Lung cancer is the leading cause of cancer-related morbidity and mortality. The estimated incidences for the year 2000 are 164,100 new cases and 156,900 deaths in the United States alone. Five-year survival figures for lung cancer have remained in the 15% range from 1974 through 1995; most of these cures involve early cancers usually treated with surgery alone. However, approximately 35% of patients present with locally advanced disease that is not amenable to surgical therapy, but is nonetheless potentially curable. Tradition- al treatment with radiation alone in these patients has yielded low cure rates. This has spurred investigations of new methods to improve outcome.
Peckham and Steele outlined several possible mechanisms of interaction between radiation and chemotherapies: spatial cooperation, enhancement of tumor response, radioprotection, and nonoverlapping toxicities are all ways that chemotherapy and radiation may interact to improve therapeutic ratio. Spatial cooperation describes a situation where disease located in a specific anatomic site is missed by one agent but treated by another. Enhancement refers to the administration of an agent that 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 the administration of a chemotherapeutic agent that would allow safe delivery of higher radiation doses.
Finally, toxicity independence, or nonoverlapping toxicities, describes when two partially effective agents can be used in combination without having to substantially reduce dose levels to avoid unacceptable side effects. Multiple phase III trials have shown benefits with the combined use of chemotherapy and radiation in the treatment of non-small-cell lung cancer at the expense of increased toxicity.[4-7] Overall, the meta-analysis from Pritchard et al suggests that traditional chemotherapy added to radiotherapy adds an average of 2 months to patient survival.
Several new active agents that hold promise for improving outcome in lung cancer patients are emerging. These include paclitaxel(Drug information on paclitaxel) (Taxol), docetaxel (Taxotere), vinorelbine (Navelbine), gemcitabine(Drug information on gemcitabine) (Gemzar), and irinotecan(Drug information on irinotecan) (Camptosar, CPT-11), which have demonstrated response rates ranging from 20% to 54% as single agents in metastatic disease. Finding a cure for this disease will require a better understanding of the mechanisms of action of these agents and their interactions with ionizing radiation, and the proper sequencing of these agents with other drugs and with radiation. This article will review the literature on the use of irinotecan in combination with thoracic irradition in the treatment of non-small-cell lung cancer.
Camptothecin and its derivatives target DNA topoisomerase I, the DNA-relaxing enzyme.[9-12] This enzyme relaxes both positively and negatively supercoiled DNA, which allows diverse essential cellular processes, including DNA replication and transcription, to proceed. The key step for drug activity is stabilization of the topoisomerase I-DNA intermediate that the enzyme forms when cleaving DNA to allow for uncoiling to occur.[9-14] It is believed that collision between the drug-trapped topoisomerase-DNA complex and the replication material leads to G2-phase cell-cycle arrest and, ultimately, cell death.
Camptothecin is the prototype drug that was initially studied in the 1970s as a chemotherapeutic agent; however, its use was discontinued because of excessive toxicity. Ongoing research has begun to focus on camptothecin derivatives that have antineoplastic activity with improved toxicity profiles. This generation of drugs includes irinotecan. Irinotecan is a prodrug that is metabolized intracellularly to its active metabolite, SN-38, by a carboxylesterase- converting enzyme. This metabolite is more than 1,000 times more potent than irinotecan as an inhibitor of topoisomerase I. All of the camptothecins have a terminal lactone ring that can be hydrolyzed to a less active carboxylate species. Under acidic conditions, however, like that in the tumor microenvironment, the active lactone species is favored.
The plasma half-life of SN-38 after a short IV infusion is 10.2 hours (range: 5.9 to 13.8 hours), so that nanomolar concentrations of the drug persist for more than 2 days. This may affect its cytotoxicity. The major method of elimination of SN-38 is hepatic glucuronidation; a decreased ability to glucuronidate is thought possibly to correlate with increased gastrointestinal side effects. Clinically, the dose-limiting toxicity of irinotecan is delayed-onset diarrhea, which can be profuse and potentially life threatening. The diarrhea is thought to be related to the high S-phase fraction of the intestinal mucosa, as well as to the action of intestinal flora glucuronidase in cleaving the camptothecin-glucuronidase conjugate, leading to release of the drug in the intestinal lumen. Other common toxicities include neutropenia, nausea, and vomiting.
In planning combined-modality chemoradiotherapy, it is important to understand the mechanism of interaction between the two modalities. Several investigators have reported that camptothecin enhances the cytotoxic effect of radiation in vitro and in vivo.[20,21] Omura et al assessed the radiosensitizing effects of SN-38 in HT-29 spheroids derived from a human colon cancer cell line. Results showed significantly enhanced cell kill with combined radiation and irinotecan; the largest gains in cytotoxicity occurred when irinotecan was administered just before or just after the radiation. The data also suggest that the mechanism of radiosensitization in the spheroids is through inhibition of potentially lethal damage repair.
Chen et al showed that camptothecin derivatives radiosensitized log-phased human MCF-7 breast cancer cells in a schedule-dependent manner. Essentially, cells exposed to 20(S)-10,11 methylenedioxycamptothecin before or during radiation had sensitization ratios of 1.6, while those treated with the drug after radiation had substantially less enhancement of radiation-induced DNA damage. The clinical implication of these results is that patients should be treated with camptothecin derivative-based chemotherapy prior to or during radiotherapy to receive the full benefits of combined-modality therapy. Emerging data also show that other camptothecin derivativesincluding 9-nitro- 20(S)-camptothecin, 9-aminocamptothecin, and topotecan(Drug information on topotecan) (Hycamtin)can potentiate the lethal effects of radiation.
There are several hypotheses, with varying amounts of supportive evidence, regarding the mechanism of interaction between radiation and irinotecan. The first hypothesis suggests that inhibition of topoisomerase I by camptothecin or its derivatives leads to inhibition of repair of radiation-induced DNA strand breaks. The second hypothesis suggests that camptothecin or its analogs causes redistribution of cells into the more radiosensitive G2 phase of the cell cycle. The third 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. The primary mechanism involved with radiosensitization may depend on which camptothecin derivative is being used; there is currently insufficient evidence to identify the underlying mechanism with certainty.
Combined-modality treatment relies on the ability of focused radiation and concurrent radiosensitizing agents to treat locally, while leaving the potential micrometastatic disease for chemotherapy to control. As such, it is also important to maximize the cytotoxic effects of chemotherapy while minimizing toxicities. This requires an understanding of the mechanisms of interaction between different drugs. Basic principles used in selecting drugs include nonoverlapping toxicities, differing mechanisms of action, and non-cross- resistance. Based on these criteria, both preclinical and clinical trials have been undertaken to evaluate the cisplatin(Drug information on cisplatin) (Platinol)/irinotecan combination in lung cancer.
In xenografts of the small-cell lung cancer tumor lines Mnsul and LX1, Kudoh et al showed that irinotecan in combination with cisplatin led to a larger reduction in tumor size than either agent alone. However, in xenografts of Mnqul, a cell line developed from human squamous cell lung carcinoma, combination cisplatin/irinotecan treatment was more effective than cisplatin alone but not more effective than irinotecan alone. According to the authors, the data clearly suggest that the combination of radiation and irinotecan should be effective in small-cell lung cancer; however, they cautioned that more data are needed, using a different non-small-cell lung cancer model, prior to concluding that the combination is better than irinotecan alone.
In patients with advanced lung cancer, early studies using irinotecan alone have yielded favorable response rates (> 30%). The combination of irinotecan and cisplatin has also been assessed in phase I and II clinical trials; early data from phase II studies revealed a 48% response rate in non-small-cell lung cancer and 78% in small-cell lung cancer. A subsequent phase I trial looked at fractionation of both the cisplatin and irinotecan doses, ie, 60 mg/m2 of cisplatin and escalating doses of irinotecan were given on days 1 and 8. Cycles were repeated every 4 weeks. An impressive 78% response rate was seen in 18 patients with non-small-cell lung cancer. A North American phase II trial examined the combination of cisplatin at 80 mg/m2 on day 1 and irinotecan at 60 mg/m2 on days 1, 8, and 15 in 4-week courses, with the possibility of escalating the irinotecan dose according to side effects. The irinotecan dose was ultimately modified to less than 40 mg/m2; the response rate was 28.8% in 52 patients.