UFT Plus Calcium Folinate Plus Radiotherapy for Recurrent Rectal Cancer

ABSTRACT: Uracil and tegafur (in a molar ratio of 4:1 [UFT]) plus calcium folinate comprise the components of the oral agent, Orzel, which appears to have activity comparable to intravenously administered 5-fluorouracil. This article describes the design of an open-label, disease-oriented, phase I trial of UFT plus calcium folinate in combination with simultaneous pelvic radiation for recurrent rectal cancer. This trial is designed to determine the maximum tolerated dose and dose-limiting toxicity of this regimen. [ONCOLOGY 7(Suppl 3):125-126, 1999]

Introduction

Despite a number of advances over the past decade in the adjuvant management of resectable rectal cancer, the disease remains a significant problem worldwide. Treatment failure results from both local disease recurrence and distant hemato- genous spread.[1] The median time to local relapse among patients treated with surgery alone is only 12 months. Pelvic irradiation can decrease local recurrence in patients with clinically resectable T3 and/or N1-3, M0 disease. The addition of systemic chemotherapy further enhances local control and improves overall survival.[2]

Despite radical surgery, local failure frequently occurs in patients with transmural or lymph node–positive rectal cancer. Treatment options for recurrent rectal cancer depend on the nature of previous treatment, the general condition of the patient, and his or her life expectancy. If possible, the same principles of management are applied as those applied for locally advanced unresectable tumors.

Radiotherapy—an important palliative treatment modality—is used to diminish symptoms such as hemorrhage, bowel obstruction, and pain resulting from nerve involvement (especially when the sacrum is destroyed by a tumor). In such cases, radiation offers symptom control for 6 to 9 months, or delays the onset of these problems.[3] Further benefit can be gained from combined chemoradiation therapy, including 5-fluorouracil (5-FU). In a series from the Mayo Clinic,[4] 65 patients with locally unresectable recurrent colorectal cancer were assigned to receive either radiotherapy and 5-FU or radiotherapy and placebo. Median survival was 10.5 months in the placebo group vs 16 months in the 5-FU group.[4]

More recently, a number of new chemotherapeutic agents, either in clinical development or already approved, are being evaluated in place of 5-FU in the combined-modality treatment of recurrent rectal cancer. Irinotecan (CPT-11 [Camptosar]), oxaliplatin, and uracil and tegafur (UFT) plus calcium folinate (Orzel) are among those agents currently in trial.

UFT Plus Calcium Folinate in Recurrent Rectal Cancer

UFT is an orally available agent that appears to have activity comparable to intravenously administered 5-FU. The combination of UFT and the biochemical modulator, calcium folinate, should compare well with conventional regimens, with the added advantages of a favorable side-effect profile and ease of administration.

Two phase I trials are currently ongoing in the United States to investigate chemoradiotherapy with UFT plus calcium folinate. In one trial, chemoradiotherapy is being administered preoper- atively, and in the other, postoperatively.

Here, we present the details of our phase I, dose-escalating trial to evaluate the toxicity and feasibility of UFT plus calcium folinate along with pelvic irradiation in the treatment of recurrent rectal cancer.

Study Design

This open-label, phase I study is designed to assess the safety, dose-limiting toxicities, and maximum tolerated dose of UFT plus calcium folinate administered during radiotherapy to patients with relapsing rectal cancer. Treatment with oral UFT plus calcium folinate will begin concurrent with radiotherapy. The agent will be administered three times per day through 5 days, or longer if a radiation boost is administered.

Chemotherapy

Calcium folinate will be administered at a fixed dose of 90 mg/day. The dose of UFT will be escalated stepwise (Table 1) from 250 mg/m²/day to 400 mg/m²/day in cohorts of three or more patients, based on toxicity. If a dose-limiting toxicity is observed in at least one of three patients at any dose level, the cohort will be expanded to six patients. If no more than two of six patients in the expanded cohort meet the dose-limiting toxicity criteria, three patients will be entered into the next dose level and dose escalation will continue. If at any dose level except the first, three or more of six patients meet the dose-limiting toxicity criteria, this dose will be defined as the maximum tolerated dose.

Once the maximum tolerated dose has been determined, an additional 10 patients will be treated at one dose level below the maximum tolerated dose. The dose level of this enlarged cohort will also be the recommended dose for the phase II studies.

Radiation

For radiation treatment, linear accelerators (minimum energy 10 megavolts [MV]) will be used via an isocentric box technique. To spare the bowel as much as possible, lateral and anterior fields will be used to treat the pelvis. A prone position and belly board will be useful aids in this technique for displacing the small bowel out of the pelvis. In rectal cancer, the internal iliac and presacral lymph nodes are at risk for tumor spread and metastatic involvement, and should, therefore, be included in the target volume. The initial radiation field will encompass the primary tumor volume and the regional lymph nodes. Thereafter, a smaller field (boost) will be used to treat the primary tumor site.

The dose for the large field, including the tumor bed and the regional lymph nodes, will be 50.4 Gy, administered in 1.8-Gy single, daily fractions five times per week for 5 to 6 weeks. This will be followed by a boost of either 5.4 Gy or 9.0 Gy, depending on the extent of radical surgery (5.4 Gy in cases with R0 or R1 resection; 9.0 Gy in cases with gross tumor resection [R2]).

Definition of Outcome Criteria

Table 2 outlines the criteria for dose-limiting toxicities. The maximum tolerated dose for UFT plus calcium folinate administered with radiation will be defined as the dose level at which a dose-limiting toxicity occurs in three or more of six patients. The recommended dose for the phase II study will be one dose level below the maximum tolerated dose. Additional patients may be treated as needed at any dose level to more fully elucidate the dose-limiting toxicities.

Summary

This open-label, disease-oriented phase I trial aims to determine the maximum tolerated dose, dose-limiting toxicities, and recommended dose of UFT plus calcium folinate with concomitant radiation therapy for the treatment of recurrent rectal cancer in a phase II trial.

References:

1. DeVita VT, Hellman S, Rosenberg S: Cancer: Principles and Practice of Oncology, 5th ed, pp 1197-1234. Philadelphia, Lippincott-Raven, 1997.

2. O’Connell MJ, Martenson JA, Wieand H, et al: Improving adjuvant therapy for rectal cancer by combining protracted infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 331:502-507, 1994.

3. Aleman BMP, Bartlink H, Gunderson LL: The current role of radiotherapy in colorectal cancer. Eur J Cancer 31A(7-8):1333-1339, 1995.

4. Moertel CG, Childs DS Jr, Reitemeier RJ, et al: Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet 2(7626):865-867, 1969.