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Adjuvant Therapy for Rectal Cancer: Results and Controversies

Adjuvant Therapy for Rectal Cancer: Results and Controversies

ABSTRACT: During the past decade, advances have been made in the adjuvant treatment of resectable rectal cancer. Postoperative combined-modality therapy significantly improves local control and survival. Recent Intergroup postoperative trials have focused on the identification of optimal chemotherapeutic agents and their method of administration. Preoperative therapy has the potential advantages of producing less acute toxicity and increasing the likelihood of sphincter preservation. New chemotherapeutic agents and radiation techniques are active areas of investigation. [ONCOLOGY 12(8):1129-1139, 1998].

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 (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 [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.

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