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March 14, 1991
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The National Cancer Institute wants to bring to the attention of clinicians
the benefits that may be achieved with adjuvant therapy of rectal cancer. The
data, presented here for your review, suggest that a sequential regimen of 5-
fluorouracil (5-FU) based chemotherapy and radiation therapy can reduce
overall tumor recurrence rates, substantially reduce local recurrence, and
prolong patient survival. Such a regimen may be recommended as therapy for
individuals with resected, TNM stage II (Dukes’ B-2, B-3) and III (Dukes’ C)
rectal cancer. While previous clinical trials have utilized a combination of
postoperative radiation therapy to the pelvis plus 5-FU and the
investigational drug, methyl-CCNU (semustine), current preliminary information
suggests that substantial treatment benefits may be achieved using irradiation
and standard doses of 5-fluorouracil. This combination avoids the potential
risks of leukemia and chronic renal insufficiency associated with protracted
administration of methyl-CCNU.
___________________________________________________________________
The intent of this announcement is to supplement the recent NIH Consensus
Development Conference statement on adjuvant therapy of rectal cancer and to
provide data to assist you in treatment planning for your patients.
Carcinoma of the rectum is one of the more common malignant diseases in the
United States, afflicting an estimated 45,000 individuals a year. The
clinical course of patients treated with surgery alone has been characterized
by a high death rate (55% of patients die within five years) and also by the
pain and disability associated with pelvic recurrence of tumor. Therapy that
simply reduces local relapse would be a meaningful advance for many patients.
Radiation alone, given in doses of 45 to 50 Gy has produced a modest reduction
in local recurrence but has not been shown to have an influence on survival
(1).
In April 1990, the "NIH Consensus Development Conference on Adjuvant Therapy
for Patients with Colon and Rectal Cancer" stated that:
Combined postoperative chemotherapy and radiation therapy
improves local control and survival in stage II and III patients
[with rectal cancer] and is recommended;
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Volume 4, Number 6 March 22, 1991
At the present time, the most effective combined modality
regimen appears to be fluorouracil plus methyl-CCNU and high
dose pelvic irradiation (45 to 55 Gy), but chronic toxicity
considerations of methyl-CCNU militate against using this
regimen outside ongoing clinical trials (2).
Newly available information, presented here, reinforces the observation that
adjuvant therapy benefits patients with rectal cancer and suggests that a
regimen of 5-fluorouracil plus pelvic irradiation without methyl-CCNU may well
be the optimal combination.
Appearing in the March 14 issue of the New England Journal of Medicine is the
final report of one major study that served as the basis for the Consensus
Conference recommendations (3,4). The NEJM-reported trial was conducted by
the North Central Cancer Treatment Group (NCCTG 794751) from 1980 to 1986 and
involved the participation of about 200 patients. Beginning four to ten weeks
after curative intent surgery for stage II or III rectal cancer, patients were
randomized to receive either combined modality radiation plus chemotherapy or
radiation therapy alone. In both treatment regimens, radiation therapy
consisted of 45 Gy to the pelvis delivered over four and one-half weeks
followed by a 5.4- Gy boost to the tumor bed. In the combined modality
treatment, patients received an initial nine-week cycle of 5-FU and methyl-
CCNU. This chemotherapy was followed by radiation plus concurrent 5-FU.
Patients then received another nine-week cycle of 5-FU and methyl-CCNU.
With further follow-up, the results of this study show a clear advantage for
the combined modality treatment in all parameters of evaluation, including
reduced overall recurrences (p = 0.0016), reduced local recurrences (p =
0.036), reduced distant metastases (p = 0.011), and improved survival (p =
0.026). There is a 46% reduction in pelvic recurrence, a 37% reduction in
distant tumor spread, and a 29% reduction in patient deaths. Survival data
are summarized in Table 1. Acute, severe toxicity was infrequent. Delayed,
severe reactions, usually bowel obstruction requiring surgical intervention,
occurred in about 6.5% of all patients and were comparable in incidence
whether patients received radiation therapy alone or radiation plus
chemotherapy.
This study confirms for the first time that the benefit achieved with
chemotherapy when combined with irradiation is superior to that produced by
radiation therapy alone, which many clinicians regard as a standard adjuvant
therapy for rectal cancer.
The NCCTG trial design evolved from earlier work, such as the Gastrointestinal
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Volume 4, Number 6 March 22, 1991
Tumor Study Group study (GITSG 7175) (5,6) that used a combined modality
regimen in which radiation (40 to 44 Gy) plus 5-FU was given initially,
followed by cycles of 5-FU and methyl-CCNU given for one and one-half years.
That study demonstrated the superiority of chemo-radiation therapy when
compared to surgery alone. A reduction in local recurrence was also noted
when compared to radiation therapy alone. The NCCTG trial now convincingly
confirms that post-surgical, combined modality therapy can improve control of
tumor relapse and patient survival not only when compared to surgery alone but
also when compared to full dose postoperative radiation therapy.
The new and confirmatory evidence of effective surgical adjuvant therapy for
rectal cancer has stimulated a search for safer and still more effective
approaches. Important questions remain.
1. Is methyl-CCNU a necessary component of the chemotherapy or
is 5-FU as a
single agent sufficient?
Methyl-CCNU is an investigational agent that currently can be obtained only
from the NCI. No long-term bone marrow or renal toxicities were observed
after limited methyl-CCNU treatment on the NCCTG trial. However, after
chronic administration, this drug has been associated with a 12-fold increased
risk for secondary leukemia or preleukemia (7) as well as with chronic renal
toxicity. One clinical study of adjuvant therapy in rectal cancer (GITSG
7180) showed no superiority for combined modality therapy that included
methyl-CCNU when compared to treatment with radiation and 5-FU (8). An
intergroup trial, led by the North Central Cancer Treatment Group (NCCTG
864751), with 453 rectal cancer patients entered between 1987 and 1990, tested
combined modality therapy with or without methyl-CCNU administered in a manner
identical to the treatment in the superior regimen of the trial reported in
the New England Journal of Medicine (NCCTG 794751). The protocol specified an
interim analysis after 50% of the predicted tumor recurrences had occurred.
That preliminary analysis of the study, which will be presented at the annual
meeting of the American Society of Clinical Oncology (ASCO) in May 1991 (9),
reveals a rate of recurrence 1.2 times higher for patients receiving methyl-
CCNU, statistically ruling out the likelihood that the addition of methyl-CCNU
actually confers a 25% or greater advantage in disease control. Severe
thrombocytopenia was seen only in patients receiving methyl-CCNU, affecting
12.4% of these individuals. To date, there are not sufficient data to compare
survival rates. But based on increased toxicity and lack of evidence for
improved effectiveness, the NCI agrees with the study’s investigators that
methyl-CCNU, delivered in this manner, is probably not a necessary component
of multimodality adjuvant therapy for rectal carcinoma. This conclusion is
provisional while we await further maturation of the intergroup study (NCCTG
864751). However, the data have been found to be sufficiently convincing that
Health InfoCom Network News Page 43
Volume 4, Number 6 March 22, 1991
the currently active, NCI-supported, Intergroup study (INT 0114) utilizes 5-FU
alone and radiation as the control treatment.
2. Do 5-FU/levamisole, 5-FU/leucovorin or other promising
therapies have a role in adjuvant therapy of rectal cancer?
The demonstration that 5-FU/levamisole can be effective adjuvant therapy of
colon cancer (10) and the acceptance that 5-FU/leucovorin combinations are
superior to 5-FU alone for metastatic colorectal tumors have produced hope for
further improvement in the systemic component of adjuvant treatment of rectal
cancer. Both of these combinations are currently being evaluated in protocols
sponsored by the National Cancer Institute and are available to eligible,
rectal cancer patients throughout North America. In these trials, all
patients receive active, postoperative, systemic therapy. Continued accrual
of patients to these trials is essential to define further advances in care.
For patients with resected rectal cancer with transmural extension (TNM stage
II or Dukes’ B-2,B-3) or with positive regional lymph nodes (TNM stage III or
Dukes’ C) who would be appropriate candidates for adjuvant care but who lack
access to or who decline participation in clinical trials, it would be
reasonable to consider the following treatment regimen based on available
evidence. This regimen is the control arm for the currently active Intergroup
study (INT 0114) mentioned above.
Treatment should be initiated from one to two months after surgery if the
patient is fully recovered from the operative procedure, maintaining a
reasonable state of nutrition, and has normal hematologic parameters.
Week 1 and 5: 5-FU 500 mg/M2/day X 5 days
Week 9: Radiation therapy to tumor area and regional
node distribution, 45 Gy over 4-6 weeks,
followed by 5.4-Gy boost in 3 fractions to the
tumor bed. Give 5-FU 500 mg/M2/day X 3
days during the first and last week of irradiation.
4 and 8 weeks after
irradiation: 5-FU 450 mg/M2/day X 5 days
5-FU should be given by rapid IV injection for all courses. Appropriate
adjustments in 5-FU dosage should be made based on toxicity to previous
courses. Careful and experienced radiation therapy treatment planning is
required with special attention to avoid small bowel injury (11).
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Volume 4, Number 6 March 22, 1991
With regard to averting these toxicities, the critical role of the surgeon
must be recognized. At the time of surgery, consideration must be given to
the possibility that radiation therapy may be a part of postoperative
treatment planning. Delineation of the limits of resection with radio-opaque
clips and incorporation of one of the surgical techniques for excluding small
bowel from the pelvis may minimize some of the treatment related sequelae.
Other doses and schedules of radiation and/or chemotherapy may be of equal
efficacy. It is the responsibility of the individual physician, in concert
with the individual patient, to develop the most appropriate plan of therapy.
Additional information about the studies cited in this Announcement and about
other clinical trials is available from the NCI’s Physician Data Query (PDQ)
database. PDQ can be accessed through a medical library or by calling NCI’s
Cancer Information Service at 1-800-4-CANCER. The NIH Consensus Development
Conference Statement from the April 1990 Conference on Adjuvant Therapy in
Colon and Rectum Cancer is available by writing to:
Consensus Development Statement: Colon/Rectum Adjuvant Therapy
Office of Medical Applications of Research
Building 1, Room 260
National Institutes of Health
Bethesda, MD 20892
Some physicians may conclude that the currently available data support a
contributory role for methyl-CCNU in an adjuvant regimen. Further information
about methyl-CCNU or other NCI sponsored investigational agents may be
obtained by calling NCI’s Drug Management and Authorization Section of the
Investigational Drug Branch at 301-496-5725.
References
1. Fisher B, Wolmark N, et al. Postoperative adjuvant chemotherapy or
radiation therapy for rectal cancer: results from NSABP protocol R-01.
J Natl Cancer Inst 1988; 80:21-29.
2. NIH Consensus Conference on Adjuvant Therapy for Patients with Colon and
Rectal Cancer. JAMA 1990; 264:1444-1450.
3. Krook JE, Moertel CG, Gunderson LL, Wieand HS, Collins RT, Beart RW,
Kubista TP, Poon MA, Meyers WC, Mailliard JA, et al. Effective
surgical adjuvant therapy for high risk rectal carcinoma. N Engl J Med
1991 Mar 14; 324 (11):709-715.
Health InfoCom Network News Page 45
Volume 4, Number 6 March 22, 1991
4. Krook J, Moertel C, et al. Radiation vs sequential chemotherapy-radiation-
chemotherapy, a study of the North Central Cancer Treatment Group,
Duke University, Mayo Clinic Proc ASCO 1987; 6:92.
5. Gastrointestinal Tumor Study Group. Prolongation of disease free interval
in surgically treated rectal carcinoma. N Engl J Med 1985; 312:1465-
1472.
6. Douglass HO, Moertel CG, et al. Survival after postoperative combination
treatment of rectal cancer (letter) N Engl J Med 1986; 315:1294.
7. Boice JD, Green MH, et al. Leukemia and preleukemia after adjuvant
treatment of gastrointestinal cancer with semustine (methyl-CCNU). N
Engl J Med 1983; 309:1079-1085.
8. Weaver D, Lindblad AS, et al. Radiation therapy and 5-fluorouracil (5-FU)
with or without MeCCNU for the treatment of patients with surgically
adjuvant adenocarcinoma of the rectum. Proc ASCO 1990; 9:106.
9. O’Connell M, Wieand H, et al. Lack of value for methyl-CCNU (MeCCNU) as a
component of effective rectal cancer surgical adjuvant therapy:
interim analysis of intergroup protocol 86-47-51. Proc ASCO 1991, in
press
10. Moertel CG, Fleming TR, et al. Levamisole and fluorouracil for adjuvant
therapy of resected colon cancer. N Engl J Med 1990; 322:352-358.
11. Gunderson LL, Russell AH, et al. Treatment planning for colorectal
cancer. Int J Radiat Oncol Biol Phys 1985; 11:1379-1393.
Table 1
Results of Completed Clinical Trials
of Adjuvant Therapy in Rectal Cancer
Five-Year Survival
Trial Regimen N Disease-Free Overall
_________________________________________________________________
NCCTG RT 100 42% 47%
794751 MeCCNU/FU + RT/FU 104 63%* 58%*
GITSG Surgery Only 58 47% 43%
7175 MeCCNU/FU 48 55% 56%
RT 50 55% 52%
Health InfoCom Network News Page 46
Volume 4, Number 6 March 22, 1991
MeCCNU/FU + RT/FU 46 71%* 59%*
NSABP Surgery Only 184 30% 43%
R-01 RT 184 33% 41%
MeCCNU/VCR/FU 187 42%* 53%*
GITSG RT/FU + MeCCNU/FU 95 54%** 66%**
7180 RT/FU + FU 104 69%** 76%**
________________________________________________________________
* p<0.05
** three-year data
Health InfoCom Network News Page 47
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