Multidisciplinary Management of Resectable Rectal Cancer

Multidisciplinary Management of Resectable Rectal Cancer

ABSTRACT: The standard adjuvant therapy for resectable T3 and/or N1-2 rectal cancer is pelvic radiation therapy plus fluorouracil (5-FU)-based chemotherapy. Two randomized intergroup trials, INT 0114 and INT 0144, will help determine the ideal chemotherapeutic agents and their routes of administration in the postoperative setting. The randomized National Surgical Adjuvant Project for Breast and Bowel Cancers trial NSABP R-03 and the INT 0147 trial will compare the efficacy and functional results of the preoperative and postoperative combined-modality therapy approaches. The delivery of effective therapies, as well as the development of more innovative approaches, is enhanced by a multidisciplinary collaboration among medical, surgical, and radiation oncologists. [ONCOLOGY 10(11):1701-1714, 1996]


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 (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,[1] as well as following less radical surgery, such as
a local excision,[2] 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.[3] 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.[4] Likewise, the ability to deliver effective doses
of chemotherapy depends on careful integration of this modality
with radiation and surgery.

Postoperative Therapy

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,[3]
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%.[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).[6] 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.[7]

Radiation Therapy

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).[11]
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.

Combined-Modality Therapy

Three major randomized trials of postoperative combined-modality
therapy have been conducted in patients with resectable rectal

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

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.[15] 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.[16]

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.[11] 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).[17] Other results are pending.

Intergroup Trials--The most recent trial to complete accrual
is the Intergroup postoperative adjuvant trial INT 0114 (Figure
). 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

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

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.[19] 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.[20]


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