Preclinical data suggest that irinotecan (Camptosar, CPT-11), a novel topoisomerase I inhibitor, has exhibited promising activity in the treatment of lung cancer. In a phase II study of non-small-cell lung cancer, irinotecan
ABSTRACT: Preclinical data suggest that irinotecan (Camptosar, CPT-11),a novel topoisomerase I inhibitor, has exhibited promising activity in thetreatment of lung cancer. In a phase II study of non-small-cell lung cancer,irinotecan demonstrated a 32% response rate. Combinations of irinotecan andcisplatin (Platinol) have also demonstrated synergistic activity against non-small-celllung cancer. A phase I trial of irinotecan combined with cisplatin in previouslyuntreated non-small-cell lung cancer patients showed an encouraging responserate of 54%, with irinotecan at 60 mg/m2 on days 1, 8, and 15, plus cisplatin at80 mg/m2. In a phase II study of chemotherapy-naive patients with stage IIIB/IVnon-small-cell lung cancer, irinotecan/cisplatin yielded a response rate of52% and a mean survival time of 44 weeks. Data from a phase III trial comparingcisplatin at 80 mg/m2 on day 1 plus vindesine at 3mg/m2 on days 1, 8, and 15with two irinotecan-containing regimenscisplatin at 80 mg/m2 on day 1 plusirinotecan at 60 mg/m2 on days 1, 8, and 15, and single-agent irinotecan at 100mg/m2 on days 1, 8, and 15have also been reported. Responses were observed in32%, 44%, and 21% of patients for the vindesine/cisplatin, irinotecan/cisplatin,and irinotecan arms, respectively, with corresponding median survival times of45.6, 50.0, and 46.0 weeks; there were no significant differences in responserate or survival between treatment groups for all patients. However, subsetanalysis of stage IV patients indicated a significant survival advantage foririnotecan/cisplatin; the median survival time was 50 weeks for patientsreceiving irinotecan/cisplatin, 36.4 weeks for vindesine/cisplatin, and 42.1weeks for irinotecan (P = .004 for the irinotecan/cisplatin arm vsvindesine/cisplatin; P = .018 for irinotecan vs vindesine/cisplatin). Anotherphase III study compared irinotecan/cisplatin and vindesine/cisplatin. There wasno difference in overall median survival time, and the median survival timeswere not significantly different for stage IV patients in the respectiveirinotecan/cisplatin and vindesine/cisplatin arms (44.7 vs 45.3 weeks). Furtherstudies are needed to determine whether irinotecan/cisplatin combinationsimprove survival in comparison with other promising platinum-containingregimens. [ONCOLOGY 15(Suppl 1):13-18, 2001]
Irinotecan (Camptosar, CPT-11) is asemisynthetic water-soluble camptothecin analog. Its mechanism of action is inhibition of DNA topoisomerase Ithrough the formulation of a topoisomerase I-DNA cleavable complex.[1,2] Inpreclinical studies, irinotecan has demonstrated a broad spectrum of activityboth in vitro and in vivo. These include synergistic effects that have beenobserved when it is administered in combination with other active anticanceragents.
Japanese Phase I Studies
Single-Dose Schedule: Taguchi and coworkers reported thefirst phase I trial of irinotecan in 1990. The human trial was initiated at adose of 50 mg/m2 on a single-dose schedule based on a dose of one-fifth of thelethal dose (LD10) in mice (52.8 mg/m2) and one-third of the toxic dose in dogs(69.3 mg/m2). The dose-escalation schedule was carried out according to themodified Fibonacci search method, and the study dose range was 50 to 350 mg/m2.A total of 17 patients with refractory solid tumors were enrolled in the trial.
The dose-limiting toxicity was myelosuppression, especiallyneutropenia, and the maximum tolerated dose was presumed to be 250 mg/m2 ormore. Other toxicities included nausea and vomiting, diarrhea, abdominal pain,alopecia, and anemia. However, interpatient variability of toxic effects wassubstantial. Antitumor effects were observed at a dose of ³ 165mg/m2 inpatients with colon cancer, gastric sarcoma, malignant melanoma, and lungcancer. The authors suggested a dose for early phase II trials of 200 mg/m2every 3 to 4 weeks (see Table 1).
Once-a-Week Schedule: Camptothecin and its derivatives havedemonstrated schedule-dependent antitumor activity and toxicity.[4,5] Inpreclinical systems, the antitumor efficacy of irinotecan increased when it wasgiven by repeated administration instead of single administration of the sametotal dose. Hence, a once-a-week administration of irinotecan appearssuperior to a once-a-month schedule in achieving a response.
Negoro and colleagues reported the results of a phase I study ofweekly IV infusion of irinotecan in patients with advanced non-small-cell lungcancer. Seventeen patients were administered a weekly schedule at dosesranging from 50 to 150 mg/m2 (50, 100, 125, and 150mg/m2). The dose-limitingtoxicities were leukopenia and unpredictable diarrhea. Simultaneous occurrenceof these toxicities was lethal in two patients, but it did not correlate to thepharmacokinetics of either irinotecan or its active metabolite SN-38(7-ethyl-10-hydroxycamptothecin).
Antitumor activity (partial responses of 3.2 and 4.0 months) wasobserved in two previously untreated patientsat the respective doses of 100 and125 mg/m2. The maximum tolerated dose on this schedule was 100mg/m2, as was therecommended dose of a weekly schedule for phase II trials, with particularattention paid to hematologic and gastrointestinal adverse events (see Table1).
Japanese Phase II Studies
Single-Dose Schedule: Nakai and coworkers conducted a phaseII multi-institutional study using a single-dose schedule of irinotecan inpatients with advanced lung cancer. Based on the previous phase I study of asingle-dose schedule, irinotecan at 200 mg/m2 was administered to 38 eligiblepatients with advanced non-small-cell lung cancer. (The total number ofeligible patients in this trial was 41, including3 patients with small-cell lung cancer.)
Among the 38 eligible patients, the response rate was 18.4% (7out of 38) with partial responses. The response rate in 22 patients with priortherapy was 14% (3 out of 22), and that for previously untreated patients was31%(4 out of 13). The major toxicities observed in this trial were leukopenia (³grade 3: 18%), diarrhea (³ grade 3: 13%), nausea/vomiting (³ grade 2: 50%),and anorexia (³ grade 2: 66%) (see Table2).
Once-a-Week Schedule: Fukuoka et al reported the results ofa phase II trial conducted on a weekly schedule between 1989 and 1990 inpatients with previously untreated advanced non-small-cell lung cancer. Atotal of 73 patients were enrolled, and all had measurable disease with anEastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Of 72evaluable patients, there were no complete responses, but 23 (31.9%) showed apartial response (95% confidence interval [CI] = 20% to 44%). The response rateswere similar for patients with a performance status of 0 or 1 (34% [18 out of53]) and those with a performance status of 2 (26.3% [5 out of 19]).
Ten of 32 patients (31%) with locoregional (stage I-IIIB)disease and 13 of 40 patients (33%) with stage IV disease comprised theresponders. The median duration of response for all patients who achieved apartial response was 15 weeks (range: 7 to 31 weeks), and that for stage IVpatients was 15 weeks (range: 7 to 31 weeks). The median survival time for alleligible patients was 42 weeks; for stage IV patients it was 40 weeks. Theoverall1-year survival rate was 40%, and that for stage IV patients was 32%.
The major toxicities observed in this trial were leukopenia,diarrhea, nausea/vomiting, anemia, alopecia, and pneumonitis. Grade 4 leukopeniaoccurred in 4 patients (6%), and grade 3 or 4 anemia was observed in 11 patients(15%). Diarrhea occurred in 48 patients (67%). This toxic effect was so severethat it was difficult to control in three patients. Nausea/vomiting was observedin 56 patients (78%), but these reactions were controllable by anti-emeticdrugs. Pulmonary toxicity was noted in six patients (8%). Five of these patientsdemonstrated a diffuse reticular nodular pattern upon chest x-ray, and oneshowed an abnormality highly suggestive of interstitial infiltrates on computedtomography of the chest;five patients developed dyspnea on exertion and four developed fever.
Ages ranged from 56 to 74 years, with a median of 69 years forthe group exhibiting pulmonary toxicity. Five patients had no preexistingpulmonary disease, but one had had a pulmonary fibrosis. The interval from thebeginning of irinotecan administration to the onset of pulmonary symptoms rangedfrom 42 to 175 days, with a median of 61 days. The median total dose ofirinotecan in these patients was 750 mg/m2 (range: 400 to 1,000mg/m2). Five ofsix patients were treated with corticosteroids, and one died of respiratoryfailure, while four improved; one patient resolved spontaneously within a week(see Table 2).
The combination of irinotecan with cisplatin (Platinol) has beencomprehensively tested in dose-finding studies in patients with advanced lungcancer. The rationale is multifold, including synergy between these two agentsin preclinical models, impressive cytotoxic activity when administeredindividually against a wide range of tumors, and nonoverlapping principaltoxicities. Combinations of irinotecan and cisplatin have been investigated infive phase I studies in Japan.
Irinotecan With a Fixed Dose of Cisplatin (80 mg/m2)
Masuda and colleagues reported data from a dose-findingstudy of irinotecan combined with a fixed dose of IV cisplatin at 80 mg/m2 onday 1. The dose of irinotecan was increased, with a starting IV dose of 30 mg/m2on days 1, 8, and 15; this regimen was repeated every 28 days. Twenty-sevenpatients were entered into this trial, and all patients with advanced stageIII/IVB non-small-cell lung cancer had no previous therapy, had measurabledisease, and had a performance status of 0 to 2. These patients were treated atdoses of irinotecan from 30 to 70 mg/m2 (30, 40, 50, 60, and 70mg/m2).
Generally, remarkably little toxicity was observed at the firstthree dose levels during the first course of therapy. At dose level 4, grade 3or 4 leukopenia occurred in 3 of 10 patients. At dose level 5, which representeda dose of 70 mg/m2 on days 1, 8, and 15, myelosuppression was more severe anddose-limiting; two of six patients developed grade 3 leukopenia. Diarrhea didnot become a significant problem until dose level 5 was reached. At dose levels1 to 4, grade 3 diarrhea was noted in only 2 of 58 courses. Diarrhea developedmore frequently at the highest dose level (70 mg/m2); two of six patientsexperienced grade 4 diarrhea during the first course.
Of 26 assessable patients for response, there were no completeresponses, while 14 (54%) showed a partial response. The response rates were 67%at dose level 2 (2 of 3), 80% at dose level 3 (4 of 5), 56% at dose level 4 (5of 9), and 50% at dose level 5 (3 of 6). Based on these results, the authorsconcluded that the major dose-limiting toxicities were leukopenia and diarrhea,and the maximum tolerated dose of irinotecan was 70 mg/m2 IV on days 1, 8, and15 plus 80 mg/m2 of cisplatin on day 1. The recommended dose for phase IIstudies was irinotecan at 60 mg/m2 IV on days 1, 8, and 15 plus cisplatin at 80mg/m2 on day 1, every 4 weeks (see Table3).
Irinotecan With a Fixed Dose of Cisplatin (60 mg/m2)
Masuda and colleagues reported another dose-finding study ofirinotecan combined with a fixed dose of cisplatin. The dose of IV cisplatin wasfixed at 60 mg/m2 on day 1, and the dose of irinotecan was increased, with astarting dose of 60 mg/m2 IV on days 1, 8, and 15; this regimen was repeatedevery 28 days. Fourteen previously untreated patients with advanced lung cancerwith a performance status of 0 to 2 were treated at doses ranging from 60 to 90mg/m2 (60, 80, and 90 mg/m2).
Hematologic toxicity was infrequent and mild to moderate at allthree dose levels. Leukopenia was the most common hematologic toxicity, but noneof the patients exhibited grade 4 leukopenia; grade 3 leukopenia occurred infive patients during six cycles. Diarrhea was the principal dose-limitingtoxicity of the combined regimen; it was observed in the early/middle parts ofthe 28-day treatment cycle, and generally ceased between days 15 and 35. Nodiarrhea worse than grade 2 occurred at dose level 1 (60 mg/m2). Two of eightpatients experienced grade 3 diarrhea at dose level 2 (80 mg/m2), but no grade 4diarrhea was observed. Diarrhea became ubiquitous at the highest dose level of90 mg/m2.
Of 14 assessable patients, therewas one complete response and five partial responses, yielding an overallresponse rate of 43%. The responserates were 67% (2 of 3) at dose level 1, 38% (3 of 8) at dose level 2, and 33%(1 of 3) at dose level 3. The response rates for non-small-cell lung cancerand small-cell lung cancer were 33% (4 of 12) and 100% (2 of 2), respectively.Based on the results of this trial, the authors concluded that the dose-limitingtoxicity was diarrhea, and that the maximum tolerated dose was irinotecan at 90mg/m2 IV on days 1, 8, and 15 plus cisplatin at 60mg/m2 on day 1. Therecommended dose for phase II trials was irinotecan at 80 mg/m2 IV on days 1, 8,and 15 combined with cisplatin at 60 mg/m2 on day 1, with the regimenadministered every 4 weeks (see Table 3).
Irinotecan and CisplatinWith rhG-CSF
Leukopenia is one of the dose-limiting toxicities observed forthe combination of irinotecan and cisplatin. With the availability ofrecombinant human granulocyte colony-stimulating factor (rhG-CSF), it ispossible to reduce the severity and duration of leukopenia induced by cytotoxicchemotherapy. Indeed, use of rhG-CSF allows higher doses of chemotherapy agentsto be given in combination without incurring significant myelosuppressionanadvantage that may potentially improve both response and survival.
Masuda and coworkers reported a phase I trial of the combinationof irinotecan and cisplatin with rhG-CSF support in advanced non-small-celllung cancer. Intravenous cisplatin was administered at a fixed dose of80 mg/m2 on day 1, with rhG-CSF at2 mg/kg/d administered on days 4 to 21. The dose of irinotecan was increased,with a starting dose of 70 mg/m2 IV on days 1, 8, and 15; the combinationregimen was repeated every 28 days. The 20 patients with advanced non-small-celllung cancer had no previous therapy and had a performance status of 0 to 2, andthey were treated at a dose range of 70 to 90 mg/m2 (70, 80, and 90mg/m2).
Leukopenia was the principal hematologic toxicity, and analysisof the first course of chemotherapy demonstrated that only 1 of 14 patientstreated at the first two dose levels (70 and 80 mg/m2) exhibited grade 3/4toxicity. At the highest dose of irinotecan (90 mg/m2), myelosuppression wasmore pronounced, and grade 3/4 leukopenia occurred in two of six patients; theprincipal dose-limiting toxicity was diarrhea. After administration of the firstcourse of therapy, there was no ³ grade 2 diarrhea at the70-mg/m2 dose level.At 80 mg/m2, grade 3 or 4 diarrhea was observed in 0% and 9% of 11 patients,respectively. However, at the 90-mg/m2 dose level, two of six patients had grade3 or 4 diarrhea.
Of 20 assessable patients, therewere 10 partial responses, and the overall response rate was 50%. The responserates were 100% (3 of 3) at the 70-mg/m2 dose level, 45% (5 of 11) at the80-mg/m2 dose level, and 33% (2 of 6) at the90-mg/m2 dose level. However, therewas no relationship between the irinotecan dose and response. The results ofthis trial indicated that the dose-limiting toxicity was diarrhea, and that themaximum tolerated dose was irinotecan at 90 mg/m2 IV on days 1, 8, and 15 pluscisplatin at 80 mg/m2 on day 1. In addition, rhG-CSF (2 mg/kg/d) wasadministered on days 4 to 21 for hematopoietic support. The data showed that therecommended dose for phase II trials was irinotecan at 80 mg/m2 IV on days 1, 8,and 15 plus cisplatin at 80 mg/m2 on day 1, with rhG-CSF support; this regimenwas repeated every 4 weeks (see Table 3).
Irinotecan With Weekly Cisplatin
Two studies examined combinations of split doses of irinotecanand cisplatin administered together on weekly schedules. Kobayashi andcollaborators reported data from a dose-finding study of a combination of weeklycisplatin with irinotecan. The dose of irinotecan was fixed at 60 mg/m2 IVon days 1, 8, and 15, while the concurrent dose of cisplatin was increased, witha starting dose of 27 mg/m2 IV on days 1, 8, and 15; this regimen was repeatedevery 28 days. In the 24 patients with advanced non-small-cell lung cancer whowere entered in this trial, leukopenia was the major toxicity. At dose level 1of cisplatin (27 mg/m2), one patient experienced grade 3 leukopenia. At doselevel 2 (33 mg/m2), two patients and one patient exhibited grade 3 and 4leukopenia, respectively. At dose level 3 (40 mg/m2), four patients exhibitedgrade 2 leukopenia on day8 or 15, forcing the cessation of the regimen.
Diarrhea worse than grade 2 occurred in two patients at doselevel 1, while at dose level 2, two patients experienced grade 2 diarrhea.However, at dose level 3, no patients experienced diarrhea. Of the 13 patientswho were evaluated for response, 7 demonstrated a partial response, and theoverall response rate was 54% (7 of 13). The dose-limiting toxicity wasleukopenia, and the maximum tolerated dose was at dose level 3 of cisplatin (33mg/m2). The authors concluded that there was value in a weekly schedule ofcisplatin in combination with a fixed dose of irinotecan (see Table3).
Ueoka et al conducted a phase I study of weekly fractionatedadministration of cisplatin and irinotecan at escalated doses. Both agentswere given IV on days 1 and 8, and the dose of cisplatin was fixed at 60 mg/m2.The starting dose of irinotecan was 40 mg/m2, and the dose was increased by 10mg/m2 for dose escalation; this regimen was repeated every 28 days. Twenty-fourpreviously untreated patients with unresectable non-small-cell lung cancer orextensive-disease small-cell lung cancer were enrolled.
At the first two dose levels (40 and 50 mg/m2), no grade 4hematologic toxicity was observed. At a dose level of 60 mg/m2, four patientsdeveloped grade 3 leukopenia, with one of these patients experiencing grade 4thrombocytopenia. At the higher dose level of 70 mg/m2, one patient developedgrade 4 leukopenia and thrombocytopenia, and another developed grade 3leukopenia. At the first two dose levels (40 and 50 mg/m2), no diarrhea wasnoted. At the irinotecan dose levels of 60 and 70 mg/m2, grade 3 or 4 diarrheawas observed in 4 of 11 (36%) and 2 of 3 (67%) of the patients, respectively,with the most prominent toxicity and the dose-limiting toxicity being diarrhea.
Of 21 evaluable patients, no complete responses were observed,and 17 patients showed a partial response, yielding an overall response rate of81%. The objective response rates were 76% (13 of 17) in non-small-cell lungcancer and 100% (4 of 4) in extensive-disease small-cell lung cancer. Theauthors concluded that based on these results, a combination of irinotecan andcisplatin in a fractionated dosing schedule was feasible and highly effectivefor lung cancer. The recommended dose for phase II trials was cisplatin at 60mg/m2 combined with irinotecan at 50 mg/m2 IV on days 1 and 8, with the regimenadministered every 4 weeks (see Table 3).
Because a phase I trial of irinotecan/cisplatin non-small-celllung cancer showed a very promising response rate of 54% in previously untreatednon-small-cell lung cancer patients, Masuda and coworkers conducted a phase IItrial of this combination regimen for previously untreated patients withadvanced non-small-cell lung cancer. The treatment schedule was irinotecanat 60 mg/m2 IV on days 1, 8, and 15 plus cisplatin at 80mg/m2 on day 1, withthe regimen administered every4 weeks. Seventy patients with stage IIIB/IV non-small-cell lung cancer wereentered, 69 patients were ultimately eligible and assessable for toxicity andsurvival, and 64 were assessable for response.
Thirty-three patients (52%; 95% CI = 39% to 64%) achievedobjective responses, with 1 complete (2%) and 32 partial responses (50%). Themedian duration of response was 19 weeks, with an overall median survival timeof 44 weeks; the 1-year survival rate was 33%. Major toxicities were leukopeniaand diarrhea. Grade 3 or 4 leukopenia, neutropenia, and diarrhea occurred in 32patients (46%), 53 patients (80%), and 13 patients (19%), respectively. Theauthors concluded that the combination of irinotecan and cisplatin exhibitedacceptable toxicities and was effective against non-small-cell lung cancer(see Table 4).
Masuda and coinvestigators conducted a prospective,multicenter, randomized phase III trial comparing three treatment arms:cisplatin at 80 mg/m2 on day 1 plus vindesine at 3mg/m2 on days 1, 8, and 15(conventional therapy in Japan) and two irinotecan-containing regimenscisplatinat 80 mg/m2 on day 1 plus irinotecan at 60 mg/m2 on days 1, 8, and 15, andsingle-agent irinotecan at 100 mg/m2 on days 1, 8, and 15. A total of 398patients with previously untreated advanced non-small-cell lung cancer wereaccrued between 1995 and 1998.
Responses were observed in 32%, 44%, and 21% of patients for thecisplatin plus vindesine, cisplatin plus irinotecan, and irinotecan alone arms,respectively, with corresponding median survival times of 45.6, 50.0, and 46.0weeks. There were no significant differences in response rate or survivalbetween treatment groups for all patients. However, when the subset of stage IVpatients was analyzed separately, the survival advantage foririnotecan/cisplatin was significant; the median survival time was 50 weeks forpatients receiving irinotecan/cisplatin, 36.4 weeks for vindesine/cisplatin, and42.1 weeks for irinotecan (P = .004 for the irinotecan/cisplatin arm vsvindesine/cisplatin; P = .018 for irinotecan vs vindesine/cisplatin).
Niho and colleagues reported data from another randomizedphase III study comparing irinotecan/cisplatin with vindesine/cisplatin. A totalof 210 patients with previously untreated advanced non-small-cell lung cancerentered this trial between 1995 and 1997. There was no difference in overallmedian survival times between the arms. Also, the median survival times were notsignificantly different for stage IV patients between the respectiveirinotecan/cisplatin and vindesine/cisplatin arms (44.7 vs 45.3 weeks; P =.668). The data suggested that the two cisplatin-containing regimens weresimilarly active.
Single-agent irinotecan demonstrates significant activityagainst non-small-cell lung cancer, with activity similar to that reported forother new agents, such as paclitaxel (Taxol), gemcitabine (Gemzar), vinorelbine(Navelbine), and docetaxel (Taxotere). The potent combination of irinotecan pluscisplatin may offer a survival advantage in metastatic non-small-cell lungcancer. Based on clinical trials data, the combination regimen of irinotecanplus cisplatin is likely to be used as the reference therapy in lieu of avindesine plus cisplatin combination in the large phase III trial in patientswith advanced non-small-cell lung cancer that is now being planned in Japan.
Acknowledgments: I thank Mr. Akira Sahashi for preparing thismanuscript. I also gratefully acknowledge the very kind support andencouragement of the members of Daiichi Pharmaceutical Co, Ltd.
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