Each year, approximately 32,000 new patients are diagnosed with pancreatic cancer (PC) in the US. The incidence has been increasing since the 1930s. Prognosis of PC is extremely poor. Approximately 31,000 patients in the US die from PC each year, making it the fourth leading cause of cancer-related death in the US.¹ Five-year overall survival (OS) rate for advanced pancreatic cancer (APC) is less than 1%.² Poor prognosis had been attributed to the inability to diagnose while the tumor is resectable and its propensity toward early vascular dissemination and spread to regional lymph nodes. In inoperable PC, gemcitabine is the only cytotoxic agent approved by the US Food and Drug Administration (FDA), based on the results of the multicentered randomized phase III clinical trial that compared 5-fluorouracil (5-FU) with gemcitabine. In this study, treatment with gemcitabine resulted in a relative improvement of 36% in median survival (MS) (5.7 versus 4.2 months for gemcitabine and 5-FU, respectively). For the past 10 years, many cytotoxic and targeted agents have been pitted against or combined with gemcitabine in randomized phase III trials and no drug has been shown to be superior to single-agent gemcitabine. Luckily, in the past year, for the first time, two large, randomized phase III studies in APC—capecitabine plus gemcitabine versus gemcitabine, and erlotinib plus gemcitabine versus gemcitabine—have demonstrated the superiority of a gemcitabine-containing combination over single-agent gemcitabine. In this paper we will review the current advancement in PC treatment.

Resectable Pancreatic Cancer

Ten percent of patients have resectable disease at the time of PC diagnosis. Prognosis of patients after complete resection of node-negative cancer is poor, with three-year disease-specific survival rate at 27% (95% confidence interval (CI): 23–32%) and MS of 15–19 months.³ The treatment plan in the adjuvant setting is currently dependent on which side of the Atlantic you are located: chemotherapy alone is mostly used in Europe—European Study Group for Pancreatic Cancer-1 (ESPAC-1), Charité Onkologie Clinical-001 (CONKO-001)—while chemoradiation therapy (CRT) is the current standard in the US—Gastrointestinal Study Group (GITSG), Radiation Therapy Oncology Group 9704 (RTOG 9704).

Adjuvant Therapy with Chemotherapy and External Beam Radiotherapy

One rationale for adjuvant CRT comes from the high risk of local and systemic disease recurrence and overall poor prognosis. One of the first studies to support adjuvant CRT in patients with resected PC was conducted by GITSG. This small study (n=43) showed survival benefit (MS: 20 versus 11 months; fiveyear survival: 18 versus 8%) in patients who received bolus 5-FU with radiation therapy (XRT) for one year compared with patients who did not.⁴ However, this study was criticized for small sample size due to early closure of the trial. The European Organization of Research and Treatment of Cancer (EORTC) compared post-operative combined 5-FU (25mg/kg/day continuous infusion for five days every four weeks) and external beam radiotherapy (EBRT) (split course 40Gy) with observation only in patients with resected pancreatic and periampullary cancer. Klinkenbiji et al. were able to show a trend toward benefit in terms of MS (24.5 versus 19 months; p=0.208). The subgroup analysis looking only at PC patients showed a trend toward benefit in MS (17.1 versus 12.6 months; p=0.099).⁵ This study was also criticized for suboptimal XRT—lower doses and split courses—that may have allowed cancer repopulation between courses, thereby underestimating the benefit of CRT. The trial ESPAC-1 was a two-by-two factorial designed study comparing adjuvant concurrent CRT (bolus 5-FU/split-course radiation), chemotherapy alone (5-FU/Leucovorin (LV)), CRT followed by chemotherapy, and observation. The chemotherapy-only arm had statistically significant benefit over the observation arm in MS (20.1 versus 15.5 months; p=0.009). However, the CRT arm showed worse MS (15.9 versus 17.9 months; p=0.05).⁶ The RTOG 9704 study randomized 538 resected PC patients to evaluate the benefit of adding gemcitabine to infusional 5-FU combined with XRT (5- FU+XRT). One arm received 5-FU+XRT and the other arm was treated with gemcitabine before and after 5-FU+XRT. Although there was no significant difference when pancreatic body and tail cancers were all included, patients with pancreatic head tumors (n=380) showed benefit in MS (18.8 versus 16.7 months; p=0.047).⁷ While the benefit of XRT was inconclusive in randomized trials (see Table 1), two recent large, uncontrolled studies support the benefits of adding radiation. Greco et al. analyzed 2,636 patients with resected PC of whom 42.6% received radiation and 57.4% did not. After a mean follow-up of 19 months, patients who underwent adjuvant radiation had improved median overall survival (OS) (18 versus 11 months; p<0.01).⁸ Corsini et al. performed a retrospective review of 472 patients who underwent complete resection with negative margins for invasive adenocarcinoma of the pancreas from 1975 to 2005 at the Mayo Clinic. The authors concluded that the addition of adjuvant concurrent CRT improves OS after complete resection of PC. Patients who received adjuvant CRT had longer median OS over patients who did not receive radiotherapy (2.1 versus 1.6 years; p=0.001).⁹

Chemotherapy Alone

In the CONKO-001 study, Oettle et al. randomized 368 patients with resected PC to gemcitabine or observation for six months. Tumor prognostic characteristics were similar in both arms. This trial showed a statistically significant disease-free survival (DFS) benefit (13.4 versus 6.9 months; p<0.001) of gemcitabine over observation (see Table 1). Treatment with gemcitabine caused a trend toward OS benefit (22.1 versus 20.2 months; p=0.06).10 This benefit of chemotherapy was consistent with the result from the ESPAC-1 trial, which showed the benefit of 5-FU/LV over no adjuvant therapy in PC patients (MS 19.7 versus 14 months) who had complete resection.⁶ The role of gemcitabine as a single agent will further be defined by the ongoing ESPAC-3 study, which is a randomized phase III study comparing observation versus 5-FU versus gemcitabine in the adjuvant setting of PC.

Locally Advanced Pancreatic Cancer

Approximately 30% of patients have locally advanced disease at the time of diagnosis with MS of six to 10 months.11 PCs are deemed unresectable when the following features are present:

• involvement of superior mesenteric artery or celiac axis;

• absence of vascular flow through the superior mesenteric vein–portal vein (SMV–PV) confluence;

• complete encasement of SMV–PV confluence leading to vascular thrombosis and cessation of blood flow in the SMV–PV;

• celiac axis involvement/encasement with tumor or direct involvement of inferior vena cava or aorta;

• extrapancreatic involvement; or

• distant metastases.