GUIDELINE SUMMARY (Fig. 1)
PM-RMS represents a very challenging site to treat with local failure remaining the dominant form of failure. Definitive chemoradiation is the preferred treatment approach for PM-RMS, with the goal of maximizing cure while minimizing loss of form and function. Radiation timing, volumes, and techniques have evolved greatly over the last 50 years with this goal in mind.
Imaging with MRI of the head neck is critical in PM-RMS to assess the extent of disease (including any possible intracranial extension), evaluate response, and fuse for accurate radiation planning. Although radiotherapy was previously delivered earlier for those with high-risk parameningeal features, the timing of primary site radiotherapy for localized PM-RMS is now similar to other sites at week 13 (and up to week 20-22 in the metastatic setting). The recommended radiation dose for PM-RMS is 50.4 Gy in 28 fractions, with a boost to 55.8 - 59.4 Gy allowed for unfavorable features. To account for the response to chemotherapy prior to radiation, the pre-chemotherapy extent of disease can be treated to 36 Gy - 41.4 Gy, with a boost to the macroscopic residual disease present at the time of radiation planning to the final dose. Radiation target volumes have reduced drastically over time, with the goal of enhancing the therapeutic ratio, from prior craniospinal irradiation to now conformal treatment of the tumor with a 1-1.5cm margin. Although prophylactic nodal irradiation is not recommended, for patients with clinical or pathologic involvement of nodes, a dose of 36-41.4 Gy over 20-23 fractions (with gross disease to 50.4 Gy) is recommended to the involved nodal chain or site. To minimize toxicity and dose to the many critical organs at risk in the head and neck, highly conformal techniques like IMRT or proton therapy must be utilized, with proton therapy specifically encouraged whenever feasible to minimize normal tissue toxicity. Despite advancements in volumes and technology, morbidity of local therapy with radiation to the head and neck remains significant, including cosmetic defects, endocrinopathies, impaired vision and hearing, dental complications, and second cancers.
Given the locally infiltrative nature and difficulty with obtaining negative margins, the role of surgical resection is often limited to initial biopsy and for local therapy in the relapsed setting. However, constant re-evaluation of the optimal treatment approach for patients with PM-RMS is necessary. Overall, we recommend a multi-disciplinary approach for treatment of PM-RMS, with the primary goal of maximizing cure while maintaining form and function.
ACKNOWLEDGMENTS
We would like to thank Suzi Birz for her organizational and administrative expertise. The International Soft Tissue Sarcoma Consortium and the Pediatric Cancer Data Commons are supported in part by Cancer Research Foundation, Children’s Research Foundation, Comer Development Board, Kick Cancer, King Baudouin Foundation, Rally Foundation for Childhood Cancer Research, Seattle Children’s Foundation from Kat’s Crew Guild through the Sarcoma Research Fund, St. Baldrick’s Foundation, and The Andrew McDonough B+ Foundation. This work is made possible through the efforts of Children’s Oncology Group, Cooperative Weichteilsarkom Studiengruppe der GPOH, The European paediatric Soft tissue sarcoma Study Group, MMT Malignant Mesenchymal Tumour Committee, and STSC AIEOP Italian Soft Tissue Sarcoma Committee.
CONFLICT OF INTEREST STATEMENT:
DC, SH, AS, BT, SW have no relevant conflicts to disclose. HM acknowledges the support of the NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research. JB acknowledges a research grant from Asco/Pfizer.
REFERENCES
1 Casey, D. L. & Wolden, S. L. Rhabdomyosarcoma of the Head and Neck: A Multimodal Approach. J Neurol Surg B Skull Base 79 , 58-64 (2018).
2 Raney, R. B., Jr. et al. Improved prognosis with intensive treatment of children with cranial soft tissue sarcomas arising in nonorbital parameningeal sites. A report from the Intergroup Rhabdomyosarcoma Study. Cancer 59 , 147-155 (1987).
3 Turner, J. H. & Richmon, J. D. Head and neck rhabdomyosarcoma: a critical analysis of population-based incidence and survival data.Otolaryngol Head Neck Surg 145 , 967-973 (2011).
4 Merks, J. H. et al. Parameningeal rhabdomyosarcoma in pediatric age: results of a pooled analysis from North American and European cooperative groups. Ann Oncol 25 , 231-236 (2014).
5 Rahman, H. A. et al. Outcome of pediatric parameningeal rhabdomyosarcoma. The Children Cancer Hospital, Egypt, experience.J Egypt Natl Canc Inst 25 , 79-86 (2013).
6 Michalski, J. M. et al. Influence of radiation therapy parameters on outcome in children treated with radiation therapy for localized parameningeal rhabdomyosarcoma in Intergroup Rhabdomyosarcoma Study Group trials II through IV. Int J Radiat Oncol Biol Phys59 , 1027-1038 (2004).
7 Siegel, M. J. Magnetic resonance imaging of musculoskeletal soft tissue masses. Radiol Clin North Am 39 , 701-720 (2001).
8 Jawad, N. & McHugh, K. The clinical and radiologic features of paediatric rhabdomyosarcoma. Pediatr Radiol 49 , 1516-1523 (2019).
9 Freling, N. J. et al. Imaging findings in craniofacial childhood rhabdomyosarcoma. Pediatr Radiol 40 , 1723-1738; quiz 1855 (2010).
10 Van Rijn, R. R. et al. Imaging findings in noncraniofacial childhood rhabdomyosarcoma. Pediatr Radiol 38 , 617-634 (2008).
11 Raney, R. B. et al. Treatment of children and adolescents with localized parameningeal sarcoma: experience of the Intergroup Rhabdomyosarcoma Study Group protocols IRS-II through -IV, 1978-1997.Med Pediatr Oncol 38 , 22-32 (2002).
12 Norman, G. et al. Mind the gap: extent of use of diffusion-weighted MRI in children with rhabdomyosarcoma. Pediatr Radiol 45 , 778-781 (2015).
13 Inarejos Clemente, E. J. et al. MRI of Rhabdomyosarcoma and Other Soft-Tissue Sarcomas in Children. Radiographics40 , 791-814 (2020).
14 Harrison, D. J., Parisi, M. T. & Shulkin, B. L. The Role of (18)F-FDG-PET/CT in Pediatric Sarcoma. Semin Nucl Med47 , 229-241 (2017).
15 Vaarwerk, B. et al. Fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) computed tomography (CT) for the detection of bone, lung, and lymph node metastases in rhabdomyosarcoma.Cochrane Database Syst Rev 11 , CD012325 (2021).
16 Lucas, J. T., Jr., Pappo, A. S., Wu, J., Indelicato, D. J. & Krasin, M. J. Excessive Treatment Failures in Patients With Parameningeal Rhabdomyosarcoma With Reduced-dose Cyclophosphamide and Delayed Radiotherapy. J Pediatr Hematol Oncol 40 , 387-390 (2018).
17 Casey, D. L. et al. Increased local failure for patients with intermediate-risk rhabdomyosarcoma on ARST0531: A report from the Children’s Oncology Group. Cancer 125 , 3242-3248 (2019).
18 Bisogno, G. et al. Addition of dose-intensified doxorubicin to standard chemotherapy for rhabdomyosarcoma (EpSSG RMS 2005): a multicentre, open-label, randomised controlled, phase 3 trial.Lancet Oncol 19 , 1061-1071 (2018).
19 Spalding, A. C. et al. The effect of radiation timing on patients with high-risk features of parameningeal rhabdomyosarcoma: an analysis of IRS-IV and D9803. Int J Radiat Oncol Biol Phys87 , 512-516 (2013).
20 Casey, D. L., Wexler, L. H. & Wolden, S. L. Worse Outcomes for Head and Neck Rhabdomyosarcoma Secondary to Reduced-Dose Cyclophosphamide.Int J Radiat Oncol Biol Phys 103 , 1151-1157 (2019).
21 Cameron, A. L. et al. The Impact of Radiation Therapy in Children and Adolescents With Metastatic Rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 111 , 968-978 (2021).
22 Donaldson, S. S. et al. Results from the IRS-IV randomized trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma–a report from the IRSG. Int J Radiat Oncol Biol Phys 51 , 718-728 (2001).
23 Berry, M. P. & Jenkin, R. D. Parameningeal rhabdomyosarcoma in the young. Cancer 48 , 281-288 (1981).
24 Donaldson, S. S., Castro, J. R., Wilbur, J. R. & Jesse, R. H., Jr. Rhabdomyosarcoma of head and neck in children. Combination treatment by surgery, irradiation, and chemotherapy. Cancer 31 , 26-35 (1973).
25 Doyen, J. et al. Outcome and Patterns of Relapse in Childhood Parameningeal Rhabdomyosarcoma Treated With Proton Beam Therapy.Int J Radiat Oncol Biol Phys 105 , 1043-1054 (2019).
26 Weber, D. C. et al. Pencil Beam Scanning Proton Therapy for Pediatric Parameningeal Rhabdomyosarcomas: Clinical Outcome of Patients Treated at the Paul Scherrer Institute. Pediatr Blood Cancer63 , 1731-1736 (2016).
27 Ladra, M. M. et al. Local failure in parameningeal rhabdomyosarcoma correlates with poor response to induction chemotherapy. Int J Radiat Oncol Biol Phys 92 , 358-367 (2015).
28 Chen, C., Shu, H. K., Goldwein, J. W., Womer, R. B. & Maity, A. Volumetric considerations in radiotherapy for pediatric parameningeal rhabdomyosarcomas. Int J Radiat Oncol Biol Phys 55 , 1294-1299 (2003).
29 Eaton, B. R. et al. Radiation therapy target volume reduction in pediatric rhabdomyosarcoma: implications for patterns of disease recurrence and overall survival. Cancer 119 , 1578-1585 (2013).
30 Wolden, S. L. et al. Local Control for Intermediate-Risk Rhabdomyosarcoma: Results From D9803 According to Histology, Group, Site, and Size: A Report From the Children’s Oncology Group. Int J Radiat Oncol Biol Phys 93 , 1071-1076 (2015).
31 Ludmir, E. B. et al. Patterns of failure following proton beam therapy for head and neck rhabdomyosarcoma. Radiother Oncol134 , 143-150 (2019).
32 Bradley, J. A. et al. Patterns of Failure in Parameningeal Alveolar Rhabdomyosarcoma. Int J Radiat Oncol Biol Phys107 , 325-333 (2020).
33 Yang, J. C., Wexler, L. H., Meyers, P. A. & Wolden, S. L. Parameningeal rhabdomyosarcoma: outcomes and opportunities. Int J Radiat Oncol Biol Phys 85 , e61-66 (2013).
34 Benk, V. et al. Parameningeal rhabdomyosarcoma: results of an international workshop. Int J Radiat Oncol Biol Phys 36 , 533-540 (1996).
35 Koscielniak, E. et al. Prognosis of patients with parameningeal rhabdomyosarcoma (PM-RMS): The long term results of five consecutive CWS studies 1981-2009. Journal of Clinical Oncology34 , 10529-10529 (2016).
36 Buszek, S. M. et al. Disease Control and Patterns of Failure After Proton Beam Therapy for Rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 109 , 718-725 (2021).
37 Ludmir, E. B. et al. Regional Nodal Control for Head and Neck Alveolar Rhabdomyosarcoma. Int J Radiat Oncol Biol Phys101 , 169-176 (2018).
38 Vern-Gross, T. Z., Indelicato, D. J., Bradley, J. A. & Rotondo, R. L. Patterns of Failure in Pediatric Rhabdomyosarcoma After Proton Therapy. Int J Radiat Oncol Biol Phys 96 , 1070-1077 (2016).
39 Gallego, S. et al. Alveolar rhabdomyosarcoma with regional nodal involvement: Results of a combined analysis from two cooperative groups. Pediatr Blood Cancer 68 , e28832 (2021).
40 Turpin, B. et al. Sentinel lymph node biopsy in head and neck rhabdomyosarcoma. Pediatr Blood Cancer 66 , e27532 (2019).
41 Constine, L. S. et al. Pediatric Normal Tissue Effects in the Clinic (PENTEC): An International Collaboration to Analyse Normal Tissue Radiation Dose-Volume Response Relationships for Paediatric Cancer Patients. Clin Oncol (R Coll Radiol) 31 , 199-207 (2019).
42 Buwalda, J. et al. A novel local treatment strategy for advanced stage head and neck rhabdomyosarcomas in children: results of the AMORE protocol. Eur J Cancer 39 , 1594-1602 (2003).
43 Schoot, R. A. et al. Adverse events of local treatment in long-term head and neck rhabdomyosarcoma survivors after external beam radiotherapy or AMORE treatment. Eur J Cancer 51 , 1424-1434 (2015).
44 Vaarwerk, B. et al. AMORE treatment as salvage treatment in children and young adults with relapsed head-neck rhabdomyosarcoma.Radiother Oncol 131 , 21-26 (2019).
45 Lin, C. et al. Effect of radiotherapy techniques (IMRT vs. 3D-CRT) on outcome in patients with intermediate-risk rhabdomyosarcoma enrolled in COG D9803–a report from the Children’s Oncology Group.Int J Radiat Oncol Biol Phys 82 , 1764-1770 (2012).
46 Childs, S. K. et al. Proton radiotherapy for parameningeal rhabdomyosarcoma: clinical outcomes and late effects. Int J Radiat Oncol Biol Phys 82 , 635-642 (2012).
47 Kozak, K. R., Adams, J., Krejcarek, S. J., Tarbell, N. J. & Yock, T. I. A dosimetric comparison of proton and intensity-modulated photon radiotherapy for pediatric parameningeal rhabdomyosarcomas. Int J Radiat Oncol Biol Phys 74 , 179-186 (2009).
48 Lockney, N. A. et al. Late Toxicities of Intensity-Modulated Radiation Therapy for Head and Neck Rhabdomyosarcoma. Pediatr Blood Cancer 63 , 1608-1614 (2016).
49 Ladra, M. M. et al. Preliminary results of a phase II trial of proton radiotherapy for pediatric rhabdomyosarcoma. J Clin Oncol32 , 3762-3770 (2014).
50 Xiang, M., Chang, D. T. & Pollom, E. L. Second cancer risk after primary cancer treatment with three-dimensional conformal, intensity-modulated, or proton beam radiation therapy. Cancer126 , 3560-3568 (2020).
51 Daya, H., Chan, H. S., Sirkin, W. & Forte, V. Pediatric rhabdomyosarcoma of the head and neck: is there a place for surgical management? Arch Otolaryngol Head Neck Surg 126 , 468-472 (2000).
52 Zevallos, J. P. et al. Modern multimodality therapy for pediatric nonorbital parameningeal sarcomas. Head Neck32 , 1501-1505 (2010).
53 Wertz, A. et al. Minimally Invasive Approach for Resection of Parameningeal Rhabdomyosarcoma. J Neurol Surg B Skull Base78 , 210-214 (2017).
54 Callender, T. A. et al. Rhabdomyosarcoma of the nose and paranasal sinuses in adults and children. Otolaryngol Head Neck Surg 112 , 252-257 (1995).
55 Carty, M. J., Ferraro, N. & Upton, J. Reconstruction of pediatric cranial base defects: a review of a single microsurgeon’s 30-year experience. J Craniofac Surg 20 Suppl 1 , 639-645 (2009).
56 Reilly, B. K. et al. Rhabdomyosarcoma of the head and neck in children: review and update. Int J Pediatr Otorhinolaryngol79 , 1477-1483 (2015).
57 Rodeberg, D. A. et al. Delayed primary excision with subsequent modification of radiotherapy dose for intermediate-risk rhabdomyosarcoma: a report from the Children’s Oncology Group Soft Tissue Sarcoma Committee. Int J Cancer 137 , 204-211 (2015).
58 Lautz, T. B. et al. Benefit of delayed primary excision in rhabdomyosarcoma: A report from the Children’s Oncology Group.Cancer 127 , 275-283 (2021).