In 2004, it is estimated that in the United States there will be 68,510 deaths among women and 91,930 deaths among men due to lung cancer, which is the leading cause of cancer deaths in the United States. Lung cancer accounts for 14% of new cancer cases and 28% of cancer deaths per year in the United States.[1] The 5-year survival rate for lung cancers has been around 15% from 1974 through 1995.[2] Most of these cures are related to surgical treatment of patients presenting with stage I and II cancers. However, about 35% of patients present with locally advanced disease that is not amenable to surgical therapy but may be potentially curable.[3] Traditional radiation treatment alone in this group of patients has yielded dismal cure rates at 5 years. Therefore, a combined-modality therapy has been sought to improve the poor outcome with single modality alone. Patients with clinical stage IIIA have an overall 5-year survival rate of 10% to 15%. However, this figure drops to 2% to 5% when there is grossly visible disease in the mediastinum on a chest x-ray.[4] The principal forms of treatment for patients with stage III non-small-cell lung cancer (NSCLC) are radiation therapy, chemotherapy, surgery, and combinations of these modalities. Several potential benefits are derived from interactions of radiothera py and chemotherapy to improve therapeutic outcome. Combined radiotherapy and chemotherapy may increase tumor response, protect normal tissues, and exhibit nonoverlapping toxicities.[ 5] There is potential synergistic increase in enhancement of tumori- cidal effect in specific anatomic sites where single-modality therapy may have limited efficacy. Chemotherapeutic agents may reduce the radiotherapy- induced normal tissue toxicity to an acceptable level for patients. Finally, two partially effective therapeutic modalities may be combined without having to significantly reduce their dose levels to avoid treatmentrelated toxicities. Multiple phase III trials have confirmed therapeutic benefits of combining chemotherapy and radiotherapy in locally advanced NSCLC, but with increased treatment-related toxici- y.[ 6-9] A large meta-analysis of 22 trials (3,033 patients and 2,814 deaths) comparing radiotherapy administered alone or with chemotherapy demonstrated a 10% reduction in the relative risk of death with chemoradiotherapy vs radiotherapy as a sole modality (P = .006), with an absolute reduction in deaths of 3% at 2 years and 2% at 5 years.[10] Another meta-analysis from Pritchard et al suggested that traditional chemotherapy added to radiotherapy adds an average of 2 months to patient survival.[11] Recent trials have shown that concurrent chemoradiotherapy results in a better overall survival compared with sequential chemoradiotherapy in NSCLC.[12,13] Combined chemotherapy and radiotherapy currently remains the standard treatment for locally advanced NSCLC. However, local failure rates can be around 80%.[6,9] Therefore, ongoing trials seek to improve the outcome for treatment of lung cancer. Multiple agents including paclitaxel(Drug information on paclitaxel), docetaxel (Taxotere), vinorelbine, gemcitabine(Drug information on gemcitabine) (Gemzar), and irinotecan(Drug information on irinotecan) (Camptosar) show a 20% to 54% response rate for single-agent treatment in metastatic NSCLC.[3] This review will focus on the data surrounding the use of topoisomerase I inhibitors in combination with thoracic radiotherapy in the treatment of locally advanced NSCLC. Camptothecin Camptothecin is an alkaloid originally found in the Chinese tree Camptotheca acuminata. The US National Cancer Institute first discovered camptothecin with antitumor activity in the 1960s.[14] In preclinical studies, the antitumor activity was seen against colon and gastric cancers and leukemia. However, unpredictable toxicities, including myelosuppression and hemorrhagic cystitis, were seen in patients treated with camptothecin. Greater understanding of the mechanisms of action of camptothecin and development of water-soluble compounds generated greater interest in camptothecin as a potential chemotherapeutic agent. Camptothecin and its derivatives target topoisomerase I, the DNArelaxing enzyme.[15-18] Although topoisomerase I was discovered in the 1970s, its mechanism of action in DNA replication was not clearly understood until the 1980s. Topoisomerase I was shown to be the target of camptothecin in 1985 by Hsiang et al.[19] This enzyme serves to relax both positively and negatively supercoiled double-helix DNA to allow replication and transcription. It causes reversible single-strand breaks, which allow rotation of the broken DNA strand around the intact strand. The critical step for drug interaction is stabilization of the topoisomerase I/DNA complex that the enzyme forms when cleaving DNA to allow for uncoiling to occur.[15-20] In the presence of camptothecin, a camptothecin/topoisomerase I/DNA complex becomes stabilized because the 5'-phosphoryl terminus of the enzyme-catalyzed DNA single-strand break is bound covalently to a tyrosine residue of topoisomerase I. These complexes are nonlethal and reversible. However, the single-strand breaks become irreversible double-strand breaks when the DNA replication fork collides with reversible complex during S phase or during unscheduled DNA replication. The resulting cell death can be recognized by the p53 damage-sensing pathway and may result in acceleration of apoptosis.[21- 24] Thus, the cytotoxic effect of the camptothecin requires active DNA replication. In vitro studies have shown that cells in S phase may be 100 to 1,000 times more sensitive to camptothecin than cells in the G1 or G2 phase of the cell cycle.[25] Irinotecan In the 1970s, camptothecin proved to be too toxic as a chemotherapeutic agent. However, one of the water soluble derivatives, irinotecan (7-ethyl- 10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) or CPT-11 (Figure 1) displayed antineoplastic activity with improved toxicity profile.[ 26] Irinotecan was first commercially available in Japan in 1994 for treatment of lung, cervical, and ovarian cancers. Irinotecan is a prodrug that is metabolized intracellullarly to its active metabolite, SN-38, by a carboxyesterase converting enzyme. This metabolite is over 1,000 times more potent as an inhibitor of topoisomerase I than irinotecan.[27,28] All of the camptothecins have a terminal lactone ring, which can be hydrolyzed to a less active form. However, under acidic conditions such as in the microenvironment of a tumor, the active lactone species is favored.[27] The plasma half-life of SN-38 after a short intravenous infusion is approximately 11.5 hours. Thus, a low concentration of the metabolite may remain after 2 days and have cytotoxic effect.[29] The major excretory pathway of SN-38 is via hepatic glucuronidation and a decreased ability to glucuronidate may possibly correlate with increased gastrointestinal side effects. One of the dose-limiting toxicities of irinotecan is delayed onset diarrhea that can be potentially life threatening. The diarrhea is felt to be related to the relatively 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 the release of the drug in the intestinal lumen.[30] Other commonly observed toxicities include neutropenia, nausea, and vomiting. Interaction of Camptothecin Derivatives and Radiation Several investigators have reported that irinotecan enhances the cytotoxic effect of radiation in vitro and in vivo.[31,32] Omura et al[33] found that the cell kill was significantly enhanced when radiation was combined with the irinotecan derivative SN-38. The largest enhancement in cytotoxicity was seen when irinotecan was given just before or just after radiation therapy. Their data suggested that radiosensitization occurs by inhibition of potentially lethal damage repair.[ 33] Chen et al[34] showed that human MCF-7 breast cancer cells that were exposed to 20(S)-10,11 methylenedioxycamptothecin before or during radiation showed radiosensitization ratios of 1.6, while those treated with the drug after radiation showed substantially less enhancement of radiation- induced DNA damage. Kim et al also found greater radiosensitization when topotecan(Drug information on topotecan) (Hycamtin) was administered 2 to 4 hours before radiation therapy compared to 2 hours after radiotherapy in the treatment of murine fibrosarcomas.[35] The radiobiology data imply that patients should be treated with a camptothecin derivative-based chemotherapy prior to or during their radiotherapy in order to derive full benefits of combined-modality therapy. Data also suggest that camptothecin derivatives including 9-nitro-20 (S)-camptothecin,[ 36] 9-aminocamptothecin,[ 37] and topotecan[38] are able to potentiate the tumoricidal effects of radiation. There are several hypotheses about mechanism of interaction between radiation and irinotecan. The first hypothesis suggests that the inhibition of topoisomerase I by camptothecin or its derivatives leads to the inhibition of repair of radiation-induced DNA strand breaks. The second hypothesis suggests that irinotecan or its analogs cause redistribution of cells into the more radiosensitive G2 phase of the cell cycle. The third hypothesis suggests topoisomerase I/DNA adducts are trapped by irinotecan at the sites of radiation-induced singlestrand breaks leading to their conversion into double-strand breaks.[36] However, there is not sufficient evidence to identify the underlying mechanism with certainty. The predominance of the particular mechanism that is involved with radiosensitization may depend on which derivative of camptothecin is being used in combined- modality therapy. Irinotecan in Combination for NSCLC Basic principles used in the selection of chemotherapy drugs include nonoverlapping toxicities, differing mechanisms of action, and non-cross resistance.[39] Based on the above criteria, both preclinical and human data address the combination of cisplatin(Drug information on cisplatin) and irinotecan in lung cancer. Kudoh et al showed that in xenografts of the small-cell lung cancer (SCLC) tumor lines MNSUL and LX1, use of irinotecan in combination with cisplatin leads to a larger reduction in tumor size than either agent alone.[31] Early clinical studies in patients with advanced NSCLC have yielded favorable response rates in excess of 30%.[40] The combination of irinotecan and cisplatin has also been used in phase I and II clinical trials; early data from phase II studies revealed a 48% response rate in NSCLC[41] and 78% for SCLC.[42] Ueoka et al[43] reported a phase I trial with fractionation of both the cisplatin and irinote- can. Cisplatin (60 mg/m²) was given on days 1 and 8 and escalating doses of irinotecan were given on the same days. Each cycle was repeated every 4 weeks. An impressive 78% response rate was seen in 18 patients with NSCLC.[43] A Vanderbilt-Ingram Cancer Center phase II trial looking at 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 was also undertaken.[44] The final irinotecan doses were modified to less than 40 mg/m² with a response rate of 29% in 52 patients. The median time to progression was 4.4 months, with a 1-year survival rate of 33%. Negoro et al[45] reported a randomized phase III trial in which the combination of irinotecan and cisplatin was compared to irinotecan alone or a cisplatin/vindesine combination. For stage IV patients, the irinotecan/ cisplatin combination was superior to cisplatin/vindesine with respect to survival. Median survival times were 50.0 and 36.4 weeks, respectively. No significant difference in survival time was seen between irinotecan/cisplatin and irinotecan alone. In addition, no significant difference in survival was seen in stage IIIB disease. However, the authors noted that no particular restriction was placed on chest irradiation in stage IIIB disease, which might have produced a heterogeneous group of IIIB patients. Masuda et al[46] reported a phase I study of docetaxel(Drug information on docetaxel) and irinotecan for stage IIIB and IV patients. Thirtytwo patients in the study were given escalating doses of docetaxel and irinotecan starting with 30/40 mg/m² given at 4-week intervals in 10-mg/ m² increments until the maximum tolerated dose was reached. The maximum tolerated dose of docetaxel and irinotecan was 50/60 mg/m² or 60/50 mg/m². Neutropenia and diarrhea were the dose-limiting toxicities. There was a partial response of 37% with a median survival time of 48 weeks. The authors recommended 50 mg/m² of irinotecan on days 1, 8, and 15 and 50 mg/m² of docetaxel on day 2 given every 4 weeks for phase II trials. Irinotecan and Radiotherapy for NSCLC Combined-modality treatment relies on the ability of radiation and chemotherapy to simultaneously address both local and micrometastatic disease. An enhancement of local control is due to the radiosensitization effects of concurrent chemotherapy. In addition, concurrent chemotherapy addresses potential micrometastatic disease that local therapy, such as radiotherapy, cannot address adequately. Understanding the basic mechanisms of interaction of different drugs is also important to maximize the tumoricidal effects of chemotherapy while minimizing treatment-related toxicities. The optimal integration of irinotecan and cisplatin or other irinotecanbased chemotherapy integrated with thoracic radiotherapy is unclear. Evidence from previously completed trials addresses sequencing of chemotherapy and radiotherapy in combined modality for lung cancer. In the Cancer and Leukemia Group B (CALGB) 9130 trial, all patients received neoadjuvant platinum-based chemotherapy followed by radiotherapy with randomization to concurrent carboplatin(Drug information on carboplatin) (Paraplatin) with no improvement in survival, but there was a decreased local relapse rate.[47] The West Japan Lung Cancer Group has also compared concurrent and sequential combined-modality treatment in 314 patients with unresectable stage III NSCLC using a combination of mitomycin (Mutamycin), vindesine(Drug information on vindesine), and cisplatin chemotherapy. Their results show a doubling of 5-year survival rates (P = .03998) with concurrent treatment.[48] Curran et al reported results of the Radiation Therapy Oncology Group's RTOG 9410, which was a phase III, threearm trial comparing standard sequential chemoradiotherapy to two different concurrent arms.[13] The sequential arm used cisplatin at 100 mg/m² on days 1 and 29 with vinblastine(Drug information on vinblastine) at 5 mg/m² weekly * 5 with 60 Gy of thoracic radiotherapy following the chemotherapy. The second arm used the same chemotherapy with 60 Gy of thoracic radiotherapy starting on day 1. The third arm used cisplatin at 50 mg/m² on days 1, 8, 29, and 36, with oral etoposide(Drug information on etoposide) at 50 mg/m² bid for 10 doses on weeks 1, 2, 5, and 6, with thoracic radiotherapy of 69.6 Gy at 1.2 Gy bid starting on day 1. Acute toxicity was higher with the concurrent treatment regimen, although late toxicities were not different between the arms. With median follow-up of 6 years, the arm with chemotherapy given concurrently with daily radiotherapy showed a median survival of 17 months (P = .046). The above trials support concurrent chemotherapy and radiotherapy for locally advanced NSCLC. Several phase I and II trials have administered irinotecan concomitantly with thoracic radiotherapy in stage III NSCLC (Table 1). Some trials added other chemotherapeutic agents to irinotecan. The response rates in these trials are in excess of 60%. These combinations appear to have reasonable acute toxicities; however, it is too early to assess the late complication rates. Takeda and colleagues examined the combination of escalating doses of weekly irinotecan with concurrent thoracic radiotherapy (60 Gy in 30 fractions over 6 weeks) in a phase I/II trial for locally advanced NSCLC.[49] They enrolled patients with stage III NSCLC who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and started irinotecan at 30 mg/m² intravenous weekly for 6 weeks. The maximum tolerated dose was 60 mg/m². At this dose level, five patients had grade 3/4 toxicity, two had grade 3/4 esophagitis, and three had grade 3/4 pneumonitis. The irinotecan dose for the phase II portion of the trial was 45 mg/m^2. A further 10 patients were treated at this dose level (17 total, including seven patients from phase I trial). One of the 10 patients in the phase II portion developed pneumonitis and died, while another patient developed grade 3 diarrhea. The overall response rate was 76.9%. After 22 months of follow-up, 1-year survival was 61.5%. Saka and colleagues performed a phase II trial in which 24 patients with locally advanced NSCLC were enrolled and received irinotecan at 60 mg/m² intravenous weekly * 6 with concurrent 60 Gy of thoracic radiation in 2-Gy/d fractions.[50] A total of 71% of patients received the planned chemotherapy, and 88% completed the planned radiotherapy with a partial response rate of 79%. Toxicities included three (12.5%) cases of grade 3 pneumonitis, two (8.3%) cases of grade 3 esophagitis, two (8.3%) cases of grade 3 neutropenia, and one (4.2%) case of a grade 3 fever. There were no grade 4 toxicities. Choy et al reported results of a phase I trial of weekly irinotecan 30 to 50 mg/m² and concurrent radiotherapy for unresectable stage III NSCLC.[51] The response rate was 58% among 13 treated patients. Nau sea, vomiting, and esophagitis were the major toxicities. The maximum tolerated dose of concurrent chest radiation therapy and irinotecan was 40 mg/m² weekly for 6 weeks. Kodoh and colleagues also performed a phase I/II trial of irinotecan and concurrent thoracic radiotherapy in locally advanced NSCLC.[52] The maximum tolerated dose was 60 mg/m² with dose-limiting toxicities of esophagitis, pneumonitis, and diarrhea.