Adjuvant Postoperative Combined-Modality Therapy for Rectal Cancer

Introduction

For patients with T3 and/or nodepositive rectal
cancer, postoperative combined-modality therapy significantly
improves local control and survival. The focus of the Intergroup
trials of postoperative combined radiation/chemotherapy has been the
identification of the optimal chemotherapeutic agents and their
method of administration. Data from ongoing and recently completed
randomized trials in the postoperative setting will be discussed in
this article. Preoperative chemotherapy in clinically resectable
disease[1] and locally advanced/unresectable disease[2] has been
previously reviewed and will not be examined here.

Postoperative Combined-Modality Therapy Rationale

The majority of patients with rectal cancer in the United States
undergo surgery and, if necessary, receive postoperative adjuvant
chemotherapy plus radiation therapy. The most compelling benefit
achieved with this approach is the opportunity for pathologic
staging. Although advances in preoperative imaging techniques allow
for more accurate patient selection than was previously possible,
surgical staging still remains the most common approach to treatment.
Disadvantages include an increased amount of small bowel in the
radiation field,[3] a potentially hypoxic postsurgical bed, and, if
the patient has undergone an abdominoperineal resection, extension of
the radiation field to include the perineal scar.

Results

Based on nonrandomized data, conventional doses of radiation alone
(4,500 to 5,500 cGy) have been reported to decrease local failure to
between 4% and 31% in patients with stage T3-4, N0, M0 rectal cancer
and to between 8% and 53% in patients with stage T3-4, N1-2, M0
disease.[4-6] Data from five randomized trials failed to show
improvement in overall survival when adjuvant postoperative radiation
therapy was used alone in stages T3 and/or N1-2 rectal cancer,[7-13]
although local failure rates decreased in two trials (National
Surgical Adjuvant Breast and Bowel Project [NSABP] R-01: 16% vs 25%,
P = .06[7]; and the Medical Research Council: 21% vs 34%, P =
.001[12]). Of the five trials, the NSABP is the only one in which
radiation was delivered as a continuous course with full doses and
modern techniques.

Randomized trials from the Gastrointestinal Tumor Study Group
(GITSG)[14] and Mayo/North Central Cancer Treatment Group (NCCTG)
79-47-51[15] revealed a significant improvement in local control
(Mayo/NCCTG) and survival (GITSG and Mayo/NCCTG) among patients with
rectal cancer who received postoperative radiation plus bolus
5-fluorouracil (5-FU)/semustine (MeCCNU). Based on these results, in
1990, the National Cancer Institute Consensus Conference concluded
that combined-modality therapy is the standard postoperative adjuvant
treatment for patients with T3 and/or N+ disease.[16] Since that
time, Intergroup postoperative trials have focused on identifying the
optimal chemotherapeutic agents and their methods of administration.

In a follow-up study to NCCTG 79-47-51, the Mayo/NCCTG designed a
four-arm trial (86-47-51) to determine if MeCCNU benefits the
treatment regimen and to compare the relative efficacy of bolus vs
continuous-infusion 5-FU. Since MeCCNU did not improve local control
or survival, it is no longer recommended for use in the adjuvant
treatment of rectal cancer.[17]

Continuous Infusion vs Bolus

Compared with bolus 5-FU (±MeCCNU), patients who received
continuous-infusion 5-FU experienced a significant decrease in
overall tumor relapse rate (37% vs 47%, P = .01) and distant
metastasis (31% vs 40%, P = .03), and realized an improvement in
4-year survival (70% vs 60%, P = .005). These data suggest that
single-agent 5-FU is more effective as a continuous infusion than as
a bolus when combined with radiation therapy. There also are
differences in the acute toxicities of continuous-infusion and bolus
5-FU. For example, during combined-modality treatment, patients who
received continuous-infusion 5-FU had significantly more grade 3+
diarrhea (24% vs 14%, P < .01) but significantly less grade 3+
leukopenia (2% vs 11%, P < .01) than did patients receiving bolus 5-FU.

Building on the positive results reported with continuous-infusion
5-FU, an Intergroup trial (INT 0144) was designed to determine
whether there is benefit associated with postoperative
continuous-infusion 5-FU throughout the complete 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. A control arm (arm 4) included bolus
5-FU/levamisole (Ergamisol). The trial opened in 1993 and is actively
accruing patients.

The NSABP R-01 was a three-arm trial comparing outcome with
postoperative MeCCNU/vincristine (Oncovin)/5-FU (MOF) vs radiation
therapy vs surgery alone. The investigators reported a significant
improvement in 5-year disease-free survival (42% vs 30%, P = .006)
and overall survival (53% vs 43%, P = .05) among patients receiving
postoperative MOF chemotherapy compared with those undergoing surgery
alone.[7] The advantage in overall survival associated with
chemotherapy was most evident in males (60% vs 37%), particularly
males < 65 years of age (44% vs 26%). In contrast, chemotherapy
was associated with a lower survival than surgery alone among treated
women (37% vs 54%).

Randomized by Gender

The NSABP subsequently designed a four-arm trial (R-02) in which
patients were randomized, depending on gender, to either MOF ±
radiation or 5-FU/calcium folinate ± radiation. Preliminary
analysis revealed a significant decrease in local failure in the two
combined-modality therapy arms compared with chemotherapy alone (7%
vs 11%, P = .045).[18] Median survival, however, did not improve.
Other results are pending.

The most recent Intergroup trial was INT 0114.[19] In this four-arm
trial, all patients received six cycles of postoperative chemotherapy
plus concurrent radiation therapy during cycles 3 and 4, with the
goal of determining whether 5-FU–based combination chemotherapy
(5-FU/low-dose calcium folinate vs 5-FU/levamisole vs 5-FU/calcium
folinate/levamisole) is superior to single-agent 5-FU. At a median
follow-up of 4 years, there were no significant differences in local
control or survival between the four arms (Table 1).
Although the total incidence of acute grade 3+ toxicity was similar
for the four arms, there were differences between the regimens. The
5-FU arm had a higher incidence of hematologic toxicity, whereas the 5-FU/levamisole
arm had a higher incidence of diarrhea.[19] A subset analysis
revealed that women had a significantly greater incidence of acute
grade 3+ toxicity than did men in all four arms. The reason for this
difference in toxicity by gender is uncertain.

The adjuvant regimen of choice in the nonprotocol setting remains
unclear. Given that results from the Mayo/NCCTG 86-47-51 trial
suggested that continuous-infusion 5-FU is more effective than bolus
5-FU, regardless of modulation with calcium folinate, levamisole, or
both (INT 0114), continuous-infusion 5-FU might seem the preferred
regimen. A direct comparison of continuous-infusion 5-FU with bolus
5-FU/calcium folinate/levamisole in INT 0144 has not yet yielded
results, however. Therefore, acceptable regimens for patients not
enrolled in a clinical trial at this time include either
continuous-infusion 5-FU or bolus 5-FU plus modulation with calcium
folinate. These regimens probably have equal efficacy and the choice
of a regimen should be based on factors such as their acute toxicity
profiles and patient compliance.

Combined-Modality Therapy With New
Chemotherapeutic Agents

Among the new chemotherapeutic agents with activity in colorectal
cancer either in development or approved by the Food and Drug
Administration are CPT-11 (Camptosar), raltitrexed (Tomudex),
trimetrexate (Neutrexin), oxaliplatin, and UFT plus oral calcium
folinate (Orzel).[20-23] Clinical phase I and II trials examining the
combination of some of these agents with pelvic radiation are under
way.[24,25] Marsh et al have combined chronobiologically shaped 5-FU
infusion with preoperative radiation therapy in the treatment of
patients with unresectable disease.[26]

Postoperative UFT/Calcium Folinate Plus Radiation Therapy

A phase I dose-escalation trial of postoperative treatment with
UFT/oral calcium folinate plus concurrent radiation therapy for
patients with primary or recurrent rectal or colon cancer has been
developed at Memorial Sloan-Kettering Cancer Center (Figure
1). The goal of this study is to compare the efficacy of the
oral regimen of UFT/oral calcium folinate (Orzel) with a
continuous-infusion 5-FU–based regimen in combined-modality
therapy. The doses and schedules of drugs are similar to those used
in current Intergroup postoperative adjuvant rectal trials. Patients
receive two cycles of 5-FU–based chemotherapy, followed by two
cycles concurrent with pelvic radiation and a 4-week rest, after
which two additional cycles are administered.

Since the schedule of chemotherapy with UFT/oral calcium folinate (28
days of daily treatment followed by a 1-week rest) is different from
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 will be made.
First, the maximum tolerated dose of UFT (tegafur and uracil) with
fixed doses of oral calcium folinate and concurrent radiation will be
defined. Then the maximum tolerated dose of UFT with fixed doses of
oral calcium folinate following completion of concurrent UFT/oral
calcium folinate and radiation therapy will be determined.

During cycle 1 (before radiation therapy), chemotherapy is delivered
at the full recommended dose with no dose escalation: calcium
folinate 25 mg orally (po) every 8 hours, concurrent with each UFT
dose of 300 mg/m²/day for 28 consecutive days. Each cycle is
followed by a 1-week rest. During chemotherapy cycle 2 (with
radiation therapy), the calcium folinate dose is fixed at 25 mg po
every 8 hours and is given concurrently with each UFT dose, which
begins lower than the recommended dose at 175 mg/m²/day po in
divided doses every 8 hours for 28 consecutive days followed by a
2-week rest.

Since the maximum tolerated dose of UFT/oral calcium folinate may be
different when given with concurrent radiation compared with
postirradiation, the maximum tolerated dose of UFT/oral calcium
folinate is determined during cycle 2 (MTD 1) independently of cycles
3 to 5 of chemotherapy (MTD 2). To determine each maximum tolerated
dose, radiation and calcium folinate doses are kept constant and the
UFT dose alone is increased 50 mg/m²/day with each subsequent
level until the maximum tolerated dose is reached. The trial is open
to accrual.

Adjuvant Therapy Following Total Mesorectal Resection

Some physicians contend that if patients undergo more extensive
surgery, postoperative adjuvant therapy is not necessary. In one
series, total mesorectal excision, involving sharp dissection around
the integral mesentery of the hind gut, decreased the local
recurrence rate to 5%.[27] These data must be interpreted with
caution, however, because they derive from personal series, include
highly selected patients, and the procedure allows the identification
and exclusion of patients with more advanced disease.

In comparison, patients treated in the adjuvant trials usually did
not receive mesorectal excision.[28,29] Furthermore, some patients
received adjuvant radiation therapy ± chemotherapy (ie, 28% in
the series from Enker et al[30] and 18% in the series by Haas-Kock et
al[31]). Total mesorectal excision also may be associated with higher
complication rates. In the Basingstoke Hospital experience, 16% of
219 patients who underwent a total mesorectal resection had
anastomotic leaks.[32] In the series from Aitken, operative deaths
were excluded from the analysis.[33]

Although total mesorectal excision is controversial, advocates of the
procedure have increased awareness of the importance of surgical
technique. Careful surgical techniques are central to the successful
management of rectal cancer. However, they should be considered a
valuable component of therapy, not competitive with adjuvant therapy.
The relative benefits and risks of total mesorectal excision
(focusing on local control, survival, sphincter preservation and
function, surgical morbidity and mortality, and quality of life) need
to be more carefully defined.

Summary

The standard management of patients with T3 and/or N1-3 rectal cancer
is postoperative combined-modality therapy, including six cycles of
5-FU–based chemotherapy and concurrent pelvic irradiation during
cycles 3 and 4. Ongoing trials will help determine the ideal
chemotherapeutic agents and methods of administration.