Standard postoperative therapy in the United States for transmural or
node-positive rectal adenocarcinoma is chemotherapy and pelvic
radiation. Postoperative radiation therapy alone may improve local
control, but has no impact on survival. However, the addition of
fluorouracil-based chemotherapy to radiotherapy has been shown to
improve tumor control and prolong survival compared to surgery
alone or radiation alone. Intergroup postoperative trials have
focused on identifying the most effective chemotherapeutic agents and
dose schedule when combined with radiotherapy.
The major focus of postoperative trials has been on the role of
semustine (MeCCNU), the modulation of fluorouracil (5-FU) with
leucovorin and/or levamisole, and the comparison between bolus and
infusional 5-FU. Semustine does not improve local control or
survival, so it is no longer recommended for use in the adjuvant
treatment of rectal cancer.[5,6]
Intergroup trial 0114 evaluated single-agent 5-FU and three
combinations of modulated fluorouracil chemotherapy (5-FU plus
leucovorin, 5-FU plus levamisole, and 5-FU/leucovorin/levamisole)
combined with postoperative adjuvant radiotherapy for rectal cancer.
All patients received six cycles of postoperative adjuvant
chemotherapy, with radiotherapy given during cycles 3 and 4. There
was no significant difference in local control or survival among the
four arms at a median 4-year follow-up. The total grade ³
3 toxicity was also similar, but there were differences in the types
of toxicity among arms.
Single-agent 5-FU had more hematologic toxicity, and 5-FU plus
levamisole had more diarrhea. Gender differences in toxicity were
noted: women had a significantly greater incidence of grade ³
3 toxicity in all arms without clear explanation. These data suggest
that there is no routine role for levamisole, but conditional
probability analysis demonstrated that the addition of leucovorin
might be an advantage on longer follow-up, despite the fact that many
expected recurrences had already occurred by the time of analysis.
Bolus vs Infusional 5-FU
Bolus vs infusional 5-FU administered concurrently with postoperative
radiotherapy was evaluated in the Mayo Clinic and North Central
Cooperative Trial Group (NCCTG) 86-47-51 study. In this trial,
bolus 5-FU was compared to continuous-infusion 5-FU during radiation.
Infusional therapy was associated with a significant decrease in
overall relapse (47% vs 37%, P = .01), distant metastases (31%
vs 40%, P = .03), and an improvement in 4-year survival (70%
vs 60%, P = .005). These data suggest that single-agent
5-FU is more effective when administered as a continuous infusion
rather than given as a single-agent bolus when combined with
It is important to note that these actual and disease-free survival
results with infusional 5-FU are very similar to those found with
bolus 5-FU plus leucovorin in the Intergroup 0114 trial. Present
data do not allow us to compare continuous-infusion 5-FU with bolus
5-FU plus leucovorin; both are considered to be acceptable regimens
in practice during postoperative adjuvant radiotherapy for rectal
cancer. An Intergroup study is ongoing to clarify further optimum
Toxicities of concurrent radiotherapy and continuous-infusion vs
bolus 5-FU were different. Infusional therapy led to a significant
increase in grade ³ 3 diarrhea (24%
vs 14%, P > .01), but there was a decrease in grade ³
3 leukopenia (2% vs 11%, P > .01). On the basis of improved
overall survival in this prospective randomized setting, however,
many investigators consider infusional 5-FU during radiation to
represent standard practice.
Practical considerations of 5-FU infusional therapy include patient
acceptance, labor intensity, requirement for prolonged venous access,
external pump cost and maintenance. Prolonged venous access has been
associated with the risk for line infection and venous thrombosis.
If an equally effective oral agent were to replace infusional 5-FU,
it would have the potential to increase convenience and may be less labor-intensive.
Other new chemotherapy agents in development or approved by the Food
and Drug Administration (FDA) for colorectal cancer include
irinotecan (Camptosar, CPT-11), raltitrexed (Tomudex), trimetrexate
(NeuTrexin), oxaliplatin, and several oral fluoropyrimidine prodrugs.
Capecitabine (Xeloda) is absorbed unmodified from the gut and
subsequently metabolized to 5-FU. Ethynyluracil (Eniluracil) is an
inhibitor of dihydropyrimidine dehydrogenase (DPD), and is combined
with oral 5-FU. BOF-A2 is a 5-FU prodrug combined with another
inhibitor of 5-FU metabolism, 3-cyano-2,6-dehydropyrimidine
(CNDP). S-1 combines tegafur with two inhibitors of 5-FU
catabolism, namely oxonic acid and 5-chloro-2,4-dihydropyridine (CDHP).
Tegafur is an oral prodrug that is converted to 5-FU in vivo. Uracil
enhances the concentration of 5-FU by inhibiting DPDmediated
5-FU catabolism. The combination of oral leucovorin and UFT
(uracil and tegafur) is being developed under the trade name Orzel.
The leucovorin additionally modulates cytotoxicity by increasing the
pool of reduced folate required as part of a covalent ternary complex
with thymidylate synthase and fluorodeoxyuridine 5´-monophosphate.[14-16]
The clinical rationale for combining leucovorin and UFT is the same
as the advantage in terms of objective tumor response for the
combination of leucovorin with intravenous bolus 5-FU over 5-FU
alone. UFT is commercially available in Japan and has been used
extensively as an alternative to 5-FU. UFT has been under
development in the United States since the early 1990s. The
recommended phase II dose is 300 mg/m²/d, but it has been
tolerated at even higher doses.
There have been two phase III trials comparing UFT plus leucovorin
with bolus 5-FU plus leucovorin in stage IV colorectal cancer. In
trial 001, patients received either UFT 300 mg/m²/d with
leucovorin 75 mg/d for 5 days per week for a total 28 days, or 5-FU
425 mg/m²/d and leucovorin 20 mg/m²/d for 5 days every 4
weeks. This international trial accrued 816 patients. There were
no significant differences in overall survival or response rate.
There was an improved toxicity profile for UFT in reduction of
neutropenia, febrile neutropenia, nausea, emesis, and diarrhea.
Common Toxicity Criteria grade 3/4 mucositis was reduced from 19% to
1% (P > .001). A confirmatory trial (012), with a similar
design, led to the same conclusion.
These data suggest that UFT plus leucovorin is a well-tolerated,
fully oral treatment for patients with metastatic colorectal cancer
with efficacy comparable to intravenous 5-FU. Because pelvic
radiation toxicities include proctitis and diarrhea, a
fluoropyrimidine regimen with less overlapping toxicity would be
preferable during pelvic radiotherapy. Additionally, a daily oral
regimen has the potential to mimic the pharmacokinetics of an
infusion, which would allow for administration of fluoropyrimidine
therapy at the optimal dose schedule before, during, and after radiation.
An ongoing phase I trial was originated at the Memorial
Sloan-Kettering Cancer Center to determine the maximum tolerated dose
of UFT plus leucovorin, and dose-limiting toxicity when given
concurrently with pelvic radiotherapy for patients with resected
rectal cancer. This trial has recently been open to accrual at the
University of Pennsylvania Cancer Center.
Patients with histologically confirmed, resected rectal
adenocarcinoma and with adequate performance status and renal,
hepatic, and hematologic reserve are eligible for the study if the
tumor has transmural spread and/or nodal metastases. Radiation
therapy consists of three- or four-field ³
10 megavolt (MV) photons directed to the pelvis at 1.8 Gy/d to 45
Gy/5 weeks with a tumor bed boost to 50.4 Gy.
UFT is administered orally three times per day, 7 days per week for
each 28-day cycle. The drug is available in nondividable 100-mg
capsules. Individual doses are rounded to the nearest 100 mg.
Leucovorin at a fixed dose of 30 mg is also taken orally three times
a day with UFT.
Five 28-day cycles of UFT plus leucovorin are given. Cycle 1 is
started within 10 weeks from surgery, with all patients receiving the
known maximum tolerated dose of 300 mg/m²/d of UFT (when given
alone) plus leucovorin. Pelvic radiation is begun on day 35, after a
1-week break, along with cycle 2 UFT plus leucovorin. The starting
dose given with radiation was 175 mg/m²/d, and UFT is escalated
in patient cohorts at 50 mg/m²/d increments. Postradiation cycle
3 starts after a 3-week rest, and cycles 4 and 5 start after 1-week
rests as summarized in Figure 1.
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