In the year 2000, approximately 36,400 patients in the United States
will be diagnosed with rectal cancer. Despite surgical resection,
a significant number of these patients will be candidates for further
adjuvant treatments. Since the 1980s, the role of postoperative
pelvic radiation and fluorouracil (5-FU)-based chemotherapy for
patients with stages II and III adenocarcinomas of the rectum has
become well established.[2,3] Continuous infusion 5-FU has proven to
be superior to bolus 5-FU schedules when given during radiation.
The modulation of 5-FU by leucovorin produced increased response
rates in metastatic colorectal cancer patients. However, the
results were similar for patients with rectal cancer undergoing
postoperative radiation with bolus 5-FU alone or in combination with
leucovorin (calcium folinate), levamisole (Ergomisol), or both.
The optimal timing as well as the optimal regimen for the adjuvant
treatment of rectal cancer remains unclear.
Over the past few years, a considerable number of oral
fluoropyrimidines have been investigated for the treatment of
colorectal cancer. Oral fluoropyrimidines represent an attractive and
convenient alternative to intravenous 5-FU. In addition, oral
chemotherapy may circumvent the problems and costs associated with
central venous lines and portable infusion pumps.
Tegafur is a prodrug converted to 5-FU by the hepatic microsomal
system. It was initially evaluated in the 1970s by the National
Cancer Institute. Studies of intravenous tegafur demonstrated
objective responses in solid tumors, but the severe toxicity halted
its development in the United States. Japanese researchers, on the
other hand, took advantage of the drugs good oral
bioavailability, and split the oral dosing, which led to a
significant improvement in its toxicity profile. Objective responses
were then observed in a variety of solid tumors.
Further research produced the combination of uracil with tegafur
(UFT), in a fixed molar ratio of 4:1. Uracil is a competitive
inhibitor of dihydropyrimidine dehydrogenase (DPD), the chief
catabolic enzyme of 5-FU. The inhibition of DPD by uracil results in
elevated and well-maintained concentrations of 5-FU.[10,11]
Preclinical experiments confirmed that leucovorin combined with UFT
has enhanced antitumor activity. This combination is currently
undergoing evaluation in various solid tumors.
UFT plus oral leucovorin (a combination being developed under the
trade name Orzel) has been investigated in the treatment of advanced
colorectal cancer, and has produced objective response rates ranging
from 25% to 42%. Preliminary results from two large randomized
studies in patients with metastatic colorectal cancer suggest that
UFT plus leucovorin may be equivalent to bolus 5-FU plus leucovorin
in terms of response rates and survival.[13,14] UFT plus leucovorin
is generally well tolerated, with diarrhea, nausea, and anorexia
being the most frequent adverse events. Grade 3 or 4 diarrhea was
observed in 4% to 21% of patients.[9,13,14] However, UFT plus
leucovorin is not associated with significant myelosuppression,
mucositis, hand-foot syndrome, or alopecia.
Based on the encouraging results reported from trials of preoperative
(neoadjuvant) chemoradiation trials,[15-17] this treatment modality
is routinely used at The University of Texas M. D. Anderson Cancer
Center for patients with stages II and III rectal cancer. Advantages
associated with preoperative adjuvant therapy include an in vivo
evaluation of drug efficacy, an intact blood supply to the tumor, and
a reduced amount of small bowel in the radiated field. In addition,
the potential for sphincter preservation with this approach
represents a major advantage. The main disadvantage of preoperative
therapy is its limited ability to stage the tumor pathologically.
Pharmacokinetic studies comparing 5-FU levels obtained with
protracted infusions of 5-FU with those obtained with oral UFT have
demonstrated a similar area-under-the-curve for both agents, with
higher peak levels of 5-FU associated with UFT. Although UFT plus
leucovorin has been administered to many patients, relatively little
is known about the combination of these agents and radiation for
rectal cancer. The primary goal of our ongoing trial is to
investigate the antitumor efficacy and safety of a preoperative
regimen of UFT plus leucovorin combined with radiation in patients
with rectal cancer. This regimen might prove to be less toxic, more
cost-effective, and a convenient adjuvant treatment for these patients.
Patients with histologically confirmed rectal cancer for whom
adjuvant chemotherapy and radiation are indicated (ie, those with T3
or T4 lesions, or nodal involvement as evidenced by endoscopy) are
eligible for the study. Other eligibility criteria include the
ability to tolerate major surgery, age over 18 years, Zubrod
performance status of 0 to 2, normal renal, hepatic, and hematologic
functions, and a life expectancy > 3 months. Patients with distant
metastasis or prior malignancies, those who have had major surgery
within the previous 3 weeks, and pregnant or nursing women are
ineligible. Written informed consent must be provided prior to study enrollment.
A complete medical history and physical examination are obtained at
baseline, and all patients undergo a complete blood count, chemistry
profile including liver and renal function tests, electrocardiogram,
chest radiograph, serum level of carcinoembryonic antigen, and
urinalysis. Complete blood counts are obtained weekly throughout treatment.
Each group of three patients receives an escalating dose of oral UFT
(starting at 250 mg/m²/d) and a fixed dose of oral leucovorin
(90 mg/d), both of which are administered in three daily doses for 5
consecutive days. Table 1
presents the UFT dose-escalation schedule. Radiation therapy is
delivered to the pelvis in daily fractions of 180 cGy on the same 5
days as the chemotherapy is administered. A 2-day rest follows, then
the 7-day cycle is repeated for a total of 5 weeks. The total dose of
radiation is 4,500 cGy. Surgical resection is performed 4 to 6 weeks
after the completion of chemoradiation.
Four weeks after surgery, patients receive fixed doses of UFT (300
mg/m²/d) and leucovorin (90 mg/d) in three daily doses for 28
consecutive days, followed by a 7-day rest period, as previously
recommended. This 35-day cycle is repeated four times. At dose
levels 0, 1, and 2, the postoperative dose of UFT is 250
mg/m²/d. Figure 1 outlines
the overall treatment plan.
Standard antiemetic therapy is prescribed as required. Antidiarrheal
drugs are not allowed prophylactically, but may be used for
symptomatic treatment of grade 2 or higher diarrhea. Toxicity is
recorded weekly according to the National Cancer Institute Common
Toxicity Criteria. If grade 2 or higher toxicity develops, therapy is
halted and not resumed until all symptoms have completely resolved.
Days lost due to withheld therapy are not made up and are counted as
This phase I trial follows the usual 3 plus 3 method,
where cohorts of three patients are entered at each dose level. If
two or three of the patients in dose level 0 develop grade 3 or 4
toxicity, a new cohort is treated at the lower dose level. If zero or
one patient develops grade 3 or 4 toxicity, three more patients are
treated at the same dose level. If up to two of six patients develop
grade 3 or 4 toxicity, escalation continues. If three or more
patients develop grade 3 or 4 toxicity, the next cohort of three
patients is entered at the next lower dose level. The maximum
tolerated dose is the dose level that is immediately below the one
producing dose-limiting toxicity in two or more of three patients, or
three or more of six patients.
As of this writing, 11 patients have been entered into this trial.
Dose escalation of UFT up to 350 mg/m2/d has been achieved. Diarrhea
is the predominant toxicity at this level, but is adequately
controlled with conventional antidiarrheal agents. Both chemotherapy
and pelvic radiation could be completed on schedule in all patients.
This phase I study will determine the tolerability of a preoperative,
combined-modality, adjuvant treatment that includes UFT plus
leucovorin and radiation therapy. The potential for sphincter
preservation and the convenience of oral chemotherapy make this
approach an attractive alternative in the adjuvant treatment of
patients with rectal cancer that is penetrating through the bowel
wall or involving regional lymph nodes. Further studies are necessary
to better define the role of preoperative chemoradiation in rectal
cancer, especially in terms of its comparability to 5-FUbased,
postoperative, adjuvant chemoradiation.
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