Phase II study of irinotecan combined with carboplatin in previously untreated small-cell lung cancer

Kinoshita, Akitoshi; Fukuda, Minoru; Soda, Hiroshi; Nagashima, Seiji; Takatani, Hiroshi; Kuba, Mutsuo; Nakamura, Yoichi; Tsurutani, Junji; Kohno, Shigeru; Oka, M.

doi:10.1038/sj.bjc.6603079

Cited by 18 publications

(38 citation statements)

References 32 publications

(41 reference statements)

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“…These results are very encouraging and superior to other trials with similar irinotecan dosages and schedules. Grade 3/4 toxicities were 50% in neutropenia and 29.6% in diarrhoea, and were comparable with previous other trials (Kudoh et al, 1998;Noda et al, 2002;Hanna et al, 2006;Kinoshita et al, 2006). However, one treatmentrelated death was observed in this trial.…”

Section: Discussionsupporting

confidence: 90%

“…Kudoh et al (1998) reported that combination chemotherapy of irinotecan and cisplatin (IP) in patients with SCLC showed a promising response rate of 84 with 29% of complete responses and median survival over 13 months. Since then, several phase II/III trials of irinotecan-based combination chemotherapy with different dose and schedule were performed with varying results in SCLC patients (Noda et al, 2002;Kudoh et al, 2005;Hanna et al, 2006;Kinoshita et al, 2006;Schmittel et al, 2006). In a previous phase III trial conducted by a Japanese group, patients were treated with 60 mg m À2 of cisplatin on day 1 and 60 mg m À2 of irinotecan on days 1, 8, and 15 every 4 weeks, and showed a good median survival of 12.8 months.…”

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confidence: 99%

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Three-week schedule of irinotecan plus cisplatin in patients with previously untreated extensive-stage small-cell lung cancer

Park

et al. 2006

Br J Cancer

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Irinotecan and cisplatin demonstrated promising outcomes in extensive-stage small-cell lung cancer. According to the dosage and schedule of irinotecan, efficacy and toxicity profiles showed subtle differences. This study was designed to evaluate efficacy and toxicity of 3-week schedule of irinotecan/cisplatin in patients with previously untreated extensive-stage small-cell lung cancer. The primary objective was to evaluate response rate and secondary objectives were overall survival and progression-free survival. Patients with previously untreated extensive-stage small-cell lung cancer were enrolled. Irinotecan 65 mg m À2 was administered on days 1 and 8 and cisplatin 60 mg m À2 on day 1. Treatment was repeated every 3 weeks. Seven out of 54 patients (13.0%) had complete response, and partial response was observed in 33 (61.1%). The overall response rate was 74.1% (95% CI; 62.0 -82.2%). Stable disease was observed in eight (14.8%) and no progressive disease was observed. After a median follow-up duration of 28.7 months, the median overall survival and progressive-free survival were 13.6 and 6.5 months, respectively. Major grade 3/4 toxicities were neutropenia (50.0%), anorexia (42.6%), diarrhoea (29.6%), fatigue (29.6%) and vomiting (13.0%). There was one treatment-related death owing to pneumonia. Three-week schedule of irinotecan/cisplatin showed effective antitumour activity and moderate toxicities in patients with previously untreated extensive-stage small-cell lung cancer. British Journal of Cancer (2006) (Jemal et al, 2004), and also in Korea (Shin et al, 2004). The proportion of histologic diagnosis with small-cell lung cancer (SCLC) in the United States is approximately 15% of patients with lung cancer (Jemal et al, 2004), and more than half of these patients are diagnosed with extensive-stage disease. Incidence of SCLC had paralleled trends in cigarette smoking, and smoking prevalence for the adult population is relatively high in Korea. During the last decade, most patients with extensivestage SCLC (ES-SCLC) have been treated with etoposide and platinum resulting in a median survival of 8 -10 months (Roth et al, 1992). Although several trials of platinum-based combination chemotherapy were performed, it failed to show a superiority to combination of etoposide and cisplatin (EP) (Mavroudis et al, 2001;Sundstrom et al, 2002).Irinotecan, which inhibits the function of topoisomerase I in cancer cells, demonstrated synergism and non-cross resistance when combined with platinum agents (Fukuda et al, 1996;Masuda et al, 1996). Kudoh et al (1998) reported that combination chemotherapy of irinotecan and cisplatin (IP) in patients with SCLC showed a promising response rate of 84 with 29% of complete responses and median survival over 13 months. Since then, several phase II/III trials of irinotecan-based combination chemotherapy with different dose and schedule were performed with varying results in SCLC patients (Noda et al, 2002;Kudoh et al, 2005;Hanna et al, 2006;Kinoshita et al, 2006;Schmittel et al, 2006). In...

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 99%

Three-week schedule of irinotecan plus cisplatin in patients with previously untreated extensive-stage small-cell lung cancer

Park

et al. 2006

Br J Cancer

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“…The efficacy data in our trial are comparable with that observed in previous phase II trials. In previous phase II trials, RR ranged from 69 to 79% and PFS ranged from 5.4 to 6.4 months with an OS of 9.7-11.0 months when patients were treated with irinotecan (50 mg/m 2 on days 1, 8, and 15) and carboplatin (AUC 5) [30,31]. The higher dose of irinotecan in our trial was not associated with an obvious improvement in therapeutic efficacy.…”

Section: Discussionmentioning

confidence: 86%

Irinotecan plus carboplatin in patients with extensive-disease small-cell lung cancer

et al. 2010

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This study was designed to evaluate the efficacy and safety of irinotecan in combination with carboplatin in previously untreated, extensive-disease small-cell lung cancer (ED-SCLC). Patients with histologically or cytologically confirmed ED-SCLC received irinotecan (60 mg/m(2) on days 1, 8, and 15) plus carboplatin (AUC 5 on day 1) every 4 weeks. Treatment was repeated until disease progression, unacceptable toxicity, or up to 6 cycles. Forty-four patients were enrolled. In an intent-to-treat analysis, the overall response rate (RR) was 75% (8 complete responses and 25 partial responses). The median progression-free (PFS) and overall survival (OS) were 5.6 and 8.7 months, respectively. The principle toxicities were neutropenia and diarrhea. Grade 3-4 neutropenia occurred in 30% of the patients and 7% of patients presented with febrile neutropenia. Grade 3-4 diarrhea occurred in 21% of the patients. A subgroup consisting of patients ≥ 65 years of age had outcomes similar to the younger group <65 years of age. The objective RR was 72% in the patients <65 years of age and 77% in the patients ≥ 65 years of age (P = .738). The median PFS and OS (<65 years vs. ≥ 65 years) were 5.3 vs. 5.6 months (P = .835) and 9.0 vs. 8.7 months (P = .648), respectively. The combination of irinotecan and carboplatin is active and tolerable in patients with ED-SCLC. This regimen could be considered as a treatment option for patients of advanced age.

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“…The hematologic toxicity observed likely demonstrates the potential additive myelosuppressive effects of irinotecan (and/or its metabolites) in previously treated patients. Multiple dosing schedules of the combination of irinotecan and carboplatin have been studied in adults with a variety of malignancies, [25][26][27] including lung cancer, [29][30][31] ovarian cancer, 28 and non-Hodgkins lymphoma. 41 As in the current study, the main toxicities were gastrointestinal and hematologic, and efficacy in phase 1 of 2 studies has been encouraging.…”

Section: Discussionmentioning

confidence: 99%

“…[25][26][27][28][29][30][31] Toxicities are mostly nonoverlapping; however, the combination can result in enhanced myelosuppression. Given the single-agent efficacy of carboplatin and irinotecan in a variety of pediatric tumors and the promising experience in adults, this combination is worthy of evaluation in pediatric patients with recurrent solid tumors.…”

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confidence: 99%

Phase 1 and pharmacokinetic study of concurrent carboplatin and irinotecan in subjects aged 1 to 21 years with refractory solid tumors

Levy

Meyers

Wexler

et al. 2008

Cancer

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Objective Spleen tyrosine kinase (Syk) has been identified as an important modulator of immune signaling in B cells and cells bearing Fcγ‐activating receptors. R788, a prodrug of active metabolite R406, has been shown to be an inhibitor of Syk kinase, active in a variety of in vitro and in vivo models, suggesting potential activity in the treatment of rheumatoid arthritis (RA). Methods We enrolled 189 patients with active RA despite methotrexate therapy in a 3‐month, multicenter, ascending‐dose, double‐blind, placebo‐controlled trial. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. Results Twice‐daily oral doses of 100 mg and 150 mg of R788 were significantly superior to placebo or twice‐daily oral doses of 50 mg at week 12 (ACR20 achieved in 65% and 72% versus 38% and 32% of patients, respectively [P < 0.01]). ACR50 (achieved in 49% and 57% versus 19% and 17% of patients, respectively) and ACR70 (achieved in 33% and 40% versus 4% and 2% of patients, respectively) scores showed a similar pattern. Clinical effect was noted as early as 1 week after initiation of therapy. Reductions in serum interleukin‐6 and matrix metalloproteinase 3 levels also occurred as early as week 1 in the groups receiving 100 mg and 150 mg R788. The major adverse effects were gastrointestinal side effects (predominantly diarrhea) and neutropenia (<1,500/mm3), both of which were dose related. Conclusion These results indicate that an inhibitor of Syk kinase produces significant clinical benefits at 12 weeks in a population of patients with active RA receiving methotrexate therapy. Syk kinase may be an important new therapeutic target in RA and related autoimmune conditions.

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Phase II study of irinotecan combined with carboplatin in previously untreated small-cell lung cancer

Cited by 18 publications

References 32 publications

Three-week schedule of irinotecan plus cisplatin in patients with previously untreated extensive-stage small-cell lung cancer

Three-week schedule of irinotecan plus cisplatin in patients with previously untreated extensive-stage small-cell lung cancer

Irinotecan plus carboplatin in patients with extensive-disease small-cell lung cancer

Phase 1 and pharmacokinetic study of concurrent carboplatin and irinotecan in subjects aged 1 to 21 years with refractory solid tumors

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