6%, P=0.069

Abbreviations: ORR, objective response rate; DCR, disease control rate; CI, confidence interval; d, day.

Figure 2 Forest plot of meta-analysis on ORR.

Notes: ^aExcluded three patients with immeasurable lesions from 15 patients; ^bexcluded 42 patients with immeasurable lesions from 106 patients. The gray squares indicate the ORR of each study; the red square indicates the pooled overall ORR of all the studies; the transverse line indicates the 95% CI.
Abbreviations: CI, confidence interval; ORR, objective response rate.

Figure 3 Forest plot of meta-analysis on DCR.

Notes: ^aExcluded three patients with immeasurable lesions from 15 patients; ^bexcluded 42 patients with immeasurable lesions from 106 patients. The gray squares indicate the DCR of each study; the red square indicates the pooled overall DCR of all the studies; the transverse line indicates the 95% CI.
Abbreviations: CI, confidence interval; DCR, disease control rate.

Figure 4 Forest plot of meta-analysis on 1-year survival rate.

Notes: The gray squares indicate the 1-year survival rate of each study; the red square indicates the pooled overall 1-year survival rate of all the studies; the transverse line indicates the 95% CI.
Abbreviation: CI, confidence interval.

Table 3 AEs on GemErlo treatment for advanced pancreatic cancer

Type	Studies (n)	Grade 1/2 % (n/N)*	Grade 3/4 % (n/N)*	Total % (n/N)*
Treatment-related deaths	7	Not available	Not available	3.0 (29/976)
Hematologic
Anemia	18	31.6 (332/1,049)	7.1 (89/1,245)	32.6 (421/1,291)
Leukocytopenia	7	38.0 (86/226)	27.4 (62/226)	61.4 (148/241)
Neutropenia	17	8.0 (82/1,020)	13.9 (159/1,147)	27.8 (356/1,282)
Thrombocytopenia	19	25.9 (277/1,069)	5.2 (63/1,216)	25.9 (343/1,326)
Gastrointestinal
Anorexia	5	18.8 (124/659)	3.6 (24/659)	22.4 (148/659)
Diarrhea	18	25.1 (293/1,167)	3.3 (44/1,328)	34.2 (340/1,404)
Nausea/vomiting	15	43.3 (402/927)	4.2 (40/953)	43.1 (443/1,029)
Stomatitis	7	16.0 (118/737)	0.8 (6/737)	16.8 (124/737)
Hepatic injury	7	47.0 (71/151)	8.4 (20/237)	36.1 (91/252)
Rash	18	34.3 (443/1,292)	3.9 (55/1,388)	34.3 (504/1,469)
Other
Asthenia/fatigue	13	27.7 (295/1,065)	6.4 (77/1,200)	29.3 (374/1,276)
Fever	3	18.7 (81/434)	0.5 (2/434)	19.2 (83/434)
Infection	5	12.4 (61/492)	9.7 (48/492)	25.2 (109/492)
Interstitial lung disease	3	3.5 (23/655)	0.4 (3/655)	3.9 (26/655)

Note:

* n/N indicates number of patients who experienced that particular AE/total number of patients in the studies that presented the particular AE.

Abbreviations: AEs, adverse events; GemErlo, gemcitabine plus erlotinib.

Figure 5 (A) Funnel plot of meta-analysis on ORR. (B) Funnel plot of meta-analysis on DCR.

Abbreviations: ORR, objective response rate; DCR, disease control rate.

DragovichTHubermanMVon HoffDDErlotinib plus gemcitabine in patients with unresectable pancreatic cancer and other solid tumors: phase IB trialCancer Chemoth Pharm200760295303

 PubMed Web of Science ®Google Scholar

MooreMJGoldsteinDHammJErlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials GroupJ Clin Oncol2007251960196617452677

 PubMed Web of Science ®Google Scholar

ArdavanisAKountourakisPKaragiannisADoufexisDTzovarasAARigatosGBiweekly gemcitabine (GEM) in combination with erlotinib (ERL): an active and convenient regimen for advanced pancreatic cancerAnticancer Res2009295211521720044638

 PubMed Web of Science ®Google Scholar

BengalaCSternieriRMalavasiNPhase II trial of erlotinib in combination with increasing dose of gemcitabine given as fixed dose rate infusion in advanced pancreatic cancer (advanced pancreatic cancer)2009ASCO Gastrointestinal Cancers Symposium [abstract number: 156] Available from: http://meetinglibrary.asco.org/content/10332-63Accessed January 28, 2009

 Google Scholar

Van CutsemEVervenneWLBennounaJPhase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancerJ Clin Oncol2009272231223719307500

 PubMed Web of Science ®Google Scholar

ChengYJBaiCMZhangZJEfficacy of gemcitabine combined with erlotinib in patients with advanced pancreatic cancerZhongguo Yi Xue Ke Xue Yuan Xue Bao20103242142320868602

 PubMedGoogle Scholar

MilellaMVaccaroVSperdutiIPhase II study of erlotinib (E) combined with fixed dose-rate gemcitabine (FDR-Gem) as first-line treatment for advanced adenocarcinoma of the pancreas (PDAC)2010ASCO Annual Meeting [abstract number: e14565] Available from: http://meetinglibrary.asco.org/content/51951-74Accessed June 4, 2010

 Google Scholar

OkusakaTFuruseJFunakoshiAPhase II study of erlotinib plus gemcitabine in Japanese patients with unresectable pancreatic cancerCancer Sci201110242543121175992

 PubMed Web of Science ®Google Scholar

BoeckSVehling-KaiserUWaldschmidtDErlotinib 150 mg daily plus chemotherapy in advanced pancreatic cancer: an interim safety analysis of a multicenter, randomized, cross-over phase III trial of the “Arbeitsgemeinschaft Internistische Onkologie.”Anticancer Drugs2010219410019770635

 PubMed Web of Science ®Google Scholar

StuebsPHabermannPZierauKFirst-line therapy for advanced pancreatic cancer with gemcitabine and docetaxel versus gemcitabine and erlotinib: a multivariate matched pair analysis2010ASCO Annual Meeting [abstract number: e14572] Available from: http://meetinglibrary.asco.org/content/52331-74Accessed: June 4 2010

 Google Scholar

KimGPFosterNRSalimMRandomized phase II trial of panitumumab (P), erlotinib (E), and gemcitabine (G) versus erlotinib-gemcitabine in patients with untreated, metastatic pancreatic adenocarcinoma2011ASCO Gastrointestinal Cancers Symposium [abstract number: 238] Available from: http://meetinglibrary.asco.org/content/71370-103Accessed January 20, 2011

 Google Scholar

FeliuJBorregaPLeónAPhase II study of a fixed dose-rate infusion of gemcitabine associated with erlotinib in advanced pancreatic cancerCancer Chemother Pharmacol20116721522120927525

 PubMed Web of Science ®Google Scholar

LlarenaMAManeJLopez-VivancoGGemcitabine (G) fixed-dose-rate infusion (FDR) plus erlotinib (E) in patients with advanced pancreatic cancer (advanced pancreatic cancer)2011ASCO Gastrointestinal Cancers Symposium [abstract number: 304] Available from: http://meetinglibrary.asco.org/content/71207-103Accessed January 20, 2011

 Google Scholar

ArandaEManzanoJLRiveraFPhase II open-label study of erlotinib in combination with gemcitabine in unresectable and/or metastatic adenocarcinoma of the pancreas: relationship between skin rash and survival (Pantar study)Ann Oncol2012231919192522156621

 PubMed Web of Science ®Google Scholar

JeonEKWonHSKoYHComparison of the efficacy and the toxicity between gemcitabine with capecitabine (GC) and gemcitabine with erlotinib (GE) in unresectable pancreatic cancerJ Cancer Res Clin Oncol20121381625163022614154

 PubMed Web of Science ®Google Scholar

ModianoMKeoghGPMangesRApricot-P: a randomized placebo-controlled phase II study of COX-2 inhibitor apricoxib or placebo in combination with gemcitabine and erlotinib in advanced or metastatic adenocarcinoma of the pancreas2012ASCO Gastrointestinal Cancers Symposium [abstract number: 253] Available from: http://meetinglibrary.asco.org/content/87740-115Accessed January 19, 2012

 Google Scholar

ParkSChungMJParkJYPhase II trial of erlotinib plus gemcitabine chemotherapy in Korean patients with advanced pancreatic cancer and prognostic factors for chemotherapeutic responseGut Liver2013761161524073321

 PubMed Web of Science ®Google Scholar

Van CutsemELiCPNowaraEDose escalation to rash for erlotinib plus gemcitabine for metastatic pancreatic cancer: the phase II RACHEL studyBJC20141112067207525247318

 PubMed Web of Science ®Google Scholar

LimJYChoJHLeeSJLeeDKYoonDSChoJYGemcitabine combined with capecitabine compared to gemcitabine with or without erlotinib as first-line chemotherapy in patients with advanced pancreatic cancerCancer Res Treat20154726627325327494

 PubMed Web of Science ®Google Scholar

WilminkJKordesSZwindermanKMathotRPuntCJARichelDA phase II randomized, placebo controlled study to evaluate the efficacy of the combination of gemcitabine, erlotinib and metformin in patients with locally advanced or metastatic pancreatic cancer2014ASCO Annual Meeting [abstract number: 4021] Available from: http://meetinglibrary.asco.org/content/129089-144Accessed May 30, 2014

 Google Scholar

PhilipPAGoldmanBRamanathanRKDual blockade of epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGF-1R) signaling in metastatic pancreatic cancer: phase Ib and randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG S0727)Cancer20141202980298525041791

 PubMed Web of Science ®Google Scholar

Diaz BeveridgeRAlcoleaVAparicioJManagement of advanced pancreatic cancer with gemcitabine plus erlotinib: efficacy and safety results in clinical practiceJOP201415192424413779

 PubMedGoogle Scholar

SemradTBarziALenzHJPharmacodynamic separation of gemcitabine and erlotinib in locally advanced or metastatic pancreatic cancer: therapeutic and biomarker resultsInt J Clin Oncol20152051852425091263

 PubMed Web of Science ®Google Scholar

BenavidesMPlazasJGGuillenCGemcitabine (G)/erlotinib (E) versus gemcitabine/erlotinib/capecitabine in the first line treatment of patients with metastatic pancreatic cancer (mPC): efficacy and safety results of a phase IIb randomized study from the Spanish TTD2014ASCO Annual Meeting [abstract number: 4122] Available from: http://meetinglibrary.asco.org/content/129070-144Accessed May 30, 2014

 Google Scholar