Kavita V. Dharmarajan, MD, MSc, 1 * Leonard H. Wexler, MD, 2 and Suzanne L. Wolden, MD 1 INTRODUCTION. Pediatr Blood Cancer 2013;60:

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1 Pediatr Blood Cancer 2013;60: 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 Background. Irinotecan is highly active against rhabdomyosarcoma (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). Procedure. 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 vincristine, 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 Gy). Radiation-related toxicities were evaluated according 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 intermediateand 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 2013;60: ß 2012 Wiley Periodicals, Inc. Key words: carboplatin; irinotecan; phase II study; radiation therapy; rhabdomyosarcoma; toxicity 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 Rhabdomyosarcoma Studies (IRS) I IV in 1972, 5-year overall survival has improved from 55% to 71% [1]. Since IRS IV ( ), 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 nonmetastatic 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 incorporated topotecan, a topoisomerase-i inhibitor, into the standard three-drug regimen of vincristine, cyclophosphamide, and dactinomycin. 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 topoisomerase inhibitor, which has even greater activity against RMS in preclinical 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 institution 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]. ß 2012 Wiley Periodicals, Inc. DOI /pbc Published online 22 May 2012 in Wiley Online Library (wileyonlinelibrary.com). 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 concurrent radiation in patients with unresectable non-small cell lung cancer [13,14] and with concurrent platinum-based chemoradiation 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 concurrent irinotecan and platinum-based chemotherapy with RT is not well established in the pediatric population. An ongoing inhouse 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 intermediate- and high-risk RMS by describing frequencies of acute toxicities and the rate of local tumor control. 1 Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York; 2 Department of Pediatrics, Memorial 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 dharmark@mskcc.org Received 3 February 2012; Accepted 2 May 2012

2 Concurrent RT With Irinotecan in RMS 243 Fig. 1. Protocol schema of Memorial Sloan-Kettering Cancer Center IRB # METHODS Patients Between November 2003 and January 2011, 60 patients with newly diagnosed RMS were enrolled onto a single-center phase II pilot study, IRB# , 47 of whom were evaluable for review for this analysis. Eligible patients were those with newly diagnosed, previously untreated, and histologically proven intermediate- or high-risk RMS. The study was approved by the institutional review board of Memorial Sloan-Kettering Cancer Center, and informed consent was obtained from each patient or patient s guardian before commencing treatment on the study protocol. The intermediate-risk cohort was defined per the standard definition of intermediate-risk RMS proposed by the Intergroup Rhabdomyosarcoma Study Group as patients having one of the following surgicopathologic and staging criteria: Group III stages 2 or 3 with embryonal, botryoid, or spindle cell RMS; Group III stages 2 or 3 ectomesenchymoma; or Groups I III stages 1 3 alveolar RMS. The high-risk cohort included patients with stage 4 disease. Patients were required to undergo biopsy or definitive surgery within 42 days of starting treatment and to meet criteria for blood counts and other standard tests. Pretreatment evaluations consisted of a history and physical, chest X-ray, computed tomography (CT) of the chest, CT and/or magnetic resonance imaging (MRI) of the primary tumor and regional lymph nodes, bone scan, regional lymph node sampling if indicated, bone marrow biopsy, audiogram, lumbar puncture for parameningeal primary tumors if indicated, and basic laboratory studies. Most underwent staging positron emission tomography (FDG PET) as well. Chemotherapy The protocol schema is depicted in Figure 1. Patients were treated with 12 cycles of combination chemotherapy with irinotecan (20 mg/m 2, days 1 5 and 8 12), carboplatin (560 mg/m 2, day 1), vincristine (1.5 mg/m 2 ), doxorubicin (45 mg/m 2 days 1, 2), and cyclophosphamide (1,600 mg/m 2 days 1, 2), or with ifosfamide (2,600 mg/m 2 days 1 5) and etoposide (100 mg/m 2 days 1 5). Irinotecan and carboplatin were administered at cycles 1 and 2, termed the phase II window, and then again at cycles 6 and 7 (with vincristine on day 1 of each cycle) for patients not progressing during cycles 1 and 2. Vincristine, doxorubicin and cyclophosphamide were administered at cycles 3 5, during the induction chemotherapy period, and at cycle 10. Vincristine, etoposide, and ifosfamide were administered at cycles 8, 9, 11, and

3 244 Dharmarajan et al. 12. Cycles were given at 21-day intervals. High-risk patients had six additional cycles of irinotecan. Supportive treatment with mesna and granulocyte colony-stimulating factor was given throughout therapy. Modification of the chemotherapy regimen was allowed for chemotherapy-related adverse effects as specified in the protocol guidelines. Local therapy with radiation and/or delayed surgical resection was stipulated to commence following cycle 5 (or at approximately week 13) of treatment, shortly before or concurrent with irinotecan and carboplatin administration. Radiation Therapy All patients underwent CT simulation with appropriate immobilization devices such as custom-made face masks or body molds. Patients <5 years old were generally simulated and treated using anesthesia. Fusion of MRI and/or PET with the simulation CT images was performed to aid in delineation of the gross tumor volume and clinical target volume. Target delineation was performed using the pre-chemotherapy and pre-surgery extent of disease and was called the clinical target volume. Dose was prescribed to the planning target volume, which was defined in the protocol guidelines by adding a 1.5 cm margin to the extent of disease prior to any surgery or chemotherapy. Patients received 6 or 15 MV photons, or electrons. The majority were treated using intensity-modulated radiation therapy (IMRT) and, in select cases, dose-painting techniques. All were seen regularly by a radiation oncologist during radiation treatment, underwent weekly laboratory tests (e.g., complete blood count with differential and basic chemistries), and were assessed for development of the following toxicities: dermatitis, mucositis, dysphagia, esophagitis, nausea, vomiting, diarrhea, proctitis, and cystitis. Upon completion of treatment, patients were monitored for development of disease relapse, late-onset therapy-related toxicities, and secondary neoplasms. Outcomes and Statistical Analysis The primary objective was to determine the safety and feasibility of incorporating irinotecan and carboplatin into the RT portion of treatment. The secondary objective was to determine whether incorporation of irinotecan and carboplatin improves local control for patients with intermediate- and high-risk rhabdomyosarcoma. Acute toxicities attributable to combined chemoradiation were graded using the National Cancer Institute s Common Terminology Criteria for Adverse Events, version 3.0 and were reported as frequencies [20]. Assessment of radiationrelated toxicity was performed by categorizing patients by anatomic regions at risk of experiencing specific toxicities of interest. Toxicity frequency was obtained by dividing the number of patients who experienced the toxicity of interest by the number of patients at risk of experiencing the toxicity based on the irradiated region. Some patients were counted in two region-at-risk categories by virtue of the location and size of the radiation field. The Kaplan Meier method was used to calculate the actuarial rate of local control with recurrence of the primary disease as the event of interest, and differences between groups were compared using the log-rank test. Local relapse was defined as progressive disease at the primary site by standard imaging criteria. Patients who developed distant metastases were followed for locoregional relapse. The local relapse endpoint was calculated from diagnosis to the earliest of the following: date of local failure, last followup, or date of last data collection. Event-free survival, overall survival, and a description of chemotherapy-related toxicities experienced during the phase II and induction chemotherapy periods will be subjects of a future, separate analysis. RESULTS A total of 60 patients were treated on the protocol but nine patients did not receive irinotecan and carboplatin concurrently with RT for logistical reasons, and four patients did not receive RT in our department. The baseline characteristics for the remaining 47 patients are outlined in Table I. The median cohort age was 9 years (range 10 months to 42 years). The majority had poor prognostic features at diagnosis as evidenced by the percentage with unfavorable primary sites (89%), alveolar histology (55%), stage 3 4 disease (89%), and group III IV disease (91%). Of the intermediate-risk group, 14 (61%) patients had alveolar RMS and 9 (39%) had embryonal RMS. Of the high-risk group, 13 (54%) had alveolar RMS and 11 (46%) had embryonal RMS. RT was delivered in a definitive manner in 34 patients and after delayed planned resection in 13 patients. With regard to radiation techniques, patients were treated with IMRT (n ¼ 40), electron-beam therapy (n ¼ 4), and conventional 2-field technique (n ¼ 3). The median dose delivered was 50.4 Gy (n ¼ 31), the standard accepted dose in the definitive setting. A lower dose (minimum 30.6 Gy) was used in the following instances: post-operative setting, very large fields that imposed normal TABLE I. Patient and Disease Characteristics of 47 Patients With Rhabdomyosarcoma Treated With Concurrent Irinotecan, Carboplatin, and Radiation Therapy Characteristic Number Percentage (%) Sex Male Female Histology Alveolar Embryonal Risk group Intermediate-risk High-risk Surgical group II 4 9 III IV Stage Site Parameningeal Extremity Trunk 5 11 Bladder/prostate Non-bladder/prostate Orbit 1 2 Other (lip) 1 2

4 Concurrent RT With Irinotecan in RMS 245 complaint among patients receiving irinotecan chemotherapy. No patient required a treatment break from radiation due to any chemoradiation-related toxicity. Hemorrhagic cystitis was rare during and immediately after radiation, and was most likely due to cyclophosphamide or ifosfamide rather than chemoradiation with irinotecan and carboplatin. There were no grade 5 acute toxicities as a result of chemoradiation. All acute toxicities resolved within 3 months post-radiation. DISCUSSION Fig. 2. Overall local control at 2.5 years is 89% for 47 patients treated with concurrent irinotecan, carboplatin and radiation therapy on the phase II pilot protocol IRB# tissue tolerance limits such as hemithoracic fields, and orbital primary sites (treated using 45 Gy). The median follow-up among all patients was 32 months (range 7 months to 7 years). At a median follow-up of 32 months, 2.5-year actuarial local control was 89% (95% confidence interval [CI] 80 99%) among all patients. There have been no local recurrences after this point to date (Fig. 2). There was no difference in local control between alveolar and embryonal histologies (96% [95% CI %] vs. 82% [95% CI %], P ¼ 0.19) or between intermediate-risk and high-risk disease (84% [95% CI %] vs. 95% [95% CI %] P ¼ 0.32). Four patients developed local relapses, summarized in Table II. All local recurrences occurred within 26 months of diagnosis and 21 months of completing primary-site RT. Three of these patients developed multifocal tumor progression along with local relapse and eventually died of disease. One patient had successful control with a large craniofacial surgical resection after local relapse and is alive and disease-free with significant morbidity (wound healing and chronic infection). Only one patient with local relapse had received less than the standard radiation dose. Toxicity data are presented in Table III and represent acute toxicity related to combined chemotherapy with irinotecan, carboplatin, and radiation. The most commonly experienced acute toxicities included dermatitis, mucositis, esophagitis, and diarrhea. Most patients also experienced mild-to-moderate fatigue. Other than dermatitis and mucositis, there were no grade 4 toxicities, including diarrhea, which was expected to be a common Our analysis of 47 patients treated in the single-institutional phase II pilot study IRB# demonstrates that concurrent treatment with irinotecan, carboplatin, and radiation is associated with acceptable rates of acute toxicity and excellent local control. To date, this group of patients comprises the largest treated in this manner with 32-month median follow-up. Preliminary data regarding disease response during the phase II window period of IRB# demonstrated irinotecan and carboplatin were strikingly active at this time-point, and these data were used in part to support the development of a currently ongoing Children s Oncology group trial, ARST0531 for intermediate-risk RMS patients [21]. Camptothecins were recently incorporated into cooperative group trials to improve outcomes for historically poorly performing RMS patients. Although preclinical, retrospective, and phase I and II data [7 10] have demonstrated preliminary evidence that administration of irinotecan-based regimens are active against RMS and are not associated with treatment-limiting toxicity, these studies did not include concurrent radiation therapy. Carboplatin and carboplatin-containing regimens have also shown moderate efficacy [17,18], and phase I data with combined carboplatin and irinotecan showed promise as well [19]. The overall local control rate of 89% is comparable to the locoregional control rate recently published from D9803 of 82 85% [22]. Importantly, our cohort of patients included intermediate- and high-risk patients in contrast to D9803 in which only intermediate-risk patients were enrolled. The local failures in our cohort all had extremely poor prognostic factors, and one of these did not receive standard-dose RT due to large field sizes. There were no further local failures beyond 26 months from diagnosis. For high-risk patients, the greatest risk of treatment failure remains distant failure; however, previously published data from Ewing s tumors suggest metastatic disease at diagnosis is an independent risk factor for inferior local control among patients treated with radiotherapy with locally curative intent [23]. It is plausible that local control may be inferior among high-risk rhabdomyosarcoma patients if these data are extrapolated to RMS. In TABLE II. Details of Local Recurrences in Four Patients Age at diagnosis Radiation dose (years) Site Histology Stage Group (Gy) Radiation field Time to relapse (months) 7 PM Embryonal 3 III 50.4 Right infratemporal 11.4 Died of leptomeningeal disease fossa/upper neck 7 PM Embryonal 3 III 50.4 Right maxillary sinus 25.7 Alive with no evidence of disease 13 Trunk Embryonal 3 III 36 Left hemithorax 15.3 Died of metastatic disease 27 Prostate Embryonal 4 IV 50.4 Pelvis 13.3 Died of metastatic disease PM denotes parameningeal. Status

5 246 Dharmarajan et al. TABLE III. Frequencies of Radiation-Related Acute Toxicities in Anatomic Regions at Risk Anatomic region and toxicity (n ¼ number at risk) Grade 1 N (%) Grade 2 N (%) Grade 3 N (%) Grade 4 N (%) Skin (n ¼ 47) Dermatitis 17 (36%) 9 (19%) 5 (11%) 2 (4%) Head/neck (n ¼ 20) Mucositis 8 (40%) 2 (10%) 4 (20%) 2 (10%) Dysphagia 6 (30%) 1 (5%) 0 0 Low neck/chest (n ¼ 4) Esophagitis 2 (50%) 2 (50%) 0 0 Abdomen/pelvis (n ¼ 17) Nausea/vomiting 4 (24%) Diarrhea 6 (35%) 2 (12%) 2 (12%) 0 Proctitis 2 (12%) 3 (18%) 0 0 Cystitis 0 2 (12%) 1 (6%) 0 light of this, it is possible that the novel combination of radiosensitization with irinotecan and carboplatin may have contributed to favorable local control results. The worst acute chemoradiation-related toxicities were mucositis and dermatitis with 30% (n ¼ 6) of patients experiencing grades 3 and 4 mucositis and 15% (n ¼ 7) experiencing grades 3 and 4 dermatitis. The rate of severe mucositis in our study was lower than was reported in the patients undergoing standard-fractionated RT on IRS IV [24] who developed grades 3 4 mucositis at a rate of 46%. The rate of severe dermatitis in our study was slightly higher than but still comparable to that reported in IRS IV, where the reported rate was 9%. Gastrointestinal toxicity was low despite the well-known adverse effects of irinotecan on the gastrointestinal tract. In particular, treatment-limiting diarrhea was anticipated in the patients receiving abdominal and pelvic radiation, but the two patients who suffered grade 3 diarrhea and the single patient who suffered grade 3 cystitis were able to continue uninterrupted treatment with supportive therapy. None suffered grade 4 diarrhea or severe nausea/vomiting. IMRT allowed sparing of dose-limiting normal tissues and may have contributed to treatment tolerability. It is possible IMRT may also contribute to the prevention of late toxicities, as has been suggested by earlier work from our institution [25]. However many years of further follow-up is necessary for meaningful conclusions in this regard. CONCLUSION Our preliminary findings using concurrent radiation with irinotecan and carboplatin demonstrate a favorable toxicity profile and excellent local control, particularly given the unfavorable clinical features in the cohort. While IMRT may be a contributing factor in the success of this treatment regimen, the possibility that concurrent irinotecan with radiation also lent to this success cannot be excluded. Further follow-up will be necessary to determine the incidence and severity of secondary malignant neoplasms and other late effects. Event-free survival, overall survival, and a full analysis of chemotherapy-related toxicities experienced during the phase II window, induction chemotherapy, and maintenance periods will be reported once trial data from IRB # has matured. The combination of irinotecan and radiation is currently under study in a cooperative group randomized trial. ACKNOWLEDGMENT The authors thank the physicians, nurse practitioners, and nurses on the Pediatric Sarcoma Team for their excellent care of the patients presented in this manuscript. REFERENCES 1. Raney RB, Maurer HM, Anderson JR, et al. The Intergroup Rhabdomyosarcoma Study Group (IRSG): Major lessons From the IRS-I through IRS-IV studies as background for the current IRS-V treatment protocols. Sarcoma 2001;5: Pappo AS, Lyden E, Breneman J, et al. Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: An intergroup rhabdomyosarcoma study. 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