Pancreatic cancer is the fourth commonest cause of death from cancer in men and women [1, 2]. Surgical therapy currently offers the only potential monomodal cure for pancreatic adenocarcinoma . However only a few patients present with tumors that are amenable to resection, end even after resection of localized cancers, long term survival is poor. At presentation, only 20% of patients with pancreatic adenocarcinoma have resectable cancers, 40% have locally advanced tumors, and 40% have metastatic disease .
However, long-term (5-year) survival rates – even for patients undergoing "complete" resection – are below 20% [4, 5]. Loco-regional recurrence and/or metastatic disease develop in the majority of patients who undergo pancreatic resection. Relapse occurs within 9–15 months after initial presentation and patients have median life expectancies of only 12–15 months without adjuvant therapy . The 5-year survival rate of patients with resected pancreatic adenocarinoma is approximately 10% . The statistics for the 80 to 90 % of patients who present with locally advanced and metastatic pancreatic cancer are even more dismal. Rarely do such patients achieve a complete response to treatment; median survival is 5–10 months and 5-year survival is near zero .
Both distant and local/regional patterns of recurrence are common, and this suggests that most patients have occult metastatic disease or local/regional (or both) at the time of resection. Postoperative chemoradiationtherapy (CRT) has been shown to improve survival in patients with resected pancreatic adenocarcinoma [8–10], although there is debate over whether radiotherapy is a beneficial component [5, 11]. The problems with the postoperative adjuvant approach include the fact that at least 25% of patients do not actually receive adjuvant therapy because of complications of surgery or patient refusal [10, 12]. A primary advantage of preoperative therapy is therefore the assurance that CRT is received by all patients in a timely fashion. Other benefits are the delivers of radiation to well-oxygenated tissues and the avoidance of radiation to fixed loops of intestine within the operative field. Another rationale for neoadjuvant treatment is that occult metastatic disease is given the opportunity to manifest, thus allowing patients to avoid the morbidity of resection or laparotomy. Finally, the potential for preoperative CRT to convert locally advanced lesions to resectable lesions could greatly increase the number of patients with pancreatic cancer who might be offered a chance of cure. Several trials could show that dose escalation in radiation therapy using either EBRT  or IORT [13, 14] resulted in improved local control in combination with potentially curative resection. The efficacy of external beam irradiation (EBRT) in pancreatic cancer is limited by the inability to deliver adequate doses of irradiation secondary to the dose tolerance limits of small bowel, spinal cord, stomach, kidney, and liver . Further, the use of combined modality approaches in pancreatic cancer is associated with increased gastrointestinal toxicity . Technical developments like intensity-modulated radiation therapy (IMRT) have the potential to significantly improve radiation therapy of pancreatic cancers by reducing normal tissue dose, and simultaneously allow escalation of dose to further enhance locoregional control .
To achieve long-term success in treating this disease it is therefore increasingly important to identify effective neoadjuvant/adjuvant multimodality therapies.
Concurrent chemoradiation is the standard of care for locally advanced non metastatic pancreatic cancers. Median survival rates vary between different trials depending on their selection criteria between 7 and 12 month, while 1 year overall survival is between 30% and 45% .
Systemic chemotherapy, a mainstay of pancreatic cancer treatment, essentially has been ineffective until recently when gemcitabine became available . In a phase III trial comparing gemcitabine versus 5-flurouracil in advanced pancreatic cancer, patients who received gemcitabine showed a modest improvement in response rate, a marginal survival advantage, and most important, superior clinical response . Therefore gemcitabine became the standard treatment of advanced pancreatic cancer. Despite these results, however median survival duration in patients with advanced pancreatic cancer continues to be less than 6 month.
Still, advantages in surgical techniques, radiation therapy techniques, chemotherapeutic regimes, and different combined-modality approaches have yielded only a modest impact on the prognosis of patients with pancreatic cancer. Thus there is clearly a need for additional strategies. One approach involves using the identification of a number of molecular targets that may be responsible for the resistance of cancer cells to radiation or to other cytotoxic agents. As such, these molecular determinants may serve as targets for augmentation of the radiotherapy or chemotherapy response. Of these, the epidermal growth factor receptor (EGFR) has been a molecular target of considerable interest and investigation, and there has been a tremendous surge of interest in pursuing targeted therapy of cancers via inhibition of the EGFR [21, 22].
The overexpression of EGFR has been demonstrated in a number of human tumor types, including head-and-neck cancers, colon cancer, breast cancer, gliomas, lung cancer and pancreatic cancer [23, 24]. The rationale for investigating of EGFR inhibitors as radiation sensitizers in cancer therapy is based on the following observations: (1) positive correlation between EGFR expression and cellular resistance to radiation in many cell types ; (2) the degree of radioresistance correlates positively with the magnitude of EGFR overexpression ; (3) cell survival and repopulation during a course of radiotherapy are influenced by activation of EGFR/transforming growth factor alpha that is induced after exposure to radiation ; and (4) inhibition of EGFR signaling-enhanced radiation sensitivity [27, 28].
Cetuximab is a monoclonal antibody that specifically binds to the EGFR, thereby inhibiting downstream signal transduction pathways . It has been shown in vivo and in vitro to enhance radiosensitivity, to promote radiation induced apoptosis, to decrease cell proliferation, to inhibit radiation-induced damage repair, and to inhibit tumor angiogenesis .
Phase I studies have shown that cetuximab has tolerable toxic effects. Acneiform rash is the most common toxic effect. Besides skin toxicity cetuximab has the potential to cause allergic reactions, including anaphylaxis. However, this has not been shown to be a significant clinical problem .
Phase I and II clinical studies on EGFR antibodies given as a single agent were performed in patients with advanced NSCLC, ovarian, head and neck, prostate, and colorectal cancer. Stable disease with tolerable side effects was seen in about 20% of the patients . Several phase I-III trials testing the effect of different EGFR inhibitors combined with radiotherapy or radiochemotherapy are currently ongoing. The so far most important trial testing EGFR inhibition in combination with radiotherapy was a randomized phase III trial testing radiotherapy alone versus radiotherapy plus cetuximab . 424 patients with loco-regionally advanced squamous cell carcinoma or head-and-neck cancers were randomized into curative radiotherapy plus/minus cetuximab. Cetuximab was applied once at a dose of 400 mg/m2 in the week prior to radiotherapy (week1) and weekly during the course of radiotherapy at a dose of 250 mg/m2 before irradiation. Locoregional tumor control rates after 1 and 2 years were 69% and 56% for patients treated simultaneously with cetuximab versus 59% and 48% for patients who received radiotherapy alone (p = 0.02). Overall survival rates at 2 and 3 years after treatment were 62% and 57% for cetuximab treated patients and 55% and 44% for patients with irradiation alone (p = 0.02). Median survival times were 54 months (95%C.I.36;58) and 28 months (21;38), respectively.
A recently completed phase II trial of cetuximab in combination with gemcitabine for patients with advanced pancreatic cancer showed promising results . In that trial 41 patients received cetuximab with gemcitabine and were evaluated for efficacy and toxicity. The toxicity profile of this combination was consistent with that of gemcitabine, except for acneiforme rash induced by cetuximab. A partial response rate of 12.2% (5 patients) and stable disease rate of 63.4% was observed in this study. Medial time to progression and medial survival duration were 3.8 months and 7.1 months, respectively, while 1-year survival rates and progression-free survival rates were 31.7% and 12%, respectively. This 1-year survival is considerably better than that achieved using gemcitabine alone as documented in a previous phase III trial . Recently a phase three study could demonstrate the benefit of the combination of an EGFR tyrosine kinase inhibitor in combination with chemotherapy in pancreatic cancer . A total of 569 patients with advanced pancreatic cancer were randomized to receive standard dose gemcitabine, 1000 mg/m2 iv weekly in 7 out of 8 weeks, than weekly 3 out of four weeks plus either erlotininb 100 mg daily (n = 285) or placebo (n = 284). Combined erlotinib therapy with gemcintabine resulted in a 24% improvment in survival as compared to placebo (p = 0.025) with corresponding 1-year survival rate of 24% and 17% (erlotinib and placebo arm, respectively).
Regarding the benefits of EGFR-targeted therapy in the combined modality treatment using either irradiation or chemotherapy, it is increasingly becoming clear that EGFR-targeted therapy is an important novel strategy for the treatment of pancreatic cancers. Since chemoradiation is the standard of care for locally advanced non metastatic pancreatic cancer, there has been considerable interest in gaining increased experience with this therapy in combination with chemoradiation in an effort to evaluate the efficacy and the toxicity profile of this regimen.