In 1994, the results of a randomized intergroup trial coordinated by
the North Central Cancer Treatment Group (NCCTG 86-47-51) indicated that
protracted fluorouracil (5-FU) infusion during postoperative adjuvant radiation
therapy results in better survival than concurrent bolus 5-FU and pelvic
radiation therapy in patients with resected high-risk rectal cancer.
The important prior work of Dr. Tyvin Rich had laid much of the groundwork
for NCCTG 86-47-51, and Dr. Rich was a coauthor of the paper that described
the results of that study. In his review article, "Infusional chemotherapy
for operable rectal cancer: Post-, pre-, or nonoperative management?"
Dr. Rich places this work within the context of results from other related
Postoperative or Preoperative Chemoradiation?
In the postoperative adjuvant setting, the prolonged infusion chemotherapy
regimen used in NCCTG 86-47-51 is the only one demonstrated in a randomized
clinical trial to improve survival in resected high-risk rectal cancer
patients when compared to a more conventional bolus regimen. Although
the other adjuvant prolonged infusion regimens mentioned by Dr. Rich may
be theoretically appealing, none has been scientifically demonstrated to
be effective. Because of this, the regimen used in NCCTG 86-47-51 should
be considered the standard adjuvant treatment of rectal cancer. The use
of other infusion regimens in patients receiving adjuvant therapy for rectal
cancer should be confined to peer-reviewed, institutionally approved clinical
The possible use of "neoadjuvant," or preoperative, treatment
is also discussed by Dr. Rich. A Swedish trial that compared short-course
preoperative radiation therapy with conventional postoperative radiation
is mentioned as an example of a study that demonstrated reduced local recurrence
with the preoperative approach. It is important to point out, however,
that this study did not demonstrate improved survival for preoperative
radiation therapy. Indeed, no phase III study has documented
a statistically significant improvement in survival with preoperative adjuvant
treatment, when all randomized patients are considered for analysis. Because
postoperative chemoradiation is the only adjuvant approach demonstrated
to improve survival in randomized studies, the use of other adjuvant treatment
approaches, including preoperative radiation therapy (with or without chemotherapy),
should be confined to clinical trials.
Minimizing Radiation Related Toxicity
In oncology, significant short- or long-term morbidity is sometimes
the price of success. This is definitely true of adjuvant therapy for rectal
cancer. Dr. Rich appropriately emphasizes the value of radiation therapy
techniques to minimize toxicity. At the Mayo Clinic, methods for reducing
radiation therapy-related toxicity similar to those mentioned by Dr. Rich
are routinely used. Despite these efforts, significant long-term treatment-related
morbidity occurs in a significant number of patients. Kollmorgen and
colleagues used a simple telephone survey to assess bowel function in patients
treated by surgery plus postoperative chemoradiotherapy or by surgery alone.
Results of this study strongly suggest that long-term bowel function is
adversely affected by adjuvant radiation therapy and chemotherapy. For
each of the 11 categories of bowel function evaluated, worse function was
seen in the irradiated patients. For example, 56% of the patients treated
by chemotherapy and irradiation described at least occasional incontinence,
in contrast to only 7% of the nonirradiated patients (P <.001).
Recent evaluations of Swedish trials suggest that preoperative radiation
therapy may also be associated with significant long-term morbidity.[3,5]
Future clinical trials should prospectively evaluate the impact of adjuvant
treatment on long-term bowel function. Methods for decreasing treatment-related
morbidity should also be evaluated.
Further Improvement Needed
Further improvement is needed in the adjuvant treatment of rectal cancer.
Approximately 30% of patients with high-risk rectal cancer die within 4
years despite delivery of the best currently available adjuvant therapy.
It is certainly possible that alternative treatment chemoradiation schedules,
such as those discussed in Dr. Rich's thoughtful review, will result in
improved outcomes. An ongoing clinical trial (INT 0147) will provide valuable
information about whether preoperative or postoperative treatment is better
in this group of patients. Methods for decreasing treatment-related morbidity
are needed. Prospective clinical trials remain the best method for increasing
our scientific understanding of these issues and for improving survival
of patients with rectal cancer.
1. O'Connell MJ, Martenson JA, Weiand HS, et al: Improving adjuvant
therapy for rectal cancer by combining protracted infusion fluorouracil
with radiation therapy after curative surgery. N Engl J Med 331:502-507,
2. Rich TA, Lokich JJ, Chaffey JT: A pilot study of protracted venous
infusion of 5-fluorouracil and concomitant radiation therapy. J Clin Oncol
3. Frykholm GJ, Glimelius B, Pahlman L: Preoperative or postoperative
irradiation in adenocarcinoma of the rectum: Final treatment results of
a randomized trial and an evaluation of late secondary effects. Dis Colon
Rectum 36:564-572, 1993.
4. Kollmorgen CF, Meagher AP, Pemberton JH, et al: The long term effect
of adjuvant postoperative chemoradiotherapy for rectal cancer on bowel
function. Ann Surg 220:676-682, 1994.
5. Holm T, Singnomkiao T, Rutqvist L, et al: Adjuvant preoperative radiotherapy
in patients with rectal carcinoma: Adverse effects during long term follow-up
of two randomized trials. Cancer 78:968-976, 1996.