Abstract
Overexpression of epidermal growth factor receptors (EGFR) occurs in >90% of pancreatic ductal adenocarcinomas (PDACs) and is associated with a poorer prognosis. A systematic review of electronic databases identified studies exploring the addition of EGFR-targeted treatment to chemotherapy in patients with locally advanced (LA)/metastatic PDAC. Efficacy, safety and tolerability of EGFR-targeted therapy were explored using meta-analysis of randomised controlled trials (RCTs). Meta-regression was utilised to explore factors associated with improved prognosis (all studies) and benefit from EGFR-targeted therapy (RCTs). Twenty-eight studies (7 RCTs and 21 cohort studies) comprising 3718 patients were included. The addition of EGFR-targeted treatment to chemotherapy did not improve progression-free (pooled hazard ratio (HR): 0.90, p = 0.15) or overall survival (HR: 0.94, p = 0.18). EGFR-targeted therapy was associated with increased treatment-related deaths (pooled odds ratio (OR): 5.18, p = 0.007), and grade (G)3/4 rash (OR: 4.82, p = 0.03). There was a borderline significant increase in G3/4 diarrhoea (OR: 1.75, p = 0.06), but no effect on treatment discontinuation without progression (OR: 0.87, p = 0.25). Neither G3/4 rash nor diarrhoea were associated with increased survival benefit from EGFR-targeted therapy. The effect of EGFR-targeted therapy on overall survival (OS) appeared greater in studies with a greater proportion of LA rather than metastatic patients (R = −0.69, p < 0.001). Further studies in unselected patients with advanced PDAC are not warranted. The benefit from EGFR inhibitors may be limited to patient subgroups not yet clearly defined.
Highlights
Pancreatic cancer is a disease with an extremely poor prognosis (5-year survival of 3%–5%) [1,2,3]
In the European Study Group for Pancreatic Cancer-4 (ESPAC-4) randomised-controlled phase 3 clinical trial, the median survival in patients treated with the adjuvant gemcitabine/capecitabine combination was 28.0 months (95% confidence interval (CI) 23.5–31.5) while in those treated with gemcitabine monotherapy median survival was 25.5 months [7]
Single-agent gemcitabine has been the mainstay of treatment for patients with late-stage pancreatic cancer for many years, following a randomised trial of single-agent gemcitabine versus 5-fluorouracil (5-FU), which demonstrated better efficacy for gemcitabine over 5-FU where a clinical benefit response was experienced by 23.8% of patients treated with gemcitabine compared with 4.8% of patients treated with 5-FU (p = 0.0022) and median overall survival of 5.65 months versus 4.41 months was reported, p = 0.0025) [8]
Summary
Pancreatic cancer is a disease with an extremely poor prognosis (5-year survival of 3%–5%) [1,2,3]. Single-agent gemcitabine has been the mainstay of treatment for patients with late-stage pancreatic cancer for many years, following a randomised trial of single-agent gemcitabine versus 5-fluorouracil (5-FU), which demonstrated better efficacy for gemcitabine over 5-FU where a clinical benefit response was experienced by 23.8% of patients treated with gemcitabine compared with 4.8% of patients treated with 5-FU (p = 0.0022) and median overall survival of 5.65 months versus 4.41 months was reported, p = 0.0025) [8]. In a phase 2/3 randomised trial in patients with treatment-naïve metastatic pancreatic cancer with good ECOG PS 0–1, the combination of 5-FU, folinic acid, irinotecan and oxaliplatin (FOLFIRINOX) resulted in a better survival rate, but increased toxicity over gemcitabine alone; median overall survival 11.1 months versus 6.8 months respectively, p < 0.001 [10]. Anti-EGFR monoclonal antibodies like cetuximab and panitumumab block ligand-induced lapreacteinpitborcoamctipveatteiown,itwh haidleensmosainllemtroilpehcouslephEaGteFR(AinThPi)btiotobrsinsducthheascaetralolytitnicibd, ogmefiatiinniobf atnhde lkaipnaatsien,ib whcoicmhpientetuwrnithinahdibenitossEinGeFtRripahuotospphhoatseph(AoTryPl)attoiobninadndthdeocwatnaslytrteicamdosmiganinalolifntghe[2k4i]n. aTshee, wmhaijcohriitny toufrn taringhetibedits tEhGeFraRpaieustopaghaoisnpshtorEyGlaFtRionhaanvdednowotnsdtreemamonssitgrnataelldingth[e24]b.eTnheefimt atjhoartitywoofutaldrgehteadvethebreaepnies thaegoareintisctaEllGyFeRxpheacvteednoitndcelminoicnasltrtartieadlsthine pbeantieefinttsthwatitwhoaudldvahnacveedbpeeanncthreeaotriecticcaanllcyeer.xpTehcetreedfoinrec,litnhiecal betnrieaflist oinf apdadtiienngtsEGwFitRh-taadrvgaentecdedagpeanntscrteoactihcecmanotcheer.raTphyerineftohree,atdhveabnecnedefistetotfinagddisinugncEleGaFr.R-targeted ageTnhtsistosycshteemmaottihcerreavpiyewinatnhde amdevtaan-acnedalsyestitsinwgaisscuonncdleuacrt.ed to evaluate the efficacy and safety of additioTnhoisf EsyGsFteRm-taartigcerteevditehweraanpdy mtoecthae-amnoatlhyesirsapwyaisncpoantdieuncttsewd ittohelvoacalullayteadthveanecffiedcaacnydamndetsaasfteattyicof paandcdreitaiotinc coafnEcGerF.R-targeted therapy to chemotherapy in patients with locally advanced and metastatic pancreatic cancer
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