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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 3  |  Page : 208-216

Advances in radiation therapy in malignant brain tumors


Apollo Proton Cancer Centre, Chennai, Tamil Nadu, India

Date of Web Publication02-Nov-2021

Correspondence Address:
Dr. Rakesh Jalali
Apollo Proton Cancer Centre, Taramani, Chennai - 600 041, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJNO.IJNO_429_21

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  Abstract 


Radiation therapy (RT) plays a key role in the optimal management of a range of primary and secondary brain tumors. RT has evolved from conventional radiotherapy to three-dimensional (3D) conformal, intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), stereotactic techniques such as stereotactic radiosurgery or fractionated stereotactic radiotherapy to particle beam therapies such as the proton beam therapy (PBT) and carbon ion therapy. Further, there is increased evidence of molecular-based approach in the treatment of malignant brain tumors. Tumors such as the high-grade gliomas tend to have inferior outcomes as compared to the low-grade gliomas. Pediatric brain tumors tend to do better, in terms of local control, progression-free survival, and overall survival. In such scenarios, sparing of critical structures is essential as it tends to reduce the dose to the normal brain tissue, thereby improving neurocognitive outcomes, reduces hormonal impairment and risk of secondary malignant neoplasms. Modern techniques such as the IMRT, VMAT, and PBT, especially image-guided intensity-modulated proton therapy, spare the critical structures to bare minimum, which in turn leads to superior dose distribution without any low dose spillage to the nearby areas. These advanced techniques not only behave therapeutically but are also cost-effective, resulting in improved quality of life.

Keywords: Brain tumors, gliomas, intensity-modulated radiotherapy, proton therapy, radiation therapy


How to cite this article:
Jalali R, Sudarsan RT. Advances in radiation therapy in malignant brain tumors. Int J Neurooncol 2021;4, Suppl S1:208-16

How to cite this URL:
Jalali R, Sudarsan RT. Advances in radiation therapy in malignant brain tumors. Int J Neurooncol [serial online] 2021 [cited 2021 Dec 5];4, Suppl S1:208-16. Available from: https://www.Internationaljneurooncology.com/text.asp?2021/4/3/208/329824




  Introduction Top


Radiation therapy (RT) plays a key role in the optimal management of a range of primary and secondary brain tumors. In the past few decades, radiotherapy (RT) has witnessed several technical advances in almost all aspects of treatment, with improvement in patient immobilization, imaging, treatment planning, and delivery. Advances in imaging and RT technology have enabled more precise tumor localization and dose delivery, leading to a reduction in the volume of normal brain tissue irradiated at high radiation doses. RT has evolved from conventional radiotherapy to 3D conformal, intensity-modulated radiotherapy (IMRT), volumetric-modulated arc therapy (VMAT), stereotactic techniques such as stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (SRT) to particle beam therapies such as the proton beam therapy (PBT) and carbon ion therapy. One of the major factors that impacts the prognosis of malignant brain tumors is histology, and aggressive histopathology such as glioblastoma (GBM) are usually associated with poor prognosis, whereas tumors such as medulloblastomas (MBs) have a favorable prognosis. They are, however, associated with long-term quality of life issues. We hereby provide a systematic review of the advancements in radiation oncology both on technological and disease aspects in malignant brain tumors.[1],[2]


  Technological Advancements Top


IMRT allows an excellent dose distribution to target volume by modulating beam intensities by a multi leaf collimator and use of advanced inverse planning algorithms. A further evolution is represented by VMAT, in which dose is continuously delivered as the gantry of linear accelerator rotates around the patient in single or multiple arcs. This reduces the treatment time compared to IMRT, with the help of intensity, dose rate, and gantry rotation speed, thereby resulting in more comfort to the patient compared to conventional IMRT. Helical tomotherapy (HT) represents a rotational form of IMRT, in which the patient is moved through the bore of the machine while the gantry rotates around resulting in treating the target slice by slice as done in a computed tomography scanner. This helps in confining the dose to the critical structures, thereby resulting in comparatively lesser toxicities to that of IMRT and VMAT. Stereotactic radiotherapy is a high-precision RT technique delivering doses either in a single fraction (SRS) or in a fractionated stereotactic manner (SRT).

In the recent past, PBT has generated a lot of interest including in the management of several central nervous system (CNS) tumors. PBT has several inherent physical and biological characteristics, which utilizes delivery of little to no energy deposition distal to the target, a phenomenon known as the Bragg peak, thereby leading to no exit dose. Evolution of technology using pencil beam scanning, image guidance, and highly sophisticated physical and modern mathematical algorithms can result in literally dose painting the most complex tumor shapes with ultra-high precision including delivery of intensity modulated proton therapy (IMPT).[3],[4]


  Disease Specific Advancements Top


Diffusely infiltrating gliomas/high grade gliomas

The standard of care for GBM is surgery followed by radiotherapy with Temozolomide (TMZ).[5],[6] The gross tumor volume for RT planning includes the T1-enhanced region with 2 cm clinical target volume and taking into account all relevant T2/FLAIR abnormality.

Dose and fractionation: Depending upon the patient's prognosis:

  • Favorable prognosis patients: 59.4–60 Gy in 30 fractions over 6 weeks
  • Poor prognosis patients: 35–40 Gy in 10–15 fractions over 2 weeks.


Altered radical fractionation schemes giving higher effective doses as accelerated hyperfractionated or hypofractionated regimens have not been shown to be associated with survival benefit.[7],[8] The additional radiosurgery/stereotactic radiotherapy boost also does not prolong survival. In gliomatosis cerebri, whole brain radiotherapy to doses of 50 Gy or more achieves disease control in a proportion of carefully selected patients.[9],[10] Various trials conducted earlier wanted to answer whether or not dose escalation was superior in GBM's. Trials included dose escalation of more than 60 Gy (66–90 Gy) with external beam radiotherapy, SRT, brachytherapy boost but did not show any improved outcomes.[11],[12],[13],[14] However, some recent data revealed moderate dose escalation up to 66 Gy was associated with improved median overall survival.[15],[16] Some early data suggested that PBT is superior to conventional radiotherapy in improving outcomes with median survival of 45.9 versus 29.7 months, with a median follow-up of 62.1 months.[17] A recent NRG-BN001 is underway to show the efficacy of photon versus proton dose escalation compared to the standard dose radiation therapy, where dosage of up to 75 Gy both in photon and proton arms were used. Group 1 results with Dose intense (DI) IMRT showed median overall survival of 18.7 months versus 16.3 months with standard dose RT (statistically not significant).[18]

Role of lymphopenia in brain tumors

One of the niche areas during the treatment of brain tumors is the association of radiotherapy with body's immune system. Radiotherapy has been shown to be associated with lymphopenia, and host immunosuppression, thereby leading to inferior outcomes for high-grade gliomas and other types of tumors.[19],[20] Correction of lymphopenia is complex and may range from depletion of regulatory T-cell population, shifting of bone marrow-derived suppressor cells including macrophages away from immunosuppressive phenotypes to altered systemic therapy and usage of cytokines that stimulate lymphocyte proliferation and other pathways.[19],[20] Recent data suggest that female sex, baseline absolute lymphocyte count, and whole brain dose receiving V20 (V20 is defined as the percentage of normal target tissue receiving at least 20 Gy and is dependent on the total volume of the tissue) were the most significant prognostic indicators for Grade 3 lymphopenia, which may be associated with decreased overall survival. PBT, by virtue of its reduced dosage to nearby structures, leads to sparing of circulating lymphocyte population, thereby resulting in reduced Grade 3 lymphopenia (14% vs. 39%) and may potentially improve outcomes also.[21] Data for mature results of this intervention are awaited.

Diffusely intermediate low/lower grade gliomas

Management options for these tumors have ranged from observation to a biopsy for histological confirmation to aggressive radical resections followed by adjuvant radiotherapy with or without additional chemotherapy. Hence, the goal of treatment for patients with these tumors includes prolonging overall and progression-free survival and minimizing morbidity. Recent clinical and molecular insights are helping shape more evidence-based optimal management in this group of patients. Molecular markers have been incorporated in the recent World Health Organisation (WHO) classification of CNS tumor updates.[22] Surgery alone may not be curative in patients with diffuse intermediate-low grade glioma, and additional treatment may be required. The factors to consider when selecting patients for immediate postoperative therapy include the presence of tumor-related symptoms and risk factors, which include age ≥40 years, large preoperative tumor size (e.g., ≥5 cm), incomplete resection, astrocytic histology, elevated MIB-1 index (>3%), and absence of a 1p/19q-codeletion.[23] Alkylating chemotherapy using the PCV regimen initially and TMZ more recently has assumed a firm place in the treatment of patients with low grade gliomas. The RTOG 9802 trial comparing RT alone or RT followed by six cycles of PCV chemotherapy showed that the progression free survival (PFS) at 10 years was 51% in the group that received radiation therapy plus chemotherapy versus 21% in the group that received radiation therapy alone; the corresponding rates of overall survival at 10 years were 60% and 40%, respectively.[24]

This management approach has been particularly adopted as per evidence gathered from two large cooperative group trials (RTOG 9402 and RTOG 0424 studies). RTOG 9402 was a phase III trial of chemo-radiotherapy for patients with anaplastic oligodendroglioma (AO). It has shown favorable results with PCV plus RT versus RT alone with median PFS of 9.8 versus 2.9 years and median overall survival (OS) of 13.2 versus 7.3 years, respectively.[25] RTOG 0424 investigated hazardous high risk low grade gliomas (LGGs) treated with TMZ and RT, and results were contrasted with those of historic controls. The 3-year OS rate was 73.5%, which was significantly improved compared to that of historical control of 54%. 5- and 10-year OS was 60.9% and 34.6%, respectively.[26] Results from the CATNON trial comparing concurrent and adjuvant TMZ with RT showed that, adjuvant and not concurrent TMZ was associated with significant survival benefit with a median overall survival of 82.3 months versus 46.9 months (with and without adjuvant TMZ) respectively.[27] CODEL was a Phase III Intergroup study of TMZ alone versus radiotherapy with concomitant and adjuvant TMZ versus radiotherapy with adjuvant PCV chemotherapy in patients with 1p/19q co-deleted anaplastic glioma or low-grade glioma. TMZ alone treated patients experienced shorter PFS, OS, and time to death from progression versus those treated with RT or RT + TMZ. Based on initial reports, the TMZ alone arm was closed, also the RT alone arm was closed based on the reports of RTOG 9402 trial. CODEL is currently ongoing as a two-arm comparison of RT + adjuvant PCV versus RT + concomitant/adjuvant TMZ.[28]

Radiation dose

The recommended radiation dose is 54 Gy-59.4 Gy in 30–33 fractions with concurrent TMZ followed by 12 monthly adjuvant TMZ cycles. However, emerging interest is in giving 54–55.8 Gy in 31 fractions in co-deleted AO.

Role of PBT in LGGs are well noted, with the fact that it spares normal brain tissue and other organs at risk. Studies have shown that PBT is superior in reducing dose to developing brain tissue resulting in acceptable toxicities, without compromising on disease control, thereby preserving neurocognitive function and quality of life [Figure 1].[29],[30] Prospective data from a series involving adult LGG with a median follow-up of 5.1 years showed OS at 1,3 and 5 years were 100%, 95%, and 84%, respectively, and corresponding PFS at 1, 3, and 5 years were 100%, 85%, and 40%.[31] A recent randomized NRG-BN005 trial is assessing PBT in comparison to IMRT in preservation of cognitive outcomes as measured by Clinical Trial Battery Composite (CTB-COMP) score which is calculated from the Hopkins Verbal learning test.[32]
Figure 1: Dose distribution in LGGs comparing helical tomotherapy and proton beam therapy

Click here to view


Diffuse midline gliomas

Brain stem gliomas are usually not amenable to radical surgical resection, and hence if a biopsy is feasible, it is advisable to proceed it with the same followed by RT. Role of TMZ was analyzed in various trials in diffuse midline gliomas; however, it did not improve outcomes compared to RT alone. The prognosis remains poor even if treated with various RT modalities reinforcing the aggressiveness of these tumors.[33],[34] Molecular analyses are being investigated, as these tumors are more prone for H3K27M mutations, where a prospective trial is ongoing, assessing the benefits of selective Dopamine receptor agonist (DRD2), ONC 201. Preliminary results from the ONC-201 study show favorable clinical and radiological outcomes compared to historical cohorts.[35]

Medulloblastomas

Being the most common primary brain tumor in children, MB has witnessed tremendous biological, molecular, and technological advancements in the last decade, leading to better improvements in outcome, making it one of the ideal tumors in pediatric neuro-oncology practice. The initial treatment will be gross total resection followed by chemoradiation depending upon risk stratification followed by adjuvant chemotherapy. Postoperative RT remains an integral component in the curative intent of treatment in MB. In view of high propensity of the tumor to spread across the entire neuraxis, it is imperative to treat with craniospinal irradiation (CSI) followed by focal boost to the tumor bed.[36] It is recommended to start treatment before 4 weeks and it should be carried without interruptions. Some of the most common interruptions faced by radiation oncologists are neutropenia and thrombocytopenia during radiotherapy, which in turn, may result in inferior outcomes. It may be prudent in these situations to switch over to boost plan such that there won't be interruptions during treatment delivery.

Dose and fractionation

  • Standard/average risk: 23.4 Gy in 14 fractions at 1.67 Gy/fraction for CSI and 30.6 Gy/17 fractions to the tumor-bed at 1.8 Gy/fraction
  • High risk: 35–36 Gy in 20–21 fractions at 1.67 or 1.8 Gy/fraction for CSI followed by tumour-bed boost of 18–19.8 Gy in 10–11 fractions at 1.8 Gy/fraction
  • Diffuse leptomeningeal dissemination: 39.6–40 Gy in 22-24 fractions (extended dose CSI) along with entire posterior fossa (PF) boost 14.4 Gy in 8 fractions, with an additional boost of 5.4–9 Gy in 3–5 fractions.


COG ACNS 0331 explored the option of reducing CSI dosage from 23.4 to 18 Gy in standard risk MBs. The study analyzed 464 children with a median follow up of 6.6 years, with 5-year OS for standard dose CSI versus low dose CSI being 86% and 79% and was associated with inferior outcomes.[37] Molecular analyses of MB shows four subgroups, namely sonic hedgehog (SHH), wingless (WNT), Group 3 and Group 4.[38],[39],[40] Based on the TP53 status, Chromosome 11 loss and metastasis, risk stratification system was updated into four groups-low risk (>90% survival), standard risk (75%–90% survival), high risk (50%–75% survival) and very high risk (<50% survival).[40] In view of the WNT pathway mostly belonging to low risk category, COG ACNS 1422 trial aims to assess whether dose de-escalation in these tumors with reduced dose CSI (18 Gy) and boost without vincristine followed by adjuvant chemotherapy helps in reduction of long term toxicities without compromising on disease control.[41] Similarly, promising trials are underway such as SJMB12 and FOR-WNT to assess reduced dose CSI (15 Gy) in WNT tumors to assess survival and toxicities when compared to other subgroups.[42],[43]

Another subgroup of concern is the SHH type, where a study comparing pediatric with adult SHH analyzed it in three groups: Infantile SHH (i-SHH, ≤3 years), pediatric (p-SHH, 3–18 years) and adult (a-SHH, >18 years). Large cell anaplastic variant was more in p-SHH, whereas nodular/desmoplastic variant were common in i-SHH and a-SHH. Median follow up was 38 months with 5-year event free survival (EFS) was 80%, 31% and 52% and OS were 91%, 31% and 70% for i-SHH, p-SHH and a-SHH respectively. Moreover, p-SHH are associated with early relapses, whereas a-SHH are associated with relapses later than 2 years. Hence, it is worth to evaluate treatment intensification in p-SHH, especially TP53 mutant MBs.[44]

Non-WNT/Non-SHH pathway (namely Group 3 and 4 MB), are classified either as standard, high or very high risk MBs. Group 3 is usually associated with poor outcome. Some of the favorable prognostic factors include Chromosome 7 gain, 8 and 11 loss, which when taken into consideration, can be useful in standard risk Group 4 MBs, with a 5-year PFS of 94% in favorable versus 58.6% in unfavorable groups, can be considered for future dose de-escalation studies.[45]

Radiation planning

One of the major challenges faced during CSI planning is that of junction matching, which was superseded by HT. In HT, there are no separate fields to treat, and the gantry moves over in a continuous fashion, thereby mitigating the junction match and increasing the accuracy of treatment delivery. HT is superseded only by PBT especially with pencil beam scanning technology, where two posterior-oblique beams for the cranial field, and one or two posterior beams to the spinal fields are chosen depending upon the length of the CSI to be treated. In this scenario, rather than junctional matching which is commonly done using “feathering” technique, usage of dose gradients improve the junction matching thereby removing the hot spots in the overlapping region. We practice the dose gradient technique, which takes a particular overlapping area into consideration, and the same is treated with two fields, such that, the sum of both beams delivers 100% dose to the area without any hotspots [Figure 2] and [Figure 3].[46],[47] In view of no exit dose, targets anterior to the spine receives nil to very minimal dose, thereby reducing the late side effects that are associated with conventional radiotherapy. Analysis from PBT study of 59 patients, with median follow-up of 7 years showed 5-year PFS of 80% and OS of 83%, without any major toxicities, especially without any cardiac, pulmonary, or gastrointestinal toxicities. The cumulative incidence of Grade 3–4 ototoxicity was 16% compared to 24% in the traditional cohort, with emphasis on treatment of these tumors with PBT.[48]
Figure 2: Dose distribution of craniospinal irradiation comparing helical tomotherapy and proton beam therapy

Click here to view
Figure 3: Dose gradient technique in craniospinal irradiation in proton beam therapy

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One of the landmark studies regarding PBT versus photon therapy in MBs tried to assess the intellectual outcomes associated with treatment of CSI with PBT and photon therapy. In this study, longitudinal intelligence data from 79 patients were examined over the years 2007–2018. PBT showed superior intellectual outcomes in terms of global intelligence quotient (IQ), perceptual reasoning, working memory, verbal reasoning compared to photon group, with no difference in processing speed in both the arms.[49] Similarly, another study assessed 125 patients and demonstrated favorable outcomes in both intelligence and processing speed with PBT compared to photon therapy.[50] Other toxicities such as hematological toxicity with reduction in lymphopenia and thrombocytopenia was seen with PBT compared to conventional RT.[51] Risk of second malignant neoplasms (SMN) were also less with PBT compared to conventional RT with crude rate of SMN being 5.2% versus 7.5%, respectively.[52],[53]

Other embryonal tumors

Some of the other tumors that are seen in pediatric age group are embryonal tumors, like the atypical teratoid/rhabdoid tumor (ATRT), embryonal tumor with multi-layered rosettes (ETMR) and others. One of the first cooperative group trials, ACNS0333 evaluated ATRT in children, and concluded that maximal safe resection, chemotherapy, peripheral stem cell transplant followed by focal radiotherapy to a total dose of 50.4–54 Gy showed 4 years event free survival (EFS) and OS of 37% and 43%, respectively, compared to poor outcomes reported in historical cohorts.[54] Similarly, ETMR, being a highly aggressive and rare pediatric tumor, does not have a standard treatment protocol and mostly its managements are extrapolated from other studies like the ACNS0333 and other historical cohorts. However, two recent trials, showed that maximal safe resection followed by early radiotherapy and high dose adjuvant chemotherapy are associated with better results compared to delayed radiotherapy (1 year EFS 35%, 1-year OS 45%). However, randomized trials in these tumors will be difficult in view of the rarity of these tumors.[55],[56]


  Ependymomas Top


Ependymomas, which represent 5%–8% of pediatric brain tumors, vary in clinicopathologic features, molecular characteristics and lethality. The standard of choice is maximal surgical resection followed by radiotherapy. Age and location of tumor decided treatment options in the past, such as age <3 years were treated with surgery, chemotherapy and radiotherapy delayed by 1 or 2 years or until progression has occurred, and secondly, age more than 3 years were treated with surgery, radiotherapy with or without chemotherapy. However, there is now enough evidence to suggest children <3 years will also benefit from immediate postoperative radiotherapy as evident from ACNS0121 trial which showed 5 years EFS of 57% versus 24% as in POG9233 trial and 5-year OS of about 85% versus 43%. However, the trial also showed inferior outcomes of 1q gain, with 5-year EFS of 35.7% versus 81.5% without 1q gain.[57],[58]

Current scenario is to treat with surgery, followed by postoperative adjuvant radiotherapy in patients more than 12 months of age, in Grade II and III ependymomas, to the tumor bed to a dose of 54–59.4 Gy in 30–33 fractions over 6–6.5 weeks. At the time of recurrence, it is often challenging as there is no standard of care. Salvage therapy consists of surgical re-excision, re-irradiation, or systemic chemotherapy, either singly or in combination, and/or enrolment in clinical trial testing newer/novel therapies. During such cases, it is imperative to treat with CSI, as it was shown to be safe, effective and improved disease control compared to focal irradiation, especially in infratentorial tumors (5 year Freedom from progression (FFP) 83.3% with CSI vs. 15.2% with focal RT).[3],[57] PF type-A and other molecularly aggressive tumors such as those with 1q gain were associated with inferior outcomes.

Dose and fractionation

  • Primary-Focal RT: 54–59.4 Gy in 30–33 fractions
  • Recurrent-CSI: 35 Gy in 21 fractions followed by focal RT to tumor bed 18–19.8 Gy in 11 fractions.


Consensus report from the Stockholm pediatric PBT conference was in favor of PBT for ependymomas and other pediatric tumors compared to conventional RT.[59] Role of PBT was assessed in various studies, one among them included 70 patients treated with PBT showed 3-year local control (LC), PFS and OS were 83%, 76% and 95%, respectively, with substantial reduction of normal tissue irradiated with IMPT.[58] Similarly, another study assessed the need for reirradiation with PBT in 20 patients with infratentorial tumors with a median follow-up of 38.1 months, showed 3-year OS of 78.6% and PFS of 28.1%, with minimal doses to the nearby critical structures.[60] PBT in re-irradiation setting is superior in terms and is of dose coverage with reduced dose to nearby structures, and is well tolerated with acceptable toxicities.

Intracranial germ cell tumors

Intracranial germ cell tumors (ICGCTs), which are classified into germinomas (GCT) and nongerminomatous germ cell tumors (NGGCT) represents a rare group compromising 1%–2% of brain tumors and 3% in the pediatric population. Treatment of these tumors includes maximal safe resection, followed by chemotherapy and radiotherapy. NGGCTs are usually treated with CSI to a total dose of 30.6 Gy in 17 fractions followed by focal boost of 23.4 Gy in 13 fractions up to a total dose of 54 Gy in 30 fractions. Germinomas, on the other hand, are usually treated with whole ventricular radiotherapy in localized germinomas and CSI in disseminated germinomas (Total dose: 40 Gy in 23–25 fractions, 23–24 Gy in 14–15 fractions for whole ventricular radiotherapy/CSI and 16 Gy in 9–10 fractions focal boost) [Figure 4]. Radiotherapy is an integral part of treatment in ICGCT, and PBT can reduce the considerable late effects including neurocognitive disturbances and risk of secondary cancers that are associated with conventional radiotherapy. With recent advances in chemotherapy and radiation techniques, 5-year OS of germinomas is expected to be >90% and 70%–90% for NGGCT. Impact of PBT in ICGCTs is well noted, with our experience showing that the treatments are well tolerated, with minimal toxicities, with encouraging results and preserved quality of life.[61],[62],[63],[64],[65]
Figure 4: Dose distribution of whole ventricular radiotherapy in intracranial germ cell tumors

Click here to view



  Late Effects of RT Top


Apart from the neuro-psychological sequel and secondary malignant neoplasm (SMNs) mentioned above, another most common late effect noted is that of endocrine impairment, especially when the patient is treated with conventional RT. PBT is much superior as even a difference of reduction of 10 Gy exposure to hypothalamus is cost-effective, when taking into account the growth hormone replacement required during the patient's lifetime. Use of PBT was also associated with reduced risk of hypothyroidism and sex hormone deficiency.[66] Cost effectiveness of hormonal replacement was also proven in another study, where intelligence quotient (IQ) preservation, reduced growth hormone (GH) deficiency and reduced adverse events with PBT was superior to conventional RT.[67] Some of the other side effects noted are cerebrovascular accidents and radiation induced necrosis, which are noted in about 1%–2% patients after RT. The rates increase up to 14% when treated for HGG with concurrent RT and TMZ.[68]

Another notable advancement in RT was that of neurocognitive preservation by hippocampal sparing. It was seen over the years especially in the treatment of brain tumors. Jalali et al., in a large Phase III randomized trial with carefully chosen and clinically relevant endpoints demonstrated that with modern technology, tight radiation margins around the tumor can be achieved without compromising on local control and overall survival. The study provided level 1 evidence demonstrating superior neurocognitive (29% vs. 52%; P = 0.02) and neuroendocrine functional (31% vs. 51%; P = 0.01) outcomes at 5 years in favor of high precision fractionated stereotactic conformal RT over conventional RT.[69] The study along with emerging literature on radiation late effects, provides robust proof of principle data for modern conformal RT techniques and should act as a suitable template for confirming efficacy for particle beam therapy with protons and heavy ions, as well.[70] Further refinements in PBT using pencil beam scanning and image guidance are likely to further improve the efficacy of radiation therapy.

Data from a prospectively accrued cohort of 48 young patients assessed the neurocognitive data prospectively, at baseline, before SCRT, and periodically up to 5 years. The study concluded that mean dose <30 Gy to left hippocampus served as a dose constraint in preserving IQ, as increased doses were associated with clinically relevant decline in certain neurocognitive domains.[71],[72] Similarly, data following PBT administration was assessed using Full scale intelligence quotient (FSIQ) and its components (verbal comprehension, perceptual reasoning/organization, working memory and processing speed) in 60 pediatric patients with brain tumors. FSIQ, verbal and nonverbal intelligence, and working memory were stable at a mean duration of 2.5 years follow-up, whereas progressive cognitive decline was evident at 1–2 years after photon radiotherapy; however, the scores for processing speed, especially for younger patients <12 years, were found to be reduced.[73]

Brain stem toxicity is also a concern in PBT. Proton beams are regarded to have similar linear energy transfer (LET) and relative biological effectiveness (RBE) to photon radiotherapy, as discussed above. However, RBE slightly increases in the very distal part of the spread-out Bragg's peak (SOBP) relative to the mid SOBP. In pediatric patients who received PBT of ≥ 50.4 GyE to the brainstem, 2-year incidence of brain stem toxicity of Grade 3 or more ocurred in 2.1%. This risk of brainstem toxicity is similar to that with photon radiotherapy, and it was recommended that no more than one-third of proton beams should reach brainstem tissue outside the planning target volume. Other analyses of brainstem injury attributed to proton beam characteristics have also suggested a clinical incidence similar to that with photon radiotherapy.[74],[75],[76]


  Conclusions Top


Maximal safe resection has been the goal for almost all brain tumors, irrespective of age group. Molecular analyses can help customize RT doses to de-escalate in certain sites (especially in pediatric brain tumors) and optimally combine with systemic therapies in HGGs. Modern techniques such as high-precision IMRT and PBT are significantly superior in sparing critical structures with optimal target coverage compared to conventional radiotherapy and are being investigated upon to improve outcomes even in HGGs. In the era of minimizing toxicities and preservation of quality of life, it is imperative to keep the doses to the normal structures to the minimum, and hence advanced radiation techniques are vital and will be both therapeutic and cost-effective, resulting in preserved quality of life.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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