Role of Topoisomerase I Inhibitors in Small-Cell Lung Cancer

ABSTRACT: Combination chemotherapy is the cornerstone of treatment thatconfers a meaningful survival benefit for patients with small-cell lung cancer.However, because there have been no major therapeutic advances for small-celllung cancer during the last decade, more effective new treatments are necessaryto improve the outcome of therapy. Irinotecan (CPT-11, Camptosar), atopoisomerase I inhibitor, is one of the new active agents that provide hope formore effective therapies. In single-agent phase II studies, irinotecan yieldedresponse rates between 16% and 47% in patients with previously treatedsmall-cell lung cancer. A phase II study of irinotecan in combination withcisplatin (Platinol) resulted in a response rate of 86% and a median survival of13.0 months in patients with extensive-disease small-cell lung cancer. A phaseIII trial that was conducted by the Japan Clinical Oncology Group (JCOG) clearlydemonstrated a survival advantage for the combination of irinotecan andcisplatin vs the standard regimen of etoposide (VP-16, VePesid) and cisplatin.Based on these results, the irinotecan and cisplatin combination is a newstandard regimen in the treatment of extensive-disease small-cell lung cancer. [ONCOLOGY 15(Suppl8):9-14, 2001]

Introduction

Small-cell lung cancer accountsfor approximately one-fifth ofprimary lung cancer cases. It possesses different biologic characteristicscompared with other types of lung cancers, including rapid tumor growth, earlymetastases, and high level of sensitivity to chemotherapy and radiotherapy.Since patients with small-cell lung cancer usually present with disseminateddisease, combination chemotherapy is the cornerstone of treatment for patientsin all disease stages, with major responses in 65% to 85% of cases, including25% to 50% complete responses.

Most patients experience tumor relapse and die within 2 years,however. With chemotherapy and thoracic radiotherapy, the median survivalduration is 10 to 15 months for limited-disease patients, and patients withextensive disease show a median survival time of 7 to 11 months withchemotherapy.[1]

Combination chemotherapy regimens include CAV (cyclophosphamide[Cytoxan, Neosar], doxorubicin [Adriamycin], and vincristine [Oncovin]); CAE(cyclophosphamide, doxorubicin, and etoposide [VP-16, VePesid]); CAVE(cyclophosphamide, doxorubicin, vincristine, and etoposide; PE (cisplatin(Platinol) and etoposide; and CE (carboplatin [Paraplatin] and etoposide). Inrandomized trials, three regimens—CAV, PE, and CAV alternating with PE—yieldedsimilar survival rates, but PE resulted in less myelosuppression.[2,3]Therefore, the most widely used regimen is the combination regimen PE.

There have been no major advances in the treatment of small-celllung cancer during the last decade. The recent advent of new active agentsincluding camptothecins, the taxanes, and gemcitabine (Gemzar) provides hope formore effective therapies and, among these drugs, irinotecan (CPT-11, Camptosar)is the most promising agent.

Irinotecan is a water-soluble derivative of camptothecin, andexhibits strong antitumor activity in a broad spectrum of experimentalmodels.[4,5] Camptothecin and its derivatives possess a unique mechanism ofaction that inhibits DNA topoisomerase I.[6] Irinotecan is transformed to anactive metabolite (SN-38) by carboxylesterase, an enzyme that is mainly found inthe liver, bowel mucosa, and tumor tissue. Clinical studies have now shown thatirinotecan possesses significant activity against a variety of malignantdiseases, including small-cell lung cancer.

Phase II Trials of Irinotecan Monotherapy

A Japanese phase I trial of irinotecan administered as a weeklyIV infusion demonstrated that its dose-limiting toxicities included leukopeniaand diarrhea, and the recommended dose for phase II studies was 100 mg/m².[7]Based on these results, irinotecan was administered at a dose of 100 mg/m² IVonce weekly in two phase II studies.[8,9] The results from four phase II trialsof irinotecan monotherapy in small-cell lung cancer are enumerated in Table1.

In a multi-institutional phase II trial, Negoro and coworkersenrolled 41 patients, 35 of whom were evaluable for response.[8] The overallresponse rate was 37%, with a median response duration of 7 weeks. The responserate was 33% in 27 previously treated patients and 50% in 8 previously untreatedpatients. The median survival time was 35 weeks for all patients. The majortoxicities were grade 3 or higher leukopenia (31%) and diarrhea (15%).

A single-institution trial by Masuda and colleagues[9] deliveredthe same dose and schedule of irinotecan to 16 patients with refractory orrelapsed small-cell lung cancer, of whom 15 were evaluable for response andtoxicity. (All 15 patients had been heavily pretreated with some form ofcisplatin-based regimens.) Only one patient was refractory to chemotherapy asdefined by tumor growth during chemotherapy. Although there were no completeresponses in the 15 patients, a partial response was obtained in 47% ofpatients, with a median duration of response of 8 weeks (range, 4 to 22 weeks).The median survival time from the onset of irinotecan therapy was 27 weeks.

The most frequent adverse event was myelosuppression: 34% and 0%of patients had severe leukopenia and thrombocytopenia (WHO grade 3 or 4),respectively. Greater than grade 2 nausea and vomiting occurred in 13% ofpatients, and diarrhea was observed in 7%. One patient (7%) experienced grade 4paralytic ileus. Grade 3 or 4 pulmonary adverse events occurred in two patients(13%).

A French trial used a different approach with a dosage of 350mg/m² every 3 weeks that resulted in a lower overall response rate of 16% in 32previously treated patients who had received etoposide-cisplatin-basedfirst-line chemotherapy.[10] The median duration of response was 131 days, andmedian survival was 125 days. The major grade 3 or 4 toxicities were neutropenia(58%), febrile neutropenia (22%), delayed diarrhea (37%), and nausea andvomiting (22%).

Seventeen sensitive-relapse patients (those who initiallyresponded but progressed after a treatment-free interval of at least 90 days)and 27 refractory patients (those who failed first-line treatment, or whoinitially responded but progressed within 90 days of the end of therapy) wereenrolled in a US phase II study conducted by DeVore et al.[11] Patients receivedirinotecan at an initial dosage of 125 mg/m2 weekly for 4 of 6 weeks. Responserates were 35.3% in patients with sensitive disease and 3.7% in patients withrefractory disease, and median survivals were 5.9 and 2.8 months, respectively.Overall survival was 4.8 months. Grade 3 or 4 late diarrhea was reported in26.6% of patients, and grade 3 or 4 neutropenia in 26.7%.

Overall, single-agent irinotecan exhibited encouraging responserates in pretreated small-cell lung cancer patients, although studies examiningirinotecan in first-line therapy were lacking.

Combination Regimens With Irinotecan

Irinotecan and Cisplatin

The preclinical synergism between irinotecan and cisplatin,[12]irinotecan’s lack of cross-resistance,[9] and differing mechanisms of actionand toxicity profiles between the two drugs provided a rationale for examiningthe use of these agents in the treatment of small-cell lung cancer. Masuda andco-workers[13] conducted a phase I trial to determine the maximum tolerated doseof irinotecan together with a fixed dose (60 mg/m²) of cisplatin in patientswith advanced lung cancer, and the dose-limiting toxicities of this combination.The maximum tolerated dose of irinotecan was 90 mg/m² on days 1, 8, and 15, pluscisplatin 60 mg/m² on day 1, every 4 weeks, with diarrhea being thedose-limiting toxicitiy. In this phase I study, five (36%) partial responses andone (7%) complete response were observed for an overall response rate of 43%.The response rates for non-small-cell lung cancer and small-cell lung cancerwere 33% (4 out of 12 patients) and 100% (2 out of 2 patients), respectively.The recommended dosages for phase II studies were irinotecan 80 mg/m² on days 1,8, and 15, plus cisplatin 60 mg/m² on day 1, every 4 weeks.

The West Japan Thoracic Oncology Group (WJTOG) conducted a phaseII trial of this combination regimen in previously untreated small-cell lungcancer patients.[14] Kudoh et al initially administered irinotecan at80 mg/m² to 10 patients on days 1, 8, and 15, in combination with cisplatin 60mg/m² on day 1. The irinotecan dose was reduced to 60 mg/m² because 3 of theinitial 10 patients experienced severe toxicity, and 1 of them died of diarrheaand neutropenia.

Among the 75 patients that were enrolled, 72 were evaluable forresponse, and all were assessable for toxicity (Table2). Forty patients withlimited disease achieved an overall response rate of 83% and a complete responserate of 30%; 35 patients with extensive disease achieved an overall responserate of 86% and a complete response rate of 29%. The median response durationwas 8.0 months for limited-disease patients and 6.6 months for extensive-diseasepatients. The median survival was 14.3 months for limited-disease patients and13.0 months for extensive-disease patients. The 2-year survival rate was 21.7%for limited-disease patients and 17.5% for extensive-disease patients. The majorgrade 3 or 4 toxicities were neutropenia (77%), anemia (39%), and diarrhea(19%).

In a similar study, patients with prior chemotherapy alsoreceived irinotecan 60 mg/m² on days 1, 8, and 15 with cisplatin 60mg/m² on day1.[15] Sixteen patients were enrolled; the chemotherapy-free interval was morethan 90 days in nine patients, and less than 90 days in seven patients. Theoverall response rate was 19%, and the median survival was 5.7 months. Thepercentage of the projected dose of irinotecan administered was relative low(57%), mainly due to leukopenia.

Other schedules have also been investigated. Both irinotecan (60mg/m²) and cisplatin (30 mg/m²) were administered together on days 1, 8, and 15,every 4 weeks.[16] Among the five patients with refractory small-cell lungcancer, one achieved a partial response.

Irinotecan and Etoposide

Combinations of agents that specifically target topoisomerases Iand II appear to inhibit completely both DNA and RNA syntheses, resulting insynergistic cytotoxicity. Preclinical studies suggested an additive orsynergistic activity between etoposide and irinotecan (or its active metabolite,SN-38) when the agents are given simultaneously.[17] Based on these data, Masudaet al conducted a phase I trial of this combination regimen.[18] The maximumtolerated dose of irinotecan was 90 mg/m² on days 1, 8, and 15, in combinationwith a fixed etoposide dose of 80 mg/m² on days 1 to 3. Diarrhea and leukopeniawere the dose-limiting toxicities. The response rates for small-cell and non-small-celllung cancer were 58% (7 out of 12 patients) and 22% (2 out of 9 patients),respectively.

For phase II studies in previously untreated patients, therecommended dose was irinotecan 80 mg/m² on days 1, 8, and 15, and etoposide 80mg/m² on days 1 to 3 with granulocyte colony-stimulating factor (G-CSF,[Neupogen]) support. In addition, irinotecan at 70 mg/m² appeared to be theappropriate dose for previously treated patients receiving this regimen.

The results of this study led Masuda and colleagues to conduct aphase II study evaluating the antitumor activity and toxicity of the combinationof irinotecan and etoposide (with G-CSF support) in previously treated patientswith small-cell lung cancer.[19] Twenty-five patients with refractory orrelapsed small-cell lung cancer were treated at 4-week intervals usingirinotecan at a starting dose of 70 mg/m² IV on days 1, 8, and 15, plusetoposide 80 mg/m² IV on days 1 to 3, with G-CSF support (2 mg/kg/day on days 4to 21, except on the days of irinotecan administration).

Twenty-four patients were evaluable for response, and all 25were assessable for toxicity and survival. There were 14 partial and 3 completeresponses for an overall response rate of 71%. The median duration of responsewas 4.6 months, and the median survival duration was 271 days. Grade 3 to 4neutropenia and thrombocytopenia occurred in 56% and 20% of patients,respectively; grade 3 to 4 diarrhea was observed in 4% of patients. These dataindicated that this combination regimen was very active against refractory orrelapsed small-cell lung cancer, and that further study was warranted in a phaseIII trial.

In a similar WJTOG study, 51 extensive-disease patients with noprior therapy received irinotecan 60 mg/m² on days 1, 8, and 15, and etoposide80 mg/m² on days 2 to 4, every 4 weeks.[20] The overall response rate was 66%,with a 10% complete response rate; the median survival time was 12 months. Grade3 or 4 toxicities were neutropenia (72%), leukopenia (28%), anemia (4%),thrombocytopenia (4%), pneumonitis (2%), and diarrhea (2%).

Phase III Trials of Combination Therapy

A phase III study (JCOG 9511) compared the combination regimensCP (irinotecan [Camptosar] and cisplatin [Platinol]) with PE (cisplatin[Platinol] and etoposide) in patients with extensive-disease small-cell lungcancer.[21] Eligibility criteria included histologic or cytologic proof ofsmall-cell lung cancer, extensive-stage disease, no prior therapy, measurabledisease or evaluable disease, Eastern Cooperative Oncology Group (ECOG)performance status of 0 to 2, age ≤ 70 years, adequate organ function, noactive concomitant malignant disease, and written informed consent.

The primary end point of JCOG 9511 was overall survival.Patients in the CP study arm received irinotecan 60 mg/m² on days 1, 8, and 15,plus cisplatin 60 mg/m² on day 1, every 4 weeks for four courses; those in thePE standard arm received etoposide 100 mg/m² on days 1 to 3, plus cisplatin 80mg/m² on day 1, every 3 weeks for four cycles. While an original sample size of230 was planned, the trial ended early when the second interim analysis clearlydemonstrated a significant survival benefit in the CP study arm (Table3).

As compared with the PE regimen, treatment with CP resulted in asignificantly higher overall response rate (83.1% vs 67.5%; P = .013), longeroverall median survival (12.8 vs 9.4 months; P = .0021), and a higher1-year survival rate (58.4% vs 37.7%). Grade 3 or 4 neutropenia and grade 3 or 4thrombocytopenia were more frequent during treatment with PE (92% and 19% for PEvs 66% and 5% for CP, respectively; P = .0002). Grade 3 or 4 diarrhea was morefrequent during treatment with CP (16% vs 0%; P = .0001). The investigatorsconcluded that treatment with CP was superior to the widely used standardregimen of PE for extensive-disease small-cell lung cancer in terms of responserate and survival.

To confirm these results, two randomized phase III trials arebeing planned in North America. The Southwest Oncology Group will conduct amulticenter phase III trial using the same JCOG 9511-dosing regimen. Anotherrandomized trial will administer a slightly different dose and schedule:irinotecan 65 mg/m² and cisplatin30 mg/m² on days 1 and 8, every3 weeks vs cisplatin 60 mg/m² on day 1 and etoposide 100 mg/m² on days 1 to 3,every 3 weeks).

Conclusions

Most of the trials have explored weekly IV infusions ofirinotecan as a single agent or in combination with other agents, andsingle-agent activity has been established in recurrent small-cell lungcancer.[8,9,11] Results from a randomized phase III trial in extensive-diseasecarried out in Japan have clearly demonstrated that a combination of irinotecanand cisplatin is superior in response rate and overall survival to the widelyused standard regimen of cisplatin and etoposide.[12]

Although knowledge of the biology of small-cell lung cancer hasincreased substantially during the last decade, this has not translated directlyinto an increased survival benefit for patients. The median survival forextensive-disease small-cell lung cancer is not much different from thatobtained 20 years ago, and the need for new combinations, which will improve theefficacy of chemotherapy in small-cell lung cancer without compromising safety,is evident.

In this context, irinotecan has emerged as a promising newantineoplastic agent in the treatment of small-cell lung cancer and a variety ofother malignancies. Its novel mechanism of action as a topoisomerase I inhibitorand its relatively low cross-resistance with existing agents offer a cleartherapeutic option to patients with small-cell lung cancer. The JCOG 9511 phaseIII randomized study that compared irinotecan and cisplatin with cisplatin andetoposide demonstrated a significant survival advantage in theirinotecan-containing study arm.[21]

An approximately 3-month prolongation of the median survivaltime is a decisive rationale to alter the standard of practice, particularlywhen there was also a significant improvement in the 1- and 2-year survivalrates (58.4% and 18.9% vs 37.7% and 6.5%, respectively).[21] If the two NorthAmerican randomized trials confirm the Japanese trial data, treatment withirinotecan and cisplatin will become the new worldwide standard of care forextensive-disease small-cell lung cancer.

Other combinations with irinotecan are also being investigatedwith promising results [19,20]; however, randomized controlled trials arenecessary. In this regard, the clinical role of irinotecan in the treatment ofsmall-cell lung cancer is still developing.

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