Description of the condition

Adenocarcinoma of the pancreas, also known as pancreatic cancer , is the fourth most common cause of cancer death in the United States and the fifth in Europe with an estimated 43,000 new cases in the United States and approximately 58,000 new cases in Europe occurring annually (Ferlay 2007; Siegel 2012). In Japan and China, available data showed an incidence rate of 8.5 and 3.6 per 100.000, respectively, and a mortality rate of 7.7 and 3.5 per 100.000, respectively (data projected to 2012, represented as age‐standardised rate). In South Africa, incidence is 4.7 and mortality 4.6 per 100,000. These data show that mortality is nearly equal to incidence (IARC 2012) (Figure 1). Less than 20% of pancreatic cancer patients are susceptible of curative surgical resection. Etiology of pancreatic cancer remains still unknown, although several advances in the understanding of its molecular pathogenesis and in the management of early‐stage disease have been done (Hidalgo 2010; Wörmann 2013). Only tobacco use has been described to be associated with an increased risk of pancreatic cancer, although alcohol intake, consumption of coffee and use of aspirin may be contributing factors as well as chronic pancreatitis, family history, diabetes, chronic cirrhosis, a high‐fat, high‐cholesterol diet, and previous cholecystectomy (Hsu 2011; Landi 2009). New‐onset diabetes mellitus with no risk factors has been associated with pancreatic cancer (Hsu 2011). Diagnosis is often delayed due to non specific clinical presentation and vague symptomatology, which can include pain, weight loss, dyspepsia, nausea, vomiting, depression, deep venous thrombosis and, in end‐stage disease, steatorrhoea (due to malabsorption). Unfortunately, there are no specific warning signs of pancreatic cancer and only few patients present with jaundice, cholestasis and cholangitis, being more likely to receive an early diagnosis. Since the majority of patients already have metastatic, non‐operable disease at diagnosis with a median survival time of three to six months (NCI 2014); even after curative resection, patients often develop distant metastases, efforts have been focused on the treatment of advanced, unresectable pancreatic cancer. According to guideline released by the National Comprehensive Cancer Network, treatment with chemotherapy or radiotherapy, or both, is applicable for pancreatic cancer staged as “locally advanced” (not resectable) or metastatic pancreatic cancer, or in recurrences after resection (NCCN 2014). Different combination treatments are chosen on the basis of the feasibility of surgery and patients' performance status according to the Eastern Cooperative Oncology Group/World Health Organization (WHO) classification, defined as “good” (grade 0 to 2: good pain management, patent biliary stent and adequate nutritional intake), or poor (grade 3 to 4) (Oken 1982) (Table 1). The use of palliative chemotherapy has been reported to improve survival and quality of life, despite a modest gain in overall survival (Sultana 2007).

Figure 1

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Incidence and mortality of pancreatic cancer (age standardised rate) per 100,000 in the world. Data projected to year 2012, both sexes, all ages. Available from WHO‐IARC (http://globocan.iarc.fr/Pages/online.aspx; accessed 10 November 2014).

Description of the intervention

Gemcitabine, a cytotoxic agent, has been considered as the mainstream therapy for advanced pancreatic disease since 1997 (Burris 1997). Several alternative cytotoxic and biological or target agents have been studied in various combination regimens with or without gemcitabine for the treatment of pancreatic cancer, but have not produced any superior result over gemcitabine alone (Bramhall 2002; Cheverton 2004; Louvet 2005; Moore 2003; Oettle 2005; Rocha Lima 2004; Van Cutsem 2004). Two recent studies have compared gemcitabine alone as control to gemcitabine plus nab‐paclitaxel (Von Hoff 2013), and to a combination regimen without gemcitabine named FOLFIRINOX, consisting of folinic acid (FOL), fluorouracil (F), irinotecan (IRIN) and oxaliplatin (OX) (Conroy 2011), resulting in a statistically significant improvement in terms of overall survival for the experimental arm in both trials. Many efforts have been made to identify molecular markers (for example, epidermal growth factor receptor gene copy number and mutation of the Kirsten rat sarcoma viral oncogene) that are able to predict response rate and survival benefit from treatment with agents acting against biologic targets overexpressed in specific cancers, highlighting the importance of a better understanding of molecular mechanisms underlying targeted therapies (da Cunha Santos 2010). Human epidermal growth factor receptor type 1 is overexpressed in many pancreatic tumours, showing an association with poor prognosis and disease progression (Ueda 2004). Targeted therapies against epidermal growth factor receptor‐mediated signalling are, therefore, a recent cornerstone of treatment of pancreatic cancer and include two main modalities: monoclonal antibodies against the extracellular domain (for example, cetuximab and bevacizumab) and small molecule tyrosine kinase inhibitors, which interfere with the signalling pathway (for example, erlotinib). Erlotinib is an oral human epidermal growth factor receptor type 1 tyrosine kinase inhibitor, recently proposed as first‐line treatment for advanced pancreatic cancer in combination with gemcitabine. Epidermal growth factor receptor inhibitors have been shown to be clinically effective in various cancers (Lurje 2009). Combination of gemcitabine with capecitabine or erlotinib have been both indicated as new potential treatment platforms for advanced pancreatic cancer (Cunnigham 2009). In a relatively recent clinical trial, the combination of gemcitabine plus erlotinib has been reported to produce a significant increased survival compared to gemcitabine alone, but with an increased toxicity (Moore 2007). Radiotherapy combined with chemotherapy seems to offer no advantages in the treatment of pancreatic cancer (Hammel 2013). Very recently, two network meta‐analyses have been published. The first (Gresham 2014), including 19 studies, concluded that gemcitabine/erlotinib was superior over gemcitabine alone, and over gemcitabine/cetuximab in terms of overall survival. The second (Chan 2014), including 16 studies, demonstrated the superiority of FOLFIRINOX over other treatments in terms of overall survival, progression‐free survival and objective response rate.

Erlotinib as a single agent appeared to be well tolerated, with diarrhoea, acneiform skin rash, headache, nausea, vomiting, fatigue and mucositis being the main reported dose‐limiting side effects (Hidalgo 2001; Starling 2006). Patients who developed ≥ grade 2 rash under treatment with erlotinib and gemcitabine were reported to get the major benefit from the treatment in terms of survival (Wacker 2007). Interstitial lung disease‐like syndrome has been also reported as a more severe side effect due to both gemcitabine and erlotinib (Moore 2007). Despite these positive results, many patients still progress quickly even under treatment with gemcitabine and erlotinib (Moore 2007). Further investigation on alternative therapeutic options are therefore needed. Among available trials, everolimus (Javle 2010), ascorbic acid (Monti 2012), paclitaxel combined with radiation (Iannitti 2005), or radiotherapy alone (Duffy 2008) have been administered in combination with erlotinib/ gemcitabine with heterogenous and often preliminary results. Recently, a phase III trial focused on the combination of bevacizumab with gemcitabine‐erlotinib (Van Cutsem 2004), showing an improved progression‐free survival, despite no significant benefit for overall survival.

How the intervention might work

Erlotinib is a type of anticancer medicine defined as a tyrosine kinase inhibitor. It is taken orally, once a day in a dose of 100 mg or 150 mg. It works by potent inhibition of the intracellular phosphorylation of epidermal growth factor receptor, which is expressed on the cell surface of both normal and cancer cells. Mutation of epidermal growth factor receptor may lead to abnormal activation of anti‐apoptotic and proliferation signalling pathways. Erlotinib blocks epidermal growth factor receptor‐mediated signalling interacting with adenosine triphosphate‐binding site in the mutated kinase domain of the epidermal growth factor receptor. Due to the blocking of downstream‐signalling, the proliferation of cells is stopped and cell death is induced through the intrinsic apoptotic pathway. Treatment with Erlotinib could be clinically relevant if ongoing research will demonstrate a delay in cancer progression, and hopefully, an extension of survival and improvement in quality of life.

Why it is important to do this review

Pancreatic cancer is often diagnosed late because symptoms are vague or confounding. Due to the late diagnosis, surgical intervention is often no possible. Chemotherapy is often considered as a palliative measure. Erlotinib is showing promise in the treatment of advanced pancreatic cancer, and is the only target therapy that has reached a commercial authorisation as a treatment for pancreatic cancer, in association with gemcitabine, although it is questionable whether results in overall survival are clinically meaningful. A number of new studies have been conducted with the aim to test erlotinib in combination with cytotoxic or biological agents or to improve the selection of eligible patients. Probably new results will be available in the near future. Patients' expectations are dramatically higher, assuming that they hope for improved prognosis and lengthened life, during which time they would have an acceptable quality of life with minimum adverse effects due to treatment. A systematic review of all the studies can provide practitioners a source of good evidence for decision making.