Irinotecan in Small-Cell Lung Cancer-Japanese Trials

ABSTRACT: Irinotecan has appeared to have significant activity against previously treated and untreated small-cell lung cancer (SCLC). The major toxicities of irinotecan are neutropenia and diarrhea, although there is interpatient variability in the severity of symptoms. The combination of irinotecan and cisplatin is likewise significantly active against SCLC, with an acceptable toxicity profile. A phase III study comparing irinotecan and cisplatin with etoposide and cisplatin has been conducted in the treatment of previously untreated patients with extensive disease SCLC. The results of this study may define a new standard care for SCLC. Irinotecan and etoposide is also an active new combination in the treatment of both previously treated or untreated SCLC. Neutropenia was the most commonly observed toxicity in this combination; there were no severe gastrointestinal toxicities, including diarrhea. [ONCOLOGY 14(Suppl 5):57-62, 2000]

Introduction

Since 1998, lung cancer has been the leading cause of cancer death in Japan. Small-cell lung cancer (SCLC) comprises approximately 20% of all lung cancers. Characterized by early metastatic involvement, recurrence at multiple distant sites, and frequent nodal spread, SCLC is a systemic disorder that is highly sensitive to chemotherapy and, in limited disease, to radiotherapy. Three decades of clinical studies have shown that first-line combination chemotherapy with or without radiotherapy improves survival in SCLC.[1] Nonetheless, most patients relapse and die with drug-resistant tumors within 2 years of initial treatment. New, more active agents are needed to increase survival in SCLC. Irinotecan (Camptosar, CPT-11), a new semisynthetic water-soluble analog of the plant alkaloid camptothecin, has demonstrated significant activity against a variety of solid tumors, including SCLC.[2,3] Irinotecan is transformed to an active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38) by carboxyl-esterase, an enzyme that is mainly found in the liver, bowel mucosa, and tumor tissue.[4] SN-38 plays an essential role in the cytocidal activity and toxicity of the parent compound.[5] Camptothecin and its derivatives have a unique mechanism of action that inhibits the nuclear enzyme topoisomerase-I, which relieves torsional strain in DNA by inducing reversible single-strand breaks.[6,7] The results of Japanese clinical studies of irinotecan in the treatment of SCLC are described in this article.

The single-agent activity of irinotecan (camptosar, CPT-11) in small-cell lung cancer (SCLC) has been evaluated in two phase II studies in Japan.[8,9] One study was multi-institutional, involving both previously treated and untreated patients.[8] The second was a single-institution study conducted at Osaka Prefectural Habikino Hospital in patients with refractory or relapsed SCLC.[9]

In both studies irinotecan was administered at a dose of 100 mg/m² by intravenous infusion over 90 minutes on a weekly schedule. If a patient’s white blood cell (WBC) count was 2,000 to 2,999/µL on the day of administration, irinotecan was omitted. Dosing of irinotecan was resumed only after recovery of the WBC count. If the WBC count was 1,000 to 1,999/µL, irinotecan at 80 mg/m² was administered after recovery. If the WBC count was < 1,000/µL, or a grade 3 or 4 nonhematologic toxicity was observed, irinotecan was discontinued. Tumor responses and drug toxicity were classified in accordance with the World Health Organization (WHO) criteria. The duration of survival was calculated from the start of irinotecan administration until death or last follow-up. The characteristics of the patients in these phase II studies are shown in Table 1, and the results are shown in Table 2.

Forty-one patients (33 male; 8 female) were enrolled in the multi-institutional study. The patients ranged in age from 40 to 74 years, with a median of 62 years. Based on criteria established by the Eastern Cooperative Oncology Group (ECOG), 28 patients (68%) had a performance status (PS) of 0 or 1, and 13 patients (32%) had a PS of 2. Twelve patients had limited disease (LD) and 29 had extensive disease (ED). Eight patients were previously untreated, and 33 were treated.

Four of the eight previously untreated patients (50%) achieved a partial response (PR). Twenty-seven of the 33 patients with previously treated disease were evaluable for response. Two of them achieved a complete response (CR) and seven achieved a PR, for an overall response rate of 33%. The median survival time was 35 weeks for all patients. The major toxicities of grade 3 or 4 were leukopenia (31%) and diarrhea (15%); the diarrhea was persistent in some patients. Marked interpatient variation in the severity of diarrhea was observed during the trial.

Between May 1990 and May 1991, 16 patients with refractory or relapsed SCLC were enrolled in a phase II study at Osaka Prefectural Habikino Hospital, 15 of whom were evaluable for response and toxicity. The median age of the 3 female and 12 male patients was 63 years. Six patients had an ECOG performance status of 0 or 1, and nine patients had a performance status of 2. The most common metastatic sites were the liver (four patients), adrenal gland (three patients), extrathoracic lymph node (three patients), and brain (three patients); other metastatic sites were observed in the lungs, bones, and subcutaneous nodule. All 15 patients had been heavily pretreated with cisplatin (Platinol)-based chemotherapy or concurrent cisplatin and etoposide (VePesid, VP-16) plus thoracic radiotherapy. Fourteen patients proved to be sensitive to chemotherapy, defined as the recurrence of tumor with a chemotherapy-free interval of 90 days or longer. A total of 102 cycles of weekly irinotecan were administered (median, 7 per patient; range, 2 to 13).

Although there were no complete responses, seven patients achieved a partial response (47%), with a median duration of 8 weeks (range, 4 to 22 weeks). Seven patients showed no change, and one patient exhibited disease progression. The median survival time for all 15 eligible patients was 27 weeks. The most frequently observed adverse event was myelosuppression, which primarily affected the leukocytes (33% grade 3 or 4 leukopenia). Planned dosages remained unchanged in seven patients and were withheld for more than 14 days in seven patients. The dosage was reduced and delayed in only one patient due to leukopenia and diarrhea. No patient experienced febrile neutropenia. One patient had diarrhea of grade 3 or 4 (7%); the diarrhea resolved 18 days following termination of treatment with irinotecan. One patient (7%) experienced grade 4 paralytic ileus, which was severe enough to stop administration of irinotecan after four weekly doses. Grade 3 or 4 pulmonary toxicity occurred after the administration of five and seven doses of irinotecan, respectively, in two patients (13%). In one patient, pneumonitis responded well to steroid therapy, but a second patient with pneumonitis did not respond to the same treatment and subsequently died of progressive respiratory insufficiency.

Irinotecan and Cisplatin in SCLC

Cisplatin is one of the most active and important drugs in the treatment of SCLC. In addition, cisplatin has a different mechanism of action from irinotecan and its principal toxicities do not overlap with those of irinotecan. Cisplatin and irinotecan have shown a synergistic effect against human SCLC cell lines and small-cell lung tumor xenografts in nude mice.[10] Our phase I study of the combination of irinotecan and cisplatin in the treatment of non–small-cell lung cancer (NSCLC) and SCLC[11] showed promising antitumor activity with acceptable toxicity, especially against SCLC. Because a phase II study of this combination produced excellent results in NSCLC,[12] we planned to conduct clinical trials of the irinotecan and cisplatin combination in SCLC.

First-Line Phase II Study of Irinotecan and Cisplatin in SCLC

The West Japan Thoracic Oncology Group (WJTOG) conducted a phase II study of irinotecan and cisplatin in patients with previously untreated SCLC.[13] The objectives of this study were to determine the antitumor activity and toxicity of this combination.

Irinotecan was initially administered at a dose of 80 mg/m² to 10 patients by intravenous infusion on days l, 8, and 15. After 3 of these 10 patients experienced severe hematologic toxicity, diarrhea, and hepatic toxicity, and a fourth died of diarrhea and neutropenia, the Monitoring Committee of the West Japan Lung Cancer Group reduced the dose to 60 mg/m².

On completion of the 90-minute infusion of irinotecan on day 1, cisplatin was administered intravenously at a dose of 60 mg/m² over 60 minutes. Adequate hydration with diuretics and antiemetics was provided before and after administration of cisplatin. This treatment was repeated every 4 weeks. Patients with limited disease received thoracic irradiation of 50 Gy after four cycles of this combination; those with extensive disease received six cycles of chemotherapy. Patients with disease progression after one cycle of therapy or stable disease after two cycles were to receive salvage therapy consisting of cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), and etoposide. Patients who achieved a CR were scheduled to receive prophylactic cranial irradiation (PCI).

Irinotecan was not given on day 8 or 15 if the patient's WBC count was less than 3,000/µL or if platelet counts were less than 75,000/µL. Irinotecan was also withheld if the patient experienced diarrhea of grade 2 or greater, according to the ECOG toxicity scale.

The next course of treatment could only be initiated if the WBC count was 4,000/µL or greater, the platelet count was 100,000/µL or greater, and diarrhea had resolved. However, if more than 6 weeks passed from the time of the last treatment, the patient was removed from the study. The dose of irinotecan in the next course was reduced by 10 mg/m² if the WBC count was less than 2,000/µL, the platelet count was less than 50,000/µL, or the severity of diarrhea was grade 3 or greater.

Of the 75 patients enrolled in the study, 72 were evaluable for efficacy; all were evaluable for toxicity. The characteristics of the patient population are listed in Table 3. Forty patients (53%) had limited disease and 35 (47%) had extensive disease. The median age of the 17 women and 58 men was 64 years; 85% of the patients had a performance status of 0 or 1. Three patients died before completing a full course of treatment: two patients of treatment-related causes (on day 9 and day 16, respectively) and the third following an exacerbation of underlying interstitial pneumonia.

Of the patients with limited disease, 33 (83%) achieved an objective response (OR) and 12 (30%) achieved a CR. Thirty (86%) of the patients with extensive disease achieved an OR and 10 (29%) achieved a CR (Table 4). The median duration of response was 8.0 months for patients with limited disease and 6.6 months for those with extensive disease. Median survival for patients with limited disease and extensive disease was 14.3 months and 13.0 months, respectively. The 2-year survival rate was 21.7% for patients with limited disease and 17.5% for those with extensive disease.

Toxic Effects

One patient died of treatment-related causes on day 46 of cycle 2; this death occurred as a result of sepsis during neutropenia. Another patient was removed from the study after the first cycle of treatment because of progressive disease. The mean number of chemotherapy cycles given was 4.2. Sixteen (64%) of 25 patients received the full scheduled therapy (three courses of irinotecan treatment) during cycle 1. Six patients (24%) received two doses of irinotecan (administered on days 1 and 8, or days 1 and 15). Three patients (12%) could receive only one dose of irinotecan. Treatment with irinotecan could not be administered three times in the first course due to treatment-induced leukopenia (56%), thrombocytopenia (22%), and/or diarrhea (22%).

Most of the episodes of severe leukopenia and/or diarrhea were observed during cycle 1, because dose modifications had to be made in the eight subsequent cycles. Consequently, it was possible to deliver full doses of irinotecan treatment (3 times/week) in just 71% of the entire 106 cycles. The most frequent toxicity was myelosuppression, which primarily affected leukocytes: both grade 3 and 4 neutropenia were observed in 28% of patients, respectively. The neutrophil nadir usually occurred around day 11, with recovery by day 15. Four episodes of fever during the period of leukopenia were observed. Thrombocytopenia remained infrequent throughout the study; grade 3 and 4 thrombocytopenia only occurred in 12% and 8% of patients, respectively. Forty-four percent of patients experienced grade 3 or 4 anemia.

Irinotecan and etoposide with G-CSF support is an active treatment for refractory or relapsed SCLC. The high response rate of 71% and the long median survival time of 271 days observed in previously treated patients may be explained by an additive or even synergistic cytocidal effect when this combination of topoisomerase-I and -II inhibitors is given on the schedule used. All side effects except one case of fatal neutropenic sepsis were manageable.

First-Line Phase II Study of Irinotecan and Etoposide in SCLC Patients With Extensive Disease

To evaluate the efficacy and safety of this topoisomerase I and topoisomerase II targeting combination, the WJTOG conducted a phase II study of irinotecan and etoposide in previously untreated SCLC patients with extensive disease from August 1995 to May 1998.[18]

Etoposide administered intravenously at a dose of 80 mg/m² was given on days 1, 2, and 3, and irinotecan was administered intravenously at a dose of 60 mg/m² on days 1, 8, and 15. This regimen was repeated every 4 weeks. G-CSF support was used only after the occurrence of grade 3 or greater leukocytopenia and/or neutropenia. Irinotecan dosing was omitted if the patient had a WBC count < 3,000/µL, a platelet count < 100,000/µL, or if the patient had diarrhea of grade 2 or greater. If a patient experienced grade 3 or greater hematologic or nonhematologic toxicities, the dose of irinotecan was reduced to 50 mg/m² in the subsequent chemotherapy course.

Fifty of the 51 patients entered into the study were evaluable. The median age of the 42 men and 7 women in this study was 65 years. Forty-seven (94%) patients had a performance status of 0 or 1. Thirty patients (60%) had single metastasis, and 20 (40%) had multiple metastases. Of the 50 patients evaluable for response, 5 (10%) achieved a CR and 28 (56%) achieved a PR, resulting in an overall response rate of 66%. The median duration of response for all patients was 8 months and median survival was 11.2 months. The 2-year survival rate was 43.2%. Grade 3 or 4 leukopenia and neutropenia were observed in 28% and 63% of patients, respectively. Thrombocytopenia of grade 3 or 4 was observed in only 9.3% of patients. No grade 3 or greater nausea, vomiting, or diarrhea was observed in this study. No pulmonary toxicity was observed during chemotherapy. There were no treatment-related deaths.

Conclusions

Irinotecan appears to have significant activity in the treatment of previously treated and untreated SCLC. The major toxicities of irinotecan are neutropenia and diarrhea, although there is marked interpatient variability in the severity of symptoms.

The combination of irinotecan plus cisplatin is likewise significantly active against SCLC, especially in extensive disease, with an acceptable toxicity profile. A randomized phase III study comparing irinotecan plus cisplatin with etoposide plus cisplatin has been conducted and the data are being analyzed. The results of this study may define a new standard regimen for SCLC.

The combination of irinotecan and etoposide is an active treatment for both previously treated and untreated SCLC. The degree of activity associated with this combination in the treatment of SCLC may be explained by its additive or even synergistic cytocidal effect, particularly when given on the schedule used in the studies reported here. The phase II trial in patients with refractory or relapsed SCLC.[16] has shown that irinotecan can be given safely at a dose of 80 mg/m² intravenously on days 1, 8, and 15, together with etoposide 80 mg/m² intravenously for 3 days if G-CSF is used as a prophylaxis for neutropenia. The promising results of these trials warrant a randomized study of irinotecan plus etoposide versus cisplatin plus etoposide or irinotecan in previously untreated SCLC characterized by extensive disease.

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