ORLANDOThe new frontiers in colorectal cancer include
multimodality treatment used preoperatively and a new group of oral
fluoropyramidine drugs, according to presentations at the Society of
Surgical Oncologys 52nd Annual Cancer Symposium.
Bruce D. Minsky, MD, reported early data suggesting that, with
conventional doses and techniques, preoperative radiation and
chemotherapy may improve survival, enhance sphincter preservation,
and decrease adverse effects in patients with colorectal cancer.
Dr. Minsky and his colleagues at Memorial Sloan-Kettering Cancer
Center began working with preoperative combined modality therapy out
of dissatisfaction with the 25% to 50% rates of grade 3 toxicity seen
with postoperative radiation and chemotherapy, which resulted in only
50% to 65% of patients being able to finish all planned therapy.
The researchers hoped that the preop timing would decrease cancer
seeding, increase radiosensitivity, reduce adverse effects, and
permit more patients to have sphincter-sparing coloanal anastomoses.
The preoperative approach using a short, intensive course of
radiation has been successful in only 1 of 10 previous trials. That
one, the Swedish Rectal Cancer Trial, had high morbidity.
Dr. Minsky said that careful examination of these preoperative
therapy studies suggested that their failure to improve overall
survival was due to inadequate total doses of radiation (all of which
were below the accepted standard of 180 to 200 cGy/day, to a total
5,040 cGy); poor radiation technique; and too little time between
radiation and surgery (which did not allow the tumor to shrink or the
patient to fully recover from the effects of radiation).
The Swedish trial showed significantly better local recurrence rates
and 5-year survival with preoperative radiation/surgery than with
surgery alone (local recurrence, 12% vs 27%, P < .001; 5-year
survival, 58% vs 48%, P = .004). Unfortunately, this was accompanied
by high morbidity.
Dr. Minskys group addressed these problems by improving the
radiation technique, maintaining sufficiently high radiation dosages,
and allowing 4 to 6 weeks between radiation therapy and surgery.
Their pilot study of preoperative radiation in 35 patients with
colorectal cancer found that 27 (77%) were able to have coloanal
anastomoses, that actuarial 5-year survival was 64% (Table
1), and functional results were excellent or good in more than
80% of patients (Table 2). Current
treatment programs use combined radiation plus chemotherapy.
Dr. Minsky stressed the importance of using unirradiated bowel from
outside the pelvis to construct the anastomoses. He also suspects
that the reduction in acute gastrointestinal toxicity with preop vs
postop radiation therapy (13% vs 48%, P = .045) is due to the
reduction in radiation damage to the bowel.
After surgery, the small bowel sits in the pelvis and is more
likely to be in the radiation field. We have tried to exclude it by
using mesh, but the mesh was largely resorbed by the time the
radiation was performed after surgery, Dr. Minsky said. About
one-half of the small bowel typically falls within the radiation
field with postoperative radiation (Figure
1), compared with preoperative radiation (Figure
For preoperative radiation, the researchers block the perineum from
the radiation field. For those few patients who require an
abdominoperineal resection, this decreases the incidence of perineal
wound sepsis, he said
Dr. Minsky emphasized that his data on the advantages of preoperative
combined modality therapy, although promising, require confirmation
in prospective, randomized clinical trials.
New Drugs, New Criteria?
Richard Pazdur, MD, of the University of Texas M.D. Anderson Cancer
Center, described several new oral fluoropy-rimidines being studied
in colorectal cancer. These drugs appear to have favorable toxicity
profiles with a reduction in neutropenia and oral mucositis, he said,
but these oral agents must demonstrate, in randomized phase III
trials, equivalent survival in advanced colorectal cancer to IV
fluorouracil plus leucovorin.
Researchers have begun to suspect that even drugs with relatively low
response rates may have important clinical potential if they promote
disease stabilization. The benefits appear as improvements in
performance status, pain control, and weight maintenance. This was
seen in studies of irinotecan (Camptosar), which, despite producing
only a 15% response rate, improved these clinical parameters as well
as 1-year survival.
Other new drugs that may disprove the nothing is better than
fluorouracil idea include oxaliplatin (approved in France),
capcitabine (Xeloda, approved for breast cancer), and UFT (uracil,
tegafur, oral leucovorin, known as Orzel), which is in phase III
trials in colorectal cancer. In addition, a large adjuvant colon
cancer trial under the auspices of the National Surgical Adjuvant
Breast and Bowel Project (NSABP) has recently completed accrual. This
study randomized patients to UFT plus leucovorin vs IV fluorouracil