Consensus and controversies regarding the treatment of rhabdomyosarcoma

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1 Received: 16 June 2017 Revised: 28 July 2017 Accepted: 10 August 2017 DOI: /pbc REVIEW Pediatric Blood & Cancer The American Society of Pediatric Hematology/Oncology Consensus and controversies regarding the treatment of rhabdomyosarcoma Scott C. Borinstein 1 Diana Steppan 2 Masanori Hayashi 2 David M. Loeb 2 MichaelS.Isakoff 3 Odion Binitie 4 Andrew S. Brohl 4 Julia A. Bridge 5 Mark Stavas 6 Eric T. Shinohara 6 William H. Meyer 7 Damon R. Reed 4 Lars M. Wagner 8 1 Division of Pediatric Hematology-Oncology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 2 Division of Pediatric Oncology, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 3 Center for Cancer and Blood Disorders, Connecticut Children's Medical Center, Hartford, Connecticut 4 Sarcoma Department, Adolescent and Young Adult Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 5 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 6 Division of Radiation Oncology, Vanderbilt University Medical Center, Nashville, Tennessee 7 Jimmy Everest Section of Pediatric Hematology/Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 8 Division of Pediatric Hematology/Oncology, University of Kentucky, Lexington, Kentucky Correspondence Scott C. Borinstein, Division of Pediatric Hematology-Oncology, Department of Pediatrics, Vanderbilt University Medical Center, 2220 Pierce Ave, 390 PRB, Nashville, TN Scott.c.borinstein@vanderbilt.edu [This article was modified on 18 September 2017 after initial publication to correct a misspelling in Figure 2.] Abstract Optimal treatment of rhabdomyosarcoma (RMS) requires multidisciplinary approach, incorporating chemotherapy with local control. Although current therapies are built on cooperative group trials, a comprehensive standard of care to guide clinical decision making has been lacking, especially for relapsed patients. Therefore, we assembled a panel of pediatric and adolescent and young adult sarcoma experts to develop treatment guidelines for managing RMS and to identify areas in which further research is needed. We created algorithms incorporating evidence-based care for patients with RMS, emphasizing the importance of clinical trials and close integration of all specialties involved in the care of these patients. KEYWORDS adolescent and young adult, chemotherapy, pediatric, rhabdomyosarcoma, sarcoma 1 INTRODUCTION Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, with approximately 350 cases diagnosed per year in the United States. 1 The 2013 World Health Organization classification system for RMS includes four subgroups: embryonal rhabdomyosarcoma (ERMS), alveolar rhabdomyosarcoma (ARMS), pleomorphic, and spindle cell/sclerosing. 2 There is tremendous variability in primary Abbreviations: ARMS, alveolar rhabdomyosarcoma; CT, computerized tomography; ERMS, embryonal rhabdomyosarcoma; FN-RMS, fusion-negative rhabdomyosarcoma; FP-RMS, fusion-positive rhabdomyosarcoma; IRS, International RMS Study; RMS, rhabdomyosarcoma; SRMS, spindle cell/sclerosing RMS tumor site, histology, and clinical behavior of these tumors, and new understanding of the molecular biology of RMS has helped refine risk stratification and appropriately tailor therapy. Adding to the complexity, the choice of local control options with surgery and/or radiotherapy requires thoughtful input from experienced oncologic surgeons and radiation oncologists, underscoring the need for strong multidisciplinary involvement. Furthermore, recent discoveries have changed the diagnostic testing and staging approach and have altered therapeutic strategies for RMS patients. We therefore recruited sarcoma specialists to propose a management pathway for children, adolescents, and young adults diagnosed with pediatric-type, nonpleomorphic RMS. When available, data from clinical trials support our recommendations, although some are consensus opinions. Pediatr Blood Cancer. 2018;65:e wileyonlinelibrary.com/journal/pbc c 2017 Wiley Periodicals, Inc. 1of10

2 2of10 BORINSTEIN ET AL. 2 METHODS A group of multidisciplinary pediatric and adolescent and young adult sarcoma specialists from the United States was empaneled to discuss how we treat RMS and to identify current controversies regarding this disease. We held conference calls over 6 months where we reviewed data and shared our strategies to manage both common and rare clinical scenarios pertaining to optimal RMS management. At times, our group was uniform in practice decisions; however, there were significant differing treatment strategies. These in depth discussions were synthesized to develop consensus guidelines. We framed this review to address 10 key questions, which focus on the diagnosis, staging, and comprehensive management of RMS. 3 QUESTIONS 3.1 Question 1: Should testing for FOX01 fusion in tumor cells be done for all patients with RMS? Approximately 75% of tumors with histologic features of ARMS demonstrate recurrent t(2;13) or t(1;13) translocations, resulting in fusion of the DNA binding domain of PAX3 (2q36.1) or PAX7 (1p36) with the carboxyl terminus of FOXO1 (13q14). 3 Importantly, ARMS lackingfoxo1 translocation has a gene expression signature and clinical behavior more similar to ERMS. 4 This key finding has led to a modernization of the classification of nonpleomorphic RMS into two major subgroups: fusion-positive RMS (FP-RMS) and fusion-negative RMS (FN-RMS). 4 6 Molecular testing (e.g., FISH, reverse transcription PCR, or next-generation sequencing) can readily identify PAX/FOXO1 fusions, and because results may impact treatment decisions, we recommend testing for FOXO1 fusions on all patients with alveolar or embryonal histology. Spindle cell/sclerosing RMS (SRMS) has been newly identified as an official subtype, and there has been conflicting evidence about whether it behaves more similarly to ERMS or adult-type or pleomorphic RMS. 7 These tumors occur more frequently in males and recent data suggest worse prognosis for SRMS in adults when compared to children, in patients with parameningeal tumors, or when associated with MYOD1 mutations. 8,9 In contrast, infants with SRMS and NCOA2 or VGLL2 translocations may have favorable outcomes. 8 At present, SRMS patients are stratified according to more established risk factors until more data are available to guide therapy for this uncommon subtype. The fourth subtype, pleomorphic RMS, is more common in adults and extremely rare in the pediatric population. We recommend that the pathology of pleomorphic RMS diagnosed in a pediatric patient be reviewed at a high volume sarcoma center. 3.2 Question 2: Is bone and bone marrow evaluation necessary for all patients with RMS? RMS most often spreads to lymph nodes, lungs, cortical bone, and bone marrow. Initial staging has therefore traditionally included dedicated computed tomography (CT) scan of the chest to identify lung nodules, 99 Tc bone scintigraphy to detect skeletal metastases, and bilateral bone marrow aspiration and biopsy to assess marrow involvement. Cooperative group studies have often required this entire metastatic workup for all patients. However, the overall incidence of metastatic involvement is low, and so we recommend a risk-specific rather than disease-specific approach to staging (Fig. 1A), based on the fact that nodal involvement, tumor invasiveness, and histologic subtype are the most powerful predictors of metastases. Retrospective data from 955 FN-RMS patients without nodal or lung disease treated on cooperative group studies suggest that the chance of metastases in bone or bone marrow is <1%. 10 Therefore, in these select patients (tumors < 5 cm, FN-RMS, no evidence of nodal disease), omitting assessments for bone and bone marrow disease is reasonable. We continue to obtain chest CT at initial diagnosis, although the yield of this study is low for FN-RMS patients without nodal disease. PET-CT is emerging as a useful test for staging RMS, and we routinely perform this for all newly diagnosed patients, as it may offer an additional assessment of regional lymph nodes. 11 Identification of nodal metastases is critically important in the management of RMS, and tissue sampling should be performed for all patients with clinically or radiographically suspicious lymphadenopathy. Sampling of clinically normal lymph nodes is recommended in two specific situations. First, patients with paratesticular RMS over 10 years of age should undergo staging ipsilateral retroperitoneal lymph node dissection, as the ability to identify nodal disease by imaging remains unsatisfactory. 12 Second, nodal sampling is recommended for extremity tumors, as up to 23% of these patients will have regional lymphatic metastases even with normal sized nodes. 13 Sentinel lymph node biopsy is preferable when available, as it can identify therapychanging nodal disease that occasionally may not be appreciated with PET-CT. 14 In addition to assessment of nodal disease, fluid or effusion analysis is warranted when present, as cytologic evidence of malignancy in pleural or peritoneal fluid qualifies as metastatic disease. Radiographic or pathologic identification of body cavity tumor implants is also defined as metastasis. For patients with parameningeal RMS, cerebrospinal fluid should be evaluated. 15 Most pediatric oncologists in the United States use the International RMS Study (IRS) grouping and TNM staging, as opposed to traditional soft tissue sarcoma staging systems. 16 This system takes into account the prognostic significance of tumor site, size, and extent of resection, and allows for risk stratification (Fig. 1B). 3.3 Question 3: Is genetic testing for cancer predisposition syndromes necessary for all RMS patients? There is growing evidence that sarcoma patients in general may harbor underlying germline mutations more commonly than previously appreciated, leading to recommendations by some for broader genetic screening of newly diagnosed patients. 17,18 RMS has been associated with several cancer predisposition syndromes, including neurofibromatosis type 1, Gorlin, Beckwith Wiedemann, and Li Fraumeni syndromes among others. These diagnoses have important implications not only for the patient but also for the siblings or

3 BORINSTEIN ET AL. 3of10 FIGURE 1 RMS diagnostic and staging workup other family members. In regard to Li-Fraumeni syndrome, Young et al. found that <2% of 213 intermediate-risk RMS patients had germline TP53 mutations. 19 However, the incidence may be higher in patients diagnosed with RMS before age 3 years. 20 Furthermore, Hettmer and colleagues have reported germline TP53 mutations in 11 (73%) of 15 children whose tumors have anaplastic features. 18 The collection of germline data from RMS patients is ongoing, and new findings may help further refine guidelines for genetic testing. At present, it seems reasonable at a minimum to strongly consider referral for genetic counseling patients who are younger at diagnosis, whose tumors have anaplastic features, or who have significant family histories of malignancy.

4 4of10 BORINSTEIN ET AL. A. Line therapy First Low-Risk RMS Intermediate Risk RMS High-Risk FN-RMS >10 yo High-Risk FP-RMS (Preferred) (Alternate) (Preferred) (Alternate) (Preferred) RMS Consensus Treatment Algorithm (All Reasonable) VAC x 4 VA x 4 VAC/VI (VAC x 3; VI x 2) VAC x 4 LC VA x 4 LC VA x 12 VAC/VI LC (VAC x 4; VI x 5) LC VAC x 8 VAC/VI/VDC/IE (51 weeks) VAC/VI (VAC x 7; VI x 7) VAC (VAC x 14) LC LC LC VAC/VI/VDC/IE VAC/VI VAC VAC Vincristine 1.5 mg/m 2 max 2 mg Dactinomycin mg/kg max 2.5 mg* Cyclophosphamide 1200 mg/m 2 * VA Vincristine 1.5 mg/m 2 max 2 mg* Dactinomycin mg/kg* max 2.5 mg VI Vincristine 1.5 mg/m 2 max 2 mg* Irinotecan 50 mg/m2 x 5 VDC Vincristine 1.5 mg/m 2 Doxorubicin 75 mg/m 2 ± dexrazoxane IE Ifosfamide 9 g/m 2 Etoposide 500 mg/m 2 Weekly vincristine given in alt weeks LC: Local control (surgery or radiation) * dose reduce for age < 3 years (see Supplemental Table 1 for detailed chemotherapy protocols) Up-Front Resection Radiation Recommendations Surgical Group Margin Node XRT (Gy) I (FN-RMS) Neg N0 0 IIA (FP-RMS) Neg N0 36 IIA (N0) Pos N0 36 IIB (N1) Neg N1 36 IIC (N1) Pos N III (any) N/A Nx 50.4 III (orbit) N/A Nx Delayed Resection Radiation Recommendations Resection Margin Node XRT (Gy) Neg. N0 36 Microscopic N N No Resection or Gross residual* Any 50.4 * Orbital RMS = 45 Gy and complete response to induction chemotherapy, otherwise 50.4 Gy B. Treatment Response Surveillance Complete Response or Partial Response MRI or CT of primary site q3 mo x 4; q4 mo x 6; q 6 mo x 4 CXR or Chest CT q3 mo x 4; q4 mo x 6; q 6 mo x 6 Bone scan/pet Scan as clinically indicated Echocardiogram if received anthracyclines Late effects surveillance per institutional preference Refractory/Progressive Disease mo = months Progression/Refractory Therapy C. Refractory or Recurrent RMS Treatment Suspected Relapse Refractory/ Progressive Disease Biopsy (unless unequivocal) consider tumor molecular genotyping Assess prognosis (prior Tx, age, sites of recurrence, etc.) Discuss goals of treatment and prognosis Partial Response (radiated lesions) or Complete Response Surveillance Chemotherapy (Table 1) 2-3 cycles to assess response + Local Control Resect if feasible or Radiation Therapy Clinical trial versus SOC Recurrence/ Progression Supportive/Palliative care SOC = Standard of Care FIGURE 2 RMS consensus treatment algorithm. N0, no evidence of nodal disease; N1, evidence of nodal disease; Nx, any nodal disease status; SOC, standard of care therapy 3.4 Question 4: What is the optimal management of low-risk RMS? Given the high rate of micrometastatic disease that leads to relapse in patients treated only with local therapy, all RMS patients are treated with adjuvant chemotherapy, with the extent of treatment based on established risk factors. There was strong consensus that, when feasible, all newly diagnosed RMS patients should be offered participation in a therapeutic clinical trial. Our definition of low-risk disease (Fig. 1B) is narrower than historical definitions, and using the IRS grouping and TNM staging includes those with FN-RMS who have Stage 1 2 and Group I II tumors or who have Stage 1 Group III orbital tumors. 16 For these patients, we recommend 22 weeks of therapy composed of four cycles of vincristine, dactinomycin, and

5 BORINSTEIN ET AL. 5of10 cyclophosphamide (VAC) followed by four cycles of vincristine and dactinomycin (VA), with a total cumulative cyclophosphamide exposure of 4.8 g/m 2 that may result in a lower incidence of infertility (Fig. 2A). 21 Alternatively, 45 weeks of VA may be administered with similar results, although with a significantly longer treatment course and increased medical costs (Fig. 2A, Supplementary Table S1). 22,23 Outcome for these patients is excellent, with 5-year survival greater than 90% (Fig. 1C). However, given the poor results with low-risk therapy for patients whose tumors were Stage 1 (nonorbit) Group III or Stage 3 Group I II, we believe such patients should be treated with intermediate-risk protocols. 24 demonstrate improved survival with this intensified chemotherapy regimen compared to previous trials that included VAC or VAC/VI. 27,31 This lack of benefit of the intensive kitchen sink approach for highrisk FP-RMS patients creates controversy over their management. Outside of a study (which should be strongly encouraged), we agreed that there are multiple acceptable options, but some in our group recommended limiting treatment to either VAC or VAC/VI, while others continue to offer the dose-intensive multiagent approach described after reviewing the risks and benefits of each approach, and also taking into consideration quality of life given the very poor prognosis of these patients (Fig. 2A). 3.5 Question 5: Should irinotecan be used for treatment of intermediate-risk RMS? Approximately 60% of newly diagnosed RMS patients are considered intermediate risk, and optimal treatment has evolved through sequential clinical trials, resulting in 65% 3-year event-free survival, with an inferior outcome for patients with FP-RMS (Fig. 1C). 6 A phase III investigation randomized newly diagnosed intermediate-risk patients to VAC versus VAC plus vincristine and irinotecan (VI), using a standard cyclophosphamide dose of 1.2 g/m 2 per dose in each arm. Both regimens had comparable outcomes (4-year event-free survival 65% vs. 68%), but VAC/VI was associated with fewer hospitalizations and less hematologic toxicity. 25 Furthermore, 50% reduction in cumulative cyclophosphamide dose (8.4 g/m 2 vs g/m 2 ) may decrease the risk of infertility and secondary malignancy in survivors. 26 Therefore, if an appropriate clinical trial is not available, we recommend VAC/VI chemotherapy as standard of care for intermediate-risk RMS (Fig. 2A). Because the seven courses of irinotecan (each lasting 5 days) may be logistically problematic or poorly tolerated due to gastrointestinal toxicity, VAC chemotherapy alone may be reasonable in certain patients. 3.6 Question 6: What is the best management of metastatic RMS? Treatment of metastatic RMS remains controversial. The outcome for patients with distant metastatic disease varies greatly depending on risk factors identified by Oberlin et al., including age <1 or >10 years, unfavorable primary tumor site, 3 metastatic sites, or bone/bone marrow involvement. 27,28 For example, group IV patients <10 years of age with embryonal histology were reported to have a 3-year eventfree survival of 64% with VAC alone, emphasizing that young FN-RMS patients with limited metastatic disease appear biologically different from older patients with metastatic RMS, and so we consider such patients to have intermediate-risk disease. 29 Therefore, we define high-risk RMS as group IV, stage 4 FP-RMS or group IV, stage 4 FN-RMS for patients greater than 10 years of age. A recent cooperative group trial for high-risk RMS patients incorporated interval-compressed vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide (IE) into a VAC/VI backbone. Patients >10 years old with metastatic FN-RMS did have a better outcome compared to historic controls, and thus may benefit from this more intensive chemotherapy. 30,31 However, metastatic FP-RMS patients did not 3.7 Question 7: What is the role of surgery and radiation therapy in the treatment of RMS? Surgery and/or radiotherapy are essential to the optimal management of RMS regardless of stage or risk group. Local control options must be carefully considered at the time of diagnosis, and complete resection of primary tumor is desirable if it can be achieved with minimal morbidity and negative microscopic margins. 32 Second-look surgery to resect residual disease or positive margins may be considered, thus omitting the need for adjuvant radiation therapy in select cases. When up-front resection would result in significant morbidity, biopsy alone is recommended, as there is no advantage for debulking over biopsy alone in patients with Group III tumors. 33 Adjuvant radiotherapy is recommended for all patients except those with completely resected (margin-negative) FN-RMS (Fig. 2A). 34 Radiation dosages are based on the extent of resection, FOXO1 fusion status, nodal disease, and tumor site and size. For example, a patient with completely resected FN-RMS may receive no radiotherapy, while a patient with completely resected FP-RMS will receive 36 Gy to the primary site, and a patient with regional nodal involvement will receive 41.4 Gy even if surgical margins are negative. In patients with incompletely resected or gross disease, 50.4 Gy should be considered, except for orbital primaries in which 45 Gy is often used (Fig. 2A). 35 However, patients with orbital RMS who failed to achieve a complete radiographic response to therapy had an increased local recurrence rate when receiving 45 Gy of radiation treatment, suggesting that this subset of patients may benefit from a higher dose (such as 50.4 Gy). 36 Given that patients with bulky Group III tumors > 5cm have an increased risk of local recurrence, increasing the radiation dose to 59.4 Gy in these individuals is currently being investigated in a prospective clinical trial (NCT ). Management of lymph node spread is critical in the treatment of RMS. Complete lymphadenectomy of the entire regional nodal basin is not usually performed if lymph node metastases are identified. Instead, patients with nodal involvement are usually treated with irradiation to the regional basin. However, given the toxicity of radiotherapy, histologic documentation of regional metastases is important when considering that enlarged regional nodes following primary tumor biopsy may simply be reactive but not truly neoplastic. No studies have demonstrated a benefit for specific timing of radiotherapy, although radiation is most commonly initiated after four cycles of neoadjuvant chemotherapy. Recent data suggest that even

6 6of10 BORINSTEIN ET AL. when there is cranial nerve palsy or skull base erosion from parameningeal RMS, radiotherapy can safely and effectively be given at week 12 as long as neoadjuvant chemotherapy is started promptly. 37 In cases of very young children, delaying radiotherapy until later in treatment may be beneficial, although omission of XRT will result in an increased risk of local recurrence. 38 Furthermore, when tumors are close to vital structures, proton radiotherapy or brachytherapy should be considered to minimize side effects. 39 In cases when local control is excessively complex or difficult, referral to a medical center with extensive experience in both surgical and radiation management of complex RMS patients should be considered. The majority of intermediate-risk RMS patients have only had a biopsy and are not resected before starting chemotherapy. Although historically these patients received radiotherapy alone for local control, delayed primary tumor resection following neoadjuvant chemotherapy may facilitate local control and allow lowering of radiotherapy dose, thus potentially reducing long-term sequelae. Recent data suggest that in select patients delayed primary excision with less radiation can achieve local control rates similar to historical controls treated with higher radiotherapy dosages (Fig. 2A). 40 Surgery and/or radiation remain important in the management of high-risk RMS with oligometastatic disease to decrease treatment failures. When there are widespread metastases at presentation, local control is often delayed until later in treatment, and may be customized to focus on the most symptomatic or critical sites. In almost all of these advanced cases, treatment is with palliative intent. 3.8 Question 8: How should patients with residual masses at the end of therapy be managed? Patients who complete therapy for RMS frequently do not achieve complete radiographic response by cross-sectional imaging, though PET scans are often normal. This is likely due to tumor scarring or differentiation. Because the extent of tumor response does not predict survival, resection or biopsy of residual tumor is not recommended except in cases in which they are enlarging or painful. 41 Residual masses that remain PET avid are a challenge to manage. These patients have an increased risk of both local and metastatic relapse, and a decision whether to biopsy or resect a residual PET avid tumor should be made on a case-by-case basis weighing the risks of morbidity versus benefit. 42 Given the poor outcome for high-risk RMS patients, maintenance chemotherapy regimens have been tested in a small nonrandomized clinical trial but no conclusive benefit has been established. 43 We therefore do not generally recommend maintenance chemotherapy in RMS patients, except in the context of a clinical trial. However, the European Pediatric Soft Tissue Sarcoma Group 2005 clinical trial (NCT ) incorporates a maintenance regimen with vinorelbine and oral cyclophosphamide for certain IRS Group II and III patients. Results of this study may provide valuable information on the benefit and toxicity of maintenance chemotherapy for this population. Patients should be followed closely after treatment (Fig. 2B). Some providers recommend a baseline end-of-treatment PET/CT scan in high-risk patients, but we do not routinely obtain serial surveillance PET scans. Typically, surveillance MRI of the primary tumor and chest imaging are performed at 3-month intervals during the first year, with intervals increasing over time. Some providers recommend pulmonary surveillance with chest CT scan, whereas others use chest X-ray for all patients except those with previous pulmonary metastases. Imaging after 5 years is not routinely recommended. All patients should be followed throughout their life to monitor for late effects related to therapy. 3.9 Question 9: What is the best strategy for treating relapsed RMS? At least one-third of all patients with RMS experience progressive disease or relapse. The median time to progression is 13 months from diagnosis, and 95% of all failures occur within 3 years. Approximately 40% of relapses are metastatic, usually involving the lungs, bones, or lymph nodes. The 5-year progression-free survival rate for 605 patients with relapsed RMS of all stages treated on IRS group protocols was 17%. 44 Patients with low-stage FN-RMS who have received more limited therapy usually respond well to salvage therapy and often can be cured with further chemotherapy combined with surgery or radiotherapy (if not used initially).unfortunately, this favorable group is less than 20% of those with recurrent RMS. Features associated with worse outcome include metastatic recurrence, prior radiotherapy, relapse within 18 months of diagnosis, and initial tumors with alveolar histology, size > 5 cm, or unfavorable location. Algorithms incorporating these risk factors have been proposed to help predict outcome for relapsed patients. 45 For patients with suspected relapse, biopsy is recommended unless the diagnosis is unequivocal (Fig. 2C). Given the systemic nature of RMS, patients generally are treated with chemotherapy in addition to local control. Surgery can be considered for lesions that can be resected with minimal morbidity. Radiotherapy is often used to treat the primary tumor site if not initially treated, and to treat metastatic sites such as bone or lung when such therapy is feasible. Radiotherapy may be initially delayed, particularly for metastatic sites, in an effort to assess the responsiveness and allow better bone marrow tolerance of systemic chemotherapy. The median progression-free survival following first recurrence/progression for all RMS patients is approximately 9 months. 44 Although no published data exist on the optimal length of salvage therapy, most patients receive at least eight cycles of chemotherapy if complete response is documented and tolerance is acceptable. Unfortunately, treatment often ends with either progressive disease or unacceptable toxicity. Enrollment on a clinical trial is preferable for patients with relapsed RMS. For those not on a therapeutic study, multiple salvage chemotherapy regimens with documented activity may be considered (Table 1) There has been no direct comparison of these therapies to identify one optimal treatment, so therapy decisions are often impacted by the extent and type of prior treatment, as well as patient condition and enthusiasm for further therapy. Our consensus recommendation for patients who demonstrate relapse after low-risk disease (who did not initially receive intensive therapy) is to administer irinotecan-based therapy or a more intensive

7 BORINSTEIN ET AL. 7of10 TABLE 1 Salvage chemotherapy regimens for RMS Agents Cyclophosphamide, vinorelbine temsirolimus 50 cumulative n %CR %PR Response rate (CR + PR) (%) Toxicity: high/medium/low Primary toxicities M Myelosuppression, requires G-CSF, alopecia Cyclophosphamide M Myelosuppression, and topotecan 52 requires G-CSF, alopecia Oral cyclophosphamide and vinorelbine 51 Estimated PFS at 4 months Comments 47% Pediatric phase II 75% Pediatric phase II L Mild myelosuppression 36% Pediatric phase II Vinorelbine 47, L Mild myelosuppression NA Pediatric phase II, institutional study Vincristine, M Diarrhea, irinotecan 49 myelosuppression, nausea NA Phase II window data M Myelosuppression, Gemcitabine and 60% Mostly docetaxel 46 requires G-CSF, neurotoxicity, allergic reactions, alopecia retrospective data NA, data not available; PFS, progression free survival, PR, partial response. regimen of vincristine, cyclophosphamide, and doxorubicin alternating with IE in conjunction with aggressive local control with surgery or radiotherapy. 49,53 Although carboplatin and temozolomide have also been used in combination salvage therapy, their specific contribution to efficacy is not clear. 54 For relapse of more heavily pretreated patients, we recommend the combination of cyclophosphamide, vinorelbine, and temsirolimus. 50 Cyclophosphamide combined with topotecan has also shown activity, although is more myelosuppressive than other regimens. 52 While these combinations have produced significant responses, the vast majority of patients ultimately develop disease progression, underscoring the need for new therapies. Agents commonly used for adult soft tissue sarcoma, such as gemcitabine and docetaxel or pazopanib, have been less extensively studied in RMS. 46,55,56 Furthermore, there is little published data demonstrating the efficacy of tyrosine kinase inhibitors in the treatment of relapsed RMS. Intensification of therapy followed by autologous or allogeneic stem cell transplantation has also not been routinely helpful, and is generally done only in the context of a clinical trial. 57,58 Although the use of molecular profiling or patient-derived xenografts to guide therapy is intuitively appealing and commonly done in the setting of recurrent disease, there are no prospective published data demonstrating that this strategy affects outcome for patients with relapsed RMS. Similarly, the role of immunotherapy, including checkpoint inhibitors (e.g., agents that target PD-1, PD-L1, or CTLA-4), immunomodulatory agents, or chimeric antigen receptor T-cell therapy, are being evaluated but efficacy has not yet been established Question 10. How should adults with RMS be managed? Outcomes for RMS worsen with age, even when comparing patients age years with those under 14 years. 59 The reasons for this are multifactorial and may include delays in presentation and access to care in sarcoma centers, poor adherence to aggressive treatment regimens, potential pharmacokinetic differences, and limited accrual on clinical trials. 60 There are important biologic differences in the tumors as well, with the more aggressive pleomorphic subtype comprising up to 43% of RMS diagnosed in adults. 61 This subtype behaves more like other adult soft tissues sarcomas, with less predictable chemotherapy sensitivity and historic survival rates <30%. 62 No formal trials have compared efficacy of various treatment regimens, although many patients receive adjuvant chemotherapy with anthracyclines and alkylating agents in combination with local control measures. It does not appear that conventional multiagent regimens used for pediatric patients routinely benefit those with pleomorphic RMS, and more data are needed about the biology and treatment for these tumors. In contrast, adults with nonpleomorphic RMS may indeed benefit from riskbased pediatric regimens, which have prompted cooperative groups to extend enrollment up to age CONCLUSION We describe a consensus approach to RMS that highlights recent discoveries while identifying areas in which further research is needed. The complexity, rarity, and poor outcome of this disease underscore the need for an organized approach through clinical trial enrollment when possible, and patients clearly benefit most through wellcoordinated multidisciplinary care. CONFLICT OF INTEREST The authors declare that there is no conflict of interest. ACKNOWLEDGMENTS D.R. and M.I. receive funding from the National Pediatric Cancer Foundation ( for this work. M.I. also receives funding

8 8of10 BORINSTEIN ET AL. from the Reid R. Sacco AYA Cancer Alliance. M.H. was supported by the SARC Sarcoma SPORE Career Development Award (5U54CA ). ORCID Scott C. Borinstein Damon R. Reed REFERENCES 1. Pizzo PA, Poplack DG. Principles and Practice of Pediatric Oncology. 5th ed. Philadelphia: Lippincott Williams & Wilkins; Fletcher CDM. World Health Organization., International Agency for Research on Cancer. WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon: IARC Press; Davicioni E, Finckenstein FG, Shahbazian V, Buckley JD, Triche TJ, Anderson MJ. Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas. Cancer Res. 2006;66(14): Williamson D, Missiaglia E, de Reynies A, et al. Fusion genenegative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J Clin Oncol. 2010;28(13): Missiaglia E, Williamson D, Chisholm J, et al. 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