2.1 Imaging for radiotherapy planning
2.1.1 Expert Consensus
Imaging in rhabdomyosarcoma plays a pivotal role for staging, response assessment, planning of local therapy (radiotherapy and/or surgery), relapse monitoring, and diagnosis of acute and late complications of treatment. To guide the optimal radiotherapy plan, it is essential to image the primary tumor and assess for metastatic sites. For the primary tumor, magnetic resonance imaging (MRI) is preferred over computerized tomography (CT) due to superior soft tissue contrast resolution and the absence of ionizing radiation, although CT is helpful for detection of bony involvement. PM-RMS is preferably imaged on a 3T MRI scanner because of its higher resolution in this radiologically challenging anatomical site, although imaging on a 1.5T MRI scanner is an acceptable alternative.
For radiotherapy planning, the essential MRI sequences are the morphological sequences (coronal and axial T1-, T2-weighted sequences with fat suppressed T2 sequences) and those with the administration of intravenous contrast such as gadolinium (coronal and axial T1 post- contrast with and/or without fat suppression). In specific cases, extra sagittal sequences can aid delineation as can volumetric 3D T1 post contrast sequences which allow for reformatting of the tumor site from all different views. Diffusion Weighted (DW) MRI adds to tumor characterization and differentiation of active residual tumor from reactive surrounding edema, and DW-MRI allows evaluation of tumor response, which can also inform radiotherapy planning. Including DW imaging in the radiotherapy planning protocol represents a key opportunity to integrate response evaluation with optimization of imaging to create the most accurate radiotherapy plan. If feasible, combining and integrating MRI sequences for response assessment and radiotherapy planning can also save the younger patients an additional course of anesthesia for separate scans.
For the detection of locoregional lymph nodes and distant metastases, [F18]-2-fluoro-2-deoxygluose (FDG)-positron emission tomography (PET) or FDG-MRI in combination with chest CT are the recommended investigations of choice, similar to non-PM-RMS. Histologic evaluation of any suspicious head and neck nodes seen on PET is recommended to confirm pathologic involvement.
2.1.2 Evidence
Pediatric deep or extensive soft tissue tumors, such as RMS arising from the head and neck region, are best depicted with MRI (preferably 3T) due to excellent spatial resolution, superior soft-tissue contrast, and multi-planar imaging.7,8 These properties allow for superior delineation of the extent of the tumor and involvement of adjacent structures compared to CT. This is especially critical in PM-RMS, where delineation of the extent of intracranial extension (with increased risk for focal or diffuse leptomeningeal spread), the different head and neck compartments, the boundaries with vascular and/or neural structures determining perineural spread, and invasion of bone, are of utmost importance.9,10 Additional CT imaging is helpful in some cases for detection of the extent of bone destruction and is usually acquired as part of the radiotherapy planning process. Raney et al.2,11 and Michalsky et al.6 showed that outcome in patients with PM-RMS significantly improved when high-risk features were clearly identified with MRI, highlighting the value of the MRI information in contributing to optimized treatment protocols and radiotherapy planning. DW series are standard of care in many centers given their ability to facilitate the differentiation between active residual disease and reactive surrounding tissue. However, there is still a need for systematic prospective evaluation of its role in diagnosis and response evaluation in PM-RMS, and this is being evaluated in the current EpSSG FaR RMS study.12,13
Regarding the role FDG-PET, a systemic review reported a sensitivity of 80-100% and 95-100% with a specificity of 89-100% and 80-100%, respectively, for locoregional lymph nodes and non-pulmonary distant metastases.14,15 Pathologic confirmation of any suspicious locoregional nodes seen on FDG-PET is recommended at this time given the potential for false positives and subsequent impact on radiation planning and treatment.
2.2. Timing of radiation2.2.1 Expert Consensus For patients with locoregional PM-RMS, local therapy with definitive radiotherapy, or in very rare cases, delayed surgical excision of the primary tumor prior to radiotherapy, should commence at week 13; this approximates to the 5th cycle of induction chemotherapy. Earlier radiotherapy (beginning at approximately week 4 to 6) may be considered for certain high risk scenarios, including the presence of intracranial extension where the risk of leptomeningeal relapse is higher and/or in the setting of reduced dose cyclophosphamide. In the rare case in which delayed surgical resection is performed, patients with locoregional PM-RMS requiring postoperative radiotherapy should commence radiation within 4- 6 weeks of surgery, usually with the 2nd cycle of postoperative chemotherapy. For patients with metastatic PM-RMS, local therapy can be delivered at week 13 as is done in the patients with localized disease or can be delayed until week 20- 22.
Evidence
The timing of local therapy, including radiotherapy, in the setting of multimodality treatment for these often highly chemotherapy sensitive tumors, has become increasingly aligned in recent international collaborative group protocols where previous significant differences existed. However, there are still some significant points of debate, and concerns have been raised that these recommended timings may impact local control for PM-RMS, particularly for those with high-risk features.16,17In European studies, the approach used in both the EpSSG and CWS studies for patients with localized PM-RMS is to evaluate the response to induction chemotherapy after the 3rd cycle, and then plan for the commencement of optimal local therapy at week 13, approximating to the 5th cycle of chemotherapy. Outcomes from the first RMS 2005 study randomization of EpSSG high risk rhabdomyosarcoma, where 33% of cases were parameningeal, reported the 3-year event free survivals to be 67.5% and 63.3% in the 2 arms, both significantly improved compared to historical cohorts, although the local failure outcomes are still to be reported.18 In the current EpSSG FaR-RMS study (NCT04625907), these timings continue to be recommended. By comparison, the approach for PM-RMS within COG has employed different timings, previously recommending the delivery of earlier radiotherapy given concerns about achieving local control for these challenging tumors. In these earlier protocols through the Intergroup Rhabdomyosarcoma Study Group (IRSG), there was a recommendation to commence radiotherapy at day 0. A retrospective analysis of patients treated in the IRS-IV and D9803 studies revealed no significant difference in clinical outcomes in those receiving early radiotherapy compared to patients commencing radiotherapy at week 12, with 5-year local failure rates of 19% in both studies.19Similarly, there was no difference in local control based on timing of radiation (before 4 weeks or week 12-13) in a retrospective series from Memorial Sloan Kettering.20 The ARST0531 study, which was open from 2006 until 2012, recommended radiotherapy at week 4 with the goal of improving local control, yet the local control in this study was actually inferior to the previous study, D9803.17However, there are some important confounding factors that make a direct comparison regarding timing difficult, with the dose of cyclophosphamide lower in ARST0531, and 47% of patients with PM-RMS on D9803 received radiotherapy at week 1. The proximity of the parameningeal site to the skull base and cranial nerves, and the infiltrative pattern of growth observed with rhabdomyosarcoma means that radical delayed surgical resection of the primary tumor is very rarely undertaken as discussed in more detail below. Although not recommended, for those rare cases where delayed primary excision is done, postoperative radiotherapy is indicated. Adjuvant chemotherapy is usually commenced 2 weeks after surgery, with radiotherapy commencing as soon as possible after this once the surgical wounds have healed sufficiently (although delays may be necessary for postoperative complications). Preoperative radiotherapy has not yet been fully evaluated in rhabdomyosarcoma, and although it is being investigated in the FaR-RMS study, it is unlikely to be considered for PM-RMS given the complexities and potential complications of surgery. For metastatic PM-RMS, the recommended timings for radiotherapy have historically been at later time points (week 20-22) in the international collaborative group studies from both sides of the Atlantic. However, on the now open high-risk COG study, ARST2031, radiation to the primary site is delivered at week 12-13 for all tumors including PM-RMS (similar to patients with localized disease), with this timing representing an acceptable option for treatment of metastatic PM-RMS. European recommendations in the now closed BERNIE and MTS-2008 studies were for local therapy to commence at week 22, approximating to the 8th cycle of chemotherapy, with re-evaluation of cases after the 6th cycle of chemotherapy. Yet, it is apparent that these guidelines were not always adhered to, particularly with the challenges of treating metastatic rhabdomyosarcoma and multiple disease sites leading to delays in radiotherapy. In the analysis of the BERNIE study, a cut off of day 221 was used to define radical radiotherapy to take this issue into account.21 Cases with extensive metastatic disease may require metastatic radiotherapy delivered in sequential phases, treated in succession to limit the associated bone marrow and other acute toxicities. Delayed radiotherapy for metastatic sites is also recommended in COG studies, with metastatic site radiotherapy to now occur at approximately week 40 after completion of primary chemotherapy on ARST2031 (previously, on the prior high-risk study studies, ARST0431 and ARST08P1, there was the option to deliver metastatic site radiotherapy either with primary site radiation or after completion of primary chemotherapy).2.3 Definitive radiation dosing and volumes
Expert Consensus
As surgical resection is typically limited to a biopsy alone at diagnosis (without upfront gross total resection), the majority of patients with PM-RMS will have IRS group III disease. The definitive radiation dose for treatment of the primary site is 50.4 Gy in 28 fractions, similar to the dose delivered for group III tumors at other sites. A boost to 55.8 Gy or 59.4 Gy total is permitted for treatment of parameningeal tumors at the discretion of the treating physician, with unfavorable features such as tumor size ≥ 5cm at diagnosis, poor response to induction chemotherapy, or high-risk meningeal features such as intracranial extension. Volume reduction is also permitted to account for the response to initial chemotherapy. In these cases, the pre-chemotherapy extent of disease should be treated to 36 Gy - 41.4 Gy in 20-23 fractions, with a boost to the gross residual disease that is present at the time of radiation planning to the final total dose of 50.4 Gy - 59.4 Gy. The boost may be administered either sequentially as a cone-down or concurrently as a simultaneous integrated boost with feasible fraction sizes. The pre-chemotherapy and post-chemotherapy/pre-radiation imaging including the MRI should be fused to the CT simulation scan for optimal target delineation as discussed above. The gross tumor volume at diagnosis as defined by imaging and physical exam should be transferred to a tumor volume adapted to the actual geometry at time of radiotherapy planning (taking into account any anatomical shift due to tumor shrinkage or growth). This volume should be expanded by approximately 1cm, edited for anatomical barriers to spread, to account for occult tumor volume and create the pre-chemotherapy clinical target volume or CTV1 (also known as CTVp_pre). Careful attention should be given to including any initial extent of focal dural involvement in these volumes. The gross tumor volume at the time of radiation planning as defined by imaging and physical exam after several weeks of induction chemotherapy should also be expanded by approximately 0.5-1cm, edited for anatomical barriers to spread, to create the post-chemotherapy clinical target volume or CTV2 (also known as CTVp_post). An intermediate volume consisting of the prechemotherapy extent of tumor without a margin can also be utilized as is done in the CWS group. The planning target volume then typically consists of a geometric 3-5mm expansion on each clinical target volume to account for variability in daily set-up, although this expansion is uniquely defined for proton therapy. Of note, although radical surgery is not standard of care, if pursued, adjuvant radiation is often required due to fusion status, lack of ability to obtain negative margins, and/or regional nodal involvement. In PM-RMS, inclusion of the entire surgical scar or even surgical route is not often recommended as it may mean extensive radiotherapy volumes in some children. See Table 1 for dosing recommendations by clinical group and fusion status, including those with IRS group I-II disease.
Evidence
Over successive IRS protocols, radiation volumes for parameningeal tumors drastically decreased with the goal of maximizing the therapeutic ratio, from craniospinal irradiation in the late 1970s and whole brain radiation in the 1980s for those with high-risk meningeal features, to focal radiation for all patients in the 1990s, consisting of a 1-2cm margin around the gross tumor.2 Importantly, omission of whole brain radiation in lieu of focal radiation volumes did not compromise outcomes in an analysis of IRS II-IV,2,6including risk of local failure and risk of central nervous system recurrence.
Regarding the evolution of radiation dose for parameningeal tumors, on IRS-II and III, radiation dose depended on both the size of the tumor and age of the patient, with a median dose of approximately 45 Gy and 50.4 Gy delivered for those <6 years of age and> 6 years of age, respectively. On IRS-IV, patients were randomized to receive either 50.4 Gy in 1.8 Gy fractions delivered daily or 59.4 Gy in 1.1 Gy fractions delivered twice daily, with similar local relapse rates observed in both arms.22 Overall, doses less than 47.5 Gy have been associated with worse local control for parameningeal tumors,6 in part supporting the radiation doses currently utilized on the ongoing protocols through the COG, EpSSG, and CWS. Previous smaller studies had also identified a similar relationship between improved local control and higher radiation doses for PM-RMS.23,24
Even with these doses, local relapse remains the dominant form of failure for PM-RMS, with localized failure seen in approximately 70% of those who relapse on both European and North American cooperative group trials. The majority of local failures occur in the high dose region,25-27 suggesting that marginal misses or volumetric coverage are not the issue. Furthermore, the utilization of a post-chemotherapy cone-down volume (to reduce the high-dose treatment volume) does not appear to compromise local control.28,29 Unfortunately, local failure for parameningeal tumors has actually worsened over time on the most recent COG studies from 16% on IRS-IV,22 to 19% on D9803,30 to 28% on ARST053117 with similarly high rates of local failure seen in recent single institution studies,16,20,27 thought in part to be due to the lower doses of cyclophosphamide utilized on recent trials. In addition, leptomeningeal failure is a common and devastating pattern of relapse among patients with PM-RMS, especially among those with intracranial extension at diagnosis.31-33
Ongoing strategies to overcome the possibly radioresistant phenotype of parameningeal tumors include radiation dose escalation. Hyperfractionation to 59.4 Gy on IRS-IV did not result in increased local control compared to 50.4 Gy with daily fractionation, although 59.4 Gy delivered in 54 fractions twice a day may not deliver a more biologically effective dose than 50.4 Gy in 28 daily fractions. Thus, current efforts to mitigate the worsening local control include radiation dose escalation to 59.4 Gy with daily fractionation in tumors> 5cm, as larger tumor size has consistently been associated with increased local failure rates.4,17,30,34 Given the infiltrative nature, location near many critical structures, and utilization of concurrent chemotherapy, escalation beyond 59.4 Gy may not be feasible, and doses >57 Gy did not show a benefit on the CWS studies.35 In the FaR-RMS study, all patients with PM-RMS are eligible to be randomized between 50.4 Gy and 59.4 Gy, which will provide future guidance regarding the true benefit of dose escalation for these tumors. Improvements in systemic therapy such as with higher doses of alkylating agents and/or introduction of concurrent radiosensitizers are promising for reducing the incidence of local failure. In addition, given the key role of radiotherapy in the definitive treatment of PM-RMS, efforts to identify molecular determinants of radiation response are critical to enhance local control and outcomes for patients with parameningeal disease.