Dr. Rich presents a comprehensive overview of adjuvant therapy for advanced
operable rectal cancer. He emphasizes the roles of infusional chemoradiation
in both the adjuvant setting and as sole therapy. Unless otherwise specified,
the following comments pertain to clinically resectable B2-C (T3, N0-N1)
adenocarcinoma of the rectum.
What Do We Know?
Based on Dr. Rich's review, it is apparent that:
- Surgery alone results in a high local recurrence rate.
- Moderate-dose postoperative irradiation (45 to 50 Gy at 1.8 Gy/fraction)
reduces the risk of local recurrence but does not improve survival rates.[2-4]
- Postoperative radiotherapy and fluorouracil(5-FU)/semustine-based chemotherapy
improve local control and survival rates, compared with surgery alone,
surgery plus chemotherapy, and surgery plus postoperative radiotherapy.[2-4]
- Low-dose preoperative irradiation is ineffective.[5,6]
- Moderate-dose preoperative radiotherapy reduces the incidence of local
recurrence and may improve survival rates.[7,8]
- Compared with postoperative radiotherapy, moderate-dose preoperative
radiotherapy is more likely to be completed as planned, is less morbid,
and is more efficacious.
It is also apparent from Dr. Rich's review that several questions remain
to be answered:
What Is the Optimal Chemotherapy Regimen?--The observation that
postoperative chemoradiation, using 5-FU/semustine-based chemotherapy,
improves survival rates produced a wave of enthusiasm for the use of adjuvant
chemotherapy in rectal adenocarcinoma. Because semustine is not commercially
available due to its leukemogenic potential, initial attention focused
on whether it was a necessary component of a 5-FU-based chemotherapy regimen.
Comparison of adjuvant 5-FU, with or without semustine, in a large randomized
trial showed no survival advantage associated with semustine. Therefore,
although 5-FU-based adjuvant chemotherapy without semustine has not been
shown to improve survival rates when compared "head-to-head"
with a non-chemotherapy-treated control arm, it is currently considered
to be part of the "standard of care" for advanced, operable rectal
The optimal chemotherapy regimen remains to be defined. Questions relating
to adjuvant chemotherapy include: (1) Is the dose intensity of the 5-FU
infusion important? (2) What is the role of 5-FU enhancers, such as leucovorin,
levamisole (Ergamisol), methotrexate, interferon, and N-phosphonacetyl-L-asparate
(PALA)? (3) How many courses of adjuvant chemotherapy are optimal? Chemotherapy
protocols under investigation include bolus 5-FU, continuous-infusion 5-FU,
protracted continuous-infusion 5-FU, 5-FU with levamisole, and 5-FU plus
leucovorin. As suggested by Rich, protracted-infusion 5-FU combined with
radiotherapy may be the optimal adjuvant chemoradiation schedule.
Is Preoperative Chemoradiation Better Than Postoperative Chemoradiation?--It
is unclear whether postoperative chemoradiation is better than preoperative
radiotherapy alone or combined with concomitant chemotherapy. Potential
advantages of preoperative radiotherapy include the following: (1) It may
be more effective in reducing the risk of local recurrence. (2) It may
be less morbid, both in terms of acute effects and the risk of late small
bowel obstruction. (3) It may increase the likelihood of sphincter preservation.
(4) The likelihood of completing treatment as planned is probably higher.
The main disadvantage of preoperative chemoradiation is that patients
with early-stage, A-B1 (T1-T2, N0) tumors who do not need adjuvant therapy
could potentially receive unnecessary treatment. However, the likelihood
of including patients with early cancers is remote if preoperative chemoradiation
is restricted to patients with annular and/or tethered tumors and those
with transmural invasion and/or positive nodes observed on transrectal
ultrasound or MRI.
It is highly unlikely that preoperative irradiation will be compared
with postoperative chemoradiation in a randomized trial in the United States.
However, two ongoing randomized trials (ie, the intergroup trial and the
National Surgical Adjuvant Project for Bowel and Breast Cancers [NSABP]
R-03 trial) are comparing preoperative with postoperative chemoradiation.
Can We Predict Whether an Individual Patient Will Respond to Preoperative
Chemoradiation?--Willett and colleagues found that tumor regression
following preoperative irradiation alone or combined with two 3-day courses
of 5-FU (500 mg/m2/d) during the first and last weeks of radiotherapy
was associated with smaller tumor size and high proliferative activity.
When stratified by tumor size, tumor regression occurred most often in
lesions with high Ki-67, proliferating cell nuclear antigen (PCNA), and
mitotic activity, all of which are indicators of proliferative activity.
It is likely that other biologic markers may be useful in predicting tumor
response to preoperative therapy.
Current University of Florida Guidelines
Currently, at the University of Florida, patients with clinically resectable
B2-C rectal adenocarcinoma are treated with preoperative radiotherapy (45
to 50.4 Gy at 1.8 Gy/fraction) combined with a concomitant, protracted,
continuous, chronobiologically shaped 5-FU infusion administered with a
portable, programmable pump. The dose rate varies from approximately
250 to 275 mg/m2/d. The potential advantages of a circadian-shaped,
protracted 5-FU infusion include increased dose intensity and reduced toxicity.
Patients who are found to have pathologically positive nodes are given
postoperative adjuvant 5-FU and leucovorin for 6 months.
Radical Infusional Chemoradiation Without Surgery
Although aggressive chemoradiation may result in impressive response
rates, elimination of surgery from the treatment scheme currently results
in an unacceptably high likelihood of local recurrence. Therefore, except
for the small subset of patients with very favorable tumors who are suitable
candidates for endocavitary irradiation, the use of radical chemoradiation
should be restricted to patients with unresectable cancer, those who cannot
be rendered operable by aggressive preoperative chemoradiation, and those
who are medically unsuitable for or refuse to undergo surgery. As described
by Papillon and Berard, interstitial brachytherapy and/or endocavitary
irradiation may be used in suitable patients to boost the dose of radiation
given to the primary tumor after chemoradiation, and probably results in
improved local control rates.
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radiation therapy enhance the probability of local control and survival
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2. Gastrointestional Tumor Study Group: Prolongation of the disease-free
interval in surgically treated rectal carcinoma. N Engl J Med 312:1465-1472,
3. Fisher B, Wolmark N, Rockette H, et al: Postoperative adjuvant chemotherapy
or radiation therapy for rectal cancer: results from NSABP protocol R-01.
J Natl Cancer Inst 80(1):21-29, 1988.
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carcinoma of the rectum and rectosigmoid colon: Report of a National Veterans
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8. Cedermark B, Johansson H, Rutqvist LE, et al: The Stockholm I trial
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