Irinotecan and Radiation in Combined-Modality Therapy for Solid Tumors

Introduction

Solid tumors account for the majority of all malignancies and are responsible for a large proportion of deaths in the industrialized world. In the United States in the year 2001, 1,268,000 new cases of invasive cancer will be diagnosed and 553,400 Americans are expected to die from their cancers.[1] While currently about half of all patients are cured, the other 50% will die of their disease.[1] Current treatments are based on one of three modalities: surgery, radiation, or chemotherapy. Surgical treatments often fail because either the tumor recurs in the tumor bed, since an insufficient margin of normal tissue was removed in order to preserve function and cosmesis, or distant metastases develop. Radiation treatments fail because distant metastatic disease develops or the dose required to sterilize the tumor is limited by the surrounding normal tissues, and the tumor recurs locally. Chemotherapy tends to have less of a curative effect on gross disease but may be able to decrease the risk of distant relapse when administered in an adjuvant setting.

More traditional treatments like cisplatin(Drug information on cisplatin) (Platinol) and doxorubicin(Drug information on doxorubicin) are now being joined by a new generation of drugs active against a broad range of solid tumors. These new agents—including paclitaxel(Drug information on paclitaxel) (Taxol), docetaxel (Taxotere), gemcitabine(Drug information on gemcitabine) (Gemzar), vinorelbine (Navelbine), irinotecan(Drug information on irinotecan) (CPT-11, Camptosar), and others—are associated with promising response rates of 20% to 50% in the setting of metastatic disease.[2] It is hoped that these agents may improve outcomes in patients with earlier-stage disease as well.

Multiple Treatment Modalities

Modern clinical trials are focusing more on integrating multiple treatment modalities to maximize outcomes. Steele and Peckham outlined several mechanisms for the possible interaction of radiation and chemotherapies: spatial cooperation, enhancement of tumor response, radioprotection, and nonoverlapping toxicities (or toxicity independence).[3] Spatial cooperation describes a situation in which disease located in a specific anatomic site is missed by one agent but treated by another. Enhancement occurs when the administration of one agent increases the effect of another agent, or when the effect of the combination is greater than would be expected with either agent alone. Radioprotection refers to administration of a chemotherapeutic agent that allows for safe delivery of increased radiation.

Ample literature exists on the ability of different drugs to enhance radiation effect when the two modalities are delivered concurrently. This article will provide an overview of concurrent administration of irinotecan and radiation to patients with solid tumors, with a focus on irinotecan’s mechanism of action, its radiosensitizing effects, and current clinical trials evaluating concurrent irinotecan and radiation.

Camptothecins

Background and Mechanism of Activity

Irinotecan is a member of a relatively new group of anticancer agents, the camptothecins, whose activity is believed to be achieved by targeting DNA topoisomerase I.[4-7] The human DNA topoisomerase I is a monomeric 100-kDa protein that relaxes supercoiled DNA by introducing a single-strand break in DNA, followed by the passing of the intact strand through the break prior to re-ligation.[4-9] This activity is key in many aspects of DNA metabolism, including transcription, replication, and regulation of DNA supercoiling, which is important in maintaining genomic stability. It is believed that the camptothecins function by stabilizing a topoisomerase I-DNA intermediate, called the cleavable complex, such that the 5¢ phosphoryl end of the DNA single-strand break is bound covalently to a topoisomerase I tyrosine residue.[10] It is believed that collision of this drug-trapped complex with the DNA replication machinery will lead to G2 phase cell-cycle arrest and cell death.[10]

Camptothecin, the parent compound, was initially isolated from the tree Camptotheca acuminata and found to have a broad spectrum of activity in a variety of solid tumors.[11] However, early clinical trials with the ring-open form of the drug showed excessive toxicity and the trials were terminated.[12] More recently, interest has been rekindled in these drugs with the advent of derivatives that have significant antitumor activity and much less toxicity. Irinotecan, one of these derivatives, is actually a prodrug that is metabolized intracellularly into SN-38.[13] SN-38 is approximately 1,000 times more potent than irinotecan in inhibiting topoisomerase I.[14] All of the camptothecins have a terminal lactone ring that can be hydrolyzed to a less active carboxylate species. Under acidic conditions, however, like those expected in the tumor microenvironment, the active lactone species is favored.[13]

The plasma half-life of SN-38 by intravenous infusion is 5.9 to 13.8 hours,[13] and this may have implications in terms of both direct cytotoxicity and radiosensitization. SN-38 is eliminated primarily through hepatic glucuronidation and it is thought that a decreased ability to glucuronidate the drug correlates with increased gastrointestinal side effects.[13] One of the major side effects of irinotecan is late-onset diarrhea, which is possibly related to the high S-phase fraction of the intestinal mucosa as well as action of intestinal flora glucuronidase in cleaving the camptothecin-glucuronidase conjugate, leading to the drug’s release into the intestinal lumen.[15] Other common toxicities include neutropenia, nausea, vomiting, anorexia, fatigue, asthenia, and elevation of hepatic transaminase levels.[13]

Several other camptothecin derivatives have been shown to have significant cytotoxic effects and are at varying stages of development. These include topotecan(Drug information on topotecan) (Hycamtin),[16,17] 9-aminocamptothecin (9 A-C),[18] and 9-nitrocamptothecin (RFS-2000).[19] Of these, topotecan has undergone the most extensive clinical testing; it is indicated for treatment of patients with platinum-resistant ovarian cancer and small-cell lung cancer after failure of first-line therapy.[16]

Irinotecan Activity

Response rates with irinotecan have ranged from 18% to 32% in metastatic colorectal cancer,[20,21] 15% to 32% in non-small-cell lung cancer,[22,23] and 10% to 47% in small-cell lung cancer.[24,25] It is also active in other malignancies, including cervical, gastric, ovarian, and central nervous system tumors.[13] While its activity in advanced disease is promising, convincing evidence now indicates that the camptothecins—including irinotecan—have significant radiosensitizing properties.[10,17] This discovery may potentially lead to improved local control of solid tumors when irinotecan is used concurrently with radiation. In the setting of localized and potentially curable disease, it is hoped that this enhanced activity will translate into improved survival.

Several hypotheses exist regarding the mechanism of interaction between radiation and irinotecan, each with varying amounts of supportive evidence. One hypothesis suggests that inhibition of topoisomerase I by camptothecin or its derivatives leads to inhibition of repair of radiation-induced DNA strand breaks.[18,26,27] A second hypothesis suggests that camptothecin or its analogs causes redistribution of cells into the more radiosensitive G2 phase of the cell cycle.[28]

Another hypothesis is that topoisomerase I-DNA adducts are trapped by irinotecan at the sites of radiation- induced single strand breaks, leading to their conversion into double-strand breaks.[29-31] In essence, the drug-stabilized cleavable complex, with a concealed single-strand DNA break, may potentially act as a point of sublethal DNA damage. Interaction with cellular processes like transcription and DNA repair may act to turn this "potentially sublethal damage" into "sublethal damage." It is possible that the addition of radiation may in turn change this "sublethal damage" into "lethal damage."[10] It is also suggested that high levels of topoisomerase I are associated with high levels of cleavable complex formation.[32] These high enzyme levels have been documented in several tumor specimens,[33] suggesting that irinotecan use may be beneficial in improving the therapeutic ratio vis-à-vis normal tissue effects.

Johnson and McNerney initially reported in 1985 that topoisomerase I activity increased by about 300-fold after irradiation of human peripheral blood lymphocytes or cultured lymphoblastoid cells.[34] Other investigators have not found any increase in activity.[34] This variance could be related to the cell population or to the genomic location of the topoisomerase pool under examination. The predominance of the particular mechanism involved in radiosensitization may depend on which camptothecin derivative is used; now, there is insufficient evidence to identify the underlying mechanism with certainty.