Despite a number of advances over the past
decade in the adjuvant management of resectable rectal cancer, the
disease remains a significant problem worldwide. Treatment failure
results from both local disease recurrence and distant hemato- genous
spread. The median time to local relapse among patients treated
with surgery alone is only 12 months. Pelvic irradiation can decrease
local recurrence in patients with clinically resectable T3 and/or
N1-3, M0 disease. The addition of systemic chemotherapy further
enhances local control and improves overall survival.
Despite radical surgery, local failure frequently occurs in patients
with transmural or lymph nodepositive rectal cancer. Treatment
options for recurrent rectal cancer depend on the nature of previous
treatment, the general condition of the patient, and his or her life
expectancy. If possible, the same principles of management are
applied as those applied for locally advanced unresectable tumors.
Radiotherapyan important palliative treatment modalityis
used to diminish symptoms such as hemorrhage, bowel obstruction, and
pain resulting from nerve involvement (especially when the sacrum is
destroyed by a tumor). In such cases, radiation offers symptom
control for 6 to 9 months, or delays the onset of these problems.
Further benefit can be gained from combined chemoradiation therapy,
including 5-fluorouracil (5-FU). In a series from the Mayo Clinic,
65 patients with locally unresectable recurrent colorectal cancer
were assigned to receive either radiotherapy and 5-FU or radiotherapy
and placebo. Median survival was 10.5 months in the placebo group vs
16 months in the 5-FU group.
More recently, a number of new chemotherapeutic agents, either in
clinical development or already approved, are being evaluated in
place of 5-FU in the combined-modality treatment of recurrent rectal
cancer. Irinotecan (CPT-11 [Camptosar]), oxaliplatin, and uracil and
tegafur (UFT) plus calcium folinate (Orzel) are among those agents
currently in trial.
UFT is an orally available agent that appears to have activity
comparable to intravenously administered 5-FU. The combination of UFT
and the biochemical modulator, calcium folinate, should compare well
with conventional regimens, with the added advantages of a favorable
side-effect profile and ease of administration.
Two phase I trials are currently ongoing in the United States to
investigate chemoradiotherapy with UFT plus calcium folinate. In one
trial, chemoradiotherapy is being administered preoper- atively, and
in the other, postoperatively.
Here, we present the details of our phase I, dose-escalating trial to
evaluate the toxicity and feasibility of UFT plus calcium folinate
along with pelvic irradiation in the treatment of recurrent rectal cancer.
This open-label, phase I study is designed to assess the safety,
dose-limiting toxicities, and maximum tolerated dose of UFT plus
calcium folinate administered during radiotherapy to patients with
relapsing rectal cancer. Treatment with oral UFT plus calcium
folinate will begin concurrent with radiotherapy. The agent will be
administered three times per day through 5 days, or longer if a
radiation boost is administered.
Calcium folinate will be administered at a fixed dose of 90 mg/day.
The dose of UFT will be escalated stepwise (Table
1) from 250 mg/m²/day to 400 mg/m²/day in cohorts of
three or more patients, based on toxicity. If a dose-limiting
toxicity is observed in at least one of three patients at any dose
level, the cohort will be expanded to six patients. If no more than
two of six patients in the expanded cohort meet the dose-limiting
toxicity criteria, three patients will be entered into the next dose
level and dose escalation will continue. If at any dose level except
the first, three or more of six patients meet the dose-limiting
toxicity criteria, this dose will be defined as the maximum tolerated dose.
Once the maximum tolerated dose has been determined, an additional 10
patients will be treated at one dose level below the maximum
tolerated dose. The dose level of this enlarged cohort will also be
the recommended dose for the phase II studies.
For radiation treatment, linear accelerators (minimum energy 10
megavolts [MV]) will be used via an isocentric box technique. To
spare the bowel as much as possible, lateral and anterior fields will
be used to treat the pelvis. A prone position and belly board will be
useful aids in this technique for displacing the small bowel out of
the pelvis. In rectal cancer, the internal iliac and presacral lymph
nodes are at risk for tumor spread and metastatic involvement, and
should, therefore, be included in the target volume. The initial
radiation field will encompass the primary tumor volume and the
regional lymph nodes. Thereafter, a smaller field (boost) will be
used to treat the primary tumor site.
The dose for the large field, including the tumor bed and the
regional lymph nodes, will be 50.4 Gy, administered in 1.8-Gy single,
daily fractions five times per week for 5 to 6 weeks. This will be
followed by a boost of either 5.4 Gy or 9.0 Gy, depending on the
extent of radical surgery (5.4 Gy in cases with R0 or R1 resection;
9.0 Gy in cases with gross tumor resection [R2]).
Definition of Outcome Criteria
Table 2 outlines the criteria
for dose-limiting toxicities. The maximum tolerated dose for UFT plus
calcium folinate administered with radiation will be defined as the
dose level at which a dose-limiting toxicity occurs in three or more
of six patients. The recommended dose for the phase II study will be
one dose level below the maximum tolerated dose. Additional patients
may be treated as needed at any dose level to more fully elucidate
the dose-limiting toxicities.
This open-label, disease-oriented phase I trial aims to determine the
maximum tolerated dose, dose-limiting toxicities, and recommended
dose of UFT plus calcium folinate with concomitant radiation therapy
for the treatment of recurrent rectal cancer in a phase II trial.
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