Combined Modality with Chemoradiation Therapy

5-FU-based Chemoradiation Therapy

5-FU-based CRT has been the mainstay approach since the Mayo Clinic published randomized trial data showing prolonged MS by addition of 5-FU to XRT in 1969.¹² This result was supported by GITSG when they reported a significant survival benefit (one-year survival rate 40 versus 10%) of 5-FU-based CRT over radiation only.¹³ In the US, commonly accepted practice is to use infusional 5-FU rather than bolus 5-FU as a radiosensitizer based on experience with other gastrointestinal cancers. A few small studies have demonstrated that capecitabine has the potential to be a substitute for infusional 5-FU in the treatment of locally advanced pancreatic cancer (LAPC).^14,15

Gemcitabine-based Chemoradiation Therapy

Gemcitabine-based CRT has been investigated since the benefit of gemcitabine over 5-FU in APC was reported. Optimal administration strategies for this regimen are still being investigated in clinical-trial settings. Due to high toxicity with this regimen in early trials, the Cancer and Leukemia Group B (CALGB) conducted a phase II trial of concurrent XRT (50.4Gy) and low-dose weekly gemcitabine (40mg/m2 twice weekly) in patients with LAPC. This regimen rendered a disappointing median OS rate of 8.2 months.¹⁶ However, in patients with an Eastern Co-operative Oncology Group (ECOG) performance status score of zero, MS was 13.7 months. The Hoosier Oncology Group (HOG) treated patients with LAPC with weekly gemcitabine (600mg/m2) with concurrent XRT (50.4Gy) followed by gemcitabine monotherapy. This regimen showed more favorable side-effect profiles along with a promising one-year survival rate of 31.1%.¹⁷

Paclitaxel-based Chemoradiation Therapy

Paclitaxel has shown activity against LAPC in combination with XRT. The Brown University Oncology Group reported a 26% response rate in 42 patients with LAPC.¹⁸ A phase II trial with the combination weekly paclitaxel plus XRT has been conducted (RTOG 9812) and data are maturing.¹⁹ Newer technologies in XRT, including three-dimensional conformal RT, which allows reduction of radiation fields and optimization of radiation-sensitizing chemotherapy, will improve treatment of LAPC in the future.

Is the Therapeutic Index Better with Gemcitabine Radiation Therapy than with 5-FU Radiation Therapy?

A review of the literature suggests significantly higher severe toxicity rates with gemcitabine than with 5-FU when used as a radiosensitizer in LAPC. Median and one-year survivals were not significantly different with the use of concurrent gemcitabine versus 5-FU in an exploration published by MD Anderson Cancer Center. A small number of patients with (minimal arterial involvement) unresectable disease had margin-negative resections after treatment with gemcitabine-XRT. These possible benefits and the high rate of severe toxicity define a very narrow therapeutic index for concurrent gemcitabine-based chemo-XRT given by this schedule of administration. Despite the absence of any randomized studies in LAPC comparing capecitabine with 5-FU, capecitabine offers a more convenient and relatively less toxic radiosensitizer than intravenous 5-FU.

Chemotherapy Alone

A randomized phase III trial by Chauffert et al. evaluated whether 5-FU-based CRT can improve benefits of gemcitabine monotherapy. Patients with LAPC were randomized 1:1 between the CRT arm (60Gy in six weeks, 2Gy/fraction, concomitant with 5-FU, 300mg/m2/24h as a continuous infusion, days one to five every week and cisplatin, 20mg/m2/d, days one to five at week one and week five) or gemcitabine (1000mg/m2 weekly on a schedule of seven weeks on and one week off) as induction therapy. Both arms received gemcitabine 1000mg/m2 weekly on a schedule of three weeks on and one week off as maintenance therapy. This study was closed early due to the lower survival rate in the induction CRT arm compared with the gemcitabine-alone arm (MS: 8.4 versus 14.3 months).²⁰ One potential reason for this difference is that the toxicity from CRT resulted in decreased used of maintenance gemcitabine. Patients with LAPC have been included in clinical trials for metastatic pancreatic cancer (MPC), and chemotherapy alone has been the accepted treatment of LAPC. Recent trials with various chemotherapy regimes in PC—including LAPC—patients have suggested that the palliative and survival benefits from chemotherapy alone may be equivalent to CRT. Various chemotherapy regimen tested in this setting will be discussed in the following section.

Advanced Pancreatic Cancer

Up to 60% of patients have metastatic disease at the time of diagnosis. The MS rates of these patients are dismal at between three and six months.² After the approval of gemcitabine in 1997 (see Table 3), many cytotoxic and targeted agents have been pitted against, or combined with gemcitabine in randomized phase III trials (see Tables 4 and 5). No drug was shown to be superior to single-agent gemcitabine. This bleak landscape finally changed after two large, randomized, phase III studies in APC demonstrated the superiority of a gemcitabine-containing combination over single-agent gemcitabine: capecitabine plus gemcitabine (GEMCAP) and erlotinib plus gemcitabine, as detailed below.