Since irinotecan (CPT-11, Camptosar) was approved by the US
Food and Drug Administration for use in fluorouracil (5-FU)-refractory advanced
colorectal cancer, based on its demonstrated antitumor activity, studies have
reported the utility of irinotecan in first-line treatment of colorectal
cancer.[2-9] In April 2000, irinotecan was approved by the Food and Drug
Administration for use as a component of first-line therapy in combination with
5-FU and leucovorin for metastatic colorectal cancer. Additionally, preclinical
and clinical studies have suggested the potential effectiveness of irinotecan as
a radiosensitizing agent.[10-16]
Combined-modality treatment with chemotherapy and radiation can
improve the therapeutic index in rectal carcinoma. Fluorouracil is the most
widely used chemotherapeutic agent in the clinical management of patients with
rectal cancer. The benefits of combining fluoropyrimidines and radiation are
thought to be due to radiosensitization.[18-20] Although postoperative
irradiation with systemic chemotherapy is currently considered to be the most
effective treatment in the adjuvant setting,[21-23] preoperative irradiation has
demonstrated distinct advantages in the treatment of this disease. These
include the decrease of tumor seeding while the numbers of oxygenated cells
during surgery are increased, and the elimination of postsurgical small bowel
fixation in the pelvis. In addition, preoperative radiation therapy allows the
surgeon to perform sphincter-sparing, low anterior resection.[25-37] Results of
randomized trials also indicate that preoperative irradiation is more effective
than postoperative in reducing local failure.[38-40]
Fluorouracil is an analog of uracil and is metabolized to form
several nucleotides including fluorodeoxyuridine monophosphate (F-dUMP). This
nucleotide inhibits the enzyme thymidylate synthase, thus interfering with the
synthesis of new strands of DNA.[41,42] F-dUMP with a folate cofactor binds to
thymidylate synthase, leading to depletion of the product deoxythymidine
monophosphate (dTMP) and, ultimately, of deoxythymidine triphosphate (dTTP).
This results in accumulation of the substrate dUMP and deoxyuridine triphosphate
(dUTP), so that dUTP is misincorporated into DNA. Prolonged thymidylate synthase
inhibition depletes dTTP pools, leading to inhibition of DNA synthesis, DNA
fragmentation, G1/S cell-cycle arrest, and ultimately, cell death. Fluorouracil
is also incorporated into RNA and DNA, but the inhibition of thymidylate
synthase is considered to be its main mechanism of action and ultimately
responsible for the DNA-directed effects of the drug.
Radiosensitization is related to thymidylate synthase inhibition
and is accompanied by both a decrease in double-stranded breaks[44-46] and
sublethal damage repair.[47-49] Fluorouracil radiosensitization is enhanced by
leucovorin, presumably by potentiation of thymidylate synthase
Various mechanisms have been proposed to account for
fluoropyrimidine-mediated sensitization. These include (1) alteration of
nucleotide pools, (2) redistribution of cells to a relatively radiosensitive
phase of the cell cycle, and (3) incorporation of fluorodeoxyuridine
triphosphate into DNA.
Although each of the proposed mechanisms may play a role in
fluoropyrimidine-mediated sensitization, some studies suggest that cytotoxicity
may be inconsistent with radiosensitization. The inappropriate progression
of cells through the G1/S boundary and into S phase during fluoropyrimidine
exposure has also been proposed as a mechanism of radiosensitization.
Preclinical studies have demonstrated synergistic effects and
have suggested radiosensitizing activity when the topoisomerase I inhibitor
irinotecan is combined with radiation. Irinotecan may potentiate the lethal
effects of ionizing radiation by attaching to the DNA-topoisomerase adducts in
sites of DNA single-strand breaks. Subsequently, the irinotecan-topoisomerase
I-DNA complexes interact with advancing replication forks during the S phase
of the cell cycle, converting single-strand breaks into irreversible DNA
double-strand breaks, resulting in cell death.
Fractionated irradiation synchronizes and resorbs the tumor cell
population, leaving the majority of the cells in the S phase of the cell cycle
and thus more sensitive to irinotecan. With potentiating effects more
pronounced for chromosome aberrations of the exchange type, it has been
suggested that the interaction of unrepaired radiation- and camptothecin-induced
lesions during replication may be involved in the observed drug-radiation
Further studies have demonstrated radiation sensitization with
irinotecan in human tumor xenografts. Significant tumor regression was shown
when irinotecan was administered 1 hour prior to a single dose of irradiation
compared with the response to radiation therapy alone. Other studies have
also demonstrated sensitization when the drug is given following
In a clinical phase I/II trial in which weekly irinotecan was
given with concurrent irradiation of 60 Gy administered in 30 fractions over 6
weeks to patients with non-small-cell lung cancer, the maximum tolerated dose
of irinotecan was 60 mg/m2. A total of 24 previously untreated patients
with unresectable stage IIIA or IIIB non-small-cell lung cancer received
chemoradiation with irinotecan given at a dose of 45 mg/m2. The six planned
courses of irinotecan were delivered to 71% of patients; five courses were
administered to 21% of patients. External beam irradiation was completed in 88%
of patients, with treatment delays in three patients because of fever or
fatigue. The overall objective response rate was 76%, with two patients
achieving a complete response and 16 a partial response. Dose-limiting
toxicities were esophagitis, pneumonitis, and diarrhea. The conclusion of this
study was that combined-modality therapy with irinotecan is feasible and active
in the treatment of locally advanced non-small-cell lung cancer.
In a study by Minsky and colleagues at Memorial Sloan-Kettering
Cancer Center, a divided dose bolus schedule of escalating doses of irinotecan
(Monday through Friday) was administered on weeks 1, 2, 4, and 5 during a
standard 6-week radiation therapy cycle (50.4 Gy) for preoperative treatment of
locally advanced unresectable rectal cancer. The maximum tolerated dose was 10
mg/m2/d. Because complete responses were fewer than anticipated, this regimen
How then might irinotecan be more effectively incorporated into
a combined-modality regimen in the treatment of rectal cancer? Our group at the
Kimmel Cancer Center of Thomas Jefferson University is currently conducting a
phase I study with protracted continuous infusion of 5-FU given with weekly
irinotecan after 4 consecutive weeks and concurrent external beam irradiation
(total of 45.0 Gy in 1.8-Gy fractions) given daily. The objective was to
determine the maximum tolerated dose of weekly irinotecan combined with 5-FU and
concomitant irradiation given preoperatively in previously untreated patients
with primary or recurrent clinical stage T3/T4 adenocarcinoma of the rectum.
The treatment regimen was as follows: escalating doses of
irinotecan at 30 to 50 mg/m2 over 90 minutes on days 1, 8, 15, and 22.
Fluorouracil was given as a protracted venous infusion at 300 mg/m2/day
initially and subsequently reduced to 225 mg/m2 on days 1 through 5 weekly
during radiation therapy. Surgery was performed 8 to 10 weeks following
completion of therapy. At the time of this preliminary report, a total of 38
patients were enrolled in the study. One patient was removed from the study for
noncompliance and one due to early surgical intervention. All are evaluable for
toxicity. The incidence of grade 3/4 toxicities at each dose level is outlined
in Table 1.
Hematologic toxicities were mild. The major dose-limiting
toxicities were diarrhea, intravenous catheter infections, and thrombi. Of 34
patients who have undergone surgery, 10 complete pathologic remissions and 6
patients with minimal residual disease were observed; 4 patients are awaiting
surgery. The conclusion was that the combination of irinotecan, 5-FU, and
concomitant radiation therapy given preoperatively in this patient population
was well tolerated. The maximum tolderated dose had not been achieved in this
The radiosensitizing properties of 5-FU have been well
delineated. Clinical studies evaluating the potential of irinotecan are
underway. Preclinical evidence from a murine model suggests effectiveness. The
ability to administer full doses of irinotecan and 5-FU allows the potential of
double radio enhancement. Further studies will determine the effectiveness of
this combination in the management of patients with adenocarcinoma of the
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