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.