Protracted Venous Infusion 5-Fluorouracil With Concomitant Radiotherapy Compared With Bolus 5-Fluorouracil for Unresectable Pancreatic Cancer

Abstract

Radiation therapy (RT) with concurrent 5-fluorouracil (5-FU) administered by protracted venous infusion (PVI) replaced our prior institutional protocol of RT with bolus administration of 5-FU as standard therapy for unresectable pancreatic cancer in 1994. In this article, we compare the treatment intensity, toxicity, and outcome for patients with unresectable pancreatic cancer treated on these sequential protocols. Fifty-four patients, 27 on each protocol, with biopsy-confirmed pancreatic cancer received chemoradiotherapy. The radiotherapy field included the gross tumor volume and regional lymph nodes to a dose of 45 Gy, followed by "boost" to the gross tumor volume to 54 Gy to 60 Gy. From 1987 to 1994, patients received concurrent 5-FU administered by bolus injection, at a dose of 500 mg/m2 on days 1 to 3 and days 29 to 31 of RT. After December 1994, 5-FU was administered by PVI (200-250 mg/m2) beginning on day 1 and continuing until the completion of RT. The chemotherapy treatment intensity was increased in the group receiving 5-FU by PVI, as evidenced by an increased average weekly and cumulative dose of 5-FU (p < 0.01). The radiotherapy treatment intensity was equivalent between the two groups. The incidence of objectively quantified toxicity was not statistically different between treatment groups. Overall survival remained poor in both treatment groups. With a median follow-up of 18 months (range: 3-30 months) for surviving patients, the 6-month, 1-year, and 2-year survivals for the PVI 5-FU-treated group versus the bolus 5-FU-treated group were 56% versus 52%, 34% versus 18%, and 22% versus 13%, respectively (p = 0.9). Radiotherapy with concomitant 5-FU by PVI results in a greater weekly and total dose of chemotherapy. The method of 5-FU administration (bolus versus PVI) did not change the RT treatment intensity, experienced toxicity, or overall survival.

Phase II Trial of Primary Radiation Therapy and Concurrent Chemotherapy for Patients with Locally Advanced Pancreatic Cancer

“…The best treatment in this trial was 4,000 cGy plus 5-FU [3]. Since then, many different studies have been performed, in which various schedules of chemotherapy agents (5-FU, GEM, paclitaxel, cisplatin) [4,5,6,7,8,9,23,24,25,26,27,28] were tested and different modalities of radiation treatment (conventional and rapid fractionation [8, 29]) were executed. GEM and radiation clearly show preclinical and clinical synergy but it is not possible to administer full-dose GEM with full-dose radiation.…”

“…Since then, several studies have explored different schedules of administration of 5-FU, but none has demonstrated any substantial improvement in survival [4,5,6,7,8,9]. The failure of these therapies to improve outcome has been attributed to the inability to obtain a local control and to inhibit the development of distant metastases.…”

Chemotherapy for pancreatic cancer

“…138 Protracted venous infusion of 5-FU and radiotherapy resulted in a 1-year survival of 34% compared to 18% for bolus 5-FU and radiotherapy. 139 Accelerated radiotherapy of three fractions per day (up to 50 Gy) with continuously infused 5-FU during 5 days in the first and third weeks produced a median survival of 36 weeks in locally advanced unresectable pancreatic cancer 140 and 12.7 months in another study (with folinic acid as well). 141 The maximum tolerated dose (MTD) of gemcitabine as a radiosensitiser (30-57 Gy) was determined to be between 250 and 440 mg/m 2 per week and attained median survivals of 6-12 months.…”

The Role of Neoadjuvant Therapy in Pancreatic Cancer: A Review

“…Data from prospective trials containing patients with borderline resectable disease demonstrate that the surgical resection rate ranges from 24 to 64%, and the R0 resection rate ranges from 87 to 100% [56][57][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77]. Although most of these studies are small, neoadjuvant chemoradiation appears to be associated with good potential for downstaging and R0 resection in this population, which may be in part due to careful patient selection with adequate staging studies, and strict adherence to the definition of borderline resectable.…”

“…Neoadjuvant therapy with the intent of sterilizing the margin could be considered in patients with vascular involvement, with particular attention to restaging to tailor surgical recommendations. Several studies suggest that neoadjuvant chemoradiation may enhance margin-negative resectability rates and improve local control [37,[56][57][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77]. Unfortunately, many of the studies are confounded by inclusion of patients with locally advanced unresectable tumors and lack of strict definition of borderline resectable disease.…”