2.4 Nodal irradiation
2.4.1 Expert Consensus:
For node negative PM-RMS, prophylactic nodal irradiation is not recommended. For node positive PM-RMS (clinical or pathologic involvement), 36-41.4 Gy at 1.8 Gy per fraction is recommended to the involved nodal chain or site. For nodal volumes, the GTV consists of the gross nodal disease, with a 1cm expansion edited for normal tissue barriers to disease extension to create the CTV. The CTV should also encompass the entire lymph node drainage chain or, as per EpSSG practice, a 2-3 cm expansion superiorly and inferiorly in the direction of nodal drainage, using a involved site approach as an acceptable alternative. The CTV is then expanded by 3-5mm for PTV. The recommended dose to grossly involved nodes at the time of radiation planning is 50.4 Gy at 1.8 Gy per fraction, while 36-41.4 Gy is sufficient for nodes that have had a complete response to chemotherapy at the time of radiation.
2.4.2 Evidence:
Nodal involvement at diagnosis and regional recurrence after definitive therapy are known patterns of spread in PM-RMS. In a series of 94 patients with RMS (no elective nodal irradiation), 21% developed regional recurrence and two-thirds of these relapses occurred in patients with a head and neck primary site.36 A larger percent of patients developed nodal metastases in a smaller series of head and neck RMS that included only patients with alveolar histology.37 After a median follow-up of 4.3 years, with regional radiation targeted only to involved nodes, 75% of patients with N0 disease developed isolated nodal relapse in the ipsilateral first-echelon nodal basin, and 33% of patients with N1 disease developed nodal relapse, one isolated and one concomitantly with local progression.
Given the concern for nodal progression particularly in alveolar RMS, prophylactic nodal irradiation has been investigated. In a retrospective series consisting of 47 patients with PM-RMS treated with definitive IMRT to 50.4 Gy in 28 fractions and chemotherapy, patients ≥ 14 years of age with alveolar histology (n=13) were treated to 36 Gy at 1.3 Gy per fraction the bilateral cervical nodal chains.33 Ten of these patients had N1 disease, and gross nodal disease was boosted to 50.4 Gy. Of patients with embryonal histology, none experienced regional failure (though the number with N1 disease was not reported), nor did any with alveolar histology who received bilateral cervical nodal radiation. Of those with alveolar histology who did not receive bilateral cervical nodal radiation, the 5 year regional failure rate was 37%. However, distant disease (including CNS dissemination) remained the dominant pattern of failure in these patients. Another series of 46 patients with head and neck rhabdomyosarcoma yielded similar results. In this cohort, 5-year regional control rate was 73%.31Those with alveolar histology experienced higher rates of nodal recurrence or progression compared to embryonal histology, with 5 year regional control rate of 37% vs 88%, respectively.
However, other studies have found lower rates of regional recurrence with irradiation of only the involved nodal basin for patients with node positive disease, without prophylactic nodal irradiation. In a retrospective review of a prospective database, patterns of failure were reported on 66 children with RMS across diverse primary sites.38 Overall, 7 patients developed local recurrence (n=6 with embryonal histology), achieving 88% 2-year local control for the cohort. No patients with parameningeal disease developed regional failure. Another series that used proton therapy for the treatment of RMS across primary sites reported no regional failures, with radiotherapy directed only to involved nodal levels.25 In a retrospective review of 24 patients with alveolar PM-RMS in which radiation was directed only to the involved nodal level(s) with a boost to the involved nodes, 3 year regional control was 94%.32 One patient with a node negative nasal cavity primary developed a submental nodal recurrence. None of the node-positive patients treated with nodal irradiation developed regional progression, though node positive disease was associated with inferior overall survival due to distant disease progression. An interim report on RMS13 described concerning rates of disease progression in patients with PM-RMS receiving reduced dose cyclophosphamide, prompting a change in the timing of radiotherapy.16 Local and CNS progression predominated, with no patients developing nodal relapse.
Gallego et al. reported on a combined analysis of patients with node positive alveolar RMS treated on EpSSG RMS 2005 and COG ARST0531, with parameningeal primaries in 34% and 25%, respectively.39 Metastatic progression comprised the dominant pattern of relapse in both trials. Nodal recurrence alone occurred in 12% of patients in EpSSG RMS 2005 and 9% on ARST0531, while nodal recurrence with local and/or metastatic progression occurred in an additional 10% and 8%, respectively. Of note, of those who had regional nodes evaluated pathologically, positive nodes were identified in 92% on EpSSG RMS 2005 and 74% in ARST0531, highlighting a discrepancy between clinically positive and pathologically positive nodes in rhabdomyosarcoma. Sentinel lymph node (SLN) biopsy has been evaluated as a possible tool for accurate nodal staging in patients with head and neck rhabdomyosarcoma. In a small series of 6 patients, 2 of 3 patients with radiographically suspicious nodes by PET and/or MRI had a positive SLN, while 1 of 3 with negative imaging had a positive SLN.40 Mapping of SLN yielded an unanticipated location of the SLN in 2 patients, with the nodes mapping in the contralateral neck. The use of SLN resulted in a change in the recommended treatment in 2 of the 6 patients. Overall, the use of SLN in PM-RMS remains investigational at the present time.
Radiotherapy techniques
2.5.1 Expert Consensus
Due to the proximity to relevant structures like the optic chiasm, brainstem, salivary and lacrimal glands, and pituitary, PM-RMS is a particularly challenging site when tailoring local therapy. Typical radiation doses, especially when combined with intensive chemotherapy, may exceed organ tolerance of the head and neck structures, particularly with regard to the young patient age. In order to maximize form and function and minimize toxicity, RT should be done with careful planning and attention to organs at risk (OAR), and dose constraints should be applied as per the Pediatric Normal Tissue Effects in the Clinic (PENTEC) report41 and according to current study guidelines in these young, curable patients. In addition, functional assessments (ex. hearing, vision, neuroendocrine) are encouraged prior to starting radiation to serve as a baseline.
Several highly conformal radiation techniques are available that enable protection of healthy tissue while maximizing tumor control. For PM-RMS, predominantly techniques such as proton therapy (PT) or intensity-modulated RT (IMRT) should be used. In addition, immobilization with a face mask and careful image guidance with cone-beam computed tomography (CBCT) to ensure reliable daily set up are recommended. As many of the patients with PM-RMS may be too young to consciously cooperate, sedation with anesthesia may be required to safely perform daily radiotherapy.
For younger patients and for treatment of tumors located near critical structures such as those in the head and neck or near the brainstem, modern treatment concepts encourage the use of highly conformal techniques such as PT to minimize dose to normal tissue secondary to the steep dose gradient of PT. In general, intensity modulation in PT (IMPT) can offer additional benefits when compared to single field optimization PT techniques, especially if lymph nodes of the neck are involved. However, the use of PT is restricted to radiation oncologists experienced in this field with access to a proton center, and randomized studies comparing PT versus IMRT are scarce, with ethical concerns often hampering the conduction of such studies. Given the limitations in access to proton therapy, IMRT can be used in order to achieve highly conformal treatment as well. However, due to the high integral dose and low dose bath associated with IMRT, it is typically applied in older patients or whenever PT is not available or technically restricted (e.g. lack of gantries, lack of high energies). Additionally, as social, logistical, and financial issues may make PT prohibitive, IMRT may be preferred in those scenarios. In specialized programs, brachytherapy can also be explored, particularly in the locally recurrent setting or as part of clinical protocols like AMORE, a local treatment regimen consisting of Ablative surgery, Moulage technique brachytherapy and surgical Reconstruction.42-44
2.5.2 Evidence
Evolving techniques have improved the application of radiotherapy in the last decades for PM-RMS. IMRT has enabled better target dose coverage than three-dimensional conformal radiotherapy,45 and PT has further promised the reduction of unnecessary dose to critical structures in the head and neck such as the optic apparatus, hypothalamic-pituitary axis, brainstem, musculoskeletal structures, as well as salivary glands. Thus far, several studies have examined the application of PT for PM-RMS, resulting in similar oncologic outcomes as photon therapy, with overall survival rates ranging between 58% and 88.9% and local control rates between 66% and 84%.25,26,32,46 Unfortunately, local failure in the high-dose region remains problematic after both IMRT and PT.20,25
Although local control is deemed the main focus of radiotherapy for pediatric rhabdomyosarcoma, late effects such as endocrine dysfunction, secondary cancers, and cosmetic outcomes like facial hypoplasia are a significant relevant issue, with the latter affecting up to 97% of treated patients.26,43,46 For PM-RMS specifically, dosimetric comparisons have shown that PT, as compared to IMRT, achieves improved sparing of relevant structures for a variety of organs like brainstem, pituitary, and ipsilateral and contralateral lacrimal and parotid glands.47 Regarding acute toxicity, a study examining PT versus IMRT for PM-RMS reported no overall difference in acute toxicity grade < 3. However, the risk of experiencing grade 3 dermatitis was higher after PT, while the risk of experiencing grade 3 mucositis was higher after IMRT.20 Regarding long-term toxicity after IMRT for RMS of the head and neck, among the Memorial Sloan Kettering series, after a median follow up of 7.7 years, the most common long-term toxicity was facial disfigurement (observed in 77% of patients), with other common toxicities including growth hormone deficiency, dental problems, and cataracts (all seen in 30-40% of patients).48 Overall, clinical reports on toxicity for PM-RMS have shown a low probability of adverse events after PT, although the number of patients in available studies and length of follow-up are limited. In an analysis of 46 children treated with PT, the mean maximal acute and late toxicity score according to Common Toxicities Criteria on Adverse Events (CTCAE) were 2.1 and 1.1, respectively and no acute or late toxicity exceeding grade 3 was reported.25Importantly, within this study, the risk for a field-border or marginal recurrence was low. This is in accordance with other studies reporting low rates of acute or late toxicity after PT with a toxicity ≤grade 3 free survival of 95% at five years.26 A study from Massachusetts General Hospital looking at late toxicity after PT for rhabdomyosarcoma showed overall low rates of low toxicity (35% late toxicity of any grade with median follow up of 47 months), with specific late toxicities in those with head and neck disease including facial hypoplasia (9%), dry eye (9%) and cataracts (3%).49With regard to second cancer risk, PT has also shown reduced risk when compared to IMRT across different cancer types, although prospective long-term comparison of the second cancer risk after PT versus IMRT is lacking.50
Brachytherapy only plays a minor role in current treatment of PM-RMS. As such, evidence for brachytherapy is limited. However, brachytherapy was used as part of upfront and salvage treatment after prior external beam RT in the AMORE protocol, and results seem to be promising.44