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.