Predictive role of skin rash in advanced pancreatic cancer patients treated with gemcitabine plus erlotinib: a systematic review and meta-analysis

Figures & data

Table 1 Characteristics of the studies included for analysis

Study	Design	Ethnicitya	Rash assessment criteria	Patients (rash/no rash)	Median/mean age (years)	Male (%)	ECOG PS 0–1 (%)	Exocrine tumors (%)	Patients with prior treatment (%)	Outcomes (OS/PFS/ORR)	Risk of bias
Aranda et al^Citation10	PC	White	NCI-CTCAE	82/71	63.0	82 (53.6)	126 (82.4)	153 (100)	0.0	OS, PFS, ORR	Low
Beveridge et al^Citation11	RC	White	NCI-CTCAE	37/18	62.0	32 (58.2)	43 (78.2)	NA	9.1	OS	Low
Klapdor et al^Citation14	PC	White	NCI-CTCAE	25/5	NA	16 (53.3)	NA	30 (100)	26.7	ORR	Low
Park et al^Citation18	PC	Asian	WHO-TC	22/47	62.0	50 (72.5)	41 (59.4)	NA	0.0	OS, PFS	Low
Wacker et al^Citation28	PC	Non-oriental	NCI-CTCAE	180/74	63.7	125 (49.2)	210 (83.0)b	254 (100)	7.0	OS, PFS, ORR	Low
Okusaka et al^Citation29	PC	Asian	NCI-CTCAE	78/28	62.0	56 (52.8)	106 (100.0)	106 (100)	4.7	OS, PFS, ORR	Low
Stepanski et al^Citation30	RC	White	NCI-CTCAE	34/134c	67.2	85 (50.6)	59 (92.2)b	NA	NA	OS, PFS	Low
van Cutsem et al^Citation31	PC	White	NCI-CTCAE	178/123	61.0	188 (62.5)	264 (87.7)	301 (100)	0.0	OS, PFS	Low
Vaccaro et al^Citation32	PC	White	NCI-CTCAE	22/24	64.0	25 (54.3)	36 (78.3)	46 (100)	0.0	OS, PFS	Low
Oettle et al^Citation33,d	PC	White	NA	137/243	67.0	232 (61.1)	327 (86.1)	NA	NA	OS	High
Wang et al^Citation34	PC	Asian	NCI-CTCAE	28/16	67.0	32 (72.7)	42 (95.5)	44 (100)	0.0	OS, PFS, ORR	Low
Irigoyen et al^Citation35	PC	White	NCI-CTCAE	33/27	64.0	34 (56.7)	57 (95.0)	60 (100)	5.0	OS, PFS	Low
Irie et al^Citation36,d	RC	Asian	NA	48/11	65.0	36 (61.0)	NA	NA	NA	OS	Low
Cheng et al^Citation37	RC	Asian	NCI-CTCAE	11/9	65.0	12 (60.0)	20 (100)e	20 (100)	0.0	ORR	High
Gu et al^Citation38	PC	Asian	WHO-TC	8/3	55.0	5 (41.7)	NA	NA	41.7	ORR	High
Guo et al^Citation39	PC	Asian	NCI-CTCAE	12/8	NA	14 (70.0)	16 (80.0)	18 (90)	NA	ORR	High

Notes:

a Ethnicity refers to the ethnicity of dominating patients in the studies.

b The proportion was calculated based on the available data without missing values.

c Only data of patients with high-grade (≥grade 2) rash versus low-grade (≤grade 1) rash were available.

d Only abstracts were available.

e Studies only reported the proportion of patients with Karnofsky Performance Scale ≥60 (equivalent to ECOG ≤2). Low: the study got ≥7 scores in quality assessment and was thus assessed as at a low risk of bias. High: the study had ≤6 scores in quality assessment and was thus assessed as at a high risk of bias.

Abbreviations: ECOG PS, the Eastern Cooperative Oncology Group performance status; OS, overall survival; PFS, progression-free survival; ORR, objective response rate; PC, prospective study; NCI-CTCAE, National Cancer Institute Common Toxicity Criteria; RC, retrospective study; NA, not available/applicable; WHO-TC, WHO Toxicity Criteria.

Figure 1 Flowchart of study selection.

Abbreviations: ASCO, American Society of Clinical Oncology; ESMO, European Society of Medical Oncology.

Figure 2 (A) Forest plot of HR for OS: with vs without rash. (B) Forest plot of HR for OS: high-grade rash vs low-grade rash.

Note: Both Wacker et al (2007)²⁸ and Aranda et al (2012)¹⁰ had two comparisons, because they reported the comparisons of grade-1 rash with no rash and grade-2 rash with no rash separately, and the comparison of any-grade rash with no rash was not available.
Abbreviation: OS, overall survival.

Figure 3 (A) Forest plot of HR for PFS: with vs without rash. (B) Forest plot of HR for PFS: high-grade vs low-grade rash.

Notes: Both Wacker et al (2007)²⁸ and Aranda et al (2012)¹⁰ had two comparisons, because they reported the comparisons of grade-1 rash with no rash and grade-2 rash with no rash separately, and the comparison of any-grade rash with no rash was not available. Weights are from random-effects analysis.
Abbreviation: PFS, progression-free survival.

Figure 4 (A) Forest plot of OR for objective response: with vs without rash. (B) Forest plot of OR for objective response: high-grade rash vs low-grade rash.

Note: Data analysis software automatically dropped Cheng et al (2010)³⁷ because of the zero events in both groups.

Figure S1 Funnel plot based on the data of Figure 2A (HR for OS with versus without rash).

Abbreviations: OS, overall survival; SE, standard error.

Table S1 Quality assessment of included studies by the Newcastle–Ottawa scale

Criteria	Aranda et al^Citation1	Beveridge et al^Citation2	Klapdor et al^Citation3	Park et al^Citation4	Wacker et al^Citation5	Okusaka et al^Citation6	Stepanski et al^Citation7	van Cutsem et al^Citation8	Vaccaro et al^Citation9	Oettle et al^Citation10	Wang et al^Citation11	Irigoyen et al^Citation12	Irie et al^Citation13	Cheng et al^Citation14	Gu et al^Citation15	Guo et al^Citation16
1) Representativeness of the exposed cohort	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1
2) Selection of the nonexposed cohort	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1
3) Ascertainment of exposure	1	1	1	1	1	1	1	1	1	0	1	1	0	1	1	1
4) Demonstration that outcome of interest was not present at start of study	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1
5) Comparability of cohorts on the basis of the design or analysis*	2	0	0	2	2	0	2	0	2	0	0	0	1	0	0	0
6) Assessment of outcome	1	1	1	1	1	1	1	1	1	1	1	1	1	0	0	0
7) Was follow-up long enough for outcomes to occur	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1
8) Adequacy of follow-up of cohorts	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1
Total score	9	7	7	9	9	7	9	7	9	6	7	7	7	6	6	6

Note:

* A maximum of two points can be given for this item according to the study controls for main and additional factors.

Table S2 Sensitivity analyses

	Study	Patients	HR (95% CI)
OS
Rash versus no rash (overall analysis)	10	1,421	0.57 (0.50–0.64)
Sensitivity analysis 1	9	1,366	0.57 (0.50–0.65)
Sensitivity analysis 2	6	999	0.55 (0.48–0.64)
Sensitivity analysis 3	9	1,041	0.54 (0.47–0.62)
Sensitivity analysis 4	2	105	0.32 (0.15–0.66)
Sensitivity analysis 5	1	46	0.20 (0.05–0.71)
Sensitivity analysis 6	9	1,041	0.54 (0.47–0.62)
High-grade rash versus low-grade rash (overall analysis)	4	487	0.63 (0.49–0.80)
Sensitivity analysis 1	3	317	0.60 (0.44–0.83)
Sensitivity analysis 4	2	321	0.59 (0.43–0.80)
PFS
Rash versus no rash (overall analysis)	7	927	0.53 (0.40–0.68)
Sensitivity analysis 2	4	476	0.41 (0.26–0.65)
Sensitivity analysis 4	2	115	0.22 (0.08–0.60)
High-grade rash versus low-grade rash (overall analysis)	4	487	0.59 (0.46–0.76)
Sensitivity analysis 1	3	317	0.52 (0.40–0.67)
Sensitivity analysis 4	1	168	0.79 (0.54–1.15)
Objective response
Rash versus no rash (overall analysis)	5	359	1.87 (0.87–4.02)
Sensitivity analysis 6	3	328	2.10 (0.91–4.85)

Notes: Sensitivity analysis 1: excluding the studies that recruited a small number of patients receiving an additional therapy during the treatment. Sensitivity analysis 2: excluding the studies where HR could only be estimated from survival curves. Sensitivity analysis 3: excluding the study where HR could only be estimated with median survival time and P-value. Sensitivity analysis 4: excluding the studies that did not control for any confounders to estimate HR. Sensitivity analysis 5: excluding the studies that did not control for other confounders to estimate HR. Sensitivity analysis 6: excluding the studies with a high risk of bias.

Abbreviations: OS, overall survival; PFS, progression-free survival.

Table S3 Subgroup analyses

PFS (rash versus no rash)	Studies	Patients	HR (95% CI)	Heterogeneity (I^2), %	P-value
Ethnicity
Asian	2	113	0.40 (0.25–0.63)	0.0	0.242
White	4	560	0.53 (0.44–0.64)	56.2	–
ECOG 0–1
ECOG 0–1 ≥80%	5	812	0.60 (0.52–0.70)	49.9	0.006
ECOG 0–1 <80%	2	115	0.25 (0.13–0.46)	53.8	–
Prior chemotherapy treatment for pancreatic cancer
With previously treated patients	2	314	0.70 (0.56–0.87)	68.1	0.036
With treatment-naïve patients	5	613	0.51 (0.43–0.61)	54.2	–

Abbreviations: PFS, progression-free survival; ECOG, Eastern Cooperative Oncology Group.

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 Oncol20122371919192522156621

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van CutsemEVervenneWLBennounaJPhase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancerJ Clin Oncol200927132231223719307500

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IrieKUenoMKobayashiSThe biomarkers of gemcitabine and erlotinib treatment in advanced pancreatic cancerJ Clin Oncol2014323_suppl35824366938

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ChengYJBaiCMZhangZJEfficacy of Gemcitabine Combined with Erlotinib in Patients with Advanced Pancreatic CancerActaCTA Academiae Medicinae Sinica2010324421423

 Google Scholar

GuYHShuYQHuangPWObservation of Erlotinib (Tarceva) combined with gemcitabine in advanced pancreatic adenocarcinomaChin Clin Oncol2006117515517

 Google Scholar

GuoXDXuWSunCHClinical effect of Erlotinib plus gemcitabine in treatment of advanced pancreas cancerChin J of Clinical Rational Drug Use201252B2122

 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 Oncol20122371919192522156621

 PubMed Web of Science ®Google Scholar

BeveridgeRDAlcoleaVAparicioJManagement of advanced pancreatic cancer with gemcitabine plus erlotinib: efficacy and safety results in clinical practiceJOP2014151192424413779

 PubMedGoogle Scholar

KlapdorRKlapdorSBahloMCombination therapy with gemcitabine (GEM) and erlotinib (E) in exocrine pancreatic cancer under special reference to RASH and the tumour marker CA19-9Anticancer Res20123252191219722593509

 PubMed Web of Science ®Google Scholar

ParkSChungMJParkJYPhase II trial of erlotinib plus gemcitabine chemotherapy in korean patients with advanced pancreatic cancer and prognostic factors for chemotherapeutic responseGut Liver20137561161524073321

 PubMed Web of Science ®Google Scholar

WackerBNagraniTWeinbergJWittKClarkGCagnoniPJCorrelation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studiesClin Cancer Res200713133913392117606725

 PubMed Web of Science ®Google Scholar

OkusakaTFuruseJFunakoshiAPhase II study of erlotinib plus gemcitabine in Japanese patients with unresectable pancreatic cancerCancer Sci2011102242543121175992

 PubMed Web of Science ®Google Scholar

StepanskiEJReyesCWalkerMSThe association of rash severity with overall survival: findings from patients receiving erlotinib for pancreatic cancer in the community settingPancreas2013421323622699203

 PubMed Web of Science ®Google Scholar

van CutsemEVervenneWLBennounaJPhase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancerJ Clin Oncol200927132231223719307500

 PubMed Web of Science ®Google Scholar

VaccaroVBriaESperdutiIFirst-line erlotinib and fixed dose-rate gemcitabine for advanced pancreatic cancerWorld J Gastroenterol201319284511451923901226

 PubMed Web of Science ®Google Scholar

OettleHTessenHGroschekMNon-interventional study with Erlotinib/Gemcitabine in patients with metastatic pancreatic cancerOnkologie Conference201336Supplement 7123

 Google Scholar

WangJPWuCYYehYCErlotinib is effective in pancreatic cancer with epidermal growth factor receptor mutations: a randomized, open-label, prospective trialOncotarget2015620181621817326046796

 PubMed Web of Science ®Google Scholar

IrigoyenAGallegoJGuillén PonceCGemcitabine-erlotinib versus gemcitabine-erlotinib-capecitabine in the first-line treatment of patients with metastatic pancreatic cancer: Efficacy and safety results of a phase IIb randomised study from the Spanish TTD Collaborative GroupEur J Cancer201775738228222309

 PubMed Web of Science ®Google Scholar

IrieKUenoMKobayashiSGoudaYOhkawaSManabuMThe biomarkers of gemcitabine and erlotinib treatment in advanced pancreatic cancerJ Clin Oncol2014323_suppl35824366938

 PubMed Web of Science ®Google Scholar

ChengYJBaiCMZhangZJEfficacy of Gemcitabine Combined with Erlotinib in Patients with Advanced Pancreatic CancerActaCTA Academiae Medicinae Sinica2010324421423

 Google Scholar

GuYHShuYQHuangPWZhuWYZhuCJLiWObservation of Erlotinib (Tarceva) combined with gemcitabine in advanced pancreatic adenocarcinomaChin Clin Oncol2006117515517

 Google Scholar

GuoXDXuWSunCHClinical effect of Erlotinib plus gemcitabine in treatment of advanced pancreas cancerChin J of Clinical Rational Drug Use201252B2122

 Google Scholar