Irinotecan in Combined-Modality Therapy for Locally Advanced Non-Small-Cell Lung Cancer

ABSTRACT: The management of non-small-cell lung cancer is undergoingrapid evolution. Although the advent of combined-modality therapy has led toimproved survival, most patients eventually succumb to the disease. The arrivalof a new generation of chemotherapeutic agents—including the taxanes,gemcitabine (Gemzar), and topoisomerase inhibitors such as irinotecan(Camptosar, CPT-11)—offers the hope of advances against this malignancy.Irinotecan, a camptothecin derivative, has shown impressive activity in avariety of solid tumors, including non-small-cell lung cancer. It is believedto act by stabilizing the topoisomerase-DNA complex formed during diversecellular processes, including replication and transcription. A considerable bodyof evidence also demonstrates that camptothecin and its derivatives possesssubstantial radiosensitization properties. This article will review the in vitroand in vivo data on irinotecan’s ability to render tumors more susceptible toionizing radiation. It will then focus on experience with irinotecan andthoracic radiation in the treatment of non-small-cell lung cancer, which hasyielded acceptable toxicity results and response rates in excess of 60% in earlytrials. It is hoped that newer treatment strategies—such as the combination ofradiation and irinotecan in lung cancer—will significantly impact cure ratesin the future. [ONCOLOGY 15(Suppl 1):31-36, 2001]

Introduction

Lung cancer is the leading causeof cancer-related morbidity andmortality. The estimated incidences for the year 2000 are 164,100 new cases and156,900 deaths in the United States alone.[1] Five-year survival figures forlung cancer have remained in the 15% range from 1974 through 1995[1]; most ofthese cures involve early cancers usually treated with surgery alone. However,approximately 35% of patients present with locally advanced disease that is notamenable to surgical therapy, but is nonetheless potentially curable.[2]Tradition- al treatment with radiation alone in these patients has yielded lowcure rates. This has spurred investigations of new methods to improve outcome.

Peckham and Steele outlined several possible mechanisms ofinteraction between radiation and chemotherapies: spatial cooperation,enhancement of tumor response, radioprotection, and nonoverlapping toxicitiesare all ways that chemotherapy and radiation may interact to improve therapeuticratio.[3] Spatial cooperation describes a situation where disease located in aspecific anatomic site is missed by one agent but treated by another.Enhancement refers to the administration of an agent that increases the effectof another agent, or when the effect of the combination is greater than would beexpected with either agent alone. Radioprotection refers to the administrationof a chemotherapeutic agent that would allow safe delivery of higher radiationdoses.

Finally, toxicity independence, or nonoverlapping toxicities,describes when two partially effective agents can be used in combination withouthaving to substantially reduce dose levels to avoid unacceptable side effects.Multiple phase III trials have shown benefits with the combined use ofchemotherapy and radiation in the treatment of non-small-cell lung cancer atthe expense of increased toxicity.[4-7] Overall, the meta-analysis fromPritchard et al suggests that traditional chemotherapy added to radiotherapyadds an average of 2 months to patient survival.[8]

Several new active agents that hold promise for improvingoutcome in lung cancer patients are emerging. These include paclitaxel (Taxol),docetaxel (Taxotere), vinorelbine (Navelbine), gemcitabine (Gemzar), andirinotecan (Camptosar, CPT-11), which have demonstrated response rates rangingfrom 20% to 54% as single agents in metastatic disease.[2] Finding a cure forthis disease will require a better understanding of the mechanisms of action ofthese agents and their interactions with ionizing radiation, and the propersequencing of these agents with other drugs and with radiation. This articlewill review the literature on the use of irinotecan in combination with thoracicirradition in the treatment of non-small-cell lung cancer.

Mechanism of Camptothecin Activity

Camptothecin and its derivatives target DNA topoisomerase I, theDNA-relaxing enzyme.[9-12] This enzyme relaxes both positively and negativelysupercoiled DNA, which allows diverse essential cellular processes, includingDNA replication and transcription, to proceed. The key step for drug activity isstabilization of the topoisomerase I-DNA intermediate that the enzyme formswhen cleaving DNA to allow for uncoiling to occur.[9-14] It is believed thatcollision between the drug-trapped topoisomerase-DNA complex and the replicationmaterial leads to G2-phase cell-cycle arrest and, ultimately, cell death.[15]

Camptothecin is the prototype drug that was initially studied inthe 1970s as a chemotherapeutic agent; however, its use was discontinued becauseof excessive toxicity.[16] Ongoing research has begun to focus on camptothecinderivatives that have antineoplastic activity with improved toxicity profiles.This generation of drugs includes irinotecan. Irinotecan is a prodrug that ismetabolized intracellularly to its active metabolite, SN-38, by acarboxylesterase- converting enzyme.[17] This metabolite is more than 1,000times more potent than irinotecan as an inhibitor of topoisomerase I.[18] All ofthe camptothecins have a terminal lactone ring that can be hydrolyzed to a lessactive carboxylate species. Under acidic conditions, however, like that in thetumor microenvironment, the active lactone species is favored.[17]

The plasma half-life of SN-38 after a short IV infusion is 10.2hours (range: 5.9 to 13.8 hours), so that nanomolar concentrations of the drugpersist for more than 2 days.[17] This may affect its cytotoxicity. The majormethod of elimination of SN-38 is hepatic glucuronidation; a decreased abilityto glucuronidate is thought possibly to correlate with increasedgastrointestinal side effects. Clinically, the dose-limiting toxicity ofirinotecan is delayed-onset diarrhea, which can be profuse and potentially lifethreatening. The diarrhea is thought to be related to the high S-phase fractionof the intestinal mucosa, as well as to the action of intestinal floraglucuronidase in cleaving the camptothecin-glucuronidase conjugate, leading torelease of the drug in the intestinal lumen.[19] Other common toxicities includeneutropenia, nausea, and vomiting.

Interaction of Camptothecin and Radiation Therapy

In planning combined-modality chemoradiotherapy, it is importantto understand the mechanism of interaction between the two modalities. Severalinvestigators have reported that camptothecin enhances the cytotoxic effect ofradiation in vitro and in vivo.[20,21] Omura et al assessed the radiosensitizingeffects of SN-38 in HT-29 spheroids derived from a human colon cancer cell line.Results showed significantly enhanced cell kill with combined radiation andirinotecan; the largest gains in cytotoxicity occurred when irinotecan wasadministered just before or just after the radiation. The data also suggest thatthe mechanism of radiosensitization in the spheroids is through inhibition ofpotentially lethal damage repair.[22]

Chen et al showed that camptothecin derivatives radiosensitizedlog-phased human MCF-7 breast cancer cells in a schedule-dependent manner.Essentially, cells exposed to 20(S)-10,11 methylenedioxycamptothecin before orduring radiation had sensitization ratios of 1.6, while those treated with thedrug after radiation had substantially less enhancement of radiation-induced DNAdamage.[23] The clinical implication of these results is that patients should betreated with camptothecin derivative-based chemotherapy prior to or duringradiotherapy to receive the full benefits of combined-modality therapy. Emergingdata also show that other camptothecin derivatives—including 9-nitro-20(S)-camptothecin,[24] 9-aminocamptothecin,[25] and topotecan (Hycamtin)[26]—canpotentiate the lethal effects of radiation.

There are several hypotheses, with varying amounts of supportiveevidence, regarding the mechanism of interaction between radiation andirinotecan. The first hypothesis suggests that inhibition of topoisomerase I bycamptothecin or its derivatives leads to inhibition of repair ofradiation-induced DNA strand breaks. The second hypothesis suggests thatcamptothecin or its analogs causes redistribution of cells into the moreradiosensitive G2 phase of the cell cycle. The third hypothesis is thattopoisomerase I-DNA adducts are trapped by irinotecan at the sites ofradiation-induced single-strand breaks, leading to their conversion intodouble-strand breaks.[24] The primary mechanism involved with radiosensitizationmay depend on which camptothecin derivative is being used; there is currentlyinsufficient evidence to identify the underlying mechanism with certainty.

Irinotecan in Combined-Modality Therapy

Combined-modality treatment relies on the ability of focusedradiation and concurrent radiosensitizing agents to treat locally, while leavingthe potential micrometastatic disease for chemotherapy to control. As such, itis also important to maximize the cytotoxic effects of chemotherapy whileminimizing toxicities. This requires an understanding of the mechanisms ofinteraction between different drugs. Basic principles used in selecting drugsinclude nonoverlapping toxicities, differing mechanisms of action, and non-cross-resistance.[27] Based on these criteria, both preclinical and clinical trialshave been undertaken to evaluate the cisplatin (Platinol)/irinotecan combinationin lung cancer.

In xenografts of the small-cell lung cancer tumor lines Mnsuland LX1, Kudoh et al showed that irinotecan in combination with cisplatin led toa larger reduction in tumor size than either agent alone.[20] However, inxenografts of Mnqul, a cell line developed from human squamous cell lungcarcinoma, combination cisplatin/irinotecan treatment was more effective thancisplatin alone but not more effective than irinotecan alone. According to theauthors, the data clearly suggest that the combination of radiation andirinotecan should be effective in small-cell lung cancer; however, theycautioned that more data are needed, using a different non-small-cell lungcancer model, prior to concluding that the combination is better than irinotecanalone.

In patients with advanced lung cancer, early studies usingirinotecan alone have yielded favorable response rates (> 30%).[28] Thecombination of irinotecan and cisplatin has also been assessed in phase I and IIclinical trials; early data from phase II studies revealed a 48% response ratein non-small-cell lung cancer[29] and 78% in small-cell lung cancer.[30] Asubsequent phase I trial looked at fractionation of both the cisplatin andirinotecan doses, ie, 60 mg/m² of cisplatin and escalating doses of irinotecanwere given on days 1 and 8. Cycles were repeated every 4 weeks. An impressive78% response rate was seen in 18 patients with non-small-cell lung cancer.[31]A North American phase II trial examined the combination of cisplatin at 80 mg/m² on day 1 and irinotecan at 60mg/m² on days 1, 8, and 15 in 4-weekcourses, with the possibility of escalating the irinotecan dose according toside effects.[32] The irinotecan dose was ultimately modified to less than 40mg/m2; the response rate was 28.8% in 52 patients.

Optimal Sequence of Chemoradiation

The next issue in considering irinotecan in multimodalitytherapy for non-small-cell lung cancer is the optimal way to integrateirinotecan-based chemotherapy with thoracic radiotherapy, ie, the optimalsequence of chemoradiation. In the Cancer and Leukemia Group B (CALGB) 9130trial, all patients received neoadjuvant platinum-based chemotherapy followed byradiotherapy and were randomly assigned to receive concurrent carboplatin(Paraplatin) or not. Results showed no improvement in survival with carboplatinadded, but the relapse rate in the boost volume was decreased.[33] The WestJapan Lung Cancer Group also compared concurrent and sequentialcombined-modality treatment in 314 patients. The 5-year survival rates weredoubled in thegroup receiving concurrent treatment (P = .04).[34]

Results of the Radiation Therapy Oncology Group (RTOG) 9410—aphase III, three-arm trial comparing standard sequential chemoradiotherapy totwo different concurrent arms—was presented at the 9th World Conference inLung Cancer in 2000. In the sequential arm cisplatin at 100 mg/m² wasadministered on days 1 and 29 with vinblastine at 5 mg/m² weekly ´ 5, and 60 Gyof thoracic radiotherapy following the chemotherapy. Patients in the second armreceived the same chemotherapy with 60 Gy of thoracic radiotherapy starting onday 1. In the third arm, patients received cisplatin at 50 mg/m² on days 1, 8,29, and 36 with oral etoposide at 50 mg/m² bid for 10 doses during weeks 1, 2,5, and 6, and thoracic radiotherapy—69.6 Gy at 1.2 Gy bid starting on day 1.

Acute toxicity was higher in the concurrent treatment arm,although late toxicities were not different between the arms. With a medianfollow-up of 40 months, median survival in patients receiving concurrentchemotherapy and daily radiotherapy is 17 months (P = .038).[35] The compendiumof these results thus suggests that concurrent chemoradiotherapy is a rationalstrategy to pursue in future trials.

Irinotecan and Concurrent Radiation

Several phase I and II trials have assessed concomitantadministration of irinotecan and radiation in stage III non-small-cell lungcancer, with some trials adding other chemotherapy agents as well. Thesecombinations have resulted in encouraging response rates (> 60%) and appearto have reasonable rates of acute toxicities, although it is too early tocomment on late complication rates (Table 1 andTable 2).

Takeda and colleagues examined the combination of weeklyirinotecan at escalating doses with concurrent thoracic radiation (60 Gy in 30fractions over 6 weeks) in a phase I/II trial.[36] Patients with stage III non-small-celllung cancer and Eastern Cooperative Oncology Group (ECOG) performance status 0,1, or 2 began at an irinotecan dose of 30 mg/m² IV weekly for 6 weeks. Therewere dose-limiting toxicities found at 60 mg/m². At this dose level in fivetreated patients, there were two cases of grade 3/4 esophagitis and three casesof grade 3/4 pneumonitis. Therefore, the irinotecan dose for the phase IIportion of the trial was 45 mg/m² and a further 10 patients were treated at thisdose level (17 total, including 7 patients from the phase I portion). One of the10 patients in the phase II portion developed pneumonitis and died, and anotherpatient developed grade 3 diarrhea. The overall response rate was 76.9%, and1-year survival rate was 61.5% after 22 months of follow-up.

Saka and colleagues conducted a phase II trial in which 24patients with locally advanced non-small-cell lung cancer received irinotecanat 60 mg/m² IV weekly × 6 with concurrent thoracic radiation (60 Gy in 2-Gyfractions).[37] Among all 24 patients, 71% were able to receive the plannedchemotherapy and 88% completed the planned radiotherapy. Partial responses wereseen in 79% of patients. Toxicities included three cases of grade 3 pneumonitis,two cases of grade 3 esophagitis, two cases of grade 3 neutropenia, and one caseof grade 3 fever. No grade 4 toxicities occurred. The investigators concludedthat this was an active regimen in patients with non-small-cell lung cancer.

The evaluation of irinotecan and concurrent thoracic irradiationhas expanded to incorporate platinum compounds as well, based on their activityin non-small-cell lung cancer, radiosensitizing abilities, and preclinicaldata.[20] In a phase I trial conducted from September 1994 to January 1995 byYokoyama and colleagues in the Japan Clinical Oncology Group, 12 patientsreceived escalating doses of irinotecan and cisplatin with 60 Gy of thoracicradiation.[38] Six patients were able to receive the level 1 dose of 60 mg/m² ofcisplatin and 40 mg/m² of irinotecan with the radiation; however, chemotherapywas discontinued in two patients before the planned three cycles were delivered.All patients at dose level 1 completed the radiotherapy.

At dose level 2 (60 mg/m² of cisplatin and 60mg/m² ofirinotecan), only three of six patients received all three planned chemotherapycycles. The three patients who did not complete chemotherapy also did notcomplete the radiotherapy; this included one patient who died after the secondchemotherapy course.

Due to the low dose intensity of irinotecan in dose levels 1 and2 (irinotecan was often omitted on days 8 and 15 because of leukopenia ordiarrhea) and the low radiation completion rate, the study was closed at doselevel 2. The overall response rate was 67% (8 of 12 patients had a partialresponse), but the overall survival rate at 1 year was only 33%. An ongoingphase I study at the Fox Chase Cancer Center may provide further insight intothe tolerability of concurrent irinotecan, cisplatin, and thoracic radition (seeTable 1).[39]

Two other Japanese trials of concurrent cisplatin, irinotecan,and radiation in non-small-cell lung cancer have been reported. In a trial byFukuda et al, patients received two courses of chemotherapy with split-courseradiation (irinotecan at 60 mg/m² days 1, 8, and 15 and cisplatin at 80mg/m²day 1 were the recommended doses for phase II study).[40] The overall responserate in 24 patients was 65%, with some cases of neutropenia, thrombocytopenia,and esophagitis.

The Japanese Lung Cancer Group’s follow-up study involvedinduction cisplatin and irinotecan for two cycles followed by concurrent weeklyirinotecan and thoracic radiation.[41] The significant toxicities among 68patients enrolled were neutropenia (6% of patients with grade 4), esophagitis(4% grade 3), and pneumonitis (2% grade 4). The reponse rate was 63.3% and theestimated 1-year survival rate was 71.7%. The authors concluded that inductionchemotherapy followed by combined thoracic radiation and irinotecan was apromising treatment strategy for testing in randomized trials.

Another Japanese trial examined combining thoracic radiation (60Gy) with carboplatin and irinotecan.[42] The 30 enrolled patients receivedcarboplatin at 20 mg/m² daily for 5 days a week and irinotecan IV weekly. Bothdrugs were repeated for 4 weeks and the irinotecan dose was escalated from 30mg/m² in 10-mg/m² increments. The maximum tolerated dose of irinotecan was foundto be 60 mg/m², and the dose-limiting toxicities were pneumonitis, esophagitis,neutropenia, and thrombocytopenia. Three complete and 15 partial responses wereseen, for an overall response rate of 60%. The median survival has not beenreached and the 2-year survival rate is 51.3%.

VCCAN Phase I Trial

The Vanderbilt Cancer Center Affiliate Network (VCCAN) hasconducted a phase I trial involving patients with stage III unresectable non-small-celllung cancer. The major goals of this study are to determine the maximumtolerated dose of irinotecan when administered with radiation therapy inpatients with unresectable stage IIIA/IIIB non-small-cell lung cancer, todetermine the maximum tolerated dose of irinotecan and carboplatin whenadministered with radiation therapy, and to evaluate toxicities of thecombinations of irinotecan and radiation therapy and irinotecan/carboplatin andradiotherapy. Secondary objectives are to evaluate response rate and responseduration of patients with advanced, medically inoperable and/or surgicallyinoperable non-small-cell lung cancer.[43,44]

Eligibility criteria for the trial included unresectable, stageIII non-small-cell lung cancer, including involved supraclavicular nodes.Patients with malignant pleural effusions were excluded. Patients could not havehad previous resection, chemotherapy, or radiotherapy, and only those with ECOGperformance status of 0, 1, or 2 and< 15% weight loss were eligible. In this trial, irinotecan was administeredas an IV infusion, repeated every week for 6 weeks. The weekly regimen was usedto optimize the radiosensitizing properties of irinotecan. The starting dose was30 mg/m² and doses were escalated at 10-mg/m² increments in successive cohortsof three patients (see Table 3).

Thoracic radiotherapy was administered concurrently to theprimary tumor and regional lymph nodes (40 Gy) followed by a boost to the tumor(20 Gy). Preliminary results of the first 18 patients entered in the studythrough four dose escalations (from 30 to 50 mg/m² of irinotecan weeklyincluding the addition of carboplatin at an area under the concentration-timecurve of 2 with 30 and 40 mg/m² of irinotecan) are shown in Table 3. One patientdeveloped grade 5 esophagitis at the first dose level and accrual was thereforeexpanded to seven patients. No significant esophagitis was seen in the other sixpatients. At the second dose level (40 mg/m²/wk), the worst toxicity was grade 2esophagitis in one of six patients. At the third dose level (50 mg/m²/wk), twoof three patients entered developed grade 4 nausea and vomiting, and two alsoexperienced grade 3 or 4 esophagitis.

In 18 evaluable patients, 10 had a partial response and one hada complete response, for an overall response rate of 61%. These findings showthat nausea and vomiting as well as esophagitis appear to be the maindose-limiting toxicities of concurrent weekly irinotecan and thoracic radiationin the outpatient setting. With the addition of carboplatin, leukopenia became asignificant toxicity. These preliminary data suggest that thoracic radiation canbe combined with weekly irinotecan and carboplatin with acceptable toxicity,although final results of higher doses are not yet available. The 1- and 2-yearsurvival rates are encouraging.

Conclusions

The response and survival rates seen in these phase I/II studiesare encouraging, and the toxicities associated with thoracic radiation andconcurrent irinotecan are acceptable. This treatment strategy needs to becompared with other combined-modality approaches in locally advanced non-small-celllung cancer in randomized phase II or III trials.

These promising results in non-small-cell lung cancer shouldalso encourage the study of combination irinotecan and radiation in otherdisease sites as well. The Japanese phase I trial of irinotecan and cisplatinwith concurrent thoracic radiotherapy in small-cell lung cancer yielded animpressive overall response rate of 93.8%.[45] In another phase I trial inpatients with locally advanced head and neck cancers, irinotecan was combinedwith docetaxel and conventially fractionated radiation to yield a completeresponse rate of 75% and an overall response rate of 100%.[46] The activity ofirinotecan in colorectal cancer also suggests that this could be an area inwhich to exploit irinotecan’s potential as a radiosensitizer. As such, we hopeto see trials testing irinotecan with concurrent radiation in other solidtumors, and we await results of ongoing randomized trials using irinotecan-basedregimens in non-small-cell lung cancer.

Acknowledgment: Dr. Rob MacRae is a clinicalresearch fellow funded in part by the Canadian Cancer Society (Ontario) as theGordon Richards fellowship recipient.

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