Combined-modality therapy is an integral part of 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 and, in the preoperative setting, increase the chance of sphinter preservation.[Editor's Note: An article on sphincter-preserving operations for rectal cancer begins on page 00.] In patients with locally advanced/unresectable disease, preoperative radiation therapy has the added role of increasing the resectability rate. The role of chemotherapy, regardless of the patient's resectability status, is to enhance the benefits of radiation, as well as improve survival by decreasing the incidence of distant metastasis.
This discussion will be limited to patients with resectable rectal cancer who are treated in the adjuvant setting. It will examine the results of recently completed randomized trials, as well as the rationale of the designs of the ongoing trials. The role of adjuvant therapy in patients with locally advanced/unresectable disease, as well as following less radical surgery, such as a local excision, has been previously reviewed and will not be discussed.
It must be emphasized that rectal cancer is best managed via a multidisciplinary approach. This requires close collaboration among medical, surgical, and radiation oncologists. Only with a mutual understanding of the relative benefits and risks of each modality will effective therapy be delivered and new approaches developed. For example, radiation-related complications can be reduced when the surgeon excludes the small bowel from the radiation field. Surgical complications are decreased in patients who receive pelvic radiation therapy with multiple-field (three- or four-field) techniques, as opposed to less sophisticated two-field techniques. Likewise, the ability to deliver effective doses of chemotherapy depends on careful integration of this modality with radiation and surgery.
The postoperative approach has several advantages: The stage is already known, thereby sparing patients with stages T1-2, N0, M0 or metastatic disease from treatment. Also, the placement of clips at the time of surgery allows for more accurate definition of the tumor bed for radiation planning. Disadvantages include an increased amount of small bowel in the radiation field, a potentially hypoxic postsurgical radiation field, and, if the patient has undergone an abdominoperineal resection, the need to extend the field inferiorly to include the perineal scar.
Some physicians contend that adjuvant therapy is not necessary if patients 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%. However, these data must be interpreted with caution, since this procedure permits the identification and exclusion of patients with more advanced disease. This contrasts with patients treated in the adjuvant trials, in whom more conventional surgery is performed. In addition, some patients with T3 and/or N1-2 disease received radiation therapy with or without chemotherapy (eg, 28% of patients in the series of Enker et al). Furthermore, total mesorectal excision may be associated with higher complication rates. In the Basingstoke Hospital experience of 219 patients who underwent a total mesorectal resection, 11% had major anastomotic leaks and 6% had minor leaks.
Nonrandomized data reveal a local recurrence rate of 4% to 31% in patients with stage T3-4, N0, M0 disease who receive conventional doses of postoperative radiation (4,500 to 5,500 cGy) and 8% to 53% in those with stage T3-4, N1-2, M0 disease who receive such therapy.[8-10] When local recurrence does occur, it is severely debilitating and salvage has been of limited success. Therefore, even though radiation does not influence survival, its impact on local recurrence is, by itself, an important quality-of-life end point.
Three randomized trials have examined the use of adjuvant post-operative radiation therapy alone in stages T3 and/or N1-2 rectal cancer (Table 1).[11-13,45] The only randomized trial that suggested a favorable effect of radiation therapy on local recurrence (with borderline significance) is the National Surgical Adjuvant Breast and Bowel Project (NSABP) trial R0-1. In this trial, patients who received adjuvant radiation had a decrease in local recurrence that was of borderline statistical significance, compared with patients treated with surgery alone (16% vs 25%; P = .06). It should be noted that of the three trials, NSABP R0-1 is the only one in which the radiation was delivered with a continuous course, full doses, and modern techniques.
Three major randomized trials of postoperative combined-modality therapy have been conducted in patients with resectable rectal cancer.
GITSG Trial--The Gastrointestinal Tumor Study Group (GITSG) randomized 202 patients to receive postoperative radiation therapy, 5-FU/semustine (methyl-CCNU), radiation plus 5-FU/methyl-CCNU, or surgery alone.[13,14] The survival rate was significantly higher in patients who received combined-modality therapy than in those who underwent surgery alone (54% vs 27%; P = .005). There was no significant difference in survival in the radiation-only or chemotherapy-only arms when compared with the surgery control arm.
Mayo/NCCTG Trial--In the Mayo/North Central Cancer Treatment Group (NCCTG) 79-47-51 trial, 204 patients were randomized to receive either postoperative radiation therapy or postoperative radiation plus 5-FU/methyl-CCNU. This trial had no surgery-only control arm. Patients who received combined-modality therapy had a significantly lower rate of local recurrence than did patients in the radiation therapy control arm, (14% vs 25%; P = .036), and a lower rate of distant failure (29% vs 46%; P = .011), as well as increased rates of 5-year disease-free survival (63% vs 42%; P = .0016) and overall survival (57% vs 48%; P = .025).
As a follow-up to this study, the Mayo/NCCTG designed a four-arm trial (86-47-51) to determine whether methyl-CCNU is necessary and to compare the relative effectiveness of bolus vs continuous-infusion 5-FU. All patients in the follow-up study received postoperative radiation and were randomized to receive concurrent bolus 5-FU, with or without methyl-CCNU, vs continuous- infusion 5-FU, with or without methyl-CCNU. This study showed that methyl-CCNU does not improve either local control or survival. Therefore, it is no longer used in the adjuvant treatment of rectal cancer.
Compared with patients given bolus 5-FU (with or without methyl-CCNU), 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 an improvement in 4-year survival (70% vs 60%; P = .005). The two groups did not differ with regard to the incidence of local relapse as the first site of failure.
The toxicities of continuous-infusion and bolus 5-FU were different. During the combined-modality segment, patients who received continuous-infusion 5-FU had a significant increase in grade 3 or higher diarrhea, compared with patients treated with bolus 5-FU (24% vs 14%; P less than .01), whereas the continuous-infusion group had a significant decrease in grade 3 or higher leukopenia (2% vs 11%; P less than .01). Therefore, if 5-FU is used as a single agent with radiation therapy, it is more effective as a continuous infusion than as a bolus.
NSABP Trials--In the NSABP R0-1 trial, 528 patients were randomized to postoperative MOF (methyl-CCNU, Oncovin, and 5-FU) chemo- therapy, radiation therapy, or surgery alone. For the total patient group, there were significant increases in 5-year disease-free survival (42% vs 30%, P = .006) and overall survival (53% vs 43%; P= 0.05) in patients who received chemotherapy compared with surgery. Rates of disease-free or overall survival did not differ significantly between patients who received radiation and those treated surgically.
Several concerns have been raised about the interpretation of the NSABP R0-1 data. First, the patterns of failure did not correlate with the differences in survival. For example, despite the advantage in disease-free and overall survival in the chemotherapy arm over the surgery arm, there were no differences in either locoregional failure (21% vs 25%) or distant failure (24% vs 26%). In fact, only the radiation arm showed a favorable influence on locoregional failure compared with surgery (16% vs 25%; P = .06).
The second concern centers on the conflicting results of the subset analysis. According to logistic regression analysis, the advantage in overall survival in patients who received chemotherapy vs surgery was limited to node-negative patients (80% vs 57%); no difference in overall survival between the two modalities was seen in node-positive patients (37% vs 35%). Furthermore, the benefit of chemotherapy on overall survival was limited to males (60% vs 37%) and males under 65 years of age (44% vs 26%). Indeed, chemotherapy appeared to have an adverse impact on survival in females. Females who received chemotherapy had a lower survival than those treated with surgery alone(37% vs 54%). Other series have not reported these differences by gender or nodal status.
Based on these findings, the NSABP designed the R0-2 trial, in which patients, depending on gender, were randomized to MOF, with or without radiation, or 5-FU/leucovorin, with or without radiation. Men were randomized to all four arms, whereas women were randomized only to 5-FU/leucovorin with or without radiation. Preliminary analysis revealed a significant decrease in local recurrence in the two arms that included combined-modality therapy, as compared with the two arms that used chemotherapy alone (7% vs 11%; P = .045). Other results are pending.
Intergroup Trials--The most recent trial to complete accrual is the Intergroup postoperative adjuvant trial INT 0114 (Figure 1). In this four-arm trial, all patients received six cycles of postoperative chemotherapy and concurrent radiation therapy (5,040 cGy) during cycles 3 and 4. The goal of the trial was to determine whether combinations of 5-FU-based chemotherapy--5-FU/leucovorin (low dose) vs 5-FU/levamisole (Ergamisol) vs 5-FU/leucovorin/levamisole-- were superior to 5-FU as a single agent. Preliminary results presented in abstract form suggest that the three-drug combination (5-FU/leucovorin/levamisole) is not superior to the other two combinations or to single-agent 5-FU.
Building on the positive results of continuous-infusion 5-FU reported in the Mayo/NCCTG 86-47-51 trial, the intergroup replacement postoperative adjuvant rectal trial INT 0144 (SWOG 9304) is currently testing whether there is a benefit to administering continuous-infusion 5-FU throughout the entire chemotherapy course (six cycles), as compared with giving the continuous infusion only during the combined-modality segment (two cycles) and bolus 5-FU during the remaining four cycles (Figure 2). The control arm is arm 4 of INT 0114 (bolus 5-FU/leucovorin/levamisole).
Impact on Sphincter Function--Postoperative combined-modality therapy can affect sphincter function. Kollmorgen et al compared bowel function in patients who received postoperative combined-modality therapy with function in a matched group of patients who underwent surgery alone. It should be emphasized that this was a nonrandomized, nonblinded, telephone survey. Patients who received combined-modality therapy had significant increases in the number of bowel movements, clustering of bowel movements, nighttime bowel movements, occasional incontinence, and urgency and also wore pads more often.
Data from Memorial Sloan-Kettering Cancer Center (MSKCC) also suggest that postoperative radiation therapy (with or without chemotherapy) can have a negative impact on sphincter function (increased stool frequency and difficulty with evacuation) in patients who undergo a coloanal anastomosis.