Original Article
Weekly Alternating Therapy With Irinotecan Plus Cisplatin and Etoposide Plus Cisplatin in the Treatment of Patients With Extensive Small Cell Lung Carcinoma William N. William, Jr, MD1; James Uyeki, MD2; Faye M. Johnson, MD1; Lei Feng, PhD3; Beverly O. Peeples, RN1; Frank V. Fossella, MD1; Daniel D. Karp, MD1; George R. Blumenschein, MD1; David J. Stewart, MD1; and Bonnie S. Glisson, MD1
BACKGROUND: Irinotecan has significant activity in small-cell lung cancer (SCLC). The authors’ previous phase 1 study of alternating weekly therapy with irinotecan/cisplatin (IP), etoposide/cisplatin (EP), and granulocyte–colonystimulating factor (G-CSF) support was well tolerated and active in patients with SCLC. A phase 2 trial was conducted to estimate the efficacy of this regimen in previously untreated patients with extensive SCLC. METHODS: A total of 33 patients were treated between June 2002 and July 2007. Patients received 12 weeks of therapy with cisplatin (20 mg/m2) on Day 1 and irinotecan (100 mg/m2) on Day 1 and G-CSF on Days 2 to 5 (Weeks 1, 3, 5, 7, 9, and 11) followed by cisplatin (20 mg/m2) on Day 1 and etoposide (60 mg/m2) on Days 1 to 3 with G-CSF on Days 4 to 7 (Weeks 2, 4, 6, 8, 10, and 12). The primary endpoint was 1-year survival rate. RESULTS: Grade 4 neutropenia (toxicities were determined using the National Cancer Institute Common Toxicity Criteria [version 2.0]) was noted in 5 (1.5%) of 343 courses with neutropenic fever in only 5 (1%) of 343 courses. One patient died of neutropenic sepsis. Nonhematologic toxicities grade 2 were observed in 15 (4%) of 343 courses and were limited to fatigue, hyponatremia, and diarrhea. The overall objective response rate was 89% in 28 assessable patients (no complete responses and 25 partial responses). The median progression-free and overall survivals were 6.0 months and 10.9 months, respectively. The 1-year survival rate was 33%. CONCLUSIONS: Weekly therapy with IP alternating with EP and G-CSF support was well tolerated in patients with extensive SCLC, but did not demonstrate improved progression-free or overall survival C 2010 American Cancer when compared with historical controls at the study institution. Cancer 2010;116:2409–15. V Society. KEYWORDS: cisplatin, etoposide, irinotecan, alternating, weekly, extensive, small cell lung cancer.
Small cell lung cancer (SCLC) represents 13% of total lung cancer cases in the United States, with the number of cases
for 2008 estimated at 28,000.1 The majority of patients with SCLC present with extensive disease (ED), defined as tumor that extends beyond the ipsilateral lung and regional lymph nodes.2 Combination chemotherapy with etoposide and cisplatin or carboplatin has been a standard treatment for the past 20 years.3-6 Despite high initial response rates and improved survival with combination chemotherapy, therapy for ED-SCLC is characterized by early recurrence and failure of second-line therapy to produce meaningful response rates or long survival times.6 Strategies to improve initial tumor kill have included rapid alternation of noncross-resistant regimens, increased dose density, and addition of a third drug to the etoposide/platin base.7 In general, these strategies have failed and the median survival in patients with ED-SCLC continues to be 8 months to 10 months, despite intensive investigation over the past 25 years.8,9 Irinotecan, a camptothecin analogue that inhibits topoisomerase I, has demonstrated significant antitumor activity in SCLC and may be synergistic with topoisomerase II inhibitors, such as etoposide.10-12 Topoisomerase I inhibitors have Corresponding author: Bonnie S. Glisson, MD, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Box 432, 1515 Holcombe Boulevard, Houston, TX 77030; Fax: (713) 792-1220;
[email protected]. 1 Department of Thoracic Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 2Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 3Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
We are indebted to the assistance provided by the research nurses and data managers. DOI: 10.1002/cncr.25076, Received: August 11, 2009; Revised: September 27, 2009; Accepted: September 28, 2009, Published online March 11, 2010 in Wiley InterScience (www.interscience.wiley.com)
Cancer
May 15, 2010
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Original Article
also been shown to be synergistic with cisplatin, perhaps by inhibiting repair of DNA damage.13 In addition, cells resistant to topoisomerase inhibitors have been shown to have a marked increase in cisplatin sensitivity.12 Preclinical studies indicate that resistance to drugs that target topoisomerase II may be mediated by a decrease in topoisomerase II levels. This finding has been associated with an increase in topoisomerase I levels, as well as an increased sensitivity to topoisomerase I inhibitors.11,14 The converse order of exposure has also been investigated. In xenograft studies, pretreatment with irinotecan potentiated the cytotoxic effects of the topoisomerase II inhibitor doxorubicin.15 In a lung cancer cell line, maximum synergy was achieved when topotecan preceded etoposide.16 In a phase 1 study evaluating topoisomerase targeting with irinotecan and cisplatin (IP) followed by etoposide in patients with advanced malignancy, the best response was noted in patients with increased topoisomerase II a at the time of etoposide administration.17 The concurrent administration of topoisomerase I and topoisomerase II inhibitors has been shown to be antagonistic in vitro.12 In 2000, Noda et al reported the results of the Japanese Clinical Oncology Group (JCOG) Study 9511.18 This phase 3 trial, which randomized patients with EDSCLC to receive IP or etoposide and cisplatin (EP), demonstrated a 3.4-month improvement in median survival for patients on the irinotecan arm.19 Based on those promising results and the preclinical data supporting sequential exposure to topoisomerase inhibitors, we conducted a phase 1 study of alternating weekly therapy with IP and EP, supported with granulocyte–colony-stimulating factor (G-CSF), in patients with untreated SCLC. This regimen was active and well- tolerated.20 We sought to determine the efficacy of this regimen in a subsequent phase 2 trial for patients with ED-SCLC described herein.
MATERIALS AND METHODS Patients Eligibility criteria included histologically or cytologically documented SCLC and ED, defined as disease beyond the hemithorax of origin and regional lymph nodes and demonstrated by staging that included chest x-ray, computed tomography (CT) scan of chest and abdomen, magnetic resonance imaging (MRI) of the brain, and radionuclide bone scan. Patients with cytologically positive pleural effusion as the only evidence of ED were eligible, as were patients with clinically silent brain metastases;
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adequate organ function, including absolute granulocytes 1500 lL, platelet count 100,000 lL, bilirubin 1.5 mg/dL, and creatinine clearance >59 mL/minute; Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; no previous chemotherapy or radiotherapy for SCLC; and no recent (
