Adjuvant Therapy for Rectal Cancer: Results and Controversies

Introduction

During the past decade, significant advances have been made in the adjuvant management of patients with resectable rectal cancer. In patients with clinically resectable disease, pelvic radiation therapy decreases local recurrence and, when administered preoperatively, may increase the likelihood of sphincter preservation. The addition of systemic chemotherapy further enhances local control and improves survival.

This review will examine the results of adjuvant therapy for patients with clinically resectable rectal cancer, as well as selected controversies in adjuvant management. The development and results of ongoing and recently completed randomized trials, as well as the design of innovative phase I/II programs, will be discussed. The role of adjuvant therapy in patients with locally advanced/unresectable disease[1] and following less radical surgery, such as a local excision,[2] has been reviewed previously and will not be discussed.

Is Adjuvant Therapy Necessary?

Some physicians contend that adjuvant therapy is not necessary in patients with resectable rectal cancer if they undergo more extensive surgery. In one series, total mesorectal excision, which involves sharp dissection around the integral mesentery of the hind gut, decreased the local recurrence rate to 5%.[3] However, these data must be interpreted with caution, for several reasons. First, mesorectal excision allows for the identification and exclusion of patients with more advanced disease, as compared with patients treated in the adjuvant trials, in whom more conventional surgery is performed. This results in a clear selection bias.

In addition, some patients with T3 and/or N1-2 disease who underwent total mesorectal excision received radiation therapy with or without chemotherapy (ie, 28% in the series of Enker et al[4] and 18% in the series of Haas-Kock et al[5]).

Furthermore, total mesorectal excision may be associated with higher complication rates. In the Basingstoke Hospital experience of 219 patients who underwent total mesorectal resection, 11% had major and 6% had minor anastomotic leaks.[6] In the series reported by Aitken, operative deaths were excluded from the analysis.[7]

The Dutch CKVO 95-04 trial is examining the role of intensive, short-course, preoperative radiation therapy in patients who undergo a total mesorectal excision. Patients are randomized to an intensive, short course of radiation (500 cGy × 5) followed by surgery or to surgery alone. Postoperative radiation is reserved for patients in the surgery-only arm who do not undergo a curative resection. Investigator participation is limited to surgeons who have demonstrated proficiency in performing a total mesorectal excision. This trial is open to patient accrual.

The use of total mesorectal excision has increased awareness that careful surgical techniques are central to the successful management of rectal cancer. However, properly performed surgery should be considered a valuable component of treatment, not competitive with adjuvant therapy. The relative benefits and risks of total mesorectal excision (including effects on local control, survival, sphincter preservation and function, surgical morbidity and mortality, and quality of life) need to be documented more carefully.

Postoperative Therapy

The majority of patients with rectal cancer in United States undergo surgery and, if needed, receive postoperative therapy. The most compelling advantage of this approach is that it allows for pathologic staging. Although advances in preoperative imaging techniques permit more accurate patient selection, surgery plus postoperative therapy remains the most common approach.

Disadvantages of this approach include an increased amount of small bowel in the radiation field[8] and a potentially hypoxic postsurgical bed. Also, if the patient has undergone an abdominoperineal resection, the radiation field must be extended to include the perineal scar.

Results of Postoperative Therapy

Radiation Therapy Alone--Among patients who received conventional doses of radiation (4,500 to 5,500 cGy), nonrandomized data have shown a decrease in the local failure rate to 4% to 31% in patients with stage T3-4 N0 M0 disease and to 8% to 53% in those with stage T3-4 N1-2 M0 disease.[9-11] Five randomized trials have examined the use of adjuvant postoperative radiation therapy alone in stages T3 and/or N1-2 rectal cancer.[12-18] None of these trials showed an improvement in overall survival. Two trials revealed a decrease in local failure rate with postperative radiation: the National Surgical Adjuvant Breast and Bowel Project (NSABP) R-01 trial (16% vs 25% with surgery alone; P = .06)[12] and the Medical Research Council trial (21% vs 34%;P = .001).[17] Of the 5 trials, NSABP R-01 is the only one in which the radiation was delivered with a continuous course, at full dose, and with modern techniques.

Combined-Modality Therapy--Following the publication of randomized trials conducted by the Gastrointestinal Tumor Study Group (GITSG)[19] and the Mayo/North Central Cancer Treatment Group (NCCTG) trial 79-47-51,[20] which revealed a significant improvement in local control (Mayo/NCCTG) and survival (GITSG and Mayo/NCCTG) with postoperative radiation plus bolus fluorouracil(Drug information on fluorouracil) (5-FU) and semustine (methyl-CCNU [MeCCNU]), the National Cancer Institute (NCI) Consensus Conference concluded in 1990 that combined-modality therapy is the standard postoperative adjuvant treatment for patients with T3 and/or N+ disease.[21]

Most combined-modality therapy regimens include six cycles of 5-FU-based chemotherapy plus concurrent pelvic radiation. Six cycles of chemotherapy are thought to be necessary to treat systemic disease. In a randomized trial from Norway, 144 patients were randomized to postoperative radiation plus bolus 5-FU (500 to 750 mg/m² limited to days 1 and 2 of weeks 1, 2, and 3 of radiation) vs surgery alone.[22] Despite the use of 5-FU as a radiosensitizer rather than as systemic therapy, this combined-modality therapy regimen significantly decreased local recurrence (12% vs 30% with surgery alone; P = .01) and improved 5-year survival (64% vs 50%; P = .05).

Although these results with limited-dose 5-FU are encouraging, additional experience with this approach is needed before modifying the standard recommendation of six cycles of systemic chemotherapy.

Recent and Ongoing Intergroup Trials

Since the 1990 NCI Consensus Conference, the intergroup postoperative trials have focused on the identification of the optimal chemotherapeutic agents and their method of administration. As a follow-up to trial 79-47-51, the Mayo/NCCTG designed a four-arm trial (86-47-51) to determine whether methyl-CCNU is necessary, as well as to compare the relative effectiveness of bolus vs continuous-infusion 5-FU. Since methyl-CCNU did not improve either local control or survival, it is no longer recommended for the adjuvant treatment of rectal cancer.[23]

Compared with patients given bolus 5-FU with or without methyl-CCNU, patients who received continuous-infusion 5-FU had a significant decrease in the overall rate of tumor relapse (37% vs 47%; P = .01) and distant metastasis (31% vs 40%; P = .03), as well as an improvement in 4-year survival rate (70% vs 60%; P = .005). These data suggest that when 5-FU is used as a single agent with radiation therapy, it is more effective as a continuous infusion than as a bolus.

There were also differences in the individual acute toxicities of the continuous-infusion and bolus 5-FU regimens. For example, during the combined-modality segment, the incidence of grade 3+ diarrhea was significantly higher in patients who received continuous-infusion 5-FU than in those given bolus 5-FU (24% vs 14%; P < .01), whereas the incidence of grade 3+ leukopenia was significantly lower (2% vs 11%; P < .01).

Building on the positive results of continuous-infusion 5-FU reported in the Mayo/NCCTG 86-47-51 trial, the replacement postoperative intergroup trial INT 0144 was designed to determine whether there is a benefit of continuous-infusion 5-FU throughout the entire chemotherapy course (six cycles), as compared with continuous infusion only during the combined-modality segment (two cycles) and bolus 5-FU during the remaining four cycles. The control arm is arm 4 of INT 0114 (bolus 5-FU plus leucovorin plus levamisole(Drug information on levamisole) [Ergamisol]). This trial opened in 1993 and is actively accruing patients.

The NSABP R-01 three-arm trial of postoperative MOF (methyl CCNU, Oncovin, and 5-FU) vs radiation therapy vs surgery alone revealed that postoperative MOF chemotherapy significantly improved 5-year disease free survival (42% vs 30%; P = .006) and overall survival (53% vs 43%; P = .05) compared with surgery.[12] The overall survival advantage afforded by chemotherapy was most evident in males as a group (60% vs 37%) and in males under 65 years of age (44% vs 26%). In contrast, females who received chemotherapy experienced a lower survival (37% vs 54%).

As follow-up to the R-01 trial, the NSABP designed the R-02 four-arm trial, in which patients were randomized, depending on gender, to either MOF ± radiation or 5-FU/leucovorin ± radiation. A preliminary analysis revealed a significant decrease in local failure in the two combined-modality therapy arms compared with the two that arms did not include radiation therapy (7% vs 11%; P = .045).[24] Other results of this trial are pending.

The most recent Intergroup postoperative trial to report results is INT 0114.[25] In this four-arm trial, all patients received six cycles of postoperative chemotherapy plus concurrent radiation therapy during cycles 3 and 4. The goal of this trial was to determine whether combinations of 5-FU-based chemotherapy (5-FU/low-dose leucovorin vs 5-FU/levamisole vs 5-FU/leucovorin/levamisole) were superior to single-agent 5-FU.

With a median follow-up of 4 years, there have been no significant differences among the four arms with respect to local control or survival (Table 1). Although the total incidence of acute grade 3+ toxicity was similar in the four arms, there were individual differences among the regimens. For example, the 5-FU-alone arm had a higher incidence of hematologic toxicity, whereas the leucovorin containing arms had a higher incidence of diarrhea.[25] A subset analysis revealed that in all four arms, women had a significantly greater incidence of acute grade 3+ toxicity than men. The reason for this gender-related difference in toxicity is uncertain.