The Emerging World Role of Irinotecan in Lung Cancer

July 1, 2001

Irinotecan (CPT-11, Camptosar), either alone or in combination with cisplatin (Platinol), has demonstrated activity in advanced non-small-cell lung cancer (NSCLC). In single-agent studies, response rates as high as 35%

ABSTRACT: Irinotecan (CPT-11, Camptosar), either alone or in combinationwith cisplatin (Platinol), has demonstrated activity in advanced non-small-celllung cancer (NSCLC). In single-agent studies, response rates as high as 35% havebeen observed; in combination with cisplatin, response rates have ranged as highas 50%, with 1-year survival rates of 33% to 58%. A critical phase IIIrandomized trial comparing irinotecan, either alone or in combination withcisplatin, to vindesine/cisplatin, demonstrated superior survival for stage IVpatients receiving irinotecan. The first North American effort to replicate theschedule used in the phase III trial (cisplatin 80 mg/m2 and irinotecan 60mg/m2on days 1, 8, and 15 every month) yielded a response rate of 29%, mediansurvival time of nearly 10 months, and 1-year survival rate of 37%. A subsequentmulti-institutional trial conducted through Vanderbilt Cancer Center AffiliateNetwork and Fox Chase Cancer Center combined both agents on a weekly schedule inan attempt to exploit their putative synergy and to potentially decreasetoxicity. This schedule, which employed irinotecan 65 mg/m2 and cisplatin 30mg/m2 both weekly × 4, was better tolerated than the monthly cisplatincombination with a higher response rate (36%), median survival (11.6 months),and 1-year survival rate (46%). Multiple phase I and phase II studies havecombined irinotecan with taxanes, either alone or in concert with carboplatin(Paraplatin), yielding similar response and survival rates. Finally, a criticalphase III trial from Japan has demonstrated superior outcome for irinotecan andcisplatin vs standard etoposide/cisplatin in the treatment of extensivesmall-cell carcinoma of the lung. At least one North American trial willdetermine if these results are reproducible. [ONCOLOGY 15(Suppl 8):15-21, 2001]

Introduction

Lung cancer, with more than 1million cases diagnosed worldwide annually, has become the most common malignancy in terms of incidence.Although the incidence is starting to plateau in North American men, itcontinues to rise in North American women and in both genders outside of theUnited States, particularly in Europe and the Orient. The 5-year survival ratein the United States is 14%, compared with 8% in Europe.[1] Generally, thedisease is either systemic at diagnosis, or manifests distant spread afterlocoregional therapy. Hence, new agents with improved systemic activity aredesperately needed.

This article will review the activity of irinotecan (CPT-11,Camptosar), either alone or in combination with cisplatin (Platinol) and otheragents, and will address its emerging role as a component of radiosensitizingtherapy in locally advanced non-small-cell lung cancer. Planned and ongoingphase III trials to establish the utility of irinotecan in non-small-cell lungcancer and small-cell lung cancer will also be discussed.

Irinotecan Alone and in Combination Therapy

Single-Agent Therapy

Multiple phase II studies, particularly in Japan, haveestablished the utility of irinotecan in the treatment of advanced non-small-celllung cancer. Response rates have ranged as high as 30% to 35%, usingconventional schedules of 100 to 125 mg/m2 × 4 every 6 weeks,[2-4] or doses of300 to 350 mg/m2 every 3 weeks with or without hematopoietic growth factorsupport.[5] Toxicities have generally included myelosuppression and diarrhea.Work by Kameyama and colleagues on the activation and detoxification ofirinotecan by human lung cancer cell lines has revealed expression of theenzyme(s) that convert(s) irinotecan to the active moiety, SN-38(7-ethyl-10-hydroxycamptothecin).[6] Of 25 squamous cell carcinoma cell lines,15 (60%) were strongly positive for carboxylesterase, the putative enzyme; of 25adenocarcinomas, 20 (80%) proved positive, including 4 that were stronglypositive.

Irinotecan/Cisplatin Combinations

Cisplatin remains the cornerstone of combination therapy inadvanced non-small-cell lung cancer. Consequently, investigators have soughtto assess the activity of irinotecan in combination with cisplatin. The earliestefforts in this regard were in Japan. Masuda and colleagues evaluated cisplatinat 80 mg/m2/d on day 1 every 4 weeks in combination with irinotecan at 60mg/m2/d on days 1, 8, and 15.[7] Overall response rate was 52%, time to diseaseprogression was 4.4 months, median survival time was 10.2 months, and the 1-yearsurvival rate was 33%.Ueoka assessed irinotecan and cisplatin in combination at doses of 50 and60 mg/m2, respectively, days 1 and 8 every 4 weeks.[8] Overall response rate wasslightly lower at 41%, but median survival time was 13 months, and the 1-yearsurvival rate was 58%.

Mori and colleagues conducted a phase II study of bolusirinotecan at 160 mg/m2 day 1 in combination with cisplatin 20 mg/m2/d × 4 bycontinuous infusion with granulocyte colony-stimulating factor (G-CSF[Neupogen]) support.[9] Twenty-four treatment-naive non-small-cell lung cancerpatients with advanced disease were evaluated. Overall response rate was 58.5%,median survival time was 44.8 weeks, and the 1-year survival rate was 44%. Majortoxic effects included grade 3/4 diarrhea in 23%, granulocytopenia in 20%,thrombocytopenia in 15%, and anemia in 15% of patients. There were notreatment-related deaths.

In Europe, Cardenal conducted a multi-institutional phase IItrial combining irinotecan at 200 mg/m2 as a1-hour infusion in combination with cisplatin at 80 mg/m2 every 21 days.[10]Over an 8-month period, 48 patients were recruited with 43 evaluable fortoxicity. Grade 4 neutropenia occurred in 11.6%, grade 4 diarrhea in 9.3%, andgrade 3 nausea and vomiting in 16.2% of patients. Of 32 evaluable patients, 12(37.5%) achieved a partial response.

Phase III Randomized Trials

In a phase III trial, Masuda et al assessed irinotecan as asingle agent or in combination with cisplatin vs vindesine/cisplatin.[11]Eligible patients had untreated stage IIIB or IV measurable non-small-celllung cancer, Eastern Cooperative Oncology Group (ECOG) performance status of 0to 2, and adequate marrow, hepatic, renal, and pulmonary function. Patients over75 years old were excluded. A total of 398 patients were enrolled, of whom 246had stage IV disease. Demographics—with respect to age, performance status,previous weight loss, and levels of albumin and lactate dehydrogenase—werewell matched for each arm. Patients received one of three regimens: (1)irinotecan 100 mg/m2/d on days 1, 8, and 15 every 4 weeks; (2) irinotecan 60mg/m2/d on days 1, 8, and 15, and cisplatin 80 mg/m2/d on day 1 every4 weeks; or (3) vindesine 3 mg/m2/don days 1, 8, and 15, and cisplatin80 mg/m2/d on day 1 every 4 weeks.

Trial results are shown in Table1. Leukopenia was morepronounced with the vindesine/cisplatin combination, while thrombocytopenia wasmore common in the irinotecan/cisplatin arm. Patients in both irinotecan armshad substantially more grade 3/4 diarrhea compared with those receivingvindesine/cisplatin. The cisplatin arms yielded considerably more nausea andvomiting. The incidence of anemia was driven by cisplatin: 39% grade ³ 3 foririnotecan/cisplatin compared with 23% for vindesine/cisplatin and 6% foririnotecan alone. Among stage IV patients, survival was significantly better inthose receiving irinotecan than in those receiving vindesine/cisplatin (Figure1).

In contrast, results from another phase III trial comparing thetwo platinum combinations alone did not reveal a significant advantage ordisadvantage for irinotecan.[12,13] Again, baseline demographics were wellmatched for the 117 randomized patients with stage IV disease. Grade ³ 3neutropenia was more common in the vindesine/cisplatin arm (83%) than in theirinotecan/cisplatin arm (64%). Grade ³ 3 anemia was slightly more common withthe irinotecan combination: 24% vs 17%. Likewise, grade ³ 3 nausea/vomiting anddiarrhea were more common at 19% and 15%, respectively, for irinotecan/cisplatinvs 12% and 2% for vindesine/cisplatin. Median survival for patients receivingirinotecan/cisplatin was 44.7 weeks, and 1- and 2-year survival rates were 36.4%and 8.7%, respectively, in stage IV patients. Median survival time forvindesine/cisplatin patients was 45.3 weeks, with 1- and 2-year survival ratesof 41.4% and 10.3%, respectively (P = .668) (Figure2). Significant negativeprognostic factors included male gender (P = .0028) and performance status of 2(vs 0/1) (P = .0003).

North American Trials

The initial effort in North America to assess irinotecancombinations, reported by DeVore and colleagues, was similar to the Japanesestudy of Masuda and colleagues: cisplatin at80 mg/m2/d on day 1 plus irinotecan at 60 mg/m2/wk × 3 every 4 weeks.[14]Fifty-two patients were enrolled. Overall response rate was 29%, with a mediantime to progression of 5.1 months, median survival time of 9.9 months, and a1-year survival rate of 37%. Grade ³ 3 neutropenia occurred in 46% of patients,with an 11.5% overall incidence of febrile neutropenia. Nausea, vomiting andasthenia were driven by cisplatin: grade ³ 3 incidences were 32.7%, 13.5%, and23.1%, respectively. Grade 3/4 diarrhea occurred in 17.3% of patients. Therelative dose intensity of irinotecan was 75.5%. Dose reductions of irinotecanwere required in 73% of patients; most patients ultimately had the irinotecandose reduced to ≤ 40 mg/m2.

A subsequent follow-up study assessed weekly irinotecan combinedwith weekly cisplatin.[15] The rationale for this study included the following:(1) the putative synergy of these two agents seen in vitro could be betterexploited by same-day administration; (2) improved sequencing of irinotecan andcisplatin might potentially improve efficacy; (3) potentially diminishedtoxicity could result from decreased cisplatin dose per administration. Theregimen was modeled after phase Idata of Saltz and colleagues.[16] Eligible patients received irinotecan at65 mg/m2/wk × 4, in combination with cisplatin at 30 mg/m2/wk × 4. Treatmentwas repeated at 6-week intervals. Fifty patients were enrolled.

Overall response rate (36%) was slightly higher than that in theprevious study, median time to progression was 6.9 months, median survival timewas 11.6 months, and the 1-year survival rate was 46%. These were the bestresults observed to date in the Vanderbilt Cancer Center Affiliate Network(VCCAN) trials. Overall incidence of grade ³ 3 neutropenia was 26%; febrileneutropenia occurred in 6% of patients. Grade ³ 3 thrombocytopenia occurred in14% and grade ³ 3 vomiting in 12% of patients. The relative dose intensity ofirinotecan in this combination was 89%, and the dose intensity was fairly wellmaintained for both agents. Comparison of these two regimens is shown in Table2. Data to date thus favor using weekly rather than monthly cisplatin.

Irinotecan/Taxane Combinations

Burtness and colleagues conducted a phase I trial of irinotecanand paclitaxel (Taxol), both administered weekly × 4 every 6 weeks.[17] A totalof 21 patients received 53 treatment cycles. The maximum tolerated dose at thisweekly schedule was 50 mg/m2 of irinotecan and 75 mg/m2 of paclitaxel.Pharmacokinetic evaluations revealed no drug-drug interactions based onirinotecan and SN-38 levels. In an ongoing phase II trial conducted by theseinvestigators, advanced non-small-cell lung cancer patients with performancestatus 0 to 2 are receiving an abbreviated schedule of this regimen: irinotecanat 50 mg/m2/wk × 2 every 3 weeks combined with paclitaxel at 75 mg/m2/wk × 2every 3 weeks. To date, seven patients have been accrued, and no grade 4neutropenia has yet been observed (personal communication, J. Murren, 2001). Twoof six evaluable patients have a sustained partial response (18+ weeks); threehave stable disease and one has had progressive disease. Rosen et al combinedirinotecan with paclitaxel, both given once every 3 weeks.[18] The maximumtolerated doses for each agent were 225 and 100 mg/m2, respectively. Grade³ 3 diarrhea was observed in only one of nine treatment courses at the maximumtolerated doses, whereas at higher doses, grade ³ 3 diarrhea occurred in 5 of17 patients. Objective responses were seen in non-small-cell lung cancer andoccult primary squamous malignancy. Paclitaxel coadministration did not alteririnotecan pharmacokinetics (irinotecan and SN-38 levels).

Sandler and colleagues are conducting phase I and II studies ofpaclitaxel, irinotecan, and carboplatin (Paraplatin).[19] The maximum tolerateddoses for these agents using an every-3-week schedule were paclitaxel at175 mg/m2, irinotecan at 100 mg/m2, and carboplatin at an area under theconcentration-time curve (AUC) of 5. Thirty-two patients were enrolled in thephase I effort; the overall response rate was 40% (10% complete response rate).Median time to progression was 6.8 months, median survival time was 11 months,and the 1-year survival rate was 47%. To date, 40 patients have been enrolled inthe phase II effort; the 30% response rate is comparable to that seen in thephase I portion of the trial, time to progression at 5.6 months is similar. The1-year survival rate is promising at 50%. Disappointingly, the incidence ofneutropenic fever is 30%.

Finally, a phase I study assessed irinotecan combined withdocetaxel (Taxotere).[20] Twenty-six treatment-naive non-small-cell lungcancer patients with advanced disease (22 with stage IV disease) receiveddocetaxel on day 2 and irinotecan on days 1, 8, and 15. Doses were escalatedacross sequential cohorts. Maximum tolerated dose for each agent was 50 mg/m2.Higher doses led to dose-limiting toxicity, primarily neutropenia. Overallresponse rate was 32%, median survival time was 39 weeks, and the 1-yearsurvival rate was 38%.

Future Efforts in Advanced Disease

Rocha-Lima has reported the results of a phase I assessment ofirinotecanin combination with gemcitabine (Gemzar); each agent can be administered at fulldose (irinotecan 100 mg/m2, gemcitabine 1,000 mg/m2) weekly × 3 every 4 weekswithout the need forG-CSF support.[21] The Cancer and Leukemia Group B (CALGB) is spearheading aphase II trial of irinotecan and gemcitabine in advanced non-small-cell lungcancer, and a similar trial as salvage therapy in progressive small-cell lungcancer. A phase III trial comparing cisplatin/irinotecan using a day-1, day-8schedule every 3 weeks to irinotecan/gemcitabine and gemcitabine/cisplatin isplanned. In addition, a phase III study comparing the weekly cisplatin andirinotecan × 4 every6 weeks schedule to standard therapy is being considered. Finally, in Japan, afour-arm phase III trial comparing the new Japanese standard combination ofirinotecan/cisplatin with other state-of-the-art combinations—includingvinorelbine (Navelbine)/cisplatin, gemcitabine/cisplatin, andcarboplatin/paclitaxel—is ongoing.

In summary, a survival advantage for stage IV non-small-celllung cancer patients was observed in at least one trial using monthly cisplatinand weekly irinotecan as compared with vindesine/cisplatin. On the other hand,weekly irinotecan and cisplatin appears to be more active and better toleratedthan the monthly schedule. Future studies will elucidate the status ofirinotecan combinations vis-à-vis other standard combinations, and will alsoassess the role of irinotecan, either alone or in combination with gemcitabine,as salvage therapy in previously treated patients.

Concurrent Irinotecan and Radiation Therapy

Locally Advanced NSCLC

Both irinotecan and cisplatin individually have shownsynergistic activity with radiation. Takeda et al[22] conducted a phase I studyof weekly irinotecan combined with standard thoracic radiotherapy (60 Gy) forlocally advanced non-small-cell lung cancer. The irinotecan dose was escalatedacross sequential cohorts starting at30 mg/m2 and increasing by 15 mg/m2 per cohort to a maximum of 75mg/m2. A totalof 26 patients (20 men and 6 women) were accrued. The median age was 63.5 years;22 of 26 had a performance status of 0 to 1. All but one had stage IIIB disease;16 had squamous cell histology. Dose-limiting toxicity was observed at 60 mg/m2:three of five patients experienced grade 3 or 4 esophagitis or pulmonarytoxicity. The maximum tolerated dose (recommended dose) was 45 mg/m2/wk. Theoverall response rate was 76.9%, the 1-year survival rate was 61.5%, and mediansurvival time was 15.7 months.

Fukuda and colleagues combined split-course radiotherapy withtwo cycles of cisplatin at 60 to 80 mg/m2/d on day 1, and irinotecan at 40 to60 mg/m2/d on days 1, 8, and 15.[23] The maximum tolerated doses, respectively,were 80 and 60 mg/m2. Radiation was given to a total dose of 24 Gy starting onday 2 of cycle 1; 26 to 36 Gy were administered during cycle 2. Twenty-threepatients were accrued; four experienced grade ³ 2 esophagitis. The overallresponse rate was 65%, and median survival time was approximately 1 year.

Another trial combined standard thoracic radiotherapy,carboplatin, and irinotecan.[24] Thirty-one patients were accrued (24 male); allbut two had performance status of 0 to 1. The median age was 62 years. Of 30evaluable patients, 18 had stage III disease and 19 had squamous cell histology.Patients received carboplatin at 20 mg/m2 daily, and sequential cohortsreceived escalating doses of irinotecan weekly. Again, irinotecan at a dose of60 mg/m2 resulted in unacceptable toxicity: three of three patients at this doseexperienced grade 4 pneumonitis. The overall response rate was 60%, mediansurvival time was 15.1 months, and the 1-year survival rate was 56.7%.

Yamamoto conducted a combination trial using induction therapywith irinotecan and cisplatin followed by concurrent chemoradiation withirinotecan alone.[25] Patients received two cycles of full-dose inductiontreatment: cisplatin at 80 mg/m2 days 1 and 29, and irinotecan at 60mg/m2/d ondays 1, 8, 15, 29, 36, and 43. Thoracic radiotherapy followed on day 57;60 Gy were given over 6 consecutive weeks, combined with irinotecan at30 mg/m2/wk × 6. A total of 68 patients were enrolled (52 men and 16 women);the median age was 63 years. Approximately two-thirds of the patients had aperformance status of 1, 40 had stage IIIB disease, 28 had squamous cellhistology, and 27 had adenocarcinoma histology.

The grade 3/4 toxicities that occurred during inductionchemotherapy were predictable: neutropenia in 72% of patients and diarrhea in19%. Grade 3/4 toxicities during concomitant thoracic radiotherapy/irinotecanconsisted of neutropenia in 16% of patients, esophagitis in 4%, and hypoxemia in6%. There were no treatment-related deaths. The overall response rate was 63.3%,median survival time was quite promising at 19.3 months, and the1-year survival rate was 65.8%.

North American Efforts

Combined Chemoradiation With Irinotecan

Based on the data generated in Japan,[22-25] and the observationthat weekly therapy could potentially enhance radiosensitization while limitingtoxicity,[14] Langer et al have initiated a phase I trial in which full-doseradiotherapy (63 Gy) is combined with weekly irinotecan and cisplatin.[26]Eligibility requires measurable non-small-cell lung cancer— either locallyadvanced and surgically unresectable, medically inoperable stage II/IIIA, orlocally recurrent after previous surgery. Other entry criteria include Karnofskyperformance status ³ 50, ≤ 10% weight loss, adequate physiologic indices(absolute neutrophil count ³ 2,000/mL, platelet count³ 100,000/mL, creatinine level ≤ 1.5 mg/dL, bilirubin level≤ 1.5 mg/dL), andadequate pulmonary function (FEV1 ³ 1 L).

The starting doses for irinotecan and cisplatin were 30 and 25mg/m2, respectively; seven patients were accrued at this dose level. The firstenrollee developed Aspergillus pneumonitis in the setting of neutropenic fever.The other six have not experienced dose-limiting toxicity. Accrual to dose level2 (irinotecan at 40 mg/m2 weekly, cisplatin at 25 mg/m2) continues. Grade 3fatigue and grade 2 diarrhea have been observed in one patient each.Investigators have yet to observe grade 3 esophagitis. Seven of nine evaluablepatients have responded.

In a phase I study, Chakravarthy and colleagues studiedirinotecan alone, then in combination with carboplatin weekly (at an AUC of 2)plus radical thoracic radiotherapy in 27 patients.[27] The maximum tolerateddose for single-agent irinotecan was 40 mg/m2; it was 30 mg/m2/wk for irinotecanin combination with carboplatin.

Small-Cell Lung Cancer

Results of phase II studies have demonstrated promise foririnotecan as a single agent[28-31] and in combination with cisplatin, in thetreatment of advanced small-cell lung cancer. Kudoh et al reported an overallresponse rate of 86% for this combination.[32] The complete response rate was29%, median survival time was 13.2 months, and the 2-year survival was 17%.Based on these observations, Noda and colleagues conducted a phase III studycomparing a standard regimen of EP (cisplatin [Platinol] at 80 mg/m2 on day 1and etoposide at 100 mg/m2 on days 1 to 3), every 3 weeks to CP (cisplatin[Platinol] at 60 mg/m2 on day 1 every 4 weeks and irinotecan[Camptosar] at 60mg/m2 on days 1, 8, and 15) every 4 weeks.[33] Stratification includedperformance status and institution. Patients whose tumors progressed were takenoff study. Those with partial response were observed; and those with complete ornear complete response were randomized a second time to either observation orradical thoracic radiotherapy (50 Gy, ie, 2 Gy/d × 5 weeks).

To be eligible, patients had to have cytologically orhistologically proven small-cell lung cancer; extensive disease; no previousradiotherapy, chemotherapy, or surgery; ECOG performance status of 0 to 2; age £ 70 years; and adequate physiologic indices (normal marrow, liver, and kidneyfunction). Both treatment arms were well matched with respect to demographics.The median age was 63 years (range: 30 to 70 years). Of 77 patients accrued toeach arm, 71 out of 77 in the CP arm and 67 out of 77 in the EP arm hadmetastatic involvement. Six CP patients and 10 EP patients had a performancestatus of 2.

The original accrual target for this study was 230 patients;however, enrollment was suspended in December 1998 with 154 patients accruedbecause of a statistically significant survival difference. In the firstanalysis, median survival for patients receiving CP was 14 months vs 10 monthsfor those receiving EP. An updated analysis revealed a median survival of 390days for the CP arm vs 287 days for the EP arm, with 1- and 2-year survivalrates, respectively, of 58.4% and 18.9% for CP and 37.7% and 6.5% for EP (P = .0021). The overall response rates were 83% and 68% in the CP and EP arms,respectively (P = .013). The EP regimen yielded a considerably higher incidenceof grade ³ 3 neutropenia (92% vs 66%, P = .0002) and grade ³ 3thrombocytopenia (18% vs 5%, P = .01). Not surprisingly, the CP arm causedsubstantially more grade ³ 3 diarrhea (16% vs 0%, P= .0001).

As of this writing, the irinotecan/cisplatin combination hasbecome the standard for future comparison studies in extensive disease in Japan.Two separate North American trials are planned. One will attempt to duplicatethe Japanese effort; the other will use a more standard 3-week schedule, ie,etoposide at 100 mg/m2/d × 3 and cisplatin at 80 mg/m2 on day 1 vs irinotecanat 65 mg/m2 on days 1 and 8 and cisplatin at 30 mg/m2 on days 1 and 8 every 3weeks. If either North American trial confirms the results of the Japanesestudy, then the irinotecan/cisplatin combination will likely become a standardtreatment worldwide.

Conclusions

Irinotecan is a promising agent in the treatment of advanced non-small-celllung cancer and small-cell lung cancer. Results of ongoing trials will confirmor refute the survival advantage observed for irinotecan in combination withcisplatin in extensive-stage small-cell lung cancer. One of two trials conductedin Japan has already demonstrated a significant survival advantage foririnotecan/cisplatin compared with standard treatment in patients with advancednon-small-cell lung cancer. To date, however, phase III trials focusing on therole of irinotecan in non-small-cell lung cancer have not yet been conductedin North America. Over the next few years, considerably more data on irinotecanwill become available regarding its optimal role in the treatment of lungcancer, and comparing it directly with other modern agents, includingpaclitaxel, gemcitabine, and vinorelbine.

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