Cytotoxic Agents

Gemcitabine

Gemcitabine has been compared with 5-FU in APC patients and showed its superiority in clinical response rates (24 versus 5%) and one-year survival rates (18 versus 2%) in a randomized study by Burris HA et al.²¹ (see Table 3). In addition to the survival benefit, gemcitabine was also superior to 5-FU in producing clinical benefit response (see Figure 1). This study led to the approval of gemcitabine as a first-line chemotherapy agent.²¹

Fixed Dose Rate versus Conventional 30-minute Infusion of Gemcitabine

The benefit of fixed dose rate (FDR) gemcitabine versus the standard 30-minute infusion schedule, which was proposed in a phase II trial, was contradicted by a US intergroup randomized phase III trial (ECOG-6201), which showed no difference between the two schedules^.22 Increased myelosuppression is associated with FDR gemcitabine infusion (neutropenia, thrombocytopenia).

Gemcitabine versus Gemcitabine/Platinum

Gemcitabine/oxaliplatin (GEMOX) showed encouraging results in a phase II trial and led to randomized trials comparing GEMOX with gemcitabine monotherapy. The Groupe d’Etude et de Recherche Clinique en Oncologie et Radiothérapie/Italian Group for the Study of Gastrointestinal Tract Carcinomas (GERCOR/GISCAD) intergroup study compared standard gemcitabine monotherapy versus FDR GEMOX in patients with LAPC and MPC. GEMOX showed longer progression-free survival (PFS) (5.8 versus 3.7 months; p=0.04) than that of gemcitabine. GEMOX also rendered better response rates (27 versus 17%; p=0.04). There was a trend toward MS benefit (9 versus 7.1 months; p=0.13). Toxicities from both arms were acceptable, while GEMOX was more myelosuppressive and caused more peripheral neuropathies.²³ The major criticism for this study was that it compared a 30-minute infusion with an FDR infusion in GEMOX regimen. The US intergroup trial ECOG 6201 compared standard 30-minute gemcitabine versus FDR gemcitabine versus GEMOX. Preliminary data from this study presented at the American Society of Clinical Oncology (ASCO) 2006 failed to show significant advantages of GEMOX to gemcitabine monotherapy.22 Other gemcitabine/platinum combinations gave rise to benefits. A gemcitabine and cisplatin combination showed significant improvement against disease progression and in response rates. Heinemann et al. also showed 2.2 months’ prolongation of PFS (p=0.53) by the addition of cisplatin to gemcitabine.²⁴

Gemcitabine versus Gemcitabine + Fluoropyrimidines

While phase III randomized trials did not show any benefit of adding 5-FU (infusional or bolus) to gemcitabine, the addition of oral fluoropyrimidine— capecitabine—to gemcitabine (GEMCAP) showed promising results. A multinational randomized trial by Herrmann et al. reported no advantage of adding capecitabine; however, subgroup analysis showed the benefit of GEMCAP to patients with good performance status (hazard ratio (HR): 0.76; p<0.03).²⁵ Another phase III randomized trial by Cunningham compared single-agent gemcitabine with gemcitabine three times weekly plus capecitabine 1660mg/m2 daily for 21 days in every 28-day cycle. The addition of capecitabine doubled the response rate (14 versus 7%; p=0.008) and improved OS (HR: 0.80; p=0.026). The incidence of myelosuppression was higher in the combination arm, and hand–foot syndrome was noted only in the combination arm.²⁶ The final results of the study are anxiously awaited. Addition of S-1, a novel oral fluoropyrimidine derivative, to gemcitabine in patients with MPC showed promising activity in a phase II study of 54 patients. Response rates were 44% and MS was 10.1 months with an acceptable toxicity profile. A randomized phase III trial is being undertaken.²⁷

Targeted Agents

Based upon the biology of PC, the following classes of targeted agents are being investigated actively: epidermal growth factor receptor (EGFR) inhibitors, vascular endothelial growth factor receptor (VEGFR) inhibitors, farnesyltransferase inhibitors, matrix metalloproteinase inhibitors, and cyclooxygenase-2 (COX-2) inhibitors.

Epidermal Growth Factor Receptor Inhibitors

The National Cancer Institute of Canada randomized patients with LAPC and MPC to gemcitabine/erlotinib and gemcitabine/placebo. The addition of erlotinib resulted in a statistically significant benefit in survival rate (HR: 0.81; 95% CI: 0.67–0.97; p=0.025). Improvement of MS was from 5.9 to 6.4 months, and one-year survival rate improved from 17 to 24%.²⁸ This study led to the approval of erlotinib by FDA—the first biologic plus gemcitabine combination that showed benefit after the efforts of a decade. A rash was the most common toxicity associated with erlotinib and correlated with the expected outcome.

Cetuximab, an anti-EGFR chimeric monoclonal antibody, in combination with gemcitabine showed promising activity in a phase II trial by Xiong et al.²⁹ Forty-one patients with LAPC and MPC were treated with this regimen and showed 12.2% relative risk (RR), median OS of 7.1 months, and oneyear OS of 31.7%. Cetuximab was dosed with 400mg/m2 loading followed by a 250mg/m2 weekly dose. Gemcitabine was given at 1000mg/m2 on a schedule of seven weeks on and one week off. This regimen was well tolerated with the most common side effects being neutropenia (39%) and asthenia (22%).29 In an effort to confirm this result, a phase III randomized trial is being conducted by the Southwest Oncology Group (SWOG).30 The primary study end-point of this trial is OS. Unfortunately, in April 2007 ImClone Systems and Bristol-Myers Squibb (BMS) announced that this phase III study of cetuximab plus gemcitabine in patients with locally advanced unresectable pancreatic cancer or MPC did not meet its primary end-point of improving OS. The open-label, randomized study compared cetuximab plus gemcitabine with gemcitabine alone in more than 700 patients with PC in the first-line treatment setting. The study was conducted in centers throughout the US and Canada. Seven hundred and sixty-six patients (735 eligible) with a median age of 64 (30–91) years were enrolled by SWOG and the Cancer Trials Support Unit (CTSU) between January 2004 and April 2006. Of those, 51% were male, 21.5% had locally advanced disease, and 13% had PS of 2. The study closed with full accrual. The median survival was six months in the gemcitabine arm and 6.5 months in the gemcitabine plus cetuximab arm for an overall HR of 1.09 (95% CI: 0.93–1.27; p=0.14). The corresponding PFS was three months and 3.5 months for gemcitabine and gemcitabine plus cetuximab arms, respectively (HR: 1.13; 95%CI: 97–1.3; p=0.58). This study failed to demonstrate a clinically significant advantage of the addition of cetuximab to gemcitabine for overall survival, PFS, and response in advanced PC. Kullmann et al. recently presented an abstract—at the 2007 Gastrointestinal Cancers Symposium—of a phase II trial testing first-line GEMOX plus cetuximab (GEMOXCET) in MPC patients. The addition of cetuximab to GEMOX was well tolerated and exhibited a high response rate (38%). Myelosuppresion and rashes were commonly noted toxicities with this regimen.³¹

Vascular Endothelial Growth Factor Receptor Inhibitors

Based on the encouraging results of a phase II study, gemcitabine plus bevacizumab, a recombinant humanized monoclonal antibody to VEGFR, was tested in a phase III randomized trial by CALGB. A total of 602 patients with unresectable PC were randomized to gemcitabine (1000mg/m2 D1, ^{8, 15}) plus bevacizumab (10mg/kg D1 and 15) and gemcitabine plus placebo (with a dosing schedule identical to the bevacizumab arm). The CALGB Data Safety Monitoring Board released study data in June 2006 because a futility boundary had been crossed. The study was unblinded on June 26, 2006.

Preliminary results were presented at the Gastrointestinal Symposium in January 2007. The conclusion of this study was that the addition of bevacizumab to gemcitabine did not improve survival in MPC.³² Of note is that more patients with ECOG performance status of zero were enrolled in the phase II study than in the phase III study, all patients had APC in the phase III study versus APC and LAPC in the phase II study, and 23% had received prior radiotherapy among phase II patients versus 11% in the phase III study. A GEMOX plus bevacizumab combination in a phase II trial including 82 patients with MPC showed six-month survival of 68% (95% CI: 57.1–81.0) and MS of 9.4 months (95% CI: 7.2–11.0).³³ The combination of gemcitabine with sorafenib, a small-molecule multikinase inhibitor, was tested in a small phase II trial of patients with MPC.33 Sorafenib was dosed at 400mg twice daily for 28 days along with gemcitabine 1000mg/m2 on days one, eight, and 15 in a 28-day cycle. In this small study of 17 patients, the combination regimen was well tolerated but was inactive. Sorafenib, in addition to inhibiting VEGF, inhibits the raf-1 kinase and platelet-derived growth factor receptor (PDGFR) tyrosine kinase, and may have enhanced activities compared with bevacizumab, which only inhibits VEGF. A larger study has been proposed to investigate its activity. Ras-farnesyltransferase Inhibitors and Matrix Metalloproteinase Inhibitors Ras-farnesyltransferase inhibitors and matrix metalloproteinase inhibitors were shown to be ineffective against MPC as single agents or in combination in various phase III trials. Studies combining targeted agents are being pursued in Europe and the US.³⁴

Conclusions

Although we have made incremental progress in the treatment of PC, the prognosis of patients with this disease remains extremely poor. Gemcitabine plus erlotinib or capecitabine is considered the standard of care for APC patients in North America. In pilot studies of modern combination chemotherapy, responses may exceed those of single-agent gemcitabine, but with added toxicities. However, patients with LAPC seem to derive more benefit from combination chemotherapy than those with APC, and should be studied separately in future studies. The role of XRT in the adjuvant therapy remains split between the US and Europe. We definitely need to identify surrogates for survival. In addition, oncologists need to change their attitude toward clinical trials. The development of novel agents and approaches is urgently needed in conjunction with improvement in access to clinical trials for patients.