Pediatr Blood Cancer Concurrent Radiation With Irinotecan and Carboplatin in Intermediate- and High-Risk Rhabdomyosarcoma: A Report on Toxicity and Efficacy From a Prospective Pilot Phase II Study Kavita V. Dharmarajan, MD, MSc, 1 * Leonard H. Wexler, MD, 2 and Suzanne L. Wolden, MD 1 INTRODUCTION Intensive multi-modality therapy has already been established as the backbone of treatment for patients with rhabdomyosarcoma (RMS). Since the beginning of the Intergroup Rhabdomyosarco- ma Studies (IRS) I–IV in 1972, 5-year overall survival has im- proved from 55% to 71% [1]. Since IRS–IV (1991–1997), however, efforts to improve outcomes have generally failed for patients with poor prognostic clinical features such as unfavorable site, alveolar histology, locally advanced disease, and metastatic disease. Neither has intensification of alkylating chemotherapy nor hyperfractionated radiation therapy (RT) led to improved cure rates among patients classified as intermediate risk (defined as disease at unfavorable sites with gross residual disease or non- metastatic alveolar RMS). The greatest risk of treatment failure for these patients remains locoregional. Emerging interest in camptothecins spurred the development of the fifth major cooperative group trial, D9803, which incorpo- rated topotecan, a topoisomerase-I inhibitor, into the standard three-drug regimen of vincristine, cyclophosphamide, and dacti- nomycin. Although several pilot and phase II studies showed topotecan alone or in combination with cyclophosphamide to be active in patients with newly diagnosed metastatic or recurrent disease [2–5], the addition of topotecan did not translate into improvement in failure-free survival among intermediate-risk patients. Thus, attention has shifted to irinotecan, another topoisomer- ase inhibitor, which has even greater activity against RMS in pre- clinical and pilot studies, including activity against cell lines and xenografts selected for topotecan resistance [6,7]. Several phase I trials have been conducted in children and one has demonstrated favorable results [8–10]. Retrospective experience from our insti- tution with irinotecan in seven patients with relapsed RMS yielded positive tumor response in six patients [11]. Furthermore, toxicity with irinotecan has reportedly been mild [12]. Irinotecan’s radiosensitizing properties make it an attractive choice for concurrent use with RT. Several phase I and II trials have assessed the feasibility and efficacy of irinotecan with con- current radiation in patients with unresectable non-small cell lung cancer [13,14] and with concurrent platinum-based chemoradia- tion in patients with esophageal cancer with promising results [15,16]. In addition, single-agent carboplatin has been evaluated in pediatric rhabdomyosarcoma in a single-agent phase II window study [17] and as part of combination therapy with epirubicin and vincristine [18], and it has been shown to have acceptable toxicity and moderate efficacy. Phase I data of concurrent irinotecan and carboplatin among 28 pediatric patients with refractory solid tumors demonstrated tolerability of this regimen in this small patient group [19]. However, the feasibility and efficacy of con- current irinotecan and platinum-based chemotherapy with RT is not well established in the pediatric population. An ongoing in- house phase II pilot study for intermediate-risk and metastatic RMS incorporates irinotecan and carboplatin during induction chemotherapy and radiation therapy, and for responding patients (Fig. 1). We investigated tolerability and efficacy of treatment with irinotecan, carboplatin, and concurrent radiation in interme- diate- and high-risk RMS by describing frequencies of acute toxicities and the rate of local tumor control. Background. Irinotecan is highly active against rhabdomyosar- coma (RMS), yet its tolerability and efficacy in combination with radiation is unknown. We examined local control and toxicities in RMS patients treated with radiotherapy (RT) in combination with radiosensitizing agents irinotecan þ carboplatin (I þ C). Proce- dure. From 11/2003 to 1/2011, 60 patients were enrolled on a pilot phase II protocol with newly diagnosed intermediate- or high-risk RMS at Memorial Sloan-Kettering Cancer Center. Induction therapy consisted of two cycles of I þ C followed by three cycles of vincris- tine, doxorubicin, and cyclophosphamide. At week 13, 47 patients received definitive primary-site RT or post-operative RT with two concurrent cycles of I þ C. Median RT dose was 50.4 Gy (range 30.6–50.4 Gy). Radiation-related toxicities were evaluated accord- ing to the Common Terminology Criteria for Adverse Events, version 3.0. Results. Median age of the cohort was 9 years. With median follow-up of 32 months, 2.5 year actuarial local control was 89%. Among all patients, grades 3 and 4 dermatitis were observed in 11% and 4%, respectively. Among parameningeal, orbit, and other head/ neck sites, rates of grades 3 and 4 mucositis were 20% and 10%, respectively. Among abdomen/pelvis sites, 12% developed grade 3 diarrhea and 6% developed grade 3 cystitis. No treatment breaks were necessary. Conclusions. Preliminary results of irinotecan and carboplatin administered with concurrent RT in intermediate- and high-risk RMS demonstrated favorable tolerability, efficacy, and local control. Reduced rates of acute grades 3–4 mucositis were observed when compared with historical results. Pediatr Blood Cancer ß 2012 Wiley Periodicals, Inc. Key words: carboplatin; irinotecan; phase II study; radiation therapy; rhabdomyosarcoma; toxicity 1 Department of Radiation Oncology, Memorial Sloan-Kettering Can- cer Center, New York, New York; 2 Department of Pediatrics, Memo- rial Sloan-Kettering Cancer Center, New York, New York Conflict of interest: Nothing to declare. *Correspondence to: Kavita V. Dharmarajan, MD, MSc, Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. E-mail: dharmark@mskcc.org Received 3 February 2012; Accepted 2 May 2012 ß 2012 Wiley Periodicals, Inc. DOI 10.1002/pbc.24205 Published online in Wiley Online Library (wileyonlinelibrary.com).