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 Table of Contents  
Year : 2022  |  Volume : 18  |  Issue : 3  |  Page : 629-637

Proton therapy for skull-base adenoid cystic carcinomas: A case series and review of literature

1 Department of Radiation Oncology, Apollo Proton Cancer Centre, Chennai, Tamil Nadu, India
2 Department of Medical Physics, Apollo Proton Cancer Centre, Chennai, Tamil Nadu, India
3 Department of Clinical Research, Apollo Proton Cancer Centre, Chennai, Tamil Nadu, India

Date of Submission27-Jul-2021
Date of Acceptance01-Sep-2021
Date of Web Publication01-Apr-2022

Correspondence Address:
Sapna Nangia
Department of Radiation Oncology, Apollo Proton Cancer Centre, Taramani, Chennai - 600 041, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_1236_21

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 > Abstract 

Purpose: An indolent nature, with a high risk of local recurrence along with the potential for distant metastases, makes the relatively rare adenoid cystic carcinomas (ACCs) of the head-and-neck region, a unique entity. In the base of skull (BOS) region, these cancers require radiation doses as high as 70–72 GyE in proximity to critical structures. Proton therapy (PT) confers physical and radiobiological advantages and local control at 2–5 years exceeding 80% in most series, compared with below 60% with photon-based techniques. We report a case series of ACCs of the BOS, treated with image-guided, intensity-modulated PT (IMPT).
Materials and Methods: During 2019–2020, we treated six patients with skull-base ACC IMPT with on-board, cross-sectional image guidance. Dosimetric data, toxicity, and early outcomes were studied, and a comparative review of literature was done.
Results: Three patients underwent PT/proton–photon treatment for residual/inoperable lesions and three patients underwent reirradiation for recurrent lesions. The prescription was 70 GyE in 31–35 fractions, and 95% of the clinical target volume (CTV) received 98% of the prescribed dose in five of the six patients. Grade 3 mucositis and skin reactions were noted in two patients and one patient, respectively. Five of the six patients were controlled locally at a median follow-up of 15 months.
Conclusion: The radiobiological and physical characteristics of PT help to deliver high doses with excellent CTV coverage in skull-base ACCs, adjacent to critical neurological structures.

Keywords: Adenoid cystic carcinoma, head-and-neck cancer, proton therapy, radiation therapy

How to cite this article:
Nangia S, Gaikwad U, Noufal M P, Chilukuri S, Patro K, Nakra V, Panda PK, Mathew AS, Sharma DS, Jalali R. Proton therapy for skull-base adenoid cystic carcinomas: A case series and review of literature. J Can Res Ther 2022;18:629-37

How to cite this URL:
Nangia S, Gaikwad U, Noufal M P, Chilukuri S, Patro K, Nakra V, Panda PK, Mathew AS, Sharma DS, Jalali R. Proton therapy for skull-base adenoid cystic carcinomas: A case series and review of literature. J Can Res Ther [serial online] 2022 [cited 2022 Aug 10];18:629-37. Available from: https://www.cancerjournal.net/text.asp?2022/18/3/629/342504

 > Introduction Top

The treatment of adenoid cystic carcinomas (ACCs) involving paranasal sinuses (PNS) and base of skull (BOS) is constrained by a complex anatomy and proximity of neural and vascular structures. ACCs have a propensity for locally aggressive behavior and perineural spread; a significant proportion of patients with lesions in the above-mentioned sites may have inoperable disease at presentation.[1],[2] Outcomes with definitive or postoperative photon radiotherapy (XRT) have historically been poor on account of local failure; local control (LC) rates over 5[3] and 10 years[4] have been documented to be <60% in two large retrospective reports. In addition, patients are at risk of distant metastases, often late in the course of the disease, and this impacts OS more significantly than LC.[5]

Proton therapy (PT), by virtue of its physical properties, is uniquely suited to treat slow-growing tumors in the proximity of high-risk neural structures.[6],[7] Besides physical, there is a radiobiological advantage consequent to higher linear energy transfer at the distal end of the Bragg peak, as well as higher density of double-strand DNA breaks.[8] This translates into a higher relative biological effectiveness, ranging from 1 to 1.7, universally considered 1.1 for dose prescription and reporting.[9]

PT for inoperable BOS and PNS ACCs was first reported by Pommier et al.[10] Subsequently, a number of retrospective studies have confirmed excellent LC with PT.[11],[12],[13] Since this first report in 2006, there have been a number of developments, both technological and in treatment optimization approach in PT. The first is the development of pencil beam scanning technique (PBST) which allows intensity-modulated PT (IMPT).[13] PBST is now extensively reported for head-and-neck (HN) cancers, offering the benefit of better conformality in addition to the other advantages of PT noted above.[13],[14],[15] The other development is the incorporation of on-board imaging techniques that facilitate daily accurate repositioning prior to treatment; adoption of these has been more recent in proton treatment machines compared to their widespread incorporation into photon therapy.

We present the clinical, treatment details, and early outcomes of six patients, treated for inoperable/residual and recurrent ACCs involving the BOS, using contemporary, on-board, axial, volumetric, image-guided IMPT using PBST. We also review the literature on PT for inoperable/residual ACCs in the BOS with reference to target delineation, dose prescription, concurrent therapy, and toxicity outcomes.

 > Materials and Methods Top

Patients studied

Six consecutive patients with histopathologic diagnosis of ACC lesions involving the BOS, who underwent proton beam therapy (PBT) in a newly established PT facility, between January 2019 and May 2020, after discussion in the institutional multidisciplinary tumor board, were included in this case series. Case details including demographics, clinicoradiological presentation, treatment, and follow-up details are summarized in [Table 1] and [Table 2], [Figure 1] and [Figure 2] and Supplemenatry file.
Figure 1: Digits in prefix, 1–6 represent case number. (a) Pretreatment magnetic resonance imaging/positron emission tomography computed tomography scan axial section. (b) Posttreatment magnetic resonance imaging/positron emission tomography computed tomography scan axial section. (c) Red dotted circle shows area of interest; gross primary disease

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Figure 2: Digits in prefix, 1–6 represents case number. Each image shows radiotherapy plan with iso-dose distribution axial section (red – 98%, dark blue – 73%/54 Gy, light blue – 50%, and light green – 20%). White dotted line represents high-risk clinical target volume. Yellow dotted line represents low-risk clinical target volume

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Table 1: Patient demographics: clinical details

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Table 2: Toxicities and follow-up data

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Among these six patients, two had oligometastases at presentation (case 2 and case 3), while three underwent reirradiation (cases 3, 5, and 6).

 > Results Top

Case 1

A 40-year-old female presented with loss of vision in the right eye and was diagnosed with ACCs of PNS. The lesion involved the right orbital apex, encased right optic nerve (ON), and involved the right PNS. Following debulking surgery, she was treated with a combination of IMPT with IMRT, with concurrent chemotherapy as optimal coverage of target and better brainstem sparing was achieved in the combination plan compared to either IMPT or IMRT plan, alone. Special informed consent for possible loss of vision in the right eye was taken. On the first follow-up of 3 months following treatment, her visual deficit was nearly completely resolved, with complete response (CR) in positron emission tomography computed tomography (PET CT) scan with PET magnetic resonance imaging (MRI) correlation, and no toxicities. At 17 months following treatment, she underwent bilateral Gromet insertion for otitis media and has been advised surgery for dacrocystitis and nasal synechiae.

Case 2

A 45-year-old hypertensive gentleman was diagnosed with oligometastatic ACC of maxilla (Mets-C1 vertebra and sternum). The lesion involved the hard palate bilaterally, eroding the floor of the nasal cavity and extending into the maxillary sinus. He received IMPT with concurrent chemotherapy following neoadjuvant chemotherapy. CR was noted both at primary and metastatic sites in PET-MRI done on the first follow-up. On his subsequent follow-up at 6 months, he was diagnosed with a local recurrence and metastatic lesions in new sites; ACC was confirmed on core-needle biopsy. The patient is alive with disease at 17 months and has sought alternative treatment.

Case 3

A 47-year-old previously treated female was diagnosed with a recurrent lesion at the lateral margin of the flap and in the petrous apex, encasing ICA with intracranial extension and metastatic lung nodules after disease-free interval (DFI) of 30 months. She underwent a modified trans-cochlear surgery of the right petrous apex with segmental mandibulectomy and right infratemporal fossa (ITF) clearance. She received PBT to the BOS lesion and hypofractionated helical tomotherapy (HT) to the right chest wall, as shown in [Table 1].

CR was noted at the primary site at 3 months with appearance of new lung lesions. She was later treated with six cycles of multi-agent chemotherapy; at 24 months following treatment, she is on observation with clinicoradiologically stable disease in the chest and has no local recurrence.

Case 4

A 69-year-old male was diagnosed with ACC maxillary sinus. An extensive lesion with perineural spread along the V2 division of the trigeminal nerve, causing visual field defects in the bilateral eyes, more on the right side, was noted. The patient was treated with a combination proton + photon plan due to logistical (financial) reasons. CR noted at 3 months following treatment was sustained at 22 months after treatment. Pansinusitis and dacrocystitis were noted in the later imaging, and the patient was advised surgical drainage. At 18 months, the patient lost vision in the right eye due to optic neuritis; this was foreseen due to encasement of the right ON.

Case 5

A 56-year-old gentleman was diagnosed with recurrent ACC in the postoperative, postirradiated region after DFI of 7 years. A left maxillary sinus lesion extending into the pterygopalatine fossa with an intracranial extension, abutting the temporal lobe (TL), was noted. He underwent craniofacial resection and reconstruction, left pterional craniotomy, and BOS exploration. The previous radiation plan was reviewed, the dose received by the left ON during prior radiation (35 Gy) was noted, and high-risk informed consent for optic neuritis and visual deficit/loss was obtained from the patient. He received adjuvant reirradiation using PT. CR was noted at 3 months and is sustained at 11 months.

Case 6

A 56-year-old hypertensive gentleman was diagnosed with recurrent ACC in the postoperative bed with intracranial extent to the ipsilateral TL, with the DFI from prior radiotherapy being 20 months. At presentation, the patient had significant neurological deficit with no perception of light in the ipsilateral eye, had ipsilateral facial paresis, and required opioids for pain control. He received reirradiation using PBT. In view of the previous radiation doses and the significant intracranial disease, he was treated to a dose equivalent of 64 Gy, respecting normal tissue tolerance of neurological structures. In this patient, the clinical target volume (CTV) was underdosed in regions that overlapped with the previously irradiated brainstem; ipsilateral medial TL was within the CTV and hence, both coverage and dose constraints were not achieved, as shown in [Table 2]. At 8 months following radiation, the patient is pain free; imaging at 3 months revealed no evidence of disease.

All patients were counseled prior to radiation plan implementation regarding organs at risk (OAR) doses, target coverage achieved, and its clinical implications, and informed high-risk consents were taken.

 > Discussion Top

PT limits radiation dose to OARs compared to photon therapy and improves the quality of life in HN cancer patients.[16] Its rationale and role in subsites such as sino-nasal tumors is well established.[17]

ACCs of the BOS region have been deemed inoperable in the case of involvement of the clivus, cavernous sinus, Meckel's cave, ITF, cranial nerves (CN), BOS, or the brain.[2]

In the treatment of ACCs involving the BOS, PT derives its advantage from multiple factors. The Bragg peak allows better sparing of OARs, which in turn reduces the odds for compromising CTV dose, and may instead allow dose escalation. A radiobiological advantage has been postulated.[9] ACCs have been postulated to have a low alpha–beta ratio, making the possible radiobiological advantage relevant.[18] Notwithstanding the above, careful attention to target delineation, dose prescription, and treatment delivery are mandatory.

The purpose of this case review is to document our early experience of using contemporary PBT techniques with image guidance and note that this treatment can be delivered safely with reasonable toxicity and to encourage early disease control rates. We also wish to review the technical aspects of the treatment of ACCs with PBT.

Target delineation for the primary

ACC displays a particular tendency for perineural spread, which confers a poorer prognosis. Target delineation for ACCs requires attention to inclusion of the BOS and CN pathways to dilute the negative impact of perineural spread.[19],[20]

Pelak et al., in a recent report, have detailed their target delineation strategy for clinical target delineation as gross tumour volume (GTV) plus 5–10 mm anatomically adapted margin for areas at high risk of microscopic spread.[13] An additional 5–10 mm with attention to perineural pathways was deemed the standard risk volume. Takagi et al. reported on eighty patients in whom the CTV was identified as a GTV plus 5 mm and included the BOS in 51% of patients. The authors noted poorer outcomes in instances where the BOS was not included in the CTV, or if expansion was <3 mm.[21]

Dautruche et al. also stressed the inclusion of the BOS in the target volume along with inclusion of cavernous sinus, ipsilateral sinuses, and trajectory of CNs for 15–20 mm.[22] Linton et al. have delineated CNs to the surface of brainstem.[15]

We used a margin of 10 mm around the GTV, with extension along the CN pathways in patients being treated de novo. Reirradiation necessitated smaller margins.

Treatment of the neck

The treatment of clinically uninvolved neck nodes is controversial in ACCs; the margin of benefit is smaller compared to that of squamous cancers of HN region (HNSCC). Ten percent of patients with sino-nasal ACCs may have occult lymph nodal spread;[23] while elective nodal irradiation (ENI) does not result in improvement in survival, lymph node metastases are associated with a significantly worse prognosis.[20] ENI is omitted by some groups,[13],[24] and included in others.[10],[15]

Our strategy for neck nodal treatment in HNSCC has been reported earlier.[25] In this series, the clinically uninvolved neck was not addressed. We treated all radiologically visible nodes, with a margin, to 70 GyE. The remaining part of the affected dose level was included in low-risk CTV.

Dose prescription

Pommier et al., in the earliest report of PRT for ACCs, treated the GTV to 73.34 GyE with standard fractionation and 76.4 GyE with altered fractionation.[10] Gentile et al. have reported a median dose of 73.8 Gy when treating 14 patients with nasopharyngeal ACC,[24] while Takagi et al. have reported various hypofractionated schedules, with the number of fractions varying from 16 to 26 and a median EQD2 Gy10 of 67.5 Gy and 71.5 Gy.[21] The authors have cautioned against increasing the dose per fraction beyond 2.2 Gy and have now restricted the total dose to 70.4 Gy to reduce the risk of bleeding and ulceration.

We treated patients to 70 GyE in 31–35 fractions with modest acceleration, completing the treatment of five of the six patients in <45 days [Table 1]. The dose was reduced to 64–66 GyE in 30 fractions in two patients who underwent reirradiation.

Organs at risk constraints

We prescribed constraints of 63 Gy to the brainstem surface, 54 Gy to optic apparatus with exceptions as noted below. Similar constraints have been prescribed by Bhattasali et al.[12] Pelak et al. have reported relatively higher constraints for the chiasm (OC) and ON at D2% (minimum dose received by 2% volume) <60 Gy and spinal cord surface D2% at 63 Gy and core D2% at 54 Gy.[13] TL constraints were prescribed as suggested by McDonald et al.[26] These could be achieved for the contralateral TL; for ipsilateral TL, the volume receiving 40 Gy ranged from 21 cc to 41 cc, exceeding the proposed <20 cc constraint. In one patient, due to intracranial infiltration and involvement of the brain, this constraint was not applicable.

No constraint was prescribed to the encased ipsilateral ON in three patients, with informed consent for loss of vision. In one of these patients, the lesion was noted to also be in proximity of the contralateral ON, which was constrained at 54 Gy after discussion with the patient. All patients except one have intact vision at present and in one of them, visual acuity has improved at the first follow-up.

Gentile et al.[24] and Bhattasali et al. similarly mentioned proceeding with treatment after informed consent for loss of vision in the case of encasement of the ONs.[12]

Outcome and prognostic factors

The principal site of failure in all reported series is distant metastases, with the 2-year estimate being ranging between 22.5% and 43%.[13]

Except in the study by Dautruche et al., the 2-year LC for ACCs treated with PBT in the available literature is >90%, even with infiltration of the BOS [Table 3]. Dautruche et al. treated patients with protons and/or tomotherapy and reported 2-year locoregional recurrence-free survival of 60%.
Table 3: Comparison of available literature

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The 5-year LC rates of 75.8% for patients treated with PBT and 66% for inoperable patients treated with either PBT or carbon ion therapy have been reported by Takagi et al.;[21] the authors noted no difference in patients treated with either modality in this cohort of eighty patients.

Pommier et al. identified involvement of the pterygopalatine fossa, ON, sphenoid sinus, and clivus as a poor prognostic feature for LC.[10] Takagi et al., as noted above, identified T4 stage, CTV ≤3 mm, and omission of BOS from the target volume as markers of poor prognosis.[21] Pelak et al. have also noted that skull-base infiltration was associated with a poorer outcome and have remarked that the preponderance of distant metastases rather than local failure points toward the efficacy of PT.[13]

Bhattasali et al. have noted a worse outcome in male patients diagnosed with ACCs, and multiple historical studies had mentioned similar findings, with the reasons for the same being unclear.[26],[27]

Takagi et al. had noted that inoperability confers a poor prognosis, that is, patients with inoperable lesions had a 5-year LC rate of 66% versus 96% in patients who underwent surgery.[21] However, in more recent reports, Pelak et al. have reported excellent LC rates of 92.2% at 2 years, with operability not being a significant predictor of outcome.[13] In the series reported by Pommier et al., in as many as 48% of patients, the extent of surgery was restricted to biopsy, for an eventual LC rate of 93% at 5 years.[10] These outcomes question the need for surgery for ACCs in the BOS region.

ACCs are prone to delayed metastases, and Takagi et al. noted deterioration of OS from 82% to 63% at 3 and 5 years.[21]

We noted LC in all the six patients at 3 months. Subsequently, at a median follow-up of 17 months, both patients with distant metastases at presentation had progression in the number of metastases; one of these patients also developed progression locally.


Injury to the optic pathway, hearing loss, necrosis of the TL, brainstem injury, and osteo-radio-necrosis indicate delayed toxicity of concern.[10],[15],[28] Loss of vision with prior consent due to ON encasement has been documented in a number of studies.[12],[15]

In a case report addressing delayed toxicity in a patient treated for skull-base ACC, the authors described bilateral hearing loss and sinusitis.[29] Fatal nasopharyngeal bleed was noted in three out of thirty patients treated with either proton or carbon ion therapy, by Takagi et al.,[21] who correlated it with circumferential encasement of vessels. The same authors noted Grade 3 reactions in 26% of patients and correlated this with higher dose per fraction and use of fewer beams. Gentile et al. also noted 21% of Grade 3 reactions, that is, 3/14 patients, namely, hearing loss, temporal bone necrosis occurring in the tumor bed, and one patient with ventral radionecrosis of the pons.[24] It is pertinent to note that these patients were treated with passive scattering technique without daily imaging.

In contrast, Pelak et al., using the more sophisticated PBST noted Grade 3 late adverse effects in only 6% of patients.[13]

In our case series, the treatment was tolerated well, with reasonable acute toxicity and no requirement of tube feeding or hospital admission. At a median follow-up of 17 months, one patient in our series required drainage of mucocele in the maxillary sinus as well as dacrocystectomy. One patient has been scheduled to undergo adhesiolysis for nasal blockage and dacrocystectomy.

Concurrent chemoradiotherapy

As majority of failures in patients with ACCs are at distant sites, the use of concurrent chemotherapy may be additive to its management, both as a radiosensitizer and for systemic control of the disease. The evidence in favor of this is retrospective.[30],[31],[32]

In our series, two patients who underwent reirradiation were not given concurrent chemotherapy in view of the risk of added toxicity. Concurrent weekly chemotherapy was administered to three patients, as summarized in [Table 1].

Previously reported studies have used similar regimes of chemotherapy in their patients and at the discretion of the treating oncologist. Except for the study by Bhattasali et al. in which all patients received concurrent chemotherapy, most other studies offered chemotherapy to 50%–75% of the patients.[12],[24]

 > Conclusion Top

Encouraging early treatment and toxicity outcomes of locally advanced inoperable ACC patients treated in the current case series underline the relevance of PBT in the management of ACCs. Image-guided PBST, used in our series, confers the advantages of conformality and superior sparing in addition to the inherent radiobiological advantage of PBT.[34]

Ethical consideration

Voluntary informed consent was obtained from all patients prior to starting of any treatment as per the institutional protocols.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 > Supplementary Top

Supplement – Treatment planning, quality assurance (QA), and clinical assessment details

Proton therapy

A custom mouth bite was fabricated with thermoplastic pellets (Adapt-IT, Qfix, Avondale, USA) and customized neck rest (Moldcare Cushion, Qfix, Avondale, USA), and thermoplastic mask (Fibreplast, Qfix, Avondale, USA) were used for immobilization. Computed tomography (CT) simulation was performed with 2-mm slice-thickness axial images using Canon Aquilion LB CT scanner (Canon Medical Systems, Singapore). A contrast-enhanced MRI with T1, T2, STIR, DWI, and 3DT1 sequences was also obtained in the radiation treatment position and MR images fused with planning CT images to aid target and organs-at-risk (OARs) delineation.

The primary gross tumor (GTVp) and enlarged nodes (GTVn) were delineated with the aid of MRI and/or PETCT scans. The GTV was expanded 10–15 mm to generate high-risk clinical target volume (HRCTV), except in patients with reirradiation for whom a conservative margin of 3–5 mm was used. The HRCTV was cropped from anatomical barriers and extended along the pertinent cranial nerves. All radiologically visible nodes were included in the HRCTV and the nodal level included in low-risk CTV (LRCTV). HRCTV was prescribed a dose of 70 GyE (Gray equivalent) and LRCTV, 54 GyE in 31–35 fractions, using the simultaneous integrated boost (SIB) technique.

Constraints were prescribed to the OARs, namely optic nerves, chiasm, retina, cornea, lens, lacrimal gland, eyebrows, spinal cord, brainstem, temporal lobes, hippocampi, and brain, besides parotids, dysphagia-associated structures, and thyroid gland.

Robustly optimized MFO-IMPT plan was created for each patient using four oblique fields on RayStation (Version 9.0, RaySearch Laboratories AB, Stockholm, Sweden) treatment planning system (TPS). RayStation Monte-Carlo (MC) algorithm was used for the optimization of spot position, spot weight, energy layers, as well as dose computation. A range shifter having water equivalent thickness (WET) of 7.5 g/cm2 was used, wherever applicable. Robust optimization was performed incorporating 3-mm set-up error in all translational axes and a range uncertainty of 3.5% using MiniMax algorithm available in the TPS which was also evaluated for the same parameters. Treatment plans were evaluated for target coverage and OARs dose using standard dose volume indices derived from dose–volume histograms (DVH) including the worst-case scenarios. Following successful passing of pretreatment patient-specific quality assurance, treatment was delivered on Proteus Plus under daily CBCT-based image guidance. The characterization and performance evaluation of the proton therapy unit have been reported earlier (34).

Intra-treatment change in patient motion was monitored using Align RT (Vision RT, Version 5.1.2, London, UK)-based surface guidance. Modest acceleration was practiced, with six fractions being delivered per week in the later 2 to 3 weeks of treatment, with reactions permitting.


A helical tomotherapy (HT) treatment plan was generated for each patient in Precision (V, Accuray Inc., Sunnyvale, USA) TPS using 6-MV FFF photon beam with field widths of 1 cm or 2.5 cm and variable pitch and modulation factor. The decision to choose proton or proton + photon plan and the corresponding number of fractions was made after dosimetric comparison between the proton and HT plans. Two patients (cases 1 and 4) were partially treated on RadiXact X9 HT system (Accuray, Inc., Sunnyvale, USA) under MVCT daily image guidance.

Quality assurance

The patients underwent quality assurance CT scans and assessment of quality of proton therapy plans at weekly intervals.

Adverse events

All patients were reviewed at least once weekly during radiation therapy, 4 weeks after the completion of treatment for toxicity assessment. Acute adverse events were recorded according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0).

Supportive care

None of the six patients required feeding tube placement for nutrition or hospital admission during treatment.

Follow-up schedule

All patients were assessed at 3 months post completion of treatment for clinicoradiological response with clinical examination, PET CT with MRI correlation, and QOL questionnaire and thereafter clinically every 3 months for the first 2 years, with individualized imaging protocol.

Ethical consideration

Voluntary informed consent was obtained from all patients prior to starting of any treatment as per the institutional protocols.

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  [Table 1], [Table 2], [Table 3]


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