Irinotecan in Preoperative Combined-Modality Therapy for Locally Advanced Rectal Cancer

ABSTRACT: Irinotecan (CPT-11, Camptosar) is a semisynthetic water-soluble derivative ofthe plant alkaloid camptothecin. This review will focus on the potential use ofirinotecan in combination with fluorouracil (5-FU) in the preoperativecombined-modality treatment of advanced rectal cancer. The laboratory studiesthat define the mechanism of fluoropyrimidine- and camptothecin-mediatedradiosensitization are discussed, and the rationale for combined-modalitytherapy using radiation with 5-FU and irinotecan is presented. [ONCOLOGY14(Suppl 14):56-59, 2000]

Introduction

Since irinotecan (CPT-11, Camptosar) was approved by the USFood and Drug Administration for use in fluorouracil (5-FU)-refractory advancedcolorectal cancer, based on its demonstrated antitumor activity,[1] studies havereported the utility of irinotecan in first-line treatment of colorectalcancer.[2-9] In April 2000, irinotecan was approved by the Food and DrugAdministration for use as a component of first-line therapy in combination with5-FU and leucovorin for metastatic colorectal cancer. Additionally, preclinicaland clinical studies have suggested the potential effectiveness of irinotecan asa radiosensitizing agent.[10-16]

Combined-modality treatment with chemotherapy and radiation canimprove the therapeutic index in rectal carcinoma.[17] Fluorouracil is the mostwidely used chemotherapeutic agent in the clinical management of patients withrectal cancer. The benefits of combining fluoropyrimidines and radiation arethought to be due to radiosensitization.[18-20] Although postoperativeirradiation with systemic chemotherapy is currently considered to be the mosteffective treatment in the adjuvant setting,[21-23] preoperative irradiation hasdemonstrated distinct advantages in the treatment of this disease.[24] Theseinclude the decrease of tumor seeding while the numbers of oxygenated cellsduring surgery are increased, and the elimination of postsurgical small bowelfixation in the pelvis. In addition, preoperative radiation therapy allows thesurgeon to perform sphincter-sparing, low anterior resection.[25-37] Results ofrandomized trials also indicate that preoperative irradiation is more effectivethan postoperative in reducing local failure.[38-40]

Fluoropyrimidine Cytotoxicity

Fluorouracil is an analog of uracil and is metabolized to formseveral nucleotides including fluorodeoxyuridine monophosphate (F-dUMP). Thisnucleotide inhibits the enzyme thymidylate synthase, thus interfering with thesynthesis of new strands of DNA.[41,42] F-dUMP with a folate cofactor binds tothymidylate synthase, leading to depletion of the product deoxythymidinemonophosphate (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 synthaseinhibition depletes dTTP pools, leading to inhibition of DNA synthesis, DNAfragmentation, G1/S cell-cycle arrest, and ultimately, cell death. Fluorouracilis also incorporated into RNA and DNA, but the inhibition of thymidylatesynthase is considered to be its main mechanism of action and ultimatelyresponsible for the DNA-directed effects of the drug.[43]

Fluoropyrimidine Radiation Interactions

Radiosensitization is related to thymidylate synthase inhibitionand is accompanied by both a decrease in double-stranded breaks[44-46] andsublethal damage repair.[47-49] Fluorouracil radiosensitization is enhanced byleucovorin, presumably by potentiation of thymidylate synthaseinhibition.[17,46,48]

Various mechanisms have been proposed to account forfluoropyrimidine-mediated sensitization. These include (1) alteration ofnucleotide pools, (2) redistribution of cells to a relatively radiosensitivephase of the cell cycle, and (3) incorporation of fluorodeoxyuridinetriphosphate into DNA.[17]

Although each of the proposed mechanisms may play a role influoropyrimidine-mediated sensitization, some studies suggest that cytotoxicitymay be inconsistent with radiosensitization.[19] The inappropriate progressionof cells through the G1/S boundary and into S phase during fluoropyrimidineexposure has also been proposed as a mechanism of radiosensitization.[50]

Radiation SensitizationWith Irinotecan

Preclinical studies have demonstrated synergistic effects andhave suggested radiosensitizing activity when the topoisomerase I inhibitoririnotecan is combined with radiation. Irinotecan may potentiate the lethaleffects of ionizing radiation by attaching to the DNA-topoisomerase adducts insites of DNA single-strand breaks. Subsequently, the irinotecan-topoisomeraseI-DNA complexes interact with advancing replication forks during the S phaseof the cell cycle, converting single-strand breaks into irreversible DNAdouble-strand breaks, resulting in cell death.

Fractionated irradiation synchronizes and resorbs the tumor cellpopulation, leaving the majority of the cells in the S phase of the cell cycleand thus more sensitive to irinotecan.[51] With potentiating effects morepronounced for chromosome aberrations of the exchange type, it has beensuggested that the interaction of unrepaired radiation- and camptothecin-inducedlesions during replication may be involved in the observed drug-radiationsynergism.[11]

Further studies have demonstrated radiation sensitization withirinotecan in human tumor xenografts. Significant tumor regression was shownwhen irinotecan was administered 1 hour prior to a single dose of irradiationcompared with the response to radiation therapy alone.[10] Other studies havealso demonstrated sensitization when the drug is given followingirradiation.[14]

Irinotecan in Combined-Modality Therapy

In a clinical phase I/II trial in which weekly irinotecan wasgiven with concurrent irradiation of 60 Gy administered in 30 fractions over 6weeks to patients with non-small-cell lung cancer, the maximum tolerated doseof irinotecan was 60 mg/m².[15] A total of 24 previously untreated patientswith unresectable stage IIIA or IIIB non-small-cell lung cancer receivedchemoradiation with irinotecan given at a dose of 45 mg/m². The six plannedcourses of irinotecan were delivered to 71% of patients; five courses wereadministered to 21% of patients. External beam irradiation was completed in 88%of patients, with treatment delays in three patients because of fever orfatigue. The overall objective response rate was 76%, with two patientsachieving a complete response and 16 a partial response. Dose-limitingtoxicities were esophagitis, pneumonitis, and diarrhea. The conclusion of thisstudy was that combined-modality therapy with irinotecan is feasible and activein the treatment of locally advanced non-small-cell lung cancer.

In a study by Minsky and colleagues at Memorial Sloan-KetteringCancer Center, a divided dose bolus schedule of escalating doses of irinotecan(Monday through Friday) was administered on weeks 1, 2, 4, and 5 during astandard 6-week radiation therapy cycle (50.4 Gy) for preoperative treatment oflocally advanced unresectable rectal cancer. The maximum tolerated dose was 10mg/m²/d. Because complete responses were fewer than anticipated, this regimenwas abandoned.[52]

How then might irinotecan be more effectively incorporated intoa combined-modality regimen in the treatment of rectal cancer? Our group at theKimmel Cancer Center of Thomas Jefferson University is currently conducting aphase I study with protracted continuous infusion of 5-FU given with weeklyirinotecan after 4 consecutive weeks and concurrent external beam irradiation(total of 45.0 Gy in 1.8-Gy fractions) given daily. The objective was todetermine the maximum tolerated dose of weekly irinotecan combined with 5-FU andconcomitant irradiation given preoperatively in previously untreated patientswith primary or recurrent clinical stage T3/T4 adenocarcinoma of the rectum.

The treatment regimen was as follows: escalating doses ofirinotecan 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/dayinitially and subsequently reduced to 225 mg/m² on days 1 through 5 weeklyduring radiation therapy. Surgery was performed 8 to 10 weeks followingcompletion of therapy. At the time of this preliminary report, a total of 38patients were enrolled in the study. One patient was removed from the study fornoncompliance and one due to early surgical intervention. All are evaluable fortoxicity. The incidence of grade 3/4 toxicities at each dose level is outlinedin Table 1.

Hematologic toxicities were mild. The major dose-limitingtoxicities were diarrhea, intravenous catheter infections, and thrombi. Of 34patients who have undergone surgery, 10 complete pathologic remissions and 6patients with minimal residual disease were observed; 4 patients are awaitingsurgery. The conclusion was that the combination of irinotecan, 5-FU, andconcomitant radiation therapy given preoperatively in this patient populationwas well tolerated. The maximum tolderated dose had not been achieved in thisongoing investigation.[53]

Conclusion

The radiosensitizing properties of 5-FU have been welldelineated. Clinical studies evaluating the potential of irinotecan areunderway. Preclinical evidence from a murine model suggests effectiveness. Theability to administer full doses of irinotecan and 5-FU allows the potential ofdouble radio enhancement. Further studies will determine the effectiveness ofthis combination in the management of patients with adenocarcinoma of therectum.

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