The benefit for treating locally advanced, non-metastatic pancreatic cancer remains limited, with median survival ranging from eight to ten months43
. In the current study of 78 patients, a combination of gemcitabine and 5FU with radiation therapy conferred a median OS of 12.2 months and a median TTP of 10 months. In a previous phase I/II trial of gemcitabine, 5-FU and concurrent radiation therapy, we similarly observed a median survival of 12 months in patients with locally advanced disease. These results compare favorably to prior studies of 5-FU with radiation, which reported a median OS of nine months and a median TTP of eight months or less.
Following the initial studies of 5-FU and radiation therapy in locally advanced pancreatic cancer, subsequent studies have also yielded median survivals well above the historical level of nine months. This gradual improvement in outcome over the past several years is apparent for both studies of radiation with gemcitabine10, 11, 14, 15, 17–23, 44
and for other chemoradiation combinations3, 27, 39, 40, 45–50
. The reasons for this improvement are speculative, but may include slightly improved treatment regimens, improved staging which excluded patients with not easily apparent metastatic disease, improved supportive care, and improved salvage chemotherapy.
The current trial found the combination of 5FU and gemcitabine with concurrent radiation to be tolerable, though toxicity was moderate. Twelve percent of patients discontinued protocol therapy due to adverse events and 82% had at least one treatment modification. Our incidence of adverse events was comparable to other recent cooperative group trials in this patient population including a study of radiation with concurrent capecitabine and bevacizumab39
and a trial of radiation with concurrent gemcitabine and cisplatin29
. In contrast to a prior ECOG trial51
, the incidence and severity of gastrointestinal bleeding was manageable.
Our trial met its target of 50% of patients surviving for at least 9 months; 9-month survival was 73% and median overall survival was 12.2 months. A similarly designed trial of 32 patients combining higher doses of weekly gemcitabine and infusional 5-FU with radiation, followed by gemcitabine and cisplatin, observed a median OS of 13.6 months, although toxicity in that trial was considerable40
The merits of combined chemoradiation as initial treatment for locally advanced pancreatic cancer have been questioned by the results of a recent randomized trial that demonstrated a superior outcome for patients receiving gemcitabine alone compared to chemoradiation followed by gemcitabine6
. An alternative approach has been examined in which patients receive initial chemotherapy, with chemoradiation offered only to those patients without disease progression. In one retrospective study of 188 patients who had received three months of initial chemotherapy, 128 patients who did not demonstrate progressive disease received either further chemotherapy or combined chemoradiation. Although such non-randomized data must be interpreted with caution, the median progression free survival and OS for the patients receiving chemoradiation were 10.8 and 15 months, respectively, compared to 7.4 and 11 months for those treated with chemotherapy alone52
. Other investigations have similarly suggested a benefit to selecting patients for combined chemoradiation following induction chemotherapy53–55
. Such an approach potentially avoids radiation in patients who are destined to manifest metastatic disease, limiting local therapy to those who are most likely to derive a benefit. One promising strategy for future studies may be to build on this schedule of induction chemotherapy followed by chemoradiation with the addition of targeted agents emerging from an improved understanding of pancreatic cancer biology56–59
We have demonstrated the feasibility of combining both 5-FU and gemcitabine with radiation, with several long term survivors and a superior overall survival compared to historical levels of eight to ten months. Although this regimen has achieved the pre-defined goals of improving median survival beyond nine months with acceptable morbidity, the observed median survival of 12 months is similar to the results of other recent phase II trials in patients with locally advanced pancreatic cancer. Given the multiple other treatment regimens that similarly appear to confer a 12-month median survival, we do not recommend further study of this treatment combination in future trials.