ATLANTA-In a phase III trial
of patients who had undergone surgery
for rectal cancer, three regimens of
fluorouracil (5-FU)-based chemotherapy
and radiation therapy achieved similar
rates of relapse-free and overall survival,
although the three regimens had
somewhat differing toxicity profiles.
Lead author Stephen R. Smalley, MD,
a radiation oncologist at the Olathe Regional
Oncology Center, Olathe, Kansas,
reported the results at the 46th Annual
Meeting of the American Society
for Therapeutic Radiology and Oncology
(abstract 14).
Recent trials have found that after
surgery for rectal cancer, protracted
venous infusion (PVI) of 5-FU during
radiation therapy improves outcomes
relative to bolus infusion (Intergroup
864751), and outcomes are similar with
a variety of different biochemically modulated
bolus regimens of 5-FU (Intergroup
0114), Dr. Smalley said.
The new trial (Intergroup 0144),
therefore, sought to answer three questions,
he said: "Number one, would a
protracted course of 5-FU (prior to and
following protracted 5-FU and radiation)
lead to further improvement in
outcome? Number two, could a biochemically
modulated 5-FU program
without central venous catheters produce
outcomes similar to those of the
protracted venous infusion arm? And
number three, how would pelvic control
be affected, especially in those groups
that were most rationally treated with
initial surgery?"
The investigators enrolled patients
who had undergone complete resection
of locally advanced but nonmetastatic
rectal adenocarcinoma (T3-4, N0, M0
or T1-4, N1-2, M0) in the prior 20 to 70
days; dentate involvement was allowed.
Patients were required to have adequate
organ function and no prior chemotherapy
or radiation therapy.
The patients were stratified by type
of resection (abdominoperineal vs low
anterior), T stage, N stage, and time
from surgery. They were then assigned
to three treatment arms:
- Arm 1: Bolus 5-FU before and
after radiation therapy, with 5-FU by
PVI during radiation therapy - Arm 2: 5-FU by PVI before, during,
and after radiation therapy - Arm 3: Bolus 5-FU, leucovorin,
and levamisole before and after radiation
therapy, plus bolus 5-FU and leucovorin
during radiation therapy
In all, 1,917 patients were enrolled
in the trial, and living patients had a
median follow-up of 6.1 years, making
the data mature, Dr. Smalley noted.
Study Results
The three treatment arms had statistically
indistinguishable rates of
overall survival (81% to 83%) and
relapse-free survival (67% to 69%) at
3 years follow-up, Dr. Smalley said.
For both endpoints, the findings were
the same in analyses comparing arm 1
with arm 2, and arm 1 plus arm 2 with
arm 3. (See Table 1 for 5-year survival
rates.)
"It's important to evaluate pelvic
control, especially for those patients
who are initially appropriately managed
by surgery," Dr. Smalley said,
noting that some trials have found
better pelvic control with preoperative
radiation therapy, with or without
chemotherapy. "However, preoperative
radiotherapy does produce an
increased clinically meaningful toxicity,
both gastrointestinal and sexual in nature, and it is obviously desirable to
avoid these side effects in those who
are unlikely to benefit from radiation
therapy. This would certainly include
patients who are candidates for sphincter-
sparing surgery when they present,
as well as patients who do not have
fixed primary rectal lesions."
With the 6.1-year median followup,
the rate of pelvic failure was similarly
low across treatment arms in the
entire study population (5% to 7%)
and in the subgroup of patients who
were appropriately managed with initial
surgery, namely those with non-
T4b disease who underwent low anterior
surgical resection (3% to 6%).
Toxicity
Patients in arms 1, 2, and 3 had
similar rates of treatment-related death
(approximately 1%) and gastrointestinal
toxicity of grade 3 or higher (42%
to 46%), Dr. Smalley said.
In contrast, rates of grade 3 or higher
hematologic toxicity differed, with this
complication occurring in about half
of the patients in arms 1 and 3 (50% to
56%) but in few patients in arm 2
(4%). "However this was primarily a
laboratory change because the PVI arm
[arm 2] had a 6% grade 3-5 infection
rate vs 10% to 11% in the two bolus
5-FU arms," Dr. Smalley noted. As
expected, catheter-related toxicity was
higher in arms 1 and 2 (2% to 3%)
than in arm 3 (less than 0.5%), he
added.
'Similar Outcomes'
"We conclude that all three dose
schedules lead to similar outcomes following
resection," Dr. Smalley commented.
"Hematologic toxicity was
definitely decreased with protracted
venous infusion, but it must be balanced
against the cost, inconvenience,
and risk of catheter-related toxicities
with PVI."
He told ONI that although other
recent trials have found PVI to be
superior to bolus therapy, "our trial is
by far the biggest and most satisfactorily
powered study, and really suggests
that any 5-FU regimen plus radiation
produces similar survival outcomes."
Less Extensive Treatment
The findings further suggest that
less extensive treatment is safe in some
patients, Dr. Smalley pointed out. "Initial
surgical management of nonfixed
lesions that are amenable to sphincter-
preserving surgery at presentation
is entirely justified," he said. "Those
patients who are at low risk of pelvic
recurrence following surgery-certainly
this would include T1-2, N0
patients, potentially even selected T3,
N0 patients-can avoid the toxicity of
radiation."
