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

ABSTRACT: Standard adjuvant therapy for transmural (T3) and/or node-positive rectal cancer is pelvic radiation therapy plus fluorouracil (5-FU)-based chemotherapy. Randomized trials are in progress to help determine the ideal chemotherapeutic agents and their optimal routes of administration in this setting, as well as to compare the efficacy and functional results of the pre- and postoperative bolus 5-FU/leucovorin combined-modality therapy approaches. New phase I trials will determine the recommended doses of tegafur and uracil (UFT) with oral leucovorin plus pre- or postoperative radiation therapy.[ONCOLOGY 11(Suppl 10):61-68, 1997]

Introduction

Combined-modality therapy is integral to the adjuvant management of rectal cancer. There are two components of adjuvant therapy: pelvic radiation and 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 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.

UFT Plus Postoperative Radiation Therapy

Based on the experience in patients with advanced disease, a phase I dose-escalation trial of UFT plus oral leucovorin with concurrent radiation therapy for the postoperative treatment of patients with primary or recurrent rectal or colon cancer in the pelvis has been developed at the Memorial Sloan-Kettering Cancer Center (Figure 3). The goal of this study is to serve as a potential comparison with a continuous-infusion 5-FU–based combined-modality regimen. The doses and schedules are designed to be similar to the current Intergroup postoperative adjuvant trials in patients with rectal cancer. In these Intergroup trials, patients receive two cycles of 5-FU–based chemotherapy, followed by two chemotherapy cycles concurrent with pelvic radiation. Following a 4-week rest, an additional two chemotherapy cycles are administered. Since the schedule of chemotherapy with UFT (28 days of daily treatment, followed by a 1-week rest) is different from schedules for both bolus and continuous-infusion 5-FU–based regimens, modifications have been made to reflect these differences.

Two separate determinations of the maximum tolerated dose (MTD) will be made. First, the MTD of UFT with fixed doses of oral leucovorin and concurrent radiation will be defined. The MTD of UFT with fixed doses of oral leucovorin following completion of concurrent UFT/leucovorin and radiation will also be determined.

Preoperative Combined-Modality Therapy

Although the most common adjuvant approach for patients with clinically resectable T3 and/or node-positive disease is postoperative combined-modality therapy,[2,4,21] preoperative therapy is being used more frequently. The initial trials included radiation therapy alone, and more recent trials have used combined-modality therapy.

In patients with clinically resectable disease, a principal reason for preoperative radiation therapy has been to enhance sphincter preservation. Only two series[22,23] have reported results in patients who were prospectively examined by their surgeon prior to radiation therapy and were declared to require abdominoperineal resection; neither series used chemotherapy. The data suggest that preoperative radiation therapy allows sphincter preservation in approximately 80% of patients who undergo prospective examination by their surgeon and are judged clinically to need an abdominoperineal resection. Of those 80%, approximately 75% to 80% retained good to excellent sphincter function. Similar sphincter preservation rates have been reported with preoperative combined-modality therapy.[24] Additional experience is needed to fully assess the long-term efficacy and functional results of this approach.

A number of trials have reported on the use of preoperative combined-modality therapy. Most have included patients with locally advanced or unresectable disease.[25] This discussion will focus on the four preoperative combined-modality therapy trials in patients with clinically resectable disease (Table 1).[24,26-28]

Two trials employ bolus 5-FU[24,26], and two use continuous-infusion 5-FU.[27,28] In the trial of Chari et al,[26] patients received 45 Gy, and chemotherapy began within a week of starting radiation (5-FU [500 mg/m²] and cisplatin [20 mg/m²] bolus daily × 5 for two cycles). Patients in the trial reported by Grann and associates[24] received 50.4 Gy radiation and two monthly cycles (bolus daily × 5) of concurrent leucovorin (20 mg/m²) and 5-FU (325 mg/m²), followed by postoperative 5-FU/leucovorin.

Two trials have combined continuous-infusion 5-FU with preoperative radiation. Stryker and colleagues[28] reported results from 30 patients who received 45 to 50.4 Gy plus mitomycin and continuous-infusion 5-FU, and Rich et al[27] reported results from 77 patients who received 45 Gy with concurrent continuous-infusion 5-FU (300 mg/m²).

When data from the four series are combined, the incidence of grade 3+ toxicity during combined-modality therapy was 21% to 25%, pathologic complete response rates were 9% to 29%, and the incidence of local recurrence was 0% to 5%.[24, 26-28] The limited data do not allow a valid comparison of bolus vs continuous-infusion 5-FU.

Based on the positive results achieved with continuous-infusion 5-FU and radiation therapy in the postoperative setting,[9] investigators at The M.D. Anderson Hospital have designed a phase I dose-escalation trial of UFT, oral leucovorin, and concurrent preoperative radiation therapy for patients with clinical T3-4 disease. Similar in design to the Memorial Sloan-Kettering Cancer Center postoperative UFT trial, patients receive fixed doses of radiation and leucovorin and escalating doses of UFT.

Three randomized trials have been designed to evaluate preoperative vs postoperative combined-modality therapy for clinically resectable, T3 rectal cancer. Both North American trials use bolus 5-FU and leucovorin with the end points of patterns of failure, survival, sphincter preservation and function, and quality of life. The first trial (Intergroup 0147) is a trial comparing this preoperative regimen to arm 2 of the postoperative trial Intergroup 0114 (Figure 4[7]). The design of the treatment arms is identical in this trial, but the sequencing of therapy and surgery is different. Unfortunately, this trial recently closed due to lack of accrual.

The second trial, National Surgical Adjuvant Breast and Bowel Project R-03 (Figure 5[7]), has a similar design to Intergroup 0147, but patients receive six cycles of weekly 5-FU/high-dose leucovorin followed by a 3-week rest before combined-modality therapy. The combined-modality segment is identical to the schedule in Intergroup 0147. The R-03 trial allows patients to undergo local excision, whereas Intergroup 0147 requires conventional surgery.

The third preoperative combined-modality trial is the German trial CAO/ARO/AIO 94 (Figure 6). Its design resembles Intergroup 0147, except that patients receive continuous-infusion 5-FU rather than bolus 5-FU.

Because the use of combined-modality therapy is less common in Europe, the European Organization for the Research and Treatment of Cancer is performing a four-arm randomized trial to determine if bolus 5-FU/leucovorin given pre- and/or postoperatively is superior to preoperative radiation alone (Figure 7).

New Approaches

Although the results of combined-modality therapy are encouraging, the search for innovative treatment approaches needs to continue. Selected approaches include radiation fractionation and new chemotherapeutic agents.

Altered Radiation Fractionation Schemes

Various fractionation strategies have evolved to address the goal of enhancing tumor cell damage by radiation without increasing normal tissue injury.[29] The repair of subcellular injury, regeneration, cell cycle redistribution, and reoxygenation are all factors at the cellular level contributing to differences in how various normal tissues and tumors respond to fractionated radiation. The use of hyperfractionation and accelerated fractionation schemes takes advantage of some of these factors. A phase I trial from Lausanne[30] of postoperative accelerated hyperfractionation (1.6 Gy bid to 48 Gy) found this approach tolerable. Recent data from this group suggest that preoperative bid radiation is better tolerated than postoperative radiation.[31]

Although the late toxic effects of accelerated hyperfractionation should be the same as or, more likely, less than that observed with conventional fractionation schemes, acute normal tissue toxicity represents a major limitation. It is thus unlikely that these altered fractionated schemes can be combined successfully with adequate doses of systemic chemotherapy. Other techniques, such as hyperthermia,[32] radiosensitizers and -protectors,[33-35] and three-dimensional treatment planning and delivery[36,37] are under investigation.

New Chemotherapeutic Agents

New chemotherapeutic agents active against colorectal cancer, either in development or FDA–approved, include CPT-11 (Camptosar), tomudex, trimetrexate (Neutrexin), and oxaliplatin. Clinical trials examining the combination of some of these agents with pelvic radiation are under way. In patients with unresectable disease, Marsh et al[38] have combined chronobiologically “shaped” 5-FU infusions with preoperative radiation therapy. The rationale, preliminary data, and the design of the phase I dose-escalation trials with concurrent radiation therapy plus UFT have been discussed in detail.

Conclusions

Combined-modality therapy is integral to the adjuvant management of rectal cancer. The standard adjuvant therapy for resectable T3 and/or node-positive rectal cancer is pelvic radiation therapy plus 5-FU-based chemotherapy. The Intergroup 0114 and Intergroup 0144 randomized trials will help determine the ideal chemotherapeutic agents and their routes of administration in the postoperative setting. The National Surgical Adjuvant Breast and Bowel Project R-03 and Intergroup 0147 randomized trials will compare the efficacy and functional results of the preoperative and postoperative bolus 5-FU/leucovorin combined-modality therapy approaches. Phase I trials are in progress to determine the recommended doses of oral UFT with pre- or postoperative radiation therapy. In the future, UFT may provide an alternative approach for patients who require continuous-infusion 5-FU as part of their combined-modality regimen.

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