Current and Future Directions in Adjuvant Combined-Modality Therapy of Rectal Cancer

Introduction

Combined-modality therapy is integral to the adjuvant management of rectal cancer. There are two components of adjuvant therapy: pelvic radiation and fluorouracil(Drug information on fluorouracil) (5-FU)-based chemotherapy. In patients with clinically resectable disease, the role of radiation is to decrease local recurrence; in the preoperative setting, radiation increases the chance of sphincter preservation. The role of chemotherapy, regardless of resectability status, is to further enhance the benefits of radiation, as well as improve survival.

This review will examine the current and future directions of adjuvant combined-modality therapy for resectable rectal cancer. It will focus on the results of recent randomized trials as well as on the rationale and design of ongoing and planned trials.

Postoperative Combined-Modality Therapy

Of the four major randomized trials of postoperative combined-modality therapy, one—the National Surgical Adjuvant Breast and Bowel Project R0-1 trial—did not include a combined-modality arm and will not be discussed further.[1]

The Gastrointestinal Tumor Study Group randomized 202 patients to four treatment arms: postoperative radiation therapy, 5-FU/MeCCNU chemotherapy, radiation plus 5-FU/MeCCNU combined-modality therapy, or surgery alone.[2,3] There was a significant increase in survival for combined-modality therapy patients compared with those who had surgery alone (54% vs 27%; P = .005). There was no significant difference in survival for the radiation-only or chemotherapy-only arms compared with the surgery-only control arm.

In the Mayo/North Central Cancer Treatment Group 79-47-51 trial, 204 patients were randomized to either postoperative radiation therapy or postoperative radiation plus 5-FU/MeCCNU.[4] There was no surgery-only control arm. Patients who received combined-modality therapy had significant decreases in local recurrence (14% vs 25%; P = .036) and distant failure (29% vs 46%; P = .011) and increases in 5-year disease-free survival (63% vs 42%; P = .0016) and overall survival (57% vs 48%; P = .025), compared with the radiation therapy control arm. Based on the Gastrointestinal Tumor Study Group and Mayo/North Central Cancer Treatment Group trials, the National Cancer Institute Consensus Conference concluded that pelvic radiation plus 5-FU–based chemotherapy is the standard postoperative adjuvant treatment for T3 and/or node-positive rectal cancer.[5]

In the National Surgical Adjuvant Breast and Bowel Project R0-2 trial, patients were randomized, based on gender, to either MeCCNU/vincristine (Oncovin)/5-FU ± radiation or 5-FU/leucovorin ± radiation. Men were randomized to all four arms, whereas women were randomized only to the 5-FU/leucovorin ± radiation arms. Preliminary analysis revealed a significant decrease in local recurrence in the two combined-modality arms compared with the two chemotherapy-alone arms (7% vs 11%; P = .045).[6] Other results are pending.

Since the publication of the National Cancer Institute Consensus Conference recommendations, the primary goals of the Intergroup postoperative adjuvant trials have been to determine the ideal chemotherapeutic agents and to identify their best method of delivery. The most recent trial to complete accrual, the Intergroup postoperative adjuvant trial Intergroup 0114 (Figure 1[7]), was a four-arm trial in which all patients received six cycles of postoperative chemotherapy with concurrent radiation therapy given during cycles 3 and 4. The goal of this trial was to determine whether various combinations of bolus 5-FU–based chemotherapy (5-FU/leucovorin [low dose] vs 5-FU/levamisole [Ergamisol] vs 5-FU/leucovorin/levamisole) were superior to 5-FU alone. Preliminary results presented in abstract form suggest that arm 4 (5-FU/leucovorin/levamisole) was not superior to arms 1-3.[8]

Phase II trials suggest that when 5-FU is given with radiation, protracted continuous intravenous infusion 5-FU may be more effective than bolus administration. In a follow-up study of the Mayo/North Central Cancer Treatment Group 79-47-51 trial, the Mayo/North Central Cancer Treatment Group designed a four-arm trial (86-47-51) to determine whether MeCCNU is necessary and to compare the relative efficacy of bolus vs continuous-infusion 5-FU. All patients received postoperative radiation and were randomized to receive concurrent bolus 5-FU ± MeCCNU vs continuous-infusion 5-FU ± MeCCNU. As the addition of MeCCNU did not improve either local control or survival, it is no longer used in the adjuvant treatment of rectal cancer.[9] Administration of 5-FU, however, was shown to be significant: Compared with patients who received bolus 5-FU (± MeCCNU), patients who received continuous-infusion 5-FU had significant decreases in the overall rate of tumor relapse (37% vs 47%; P = .01) and distant metastasis (31% vs 40%; P = .03), as well as improved 4-year survival (70% vs 60%; P = .005). There were no significant differences in the incidence of local failure.

The toxicities of 5-FU via bolus and continuous infusion were different. During the combined-modality segment, patients who received continuous-infusion 5-FU had a significant increase in grade 3+ diarrhea (24% vs 14% for bolus 5-FU recipients; P < .01) and a significant decrease in grade 3+ leukopenia (2% vs 11%; P < .01). Continuous infusion, single-agent 5-FU was thus shown to be more effective than bolus 5-FU when 5-FU was combined with radiation therapy.

Building on the positive results of continuous-infusion 5-FU reported in the Mayo/North Central Cancer Treatment Group 86-47-51 trial, the replacement postoperative adjuvant rectal trial, Intergroup 0144 (Southwest Oncology Group 9304), tests whether continuous-infusion 5-FU delivered throughout the entire chemotherapy course (six cycles) may be of greater benefit than continuous-infusion 5-FU delivered only during the combined-modality segment (two cycles), with bolus 5-FU administered during the remaining four cycles (Figure 2[7]). The control arm is identical to arm 4 (bolus 5-FU/leucovorin/levamisole) of Intergroup 0114. This trial is actively accruing participants.

Although the Mayo/North Central Cancer Treatment Group trial 86-47-51 revealed an advantage to continuous-infusion 5-FU over bolus 5-FU, continuous infusions are more labor-intensive to deliver: They require an external pump, weekly visits to refill the pump, and dedicated venous access. An oral agent such as UFT (tegafur and uracil) may thus offer an alternative to continuous-infusion 5-FU. In order to design trials that integrate UFT with radiation therapy in the adjuvant setting, it is important to first understand its mechanism of action, toxicity, and response rates in patients with advanced disease.

Clinical Experience With UFT in Patients With Advanced Disease

UFT is a combination of uracil and tegafur(Drug information on tegafur) in a 4:1 molar ratio. The prodrug tegafur (1-(2-tetrahydrofuryl)-5-fluorouracil) is absorbed orally and metabolized in vivo to 5-FU.[10] Laboratory studies have indicated that administration of uracil with tegafur enhances intracellular 5-FU concentrations.[11] Further studies have indicated that the addition of uracil to tegafur results in improved cytotoxicity in animal models.[12] This effect is thought to occur as a result of uracil’s saturation of hepatic dihydropyrimidine dehydrogenase, the rate-limiting enzyme in 5-FU catabolism.[13]

Leucovorin has gained wide clinical acceptance as a biomodulator of 5-FU. Pharmacokinetic evidence suggests adequate bioavailability of leucovorin when given orally (PO),[14] and clinical studies have demonstrated that prolonged low-dose 5-FU infusions are modulated by low doses of oral leucovorin.[15]

With this background, phase I studies of oral UFT and low-dose leucovorin were performed in patients with advanced rectal cancer. These studies were designed to identify the recommended phase II dose of UFT given every 8 hours with a fixed 5-mg dose of leucovorin, also given every 8 hours, for 28 consecutive days. It was postulated that this oral schedule might approximate the pharmacologic equivalent of a continuous 5-FU infusion while at the same time provide the convenience of oral administration. The choice of leucovorin dose was based on the use of similar doses and schedules of oral leucovorin with continuous 5-FU infusions.[15,16] The recommended phase II dose of UFT with 5 mg leucovorin was determined to be 350 mg/m²/d administered every 8 hours.

Following the identification of the recommended dose, a phase II trial was performed.[17] Of the 21 patients with measurable metastatic colorectal cancer who were entered into the study, 20 were evaluable for response. Five (25%) major objective responses (one complete, four partial) were documented. With a median follow-up of 12 months (range, 2 to 16+), median survival had not yet been reached.

This combination of UFT and leucovorin was generally well tolerated. No patients experienced grade ³ 3 myelosuppression. Three patients had grade 3 diarrhea (grade 4 in one patient). No patients experienced hand-foot syndrome, and only two episodes of mucositis were severe enough to delay treatment. There was no correlation between response and toxicity.

Oral treatment regimens for colorectal cancer have been explored by several investigators. Use of tegafur alone at a dose of 1 g/m²/d for 14 consecutive days yielded a 17% major response rate in 18 patients with advanced colorectal cancer; non–dose-limiting neurologic toxicity occurred in 25% of patients.[18] By potentiating the 5-FU derived from tegafur, uracil permits use of a lower total tegafur dose. This may account for the absence of neurotoxicity with UFT.

Other investigators have reported on different treatment schedules. UFT— with higher leucovorin doses (leucovorin 50 mg PO q8h with UFT for 28 days)[19] and with oral and parenteral leucovorin (leucovorin 500 mg intravenously day 1, then 15 mg PO q12h days 2 to 4, with UFT given days 1 to 14)[20]—has, in these preliminary reports, also demonstrated activity in patients with colorectal cancer. In the absence of direct randomized comparisons, however, it is impossible to determine the superiority of one regimen over another. The UFT dose of 300 mg/m²/d q8h with leucovorin 25 mg taken orally with each dose (75 mg/d) has been selected for further development in North America and comprises the investigational arm of an ongoing phase III trial in patients with metastatic colorectal cancer. This dose and schedule is also the basis for the phase I dose-escalation trials of postoperative combined-modality therapy conducted at the Memorial Sloan-Kettering Cancer Center and of preoperative combined-modality therapy at The University of Texas M.D. Anderson Hospital.

Since the drugs in this regimen are absorbed from the digestive tract, one would anticipate high drug levels in both the portal circulation and liver parenchyma. This, coupled with the convenience of oral administration, makes UFT/leucovorin an attractive regimen for investigation in the adjuvant setting.