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