Discussion
Given the paucity of data from this part of the world, we demonstrated
that image guided PBS PBT in our setting can be safely delivered with
acceptable acute toxicities in children and young adults. 28% of the
patients treated at our centre with PBT belonged to this age group.
Despite a wide variation in socio-political and cultural backgrounds of
patients and physicians, the demographic profile of patients treated at
our centre was comparable to other established PBT centres. A survey
among 253 radiation oncologists in India, there was a significant
variation in perception and knowledge regarding PBT [17]. According
to this survey, although 90% of the respondents believed PBT has a
definite role in pediatric tumors, 69% believed that there is a need
for randomized trials in pediatric population.
Due to potential benefits of PBT, increasing number of children are
being treated with this modality. The use of PBT for children in the
United States has increased nearly 10-fold in the last 15 years
[18]. A study based on US national cancer database showed that the
patients treated with PBT are more likely to be from higher
socioeconomic strata, have a residence >200 miles from the
treating centre, younger (<10 years), and have a diagnosis of
bone or soft-tissue sarcoma, ependymoma, or medulloblastoma[18]. The
demographic pattern of patients treated at our centre was very similar
to the patient profile across several established proton therapy centres
of North America and Europe and that of the pediatric proton photon
cancer registry (PPCR) [19]. The common sites for use of proton
therapy at our centre were CNS, head neck and skull base as was noted in
the PPCR. The most common histologies treated at our centre were
pediatric sarcoma (including RMS, Ewing’s and Non-RMS sarcomas),
ependymoma, glioma and medulloblastoma. 77% of our patients travelled
more than 500km and 70% of them belonged to metropolitan cities.
Therapeutic ratio in radiation therapy is the relationship between the
tumor control probability and normal tissue complications. Advances
inconventional radiation therapysuch as IMRT, image guided radiation
therapy (IGRT) and stereotactic radiation therapy (SRT) have
significantly improved this ratio in the last two decades.Several
dosimetric studies have consistently shown that PBT can improve the
therapeutic ratio even further due to significant reductions in the
total radiation dose received by the normal tissues despite the fact
that most literature is based onthe previous generation passive
scattering proton therapy (PSPT) without image guidance. This dosimetric
benefit can potentially mitigate the risk of major late toxicities such
as hearing loss, neuro-cognitive impairment, endocrinopathies, vision
impairment, cardiovascular toxicities, gonadal dysfunction, growth
defects/deformities, pneumonitis, nephropathy, late bowel complications,
xerostomia, lymphedema and SMN [20, 21, 22].In a phase 3 setting,
reduction in the dose to pituitary hypothalamic axis and hippocampus has
shown to limit neuro-cognitive decline and endocrine dysfunction
[23] and these results can be extrapolated to several other
contexts.
Apart from the potential to minimize toxicities due to sharp dose
gradients, protons atleast theoretically areradiobiologically more
effective than photons (10-70% higher radiobiological effectiveness)
[24]. However, in reality there is no conclusive clinical evidence
to prove that the increased radiobiological effectiveness leads to
improvement in local control, but there is evidence to show thatmodern
PBT plans are dosimetrically superior for most indications.
Our study demonstrated very low incidence of grade 3 acute toxicities
despite a median dose of 54CGE for CNS, 59.4CGE for non-CNS tumors, 28%
of our patients received CSI, and nearly 70% of patients of non-CNS
tumors were in the head neck region. Acute toxicities noted in our study
were comparable to other reported studies [25-28].Our study showed
that overall 62%, 26% and 0% of patients had grade 1, grade 2 and
grade 3 fatigue respectively. Among patients with non-CNS tumors,
CTV>150cc was associated with grade > 2
fatigue. Treatment related fatigue, which is multi-factorial, has been
under-reported across several studies especially in children. In a study
of 57 RMS patients treated with PBT, although grade 1 fatigue was not
reported, 14% children had grade 2 fatigue [25] whereas in another
study where 48 children were treated with PBT for CNS tumors, 77% of
children had grade 1-2 fatigue[26]. Expectedly our study also showed
that CSI and concurrent chemotherapy was associated with grade> 2 hematological toxicity. Although PBT can
potentially spare the vertebral bone marrow, 77% of our patients who
underwent CSI were of <15 years and hence the entire vertebral
body was irradiated to the prescription dose to avoid spinal
deformities. Among the three adolescents who received CSI where major
portions of vertebral bodies were spared, two of them did not have any
significant hematological toxicity.
Image guidance has shown to improve radiation therapy outcomes for
several [29]tumor sites and is practiced widely across all age
groups including the pediatric population [30].Incorporation of
on-board CBCT imaging on PBT equipment, has significantly improved the
treatment precision and efficiency. Since PBS is extremely depth
sensitive,small deformations of the tissues in the beam path could lead
to significant dose perturbations and therefore frequent volumetric
imaging is crucial.At our centre, our on-treatment imaging protocol
included 1-2 weekly check CT scans to quantify the dose perturbations
apart from the routine use of on-board CBCT. In our study, 6 patients
required adaptive re-planning during the treatment. Threepatientshada
significant weight-loss leading to loss of tissue in the proton beam
path. Increase in postoperative collection, significant deformation of
bowel due to gaseous distension and frequent setup errors due to
non-reproducibility of spinal curvature led to adaptive re-planning in 3
patients (one each). All these deformations which triggered a re-plan
were picked upduring the on-board CBCT.None of the fivepatients with
craniopharyngioma requiredadaptive re-planning. Based on these results,
our on-treatment imaging protocol was amended for most tumor sites to
include check CT’s only if the CBCT showed significant deformations. A
detailed imaging audit of the first 150 patients will be published
elsewhere.
Despite the increased adoption of PBT in Europe and North America, the
cost and access to PBTare the biggest hurdles to its widespread
dissemination.In India where nearly up to 4.4% of all cancers are seen
in children younger than 15 years[31] there would be a significant
demand for this modality. Unfortunately,since approximately 70% of
healthcare is delivered by the private sector in India and the
penetration of health insurance is limited, most patients have to pay
for healthcare services out of pocket. Only 13% of children in this
studyhad the treatment funded through insurance. 60% received partial
financial support from our institution and 20% received additional
crowdfunding support towards the treatment.
Although the upfront cost of proton therapy is higher, studies have
shown that it is more cost effective than other conventional radiation
techniques for certain pediatric tumors.[32-36]A study evaluating
cost effectiveness of PBT in medulloblastoma revealed a 52% reduction
in risk of SMN, a 33% reduction in cardiovascular and
non-cardiovascular mortality, an 88% reduction in risk of hearing loss,
endocrinopathies, osteoporosis and IQ decline with gain of 0.68
QALY/child with an estimated incremental cost-effectiveness ratio of
-23,600 Euros [32]. Most of these cost-effectiveness studies were
performed in North America and Europe and hence may not be relevant in
the context of low and middle income countries and there is a need for
generating relevant evidence based on local factors.Unfortunately there
are several challenges inevidence generation for PBT across the world.
Active engagement by professional organizations, innovative clinical
trial designs and a collaborative approach between various stake-holders
have been proposed as possible solutions to overcome some of these
challenges [37]
This study was aimed to report the demographic features and our initial
experience with treating children and young adults with PBT at our
centre. Although the data was prospectively collected in consecutive
patients, there were a few limitations to this study. The median
follow-up period was only 6 months and hence we wereonly able to report
acute toxicities. We intend to report detailed dosimetric and clinical
outcomes of relatively homogenous groups of patients after a
sufficiently longer follow-up period. Also, so far we were unable to
collect quality of life or detailed neuro-cognitive assessments, however
we would be prospectively collecting the same in the future.