Topoisomerase I-Based Nonplatinum Combinations in Non-Small-Cell Lung Cancer

ABSTRACT: Lung cancer is the leading cause of cancer-related death inmales and females in the United States. Most patients have advanced disease atdiagnosis. Chemotherapy is the treatment of choice for patients with goodperformance status. Progress in the management of patients with advanced diseasehas been slow, and platinum-based combinations result in a small survivalbenefit. The topoisomerase I inhibitors are active as single agents and incombination with platinums in non-small-cell lung cancer. Nonplatinum-baseddoublet combinations are beginning to be explored in an attempt to reducetoxicity and improve efficacy. Data available on some of the nonplatinumdoublets that include topoisomerase I inhibitors suggest that these regimensprovide efficacy equal to that achieved with platinum-based doublets. Thisarticle reviews the topoisomerase I-inhibitor nonplatinum combinations in themanagement of advanced non-small-cell lung cancer. [ONCOLOGY 16(Suppl9):25-31, 2002]

Efficacy data from studies of various combinations of platinumwith other cytotoxic drugs in non-small-cell lung cancer suggest that atherapeutic plateau has been reached. The Eastern Cooperative Oncology Group (ECOG)1594 randomized study demonstrated no efficacy differences among four differentplatinum-based chemotherapy doublets.[1] Similar results were recently reportedfor a European phase III trial.[2] The development of non-platinum-containingcombinations offers a strategy to lower toxicity and maintain efficacy in thetreatment of non-small-cell lung cancer.

The taxane plus gemcitabine (Gemzar) doublets have been the mostexplored nonplatinum combinations in non-small-cell lung cancer, and a recentEuropean Organization for Research and Treatment of Cancer (EORTC) trialcompared two platinum-containing doublets (standard arm of cisplatin/paclitaxelor cisplatin/gemcitabine) to the gemcitabine plus paclitaxel combination.[3]Although survival among the three treatment arms was not significantlydifferent, there was a trend toward worse survival with the nonplatinumcombination. This disappointing result should not hamper additional studies withother nonplatinum combinations, however.

Several topoisomerase I inhibitors have been studied in patientswith non-small-cell lung cancer. One such agent is 9-aminocamptothecin (9-AC),which is a synthetic analog of camptothecin. In a phase II study conducted byVokes et al, patients with stage IIIB or IV non-small-cell lung cancer withmeasurable disease received 9-AC at 1,416 µg/m²/d × 3 by continuousintravenous infusion followed by granulocyte colony-stimulating factor (G-CSF [Neupogen])support.[4] The 9-AC dose was decreased to 1,100 µg/m²/d after the first 13 of58 accrued patients had been treated. Cycles were repeated every 14 days.

Five patients (8.5%) achieved a partial response. Median time todisease progression was 2.3 months, and median survival for the entire studypopulation was 5.4 months with a 1-year survival rate of 30%. In another studyby Vokes and colleagues, non-small-cell lung cancer patients received 9-AC ina different administration schedule, ie, 25 µg/m²/h for 120 hours (3,000µg/m²over 5 days), given for 2 consecutive weeks of a 3-week cycle.[5] Results wereagain disappointing, with only 1 of 12 patients responding. The authorsrecommended no additional studies with 9-AC in non-small-cell lung cancer.

Exatecan mesylate, a synthetic water-soluble topoisomerase Iinhibitor, is active as single-agent therapy for non-small-cell lung cancerpatients. In a small phase II trial, 23 patients with previously untreated,advanced (11 stage IIIB, 12 stage IV) non-small-cell lung cancer receivedexatecan at 0.5 mg/m² IV over 30 minutes daily for 5 days, every 3 weeks.[6]Among 16 evaluable patients, 18% responded; survival data were not reported.Further development of this compound in non-small-cell lung cancer may bewarranted.

Karenitecin is a highly lipophilic topoisomerase I inhibitorthat has undergone limited phase II testing. The Cancer and Leukemia Group B (CALGB)is conducting an ongoing phase II trial of this semisynthetic camptothecin inpreviously treated non-small-cell lung cancer patients. The karenitecin doseis 1 mg/m²/d administered over 60 minutes by IV infusion for 5 consecutive days,with cycles repeated every 3 weeks. This dose and schedule was identified as themaximum tolerated dose in a previous phase I trial, in which 14 patients (4pancreatic, 4 colorectal, and 6 other cancers) received a total of 32 (range: 1-9,median: 2) treatment cycles.[7]

In that trial, karenitecin was administered using an accelerateddose titration design, at doses of 0.15 (n = 1), 0.3 (n = 1), 0.6 (n = 1), 1.2(n = 9), 2.4 (n = 1), and 1.0 (n = 1) mg/m². The dose-limiting toxicityconsisted of reversible grade 4 neutropenia and thrombocytopenia in three ofnine patients receiving 1.2 mg/m² and one of one patient at 2.4 mg/m²;gastrointestinal toxicities were minimal. Three patients (with colorectal,pancreatic, and tonsillar cancers) exhibited stable disease exceeding twocycles.

The topoisomerase I inhibitors irinotecan (CPT-11, Camptosar)and topotecan (Hycamtin) are available commercially in the United States.Although these agents possess similar antitumor mechanisms of action, theirsingle-agent activity in non-small-cell lung cancer differs (Tables 1 and2).[8-17] As shown in Table2, the absence of topotecan single-agent activity innon-small-cell lung cancer apparently did not compromise median survival.

The combination of irinotecan and cisplatin has been studied intwo phase III trials in non-small-cell lung cancer patients.[18,19] In bothtrials, irinotecan at 60 mg/m² was administered on days 1, 8, and 15, andcis-platin at 80 mg/m² on day 1. This regimen was compared with the standardregimen of cisplatin at 80 mg/m² given on day 1 plus vindesine (Eldisine) at 3mg/m² on days 1, 8, and 15. One of the trials also included a third armconsisting of single-agent irinotecan at 100 mg/m² on days 1, 8, and 15. Asshown in Table 3, survival results for the irinotecan/cisplatin combinationcompared with vindesine/cisplatin differed in the two trials. No phase III trialresults of topotecan in non-small-cell lung cancer are available; phase IIdata with topotecan/platinum combinations are emerging in this disease (Table4).[20,21]

Studies of non-platinum-containing combination regimens thatinclude topoisomerase I inhibitors plus gemcitabine or microtubule poisons havebeen conducted or are under way in patients with non-small-cell lung cancer.Several of these studies are reviewed herein.

Nonplatinum Combination Regimens With Topoisomerase I Inhibitorsin Non-Small-Cell Lung Cancer

Topoisomerase I Inhibitors and Gemcitabine

Preclinical data using breast and lung cancer cell linessuggested that gemcitabine and irinotecan exhibit synergistic activity when usedin combination.[22] Isobologram analysis revealed that the combination exertedsynergy over a wide range of concentrations in the MCF-7 and SCOG cell lines.Combination index analysis also indicated that at low concentrations,combinations of gemcitabine and irinotecan showed synergistic growth-inhibitoryeffects on MCF-7. In SCOG cells, however, combination index analysis showedsynergy at concentrations of gemcitabine and irinotecan > 1 µM butantagonism at concentrations < 1 µM.

Three phase I studies of three different schedules of thegemcitabine/irinotecan combination have been performed. Rocha Lima et al[23]studied the administration of both drugs on days 1 and 8 of each 21-day cycle.Gemcitabine was administered first at a fixed dose of 1,000 mg/m² over 30minutes followed by escalating doses of irinotecan given over 90 minutes. Theinitial irinotecan dose was 50 mg/m² with subsequent cohorts tested at 75, 100,and 115 mg/m². Nineteen patients with a variety of solid tumors were accrued.The maximum tolerated dose was determined to be 1,000 mg/m² of gemcitabine and100 mg/m² of irinotecan, both given on days 1 and 8. The dose-limiting toxicitywas grade 3 diarrhea in two of seven patients at the 115-mg/m² irinotecan dose.

O’Reilly and colleagues reported the results of a phase Itrial of the gemcitabine/irinotecan combination, with both drugs administered ondays 1, 8, and 15 in every 28-day cycle.[24] The gemcitabine dose was fixed at1,000 mg/m² given over 30 minutes. Irinotecan doses were escalated in fourcohorts from a starting dose of 45 mg/m², to 60, 80, and 100 mg/m² over 90minutes. When gemcitabine was given first immediately followed by irinotecan,the dose-limiting toxicities consisted of diarrhea, nausea and vomiting,neutropenia, and fatigue.

When irinotecan was given first immediately followed bygemcita-bine, the dose-limiting toxicities were neutropenic fever and diarrhea.The maximum tolerated dose with both sequences was gemcitabine at 1,000 mg/m²and irinotecan at 60 mg/m². Preliminary pharmacokinetic assessments demonstratedno differences between the two sequences in the levels of gemcitabine, theuridine metabolite of gemcitabine, irinotecan, and irinotecan metabolites SN-38and SN-38G.

Alberts et al studied both drugs administered on days 1, 8, 15,and 22, with cycles repeated every 6 weeks in 26 patients with refractory solidtumors.[25] The dose-limiting toxicity was hematologic toxicity in two of sixpatients receiving gemcitabine at 1,000 mg/m² and irinotecan at 125 mg/m², andthe recommended phase II doses for the agents in combination were gemcitabine at1,000 mg/m² and irinotecan at 100 mg/m². The dose intensity must be carefullyanalyzed in the follow-up phase II trials. One would anticipate treatmentomissions on day 15 of therapy due to diarrhea and/or myelosuppression with thisschedule at these doses.

Several phase II trials of the gemcitabine/irinotecancombination have been conducted in patients with non-small-cell lung cancer. Arandomized phase II trial CALGB 39809 is assessing two nonplatinum combinations—irinotecan/gemcitabineand docetaxel (Taxotere)/gemcitabine (Figure 1). Efficacy results were presentedat the 2002 annual meeting of the American Society of Clinical Oncology (ASCO).The efficacy results for gemcitabine and irinotecan included a response rate of12.8%, with 48.7% stable disease, a 7.9-month median survival, and a 1-yearsurvival rate of 16%. For the docetaxel/gemcitabine arm, the response rate was23.1%, with 41% stable disease, a 12.8-month median survival, and a 1-yearsurvival rate of 55%. Both doublets were well tolerated, which may reflect theadministration schedule, ie, both agents given on days 1 and 8, every 21 days.Toxicity results are summarized in Tables 5 and6.

Preclinical studies with human lung cancer cell lines H460 andH322 demonstrated an additive growth inhibition (and concentration- andtime-dependent apoptotic effects) when another topoisomerase I inhibitortopotecan was combined with gemcitabine.[26] Based on these preclinical data,two phase I studies of the gemcitabine/topotecan combination were conducted.Edelman et al[27] determined the maximum tolerated dose of topotecan to be 1mg/m²/d IV over 30 minutes daily for 5 days, and that of gemcitabine to be 1,000mg/m² over 30 minutes on days 1 and 15, in 28-day cycles. After adose-escalation study, Rainey and colleagues[28] recommended phase II doses oftopotecan at 0.75 mg/m²/d over 30 minutes for 5 days and gemcitabine at 400mg/m² on days 1 and 5, every 21 days. Neutropenia and thrombocytopenia were thedose-limiting toxicities.

In a preliminary report from US Oncology, the combination ofgemcitabine and topotecan resulted in a median survival time of 7.3 months in 53advanced non-small-cell lung cancer patients with good performance status (0or 1).[29] Doses were topotecan at 1 mg/m²/d IV over 30 minutes for 5consecutive days, and gemcitabine at 1,000 mg/m² days 1 and 15, on anevery-28-day cycle. Grade 3/4 toxicities included neutropenia (49% of patients),anemia (15%), and thrombocytopenia (9%). The response rate was 17% (all partialresponses), and 22% of patients had stable disease. Final results were presentedat ASCO’s 2002 annual meeting.

At least one phase II study of second-line topotecan plusgemcitabine in non-small-cell lung cancer has been conducted. Cole andcolleagues[30] studied topotecan at 0.75 mg/m²/d IV days 1 to 5 and gemcitabineat 400 mg/m² days 1 and 5, given every 21 days to 32 patients with refractorynon-small-cell lung cancer. A total of four patients (13%) had partialresponses, and seven (22%) had stable disease for at least four cycles. Mediansurvival time was 7 months. One year from the initiation of topotecan andgemcitabine treatment, 20% (5/25) of patients were still alive. Nonhematologictoxicity was mild. After the first treatment cycle, grade 4 neutropenia andthrombocytopenia was observed in 16% and 9% of patients, respectively.Hematologic toxicities for all cycles, to our knowledge, have not been reported.

Topoisomerase I Inhibitors and Microtubule Poisons

There have been limited numbers of studies with the combinationof irinotecan and vinorelbine (Navelbine) in non-small-cell lung cancer. Caoet al reported preliminary results from a phase II trial from Spain inpreviously treated non-small-cell lung cancer patients.[31] Thirty-threepatients (7 stage IIIB and 26 stage IV) previously treated with cisplatin,paclitaxel, and gemcitabine were enrolled. Irinotecan and vinorelbine were bothgiven on day 1, with an additional dose of vinorelbine on day 14, every 28 days.Among 26 patients evaluable for response, 3 had partial responses (12.3%, 95%confidence interval [CI] = 2.4%-30.2%), 19 (73%) had stable disease, and 4(15%) had progressive disease. The median overall survival time was 25 weeks.This regimen was well tolerated (grade 2 diarrhea observed in 7.1% of courses,grade 3/4 leukopenia in 8.6% of courses).

The combination of paclitaxel and irinotecan may have importantschedule-dependent interactions. Paclitaxel and SN-38 were studied in variousschedules in human cancer cell lines in culture.[32] Isobologram analyses ofdrug combinations at the IC80 level were studied, and cell growth inhibitionafter 5 days was determined with the diphenyltetrazolium bromide (MTT) assay. Inexperiments with the human lung cancer cell line A549, simultaneous exposure topaclitaxel and SN-38 for 24 hours produced antagonistic effects (similar tothose in breast and colon cancer cell lines). Sequential exposure to paclitaxelfollowed by SN-38 24 hours later, as well as the reverse sequence, producedadditive effects in all cell lines studied. These findings suggest thatsequential administration of these agents may be the appropriate therapeuticschedule.

Based on the preclinical interactions described above, Yamamotoet al conducted a phase I study in which irinotecan was administered as a90-minute infusion on days 1, 8, and 15, with paclitaxel given as a 3-hourinfusion on day 2 (24 hours following irinotecan infusion), every 4 weeks.[33]The maximum tolerated dose was reached at the starting dose of irinotecan at 50mg/m²/wk and paclitaxel at 135 mg/m²; all three patients had grade 4 neutropeniaas the dose-limiting toxicity. Notably, a remarkable drug-drug interaction wasobserved with this combination. In all patients, rebound increases of plasmairinotecan and SN-38 concentrations were observed after paclitaxeladministration. The authors suggested that the interaction occurred at theterminal elimination phase of irinotecan disposition.

Prior to this phase I trial, the same investigators studiedpaclitaxel and irinotecan interactions in mice.[33] The animals were dividedinto group I (paclitaxel plus irinotecan), group II (paclitaxel vehicle plusirinotecan), and group III (saline plus irinotecan). The investigatorsadministered irinotecan 30 minutes after the injection of paclitaxel, paclitaxelvehicle, or saline. The area under the concentration-time curve (AUC) values ofirinotecan and SN-38 were almost twofold higher in groups I and II than in groupIII, indicating that the paclitaxel vehicle affects irinotecan pharmacokineticsupon simultaneous administration of irinotecan and paclitaxel.

The same investigators[34] conducted another phase I trial ofirinotecan administered by 90-minute infusion on days 1 and 8, with paclitaxelgiven over 3 hours on day 8 (90 minutes after the end of the irinotecaninfusion), every 4 weeks. The pharmacokinetics of irinotecan and its metaboliteson days 1 and 8 were examined in six patients, and the data confirmed adrug-drug interaction, with the AUCs of irinotecan and its metabolitessignificantly higher on day 8 than on day 1. These results corroborated previousdata[33] that suggested that paclitaxel or its vehicle affects thepharmacokinetics of irinotecan and its metabolites.

A phase I trial in patients with non-small-cell lung cancerassessed the irinotecan plus paclitaxel combination.[35] Paclitaxel was given onday 1 (prior to irinotecan), and irinotecan was administered over 90 minutes ondays 1, 8, and 15 of a 4-week cycle. The recommended phase II dose waspaclitaxel at 180 mg/m² and irinotecan at 50 mg/m². The dose-limiting toxicitieswere grade 4 neutropenia, fever, and diarrhea at doses of paclitaxel at 180mg/m² and irinotecan at 60 mg/m². Of 23 patients evaluable for response, 9 (39%)had partial responses. Pharmacokinetic analyses were performed in 13 patients.The AUC of SN-38 was higher on day 1 than on days 8 or 15 at the maximumtolerated dose and one level below, again suggesting that paclitaxel mayinfluence the pharmacokinetics of SN-38 when the drugs are administeredsimultaneously.

The combination of irinotecan and docetaxel has also beenexplored. Adjei et al reported results of a phase I trial with four escalatingdose levels of irinotecan given by 90-minute IV infusion, and docetaxel by60-minute IV infusion. Cycles were repeated every 3 weeks. Doses of irinotecan/docetaxelwere 160/50 mg/m², 160/65 mg/m², 200/65 mg/m², and 200/75 mg/m².[36]Pharmacokinetic analysis was also performed to examine the effect of irinotecanon docetaxel disposition. Eighteen patients received 85 treatment courses(median: 2 courses; range: 1 to 15 courses). The most common severe toxicity wasgrade 4 neutropenia in 11 patients, which was generally brief in duration (lessthan 5 days), with three episodes of febrile neutropenia as the dose-limitingtoxicity. Nonhematologic toxicities were mild, except for one episode of grade 3anorexia and nausea. All patients had total alopecia. Diarrhea wasdose-dependent and severe in four patients not on adequate antidiarrhea therapy.

Five of 16 evaluable patients ( 3 non-small-cell lung cancer,1 cholangiocarcinoma, 1 leiomyosarcoma) achieved a partial remission. For phaseII investigation, the authors recommended a dose for this schedule of irinotecanat 160 mg/m² and docetaxel at 65 mg/m².

Masuda et al also conducted a phase I trial of 32 patients withstage IIIB or IV non-small-cell lung cancer.[37] Treatment consisted ofdocetaxel (given over 60 minutes, day 2) plus irinotecan (over 90 minutes, days1, 8, and 15) at 4-week intervals. The respective starting doses of docetaxeland irinotecan were 30 and 40 mg/m², with dose escalation in 10-mg/m²increments. The maximum tolerated doses of docetaxel/irinotecan were 50/60mg/m²(dose level 5A) or 60/50 mg/m² (level 5B). The coadministration of irinotecandid not affect the pharmacokinetics of docetaxel.

Among 30 evaluable patients, 11 (37%) achieved partialresponses. The overall median survival time was 48 weeks, with the 1-yearsurvival rate being 45%. The authors recommended a phase II study dose of 50mg/m² of irinotecan on days 1, 8, and 15, and 50 mg/m² of docetaxel on day 2,every 28 days.

Takeda and colleagues have reported preliminary results of arandomized phase II trial in previously untreated, good performance status (ECOG0 or 1), stage IIIB/IV non-small-cell lung cancer patients comparingirinotecan/docetaxel (DI) and cisplatin/docetaxel (DC).[38] Treatment consistedof irinotecan at 60 mg/m² on days 1 and 8 followed by docetaxel at 60 mg/m² onday 8, with cycles repeated every 21 days (DI arm, n = 59); or cisplatin at 80mg/m² plus docetaxel at 60 mg/m² on day 1 every 3 weeks (DC arm, n = 53).Respective response rates were 35% and 41%, and median survival times were 39.1and 33.9 weeks.

Hematologic toxicity was primarily grade 3/4 neutropenia inalmost 75% of patients in both arms. Nonhematologic toxicity was primarilygastrointestinal effects, with grade 2-4 vomiting more pronounced in the DCarm than in the DI arm (85%/54%, respectively; P = .001), and grade 2-4diarrhea more prevalent in the DI arm than in the DC arm (21%/41%, respectively;P = .036). These data indicated that DI was active, and the median survivalresults were similar to those achieved by platinum combinations.

Preliminary results of a trial combining oral topotecan inescalated doses and paclitaxel at a fixed dose in non-small-cell lung cancerpatients have been reported.[39] With 41 patients with performance status of 1or 2 accrued, 12% achieved a partial response and 27% stable disease. Thesuggested doses for the combination for future trials are oral topotecan at 1.25mg/m² days 1 to 5 and paclitaxel at 175 mg/m² day 1.

Bauer et al[40] reported the results of a dose-escalation studyin 29 previously untreated non-small-cell lung cancer patients. Topotecan at0.5 to 1.0 mg/m²/d administered IV for 5 days was combined with vinorelbine (Navelbine)at 20 to 30 mg/m² days 1 and 5, with cycles repeated every 21 days. Antitumoractivity was seen at all dose levels, with a 28% partial response rate (n = 8)and a 48% rate of disease stabilization (n = 13). Median survival time wasreported as 11.8 months. Toxicity was mild, and no unexpected effects wereobserved; neutropenic fever was the dose-limiting toxicity. Doses recommendedfor future studies were topotecan at 0.75 mg/m² and vinorelbine at 25 mg/m²without G-CSF, or topotecan at 1.0 mg/m² and vinorelbine at 25 mg/m² with G-CSFsupport.

Conclusions

The available efficacy data with topoisomerase I inhibitorssuggest that these drugs are well tolerated and active in patients with non-small-celllung cancer. The role of topoisomerase I inhibitors in combination regimenscontinues to be explored in multiple ongoing trials. Preliminary data oftopoisomerase I inhibitors combined with nonplatinum agents in non-small-celllung cancer suggest that efficacy is equivalent to that obtained withplatinum-based doublets (median survival times ranging from 7 to 9 months, and1-year survival from 30% to 40%). Selection of the most appropriate therapy willbe determined by differences in toxicities. Translational studies and theincorporation of novel molecular targeting agents to traditional cytotoxicchemotherapeutic regimens should provide the impetus for future studies in non-small-celllung cancer.

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