Current Role of Irinotecan in the Treatment of Non-Small-Cell Lung Cancer

ABSTRACT: Lung cancer remains the primary cause of cancer-related death in both men and women in the United States. Chemotherapy has been shown to provide a survival benefit in patients with advanced non-small-cell lung cancer (NSCLC), and current regimens have produced median survivals of approximately 8 months and 1-year survival rates of 30% to 35% in patients with stage IIIB and IV disease. Nevertheless, there remains room for improvement. Irinotecan (CPT-11, Camptosar) has demonstrated efficacy in the treatment of small-cell lung cancer (SCLC). It also appears to have promising activity in advanced NSCLC, producing overall response rates of up to 32%. Combinations of irinotecan and cisplatin or carboplatin (Paraplatin) have resulted in overall response rates of 25% to 56% in phase II and III studies in patients with advanced disease, with median survivals ranging from 9 to 13 months and 1-year survival rates of 33% to 58%. Current irinotecan-based doublet and triplet regimens appear to produce promising response rates with manageable toxicities. In addition, irinotecan has demonstrated potential as a radiosensitizing agent and is currently being evaluated in several trials of combined-modality therapy in patients with locally advanced NSCLC. Early trials of irinotecan in combination with cisplatin or carboplatin along with radiation therapy have reported overall response rates of 60% to 67%. The approach appears to have potential and warrants further study. [ONCOLOGY 16:1153-1168, 2002]

Lung cancer is the leading cause of cancer-related death in both men andwomen in the United States. In 2002, an estimated 169,400 new cases of lungcancer will be diagnosed, and the disease will cause 154,900 deaths.[1] Non-small-cellhistologies account for approximately 80% of new lung cancer cases, and themajority of these patients initially present with advanced or metastaticdisease.[2] The long-term survival prognosis for patients with advanced non-small-celllung cancer (NSCLC) remains poor. In recent years, however, more effectivechemotherapy regimens have improved the survival outlook, and hopefully progresswill continue with the development of new agents.[3]

The benefit of platinum-based therapy in the treatment of patients withadvanced NSCLC was demonstrated in a meta-analysis of clinical trials thatcompared chemotherapy to best supportive care.[4] With the use of cisplatin-basedregimens, median overall survival improved to 6 months compared to 4 monthswith best supportive care, and the 1-year survival rate rose from 15% to 25%.Based on these data, platinum-based regimens have been considered a standard ofcare for advanced NSCLC.

New Platinum Combinations

In an effort to further improve survival, investigators have evaluated theefficacy of combining platinum agents with several newer drugs that havedemonstrated promising single-agent activity in NSCLC, including paclitaxel,docetaxel (Taxotere), gemcitabine (Gemzar), vinorelbine (Navelbine), irinotecan(CPT-11, Camptosar), and topotecan (Hycamtin).[3] In the United States, effortshave focused on platinum agents combined with taxanes, gemcitabine, andvinorelbine.

Major US Trials

The preliminary results of two US randomized phase III trials evaluatingplatinum-based regimens in advanced NSCLC were recently reported. A four-armstudy conducted by the Eastern Cooperative Oncology Group (ECOG) compareddoublets of cisplatin and paclitaxel, cisplatin and gemcitabine, cisplatin anddocetaxel, and carboplatin (Paraplatin) and paclitaxel[5]; a two-arm studyconducted by the Southwest Oncology Group (SWOG) compared the combination ofcisplatin and vinorelbine to carboplatin and paclitaxel.[6]

In each of these trials, no differences in median overall survival or 1-yearsurvival were reported between arms. However, some differences did emerge withrespect to specific toxicities. At present, platinum doublet combinations suchas those used in the ECOG and SWOG trials can be expected to produce a medianoverall survival of approximately 8 months and 1-year survival rates rangingfrom 30% to 35% in patients with advanced NSCLC. Although these results indicateprogress in terms of survival, room for improvement remains, and the evaluationof newer agents and combinations is necessary.

Irinotecan in SCLC

Irinotecan, a camptothecin analog, has demonstrated meaningful clinicalactivity in a number of solid tumors, including colorectal and othergastrointestinal cancers and both small-cell lung cancer (SCLC) and NSCLC.[7] InSCLC, single-agent irinotecan has produced response rates of 50% in previouslyuntreated patients and 16% to 33% in previously treated patients.[8-10] With thecombination of irinotecan and cisplatin as first-line therapy, overall responserates of 83% and 86% were reported in patients with limited and extensive SCLC,respectively.[11]

Based on this activity, the Japan Clinical Oncology Study Group conducted arandomized phase III trial comparing the combination of irinotecan and cisplatinto a standard regimen of etoposide and cisplatin in patients with extensiveSCLC.[12,13] The median overall survival of 13.5 months in the irinotecan/cisplatinarm was significantly longer than the 9 months observed in the etoposide/cisplatinarm (P = .0021). The combination of irinotecan and cisplatin has been adopted asthe standard of care in Japan for patients with extensive SCLC and is currentlybeing evaluated in phase III randomized trials in the United States.

Given its high degree of activity in SCLC, the potential of irinotecan in thetreatment of NSCLC was considered. Investigators in Japan have been the first tosystematically evaluate the role of irinotecan in NSCLC, and interest in theagent has recently been increasing in both the United States and Europe.

Irinotecan in NSCLC

Single-Agent Irinotecan

In patients with previously untreated advanced NSCLC, phase II studies ofsingle-agent irinotecan have evaluated both weekly administration andonce-every-3-week dosing schedules (Table 1).[14-17] Fukuoka et al reported anoverall response rate of 32% in 72 evaluable patients, 40 of whom had stage IVdisease, and achieved a response rate of 32.5% with a weekly irinotecan dose of100 mg/m2.[14] The median duration of response for all patients was3.5 months, and median overall survival was 10 months. Leukopenia, nauseaand vomiting, and diarrhea were the most common toxicities, with grade 3/4toxicity occurring in 20% to 25% of patients.

In a study reported by Baker et al, irinotecan, 100 mg/m² administered weeklyfor 4 weeks of a 6-week cycle, produced an overall response rate of 15% in 41evaluable patients, with a median response duration of 4.7 months and amedian overall survival of 6 months.[15] Grade 3 neutropenia was noted in 15% ofpatients, and grade 3/4 diarrhea in 17%.

Two studies evaluated irinotecan administered on an every-3-week schedule.Nakai et al reported an overall response rate of 20% in 35 evaluable patientsgiven 200 mg/m² of irinotecan every 3 weeks, while a study by Douillard et alreported an overall response rate of 22% in 19 patients receiving a dose of350 mg/m² every 3 weeks.[16,17] Major toxicities included leukopenia, diarrhea,nausea, and vomiting.

Given the promising single-agent activity of irinotecan in advanced NSCLC,current studies are investigating platinum-based and nonplatinum doublet andtriplet regimens with irinotecan (Table 2).

Irinotecan/Platinum Doublets

Irinotecan and Cisplatin 

Preclinical studies, lung cancer cell lines,and tumor xenograft models have indicated a potential synergism betweenirinotecan and cisplatin.[18,19] Given the established role of platinum agentsin the treatment of NSCLC, their subsequent combination with irinotecan was alogical step. The combination of cisplatin and irinotecan has been studied mostfrequently.

Numerous phase I studies evaluating various administration schedules ofirinotecan and cisplatin have been conducted in patients with previouslyuntreated NSCLC.[20-27] In a series of trials, Masuda et al evaluatedcombinations of cisplatin at a fixed dose on day 1 with escalating doses ofirinotecan on days 1, 8, and 15 of a 28-day cycle in patients with advancedNSCLC. Their initial study used a fixed cisplatin dose of 80 mg/m², anddose-limiting toxicities (diarrhea and leukopenia) occurred at an irinotecandose of 70 mg/m².[20] Among 26 evaluable patients, 14 achieved partialresponses, for an overall response rate of 54%.

A second study decreased the cisplatin dose to 60 mg/m² on day 1, anddiarrhea was found to be dose-limiting at an irinotecan dose of90 mg/m².[21] The overall response rate was 43% among the 14 evaluablepatients, with one complete and five partial responses.

In an effort to increase dose intensity, a third study used a fixed cisplatindose of 80 mg/m² with escalating doses of irinotecan, and granulocytecolony-stimulating factor (G-CSF, Neupogen) added on days 4 to 21 except on thedays that irinotecan was administered. Dose-limiting diarrhea and leukopeniadeveloped at an irinotecan dose of 90 mg/m², and a partial response rate of 50%was noted in 20 evaluable patients.[22]

Using fractionated doses of both cisplatin and irinotecan on days 1, 8, and15, Kobayashi et al reported a maximum tolerated cisplatin dose of 33 mg/m² incombination with a fixed irinotecan dose of 60 mg/m².[23] Leukopenia wasdose-limiting, and 7 of 13 patients (54%) achieved partial responses. Ueoka etal administered a fixed dose of cisplatin (60 mg/m²) on days 1 and 8 withescalating doses of irinotecan.[24] The maximum tolerated dose of irinotecan was60 mg/m², with diarrhea being dose-limiting; partial responses were seen in13 of 17 evaluable patients, for an objective response rate of 76%.

Mori et al evaluated escalating doses of irinotecan in combination with a5-day infusion of cisplatin. Maximum tolerated doses were cisplatin at20 mg/m²/d × 5 in combination with irinotecan at 80 mg/m² on day 1 withoutG-CSF, and irinotecan at 160 mg/m²/d with G-CSF; overall response rates rangedfrom 47% to 55%.[25,26]

Phase II Trials

With the promising overall response rates (43% to 76%)reported in phase I trials for the combination of irinotecan and cisplatin,several phase II trials evaluating various regimens were initiated (Table3).[28-36] Masuda et al administered irinotecan, 60 mg/m² on days 1, 8, and15, in combination with cisplatin, 80 mg/m² on day 1.[28] Of the 64 patientsevaluable for response, 1 achieved a complete response and 32 had a partialresponse for an overall response rate of 52%. The median overall survival of the69 enrolled patients was 10 months, and the 1-year survival rate, 33%.Predominant toxicities included leukopenia, neutropenia, and diarrhea, althoughall were considered manageable.

In the United States, DeVore et al evaluated the combination of irinotecan at60 mg/m² on days 1, 8, and 15 and cisplatin at 60 mg/m² on day 1.[29] Irinotecanwas preferentially dose-reduced for toxicity, and actual delivered doseintensities were 75% for irinotecan and 100% for cisplatin. Among the 52evaluable patients, 29% achieved an objective response, with a median survivalof 10 months and a 1-year survival rate of 37%. Grade 3/4 neutropenia, whichoccurred in 46% of patients, was the most common serious toxicity.

As a follow-up to their phase I trial, Mori et al conducted a phase II trialof irinotecan at 160 mg/m² on day 1 with cisplatin at 20 mg/m² on days 1 to 5,with G-CSF support.[30] The overall response rate was 56% for the 41 evaluablepatients, the median survival was 10 months, and the 1-year survival rate was44%. Grade 3/4 toxicities included diarrhea in 23%, granulocytopenia in 20%, andthrombocytopenia and anemia in 15% of patients.

Coadministration of irinotecan and cisplatin on a weekly schedule,facilitating potential synergism between these agents, has also been evaluated.Based on previous clinical experience,[31] Jagasia et al administered irinotecanat 65 mg/m² with cisplatin at 30 mg/m²/wk for 4 weeks of a 6-week cycle. Ueokaet al administered irinotecan at 50 mg/m² with cisplatin at 60 mg/m² on days 1and 8 of a 28-day cycle.[31,32] Overall response rates of 36% and 41%, mediansurvivals of 12 and 13 months, and 1-year survival rates of 46% and 58%,respectively, were reported for the two studies. Both regimens were reasonablywell tolerated. Jagasia et al reported a 26% incidence of grade 3/4neutropenia and diarrhea, while grade 3/4 toxicities reported by Ueoka et alincluded leukopenia in 48%, thrombocytopenia in 43%, anemia in 42%, diarrhea in27%, and nausea and vomiting in 26%.

Cardenal and associates opted to administer an intensive irinotecan dose of200 mg/m² with cisplatin at 80 mg/m², both on day 1.[34] Grade 3/4neutropenia occurred in 51% of patients, with an 11% rate of febrile neutropenia,and grade 3/4 delayed diarrhea occurred in 31% of patients. Preliminary dataindicated an overall response rate of 41%.

Phase III Trials

Two multicenter randomized phase III trials evaluatingirinotecan and cisplatin have been completed by Japanese investigators (Table3).[28-36] The first was a three-arm trial comparing combination irinotecan/cisplatinto vindesine/cisplatin or irinotecan alone.[35] The second trial comparedirinotecan/cisplatin to vindesine/cisplatin.[36] Updated response and survivalanalyses for both studies have recently been presented.[33,37]

In the three-arm study,[35] the combination of irinotecan and cisplatinproduced an overall response rate of 43%, with a median survival of 12 monthsand a 1-year survival rate of 49%. For the vindesine/cisplatin arm and thesingle-agent irinotecan arm, overall response rates were 31% and 40%,respectively, and 1-year survival rates were 21% and 44%, with a median overallsurvival of 11 months in both arms. In the two-arm study,[36] irinotecan andcisplatin produced an overall response rate of 29%, median survival of10 months, and 1-year survival rate of 36%, compared to an overall responserate of 22%, median survival of 10 months, and 1-year survival rate of 41%for vindesine and cisplatin.

There was a trend toward improved survival in the irinotecan/cisplatin arm ofthe three-arm study that was not apparent in the two-arm study. More recently, acombined analysis of the two studies indicated that the combination ofirinotecan and cisplatin significantly improved survival over the vindesine/cisplatinregimen in patients with metastatic disease.[37] Notably, the median survival inthe irinotecan/cisplatin arms was 10 months or longer.

Irinotecan and Carboplatin

The activity of carboplatin appears to besimilar to that of cisplatin in the treatment of lung cancer,[38] and given thedrug’s favorable toxicity profile and ease of administration, the use ofcarboplatin may be preferable. Investigation of carboplatin-based regimens isnecessary, and several studies of the combination of irinotecan and carboplatinhave recently been reported (Table 4).[39-42]

Okamoto et al performed a phase I study of escalating doses of bothirinotecan and carboplatin with G-CSF support.[39] Diarrhea was dose-limiting atan irinotecan dose of 70 mg/m² administered on days 1, 8, and 15 withcarboplatin at an area under the concentration-time curve (AUC) of 5. Of 20evaluable patients, 7 (35%) achieved an objective response, and the medianoverall survival was 8 months.

Fukuda et al conducted a phase I trial of irinotecan plus carboplatin withoutG-CSF in untreated patients with advanced solid tumors, primarily lung cancerpatients.[40] Escalating doses of irinotecan were administered starting at 40mg/m² on days 1, 8, and 15 with carboplatin at AUC 5 on day 1 of a 28-day cycle.Dose-limiting toxicities, including neutropenia, thrombocytopenia, and diarrhea,occurred at an irinotecan dose of 60 mg/m². Of the 11 evaluable patients, 4(36%) with NSCLC achieved an objective response. On this schedule, irinotecan at50 mg/m² with carboplatin at AUC 5 was recommended for future testing.

Two phase II studies using this regimen were conducted by Mukohara et al andKinoshita et al.[41,42] In the preliminary reports, overall response rates of25% and 35%, median survivals of 11 and 9 months, and 1-year survival rates of39% and 34%, respectively, were reported for the two studies. Mukohara et alreported the following grade 3/4 toxicities: neutropenia (77%), thrombocytopenia(47%), anemia (25%), and nausea or vomiting (36%).[41] Febrile neutropeniadeveloped in four patients. Investigators were concerned that less than 50% ofpatients received the day 15 dose of irinotecan, possibly contributing to thelower than expected response rate. Kinoshita et al observed grade 3/4neutropenia, thrombocytopenia, and diarrhea in 55%, 22%, and 5% of patients,respectively.[42]

At the University of Colorado Cancer Center, we are currently conducting aphase I dose-escalation trial of irinotecan administered on days 1 and 8 withcarboplatin administered on day 1 every 21 days in previously treated patientswith solid tumors. The current dose level being explored is irinotecan, 50mg/m², and carboplatin, AUC 5.

Nonplatinum Doublets

Although platinum-based therapy has become standard for NSCLC, thedevelopment of several newer agents with promising activity in the treatment ofNSCLC has spurred interest in exploring non-platinum-based regimens. Severalof these combinations are listed in Table 2.

Irinotecan and Gemcitabine

Two phase I trials have evaluated thecombination of irinotecan and gemcitabine. In the first trial, conducted byRocha-Lima et al, gemcitabine was administered at 1,000 mg/m² followed byescalating doses of irinotecan from 50 to 115 mg/m² on days 1 and 8 of a 21-daycycle to 19 patients with previously treated solid tumors, including 5 patientswith NSCLC.[43] Dose-limiting diarrhea developed at an irinotecan dose of 115mg/m². The recommended doses for future trials were 100 mg/m2 of irinotecan and1,000 mg/m² of gemcitabine administered weekly for 2 of 3 weeks. This regimen iscurrently being evaluated by the Cancer and Leukemia Group B (CALGB) as one armof a randomized phase II study exploring nonplatinum doublets for the treatmentof advanced-stage NSCLC. In the second arm of this CALGB trial, patients arereceiving gemcitabine at 1,000 mg/m² with docetaxel at 40 mg/m² on the same schedule.

Irinotecan and Taxanes

Preclinical data evaluating camptothecins withtaxanes have shown the combination to be additive or synergistic. In a phase Itrial in 32 previously untreated NSCLC patients, Masuda et al administeredirinotecan on days 1, 8, and 15 with docetaxel on day 2.[44] Neutropenia was thedose-limiting toxicity, and recommended doses for phase II study were irinotecanat 60 mg/m² with docetaxel at 50 mg/m². The overall response rate was 37%, witha median survival of 11 months and a 1-year survival rate of 45%.

In a subsequent randomized phase II trial, previously untreated patientsreceived either docetaxel at 60 mg/m² and cisplatin at 80 mg/m² administered onday 1, or docetaxel at 60 mg/m² on day 8 with irinotecan at 60 mg/m² ondays 1 and 8 of a 21-day cycle.[45] The 51 evaluable patients who receiveddocetaxel and cisplatin had an overall response rate of 37%, with a mediansurvival of 11 months and a 1-year overall survival of 49%. In the 57 evaluablepatients who received docetaxel and irinotecan, the overall response rate was32%, with a median survival of 11 months and a 1-year overall survival of 41%.The investigators found no significant difference in the rates of severeneutropenia between the two arms, but the incidence of diarrhea wassignificantly higher in the irinotecan arm while the incidence of nausea andvomiting was significantly higher in the cisplatin arm. Both regimens wereconsidered active and well tolerated, with predictable differences in toxicitiesobserved.

Murren et al conducted two phase I trials of weekly docetaxel plus irinotecan.[46]In the first dose-finding study, docetaxel at 25 to 40 mg/m² was followed byirinotecan at 50 mg/m²/wk for 4 weeks of a 6-week cycle. The study enrolled 28patients. Low-grade gastrointestinal toxicity and asthenia were dose-limiting,with toxicities being most problematic during weeks 3 and 4. A subsequent trial,currently ongoing, modified treatment to two weekly doses followed by 1 weekoff. In the latter trial, the docetaxel dose was fixed at 35 mg/m², andirinotecan doses were escalated, starting at 55 mg/m². To date, 14 patientshave been enrolled, the dose of irinotecan has been escalated to 65 mg/m², andone partial response has been observed among 10 patients with NSCLC.

Adjei et al conducted a phase I study of escalating doses of docetaxel, from50 to 75 mg/m², with irinotecan at 150 to 200 mg/m², on a 21-day schedule.[47]Grade 4 neutropenia was dose-limiting at a docetaxel dose of 75 mg/m² andirinotecan dose of 200 mg/m². Of five patients with NSCLC, three had partialresponses lasting more than 6 months. These investigators are currentlyconducting a phase II trial of docetaxel at 65 mg/m² and irinotecan at150 mg/m² as second-line therapy for patients with lung cancer.

Murren et al also recently completed a phase I study of weekly paclitaxel andirinotecan administered for 4 of 6 weeks.[46] Patients received a fixed dose ofpaclitaxel at 75 mg/m² followed by or prior to irinotecan at 50 to 65 mg/m².Twenty-one patients were enrolled in this trial. The maximum tolerated dose ofirinotecan was 50 mg/m², as dose-limiting neutropenia developed in the first twopatients to receive a dose escalation to 65 mg/m². Overall, the regimen wastolerable; however, most patients required dose delays by weeks 3 and 4 to allowfor hematologic recovery. Altering the sequence of administration of irinotecanand paclitaxel did not change the toxicity profile.

Based on these data, the phase II trial design included paclitaxel at75 mg/m² with irinotecan at 50 mg/m² administered weekly for 2 of 3 weeks.To date, the regimen has been well tolerated with minimum serious hematologictoxicity, and one partial response has been observed in six evaluable NSCLCpatients.

Kasai et al reported the preliminary results of a phase I study of escalatingdoses of irinotecan administered on days 1, 8, and 15 with paclitaxeladministered on day 1 of a 28-day schedule.[48] An apparent pharmacokineticinteraction between paclitaxel and irinotecan occurred at paclitaxel doses above180 mg/m² in combination with irinotecan at 50 mg/m², promptinginvestigators to recommend this dose level for further study. Of 23 evaluableNSCLC patients, 9 (39%) achieved partial responses. The potential for apharmacokinetic interaction between paclitaxel and irinotecan, leading toincreased exposure to irinotecan and its metabolites, has been previouslyreported, but may be dose- and/or schedule-dependent.[49,50]

Irinotecan and Other Agents

Phase II studies have also evaluatedirinotecan in combination with etoposide and ifosfamide (Ifex) as first-linetherapy for patients with advanced NSCLC. The overall response rate for theetoposide combination was 21%, and for the ifosfamide combination, 29%.[51,52]Doublet combinations with these agents have been generally less active thanother irinotecan combinations, but their potential value in triplet regimens isbeing evaluated.

Triplet Regimens

Irinotecan, Paclitaxel, and Carboplatin

Socinski et al have beenstudying the triplet combination of irinotecan, paclitaxel, and carboplatin inuntreated patients with advanced NSCLC.[53,54] In the phase I study, full dosesof paclitaxel at 225 mg/m² and carboplatin at AUC 6 were administered on day 1with escalating doses of irinotecan on days 1 and 8.[53] Of the first sevenpatients treated, three experienced dose-limiting toxicity that required dosereductions. The recommended doses for further study were paclitaxel at 175mg/m², irinotecan at 100 mg/m², and carboplatin at AUC 5 administered on day 1every 21 days. The trial accrued 33 patients, and grade 3/4 neutropenia occurredin 50% of patients, with 5 patients (16%) developing febrile neutropenia.Objective responses were seen in 39% of the 31 evaluable patients, with completeresponses in 10%. Median time to progression was 6.8 months, median survival was11 months, and the 1-year survival rate was 47%.

In the subsequent phase II trial, 40 patients were enrolled.[54] Theconfirmed response rate was 30%, with a median overall survival of 13 months,and a 1-year survival rate of 50%. The rate of grade 3/4 neutropenia was high(68%). Other than neutropenia, the regimen was reasonably well tolerated, andthe survival rates thus far are very encouraging.

Irinotecan, Docetaxel, and Carboplatin

In a phase I study conducted byFujita et al, 60 mg/m² of irinotecan was found to be the maximum tolerated dosewhen administered in combination with docetaxel at 60 mg/m² and carboplatin atAUC 5 administered on day 1 of a 21-day cycle with G-CSF support.[55]Diarrhea was the dose-limiting toxicity. Among 22 evaluable patients, theoverall response rate was 38%.

A phase II study administering a weekly regimen of irinotecan at60 mg/m² with docetaxel at 20 mg/m² and carboplatin at an AUC of 2 for 3 of5 weeks was recently reported by Pectasides et al.[56] In the 50 evaluablepatients, the overall response rate was 56% and complete response rate was 8%.Median survival was 15 months, with a 1-year survival rate of 55%. Theregimen was reasonably well tolerated, with grade 3/4 toxicities of neutropeniain 26% (14% febrile neutropenia), thrombocytopenia in 22%, and diarrhea in 28%of patients. With its high level of activity and manageable toxicities, thisweekly regimen warrants further investigation.

Irinotecan, Docetaxel, and Cisplatin 

Kiura et al conducted a phase Itrial of docetaxel, cisplatin, and irinotecan in untreated patients withadvanced NSCLC.[57] The doses of docetaxel and cisplatin were fixed at 60 mg/m²each on day 1; escalating doses of irinotecan ranging from 40 to 60 mg/m² wereadministered on day 2. At the 60 mg/m² dose level of irinotecan, cisplatin wasincreased to 80 mg/m², resulting in dose-limiting diarrhea and neutropenia. Ofthe 21 evaluable patients, 52% achieved an objective response. The recommendeddose for all three drugs for phase II studies was 60 mg/m².

Irinotecan, Docetaxel, and Gemcitabine

Rocha Lima et al attempted tobuild on their experience with gemcitabine and irinotecan by adding docetaxel tothe regimen, thus creating a nonplatinum triplet combination.[58] In a phase Istudy in patients with refractory solid tumors, docetaxel administration wasfollowed 24 hours later by gemcitabine and irinotecan. Two different scheduleswere evaluated: a starting dose of docetaxel at 20 mg/m² on days 1 and 8,escalated by 5 mg/m² increments (arm A); and a starting dose of docetaxelat 45 mg/m² on day 8 only, escalated by 15 mg/m² increments (arm B). Gemcitabinewas administered at 1,000 mg/m² with irinotecan at 100 mg/m² on days 2 and9.

Arm A enrolled 17 evaluable patients to four dose levels, in whichneutropenia was the dose-limiting toxicity. Arm B enrolled six patients; thedose-limiting toxicity was reached at the first dose level, with two patientsdeveloping significant diarrhea and one additional patient developing grade 4neutropenia, thus closing accrual. No objective responses were seen among the 23evaluable patients. The recommended dose of docetaxel was 20 mg/m², to beadministered on days 1 and 8. However, these investigators plan to evaluate analternative study design including docetaxel at25 mg/m² and 30 mg/m² followed by gemcitabine at 1,000 mg/m² and a reducedirinotecan dose of 80 mg/m².

Irinotecan, Etoposide, and Cisplatin

Tsukuda et al have examined theaddition of irinotecan to the well-tolerated regimen of cisplatin and etoposideas first-line therapy in 20 patients with NSCLC.[59] Patients receivedirinotecan at 40 to 60 mg/m² on days 1, 8, 15, with etoposide at 40 to 50mg/m² on days 1 to 3 and cisplatin at 60 mg/m² on day 1 of a 28-day cycle. Allpatients received G-CSF. Dose-limiting toxicities occurred at an irinotecan doseof 60 mg/m² and etoposide dose of 50 mg/m²; one patient developedfebrile neutropenia and one patient developed hepatic toxicity. Of 20 patients,6 responded (30%), with 5 responses occurring in 10 patients treated at thehighest dose level. The regimen appears to have promising activity withmanageable toxicity.

Irinotecan, Ifosfamide, and Cisplatin

Fujita et al conducted aphase I/II study of irinotecan, ifosfamide, and cisplatin in patients withadvanced NSCLC.[60] In the phase II portion of the study, patients receivedirinotecan, 60 mg/m² on days 1, 8, and 15; ifosfamide, 1.5 g/m² on days 1 to 4;and cisplatin, 70 mg/m² on day 1 of a 28-day schedule, with G-CSF support.Dose-limiting toxicity in the phase I portion was leukopenia at a cisplatin doseof 80 mg/m². The overall response rate among the 46 evaluable patients was 62%,with a median survival of 13 months. The high response rate and promisingsurvival suggest the regimen should be studied further.

Salvage Therapy

Irinotecan has been evaluated as salvage therapy for patients with advancedNSCLC, most often as part of a doublet regimen. There are limited data on theactivity of single-agent irinotecan in the salvage setting, with one phase IIstudy reporting no responses in 26 previously treated NSCLC patients.[8]However, the activity of irinotecan in combination with platinum and otheragents appears promising as salvage treatment (Table5).[61-63]

Kakolyris et al conducted a phase I study of irinotecan and cisplatin inpatients who had relapsed following first-line therapy with a docetaxel-basedregimen.[64] Irinotecan was administered at 100 mg/m² on day 1, with the doseescalated in 10 mg/m² increments on day 8, a fixed dose of cisplatin at80 mg/m² was administered on day 8, and treatment was repeated every3 weeks. The maximum tolerated dose of irinotecan was 100 mg on day 1 and120 mg on day 8, despite the addition of G-CSF. The dose-limitingtoxicities were neutropenia, febrile neutropenia, and diarrhea. Partialresponses were observed in 2 of 12 evaluable patients (17%).

In a subsequent phase II study, these investigators administered irinotecanat 100 mg on day 1 and at 110 mg on day 8, with cisplatin at 80 mg/m²on day 8. Among 31 patients previously treated with docetaxel-basedfirst-line therapy, the overall response rate was 23%, and median survival was8 months.[61] Grade 3/4 neutropenia occurred in 52% of patients, with twopatients experiencing febrile neutropenia.

Nakanishi et al evaluated a regimen of weekly irinotecan at 60 mg/m² withcisplatin at 30 mg/m², administered for 3 of 4 weeks as salvage therapy inpatients with refractory lung cancer.[62] The 21 evaluable patients achieved anoverall response rate of 29% and a median survival of 7 months. Grade 3/4neutropenia and anemia occurred in 43% and 38% of patients, respectively, withgrade 3 diarrhea observed in 38% of patients. Dose-reductions or delays werenecessary in 76% of patients due to toxicity.

Cao et al evaluated the combination of irinotecan at 300 mg/m² on day 1 withvinorelbine at 30 mg/m² on days 1 and 14 of a 28-day schedule assecond-line therapy.[63] The regimen was associated with modest toxicity andproduced an overall response rate of 12% in 26 patients previously treated withcisplatin, paclitaxel, and gemcitabine.

Kakolyris et al enrolled 24 previously treated NSCLC patients in a phase Itrial of gemcitabine at 900 to 1,200 mg/m² on days 1 and 8 with irinotecan at200 to 300 mg/m² on day 1 of a 21-day cycle.[65] Grade 3/4 neutropenia, the mostfrequently observed toxicity, has occurred in 13% of cycles. The study isongoing, and the maximum tolerated dose has not been reached. To date, onepatient has responded (4.5%), and the median survival is 7 months.

Combined-Modality Therapy

Irinotecan has demonstrated radiosensitizing properties in severalpreclinical studies, although the exact mechanism of this activity is notdefined.[66] In a phase I/II trial reported by Takeda et al, escalating doses ofirinotecan were administered weekly with concurrent irradiation to a total doseof 60 Gy in 30 fractions over 6 weeks to patients with stage IIIA and IIIB NSCLC.[67]The maximum tolerated dose of irinotecan was 60 mg/m², and dose-limitingtoxicities included esophagitis, pneumonitis, and diarrhea. The overall responserate among the 26 evaluable patients was 77%, with 13 of 17 patients (76%)responding at the phase II dose level of 45 mg/m²/wk.

In a phase II trial, the Japan Clinical Oncology Group administeredirinotecan at 60 mg/m²/wk with concurrent radiation (60 Gy in 30 fractions over6 weeks) to patients with locally advanced NSCLC.[68] The trial enrolled 25patients, and 71% completed the full 6-week course of therapy. Partial responseswere seen in 79% of the 24 evaluable patients. No grade 4 toxicities occurred.Grade 3 toxicities consisted of esophagitis in two patients, neutropenia intwo patients, and hypoxemia in three patients.

Irinotecan, Cisplatin, and Radiation

Given the tolerability ofirinotecan with concurrent radiotherapy, investigators have elected to addcisplatin or carboplatin to the regimen. Fukuda et al reported a phase I studyin which escalating doses of irinotecan at 40 to 60 mg/m² were administered ondays 1, 8, and 15 with escalating doses of cisplatin at 60 to 80 mg/m² on day 1,delivered every 28 days with split-course radiotherapy to a total dose of 50 to60 Gy (24 Gy on cycle 1 and 24-36 Gy on cycle 2).[69] The regimen was welltolerated, with only two patients in separate cohorts experiencing adose-limiting toxicity. Among the 23 evaluable patients, 65% achieved a partialresponse. The recommended chemotherapy regimen for future studies was irinotecanat 60 mg/m² with cisplatin at 80 mg/m².

Yokoyama et al also conducted a phase I study of irinotecan at 40 to 60mg/m²on days 1, 8, and 15 and cisplatin at 60 to 80 mg/m² on day 1, administeredevery 28 days with radiotherapy to a total dose of 60 Gy in 30 fractions over6 weeks.[70] Although a traditional maximum tolerated dose was not defined,difficulty in delivering the intended doses of chemotherapy and radiation due toleukopenia, fever, diarrhea, esophagitis, and pneumonitis prompted investigatorsto suspend accrual after 13 patients had been enrolled. Among 12 evaluablepatients, 8 achieved a partial response (67%).

In an ongoing phase I study at the Fox Chase Cancer Center, escalating dosesof irinotecan from 30 to 70 mg/m²/wk in combination with cisplatin at 25mg/m²/wk for 7 weeks is being administered concurrently with radiotherapy to 63Gy.[71] In a preliminary report, 11 patients had been enrolled and had receivedirinotecan at 30 to 40 mg/m². Partial responses were reported in seven patients(64%). The combination was reasonably well tolerated, with only one patientexperiencing dose-limiting toxicity. There was no grade 3 esophagitis, althoughthree patients had grade 3 or 4 neutropenia. Accrual is continuing.

Irinotecan, Carboplatin, and Radiation

The combination of irinotecan andcarboplatin with concurrent radiotherapy has been evaluated by investigators inboth Japan and the United States. Yamada et al treated 23 inoperable stage IIINSCLC patients with escalating doses of irinotecan at 30 to 50 mg/m²/wk with afixed carboplatin dose of 20 mg/m²/wk for 4 weeks.[72] Concurrentradiotherapy to a total dose of 60 Gy in 30 fractions was delivered over 6weeks. The maximum tolerated dose of irinotecan was 60 mg/m², with esophagitis,neutropenia, pneumonitis, and thrombocytopenia being dose-limiting. Among the 30evaluable patients, the overall response rate was 60%, with 3 patients (10%)achieving a complete response. Median survival had not yet been reached, but the1-year and 2-year survival rates were 56% and 51%, respectively.

In the United States, Choy et al conducted a phase I trial of thiscombination.[66] Irinotecan was administered weekly for 6 weeks starting at 30mg/m². After the maximum tolerated dose of irinotecan was determined, a secondpart of the study evaluated the addition of carboplatin at AUC 2. Patientsreceived a total thoracic radiation dose of 60 Gy. The maximum tolerated dosesof irinotecan were 40 mg/m² alone and 30 mg/m² in combination withcarboplatin. Nausea/vomiting and esophagitis were the dose-limiting toxicitiesin the combination arm. The objective response rate among 18 patients was 65%.

Overall, the combination of irinotecan with platinum agents and concurrentradiotherapy appears to offer promising response rates with an acceptable levelof toxicity. Further study and comparison with other combined-modality regimensis warranted.

Conclusions

Irinotecan is clearly an active agent in non-small-cell lung cancer, asevidenced by overall response rates of 35% to 56% in combination withcarboplatin or cisplatin in phase II studies. Perhaps more intriguing have beenthe median survival times reported in these phase II trials and in two phase IIItrials. Median survival times for irinotecan and platinum combinations haveranged from 9 to 13 months in phase II studies and from 10 to 12 months inrandomized phase III trials. In large randomized US trials conducted in patientswith advanced NSCLC, median survival with the use of platinum-based combinationtherapy has been approximately 8 months. The potential for irinotecan/platinumcombinations to further improve survival outcomes warrants continued study andconfirmation in randomized trials.

The single-agent activity of irinotecan, along with several other neweragents such as gemcitabine and the taxanes, has prompted investigators toexplore non-platinum-containing doublet and triplet regimens in combinationwith platinum agents. Preliminary studies of doublet combinations of irinotecanand a taxane or gemcitabine in NSCLC appear promising and are currently beingpursued in phase II studies. In addition, phase II studies of tripletcombinations of irinotecan with a platinum agent and a taxane have producedmedian survivals of up to 15 months and 1-year survival rates of 50% to 55%,with generally manageable toxicity profiles. This approach appears to bepromising and should be studied further. The addition of irinotecan tocombined-modality regimens is also under evaluation, and preliminary results areencouraging.

Irinotecan is emerging as a potentially valuable agent in the treatment ofNSCLC. Based on activity demonstrated to date, this agent should be consideredfor use in combination with traditional chemotherapy drugs as well asbiologically targeted agents.

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