Proton therapy &amp; oral mucositis in oral&amp;oropharyngeal cancers: outcomes, dosimetric&amp;NTCP benefit

doi:10.21203/rs.3.rs-2021739/v1

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Proton therapy & oral mucositis in oral&oropharyngeal cancers: outcomes, dosimetric&NTCP benefit

https://doi.org/10.21203/rs.3.rs-2021739/v1

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published 19 Jul, 2023

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Introduction – Radiation Induced oral mucositis (RIOM), is a common, debilitating, acute side effect of radiotherapy for oral cavity (OC) and oropharyngeal (OPx) cancers; technical innovations for reducing it are seldom discussed. Intensity modulated proton therapy (IMPT) has been reported extensively for treating OPx cancers,and less frequently for OC cancers. We aim to quantify the reduction in the likelihood of RIOM in treating these 2 subsites with IMPT compared to Helical Tomotherapy.

Material and methods – We report with acute toxicities and early outcomes of 22 consecutive patients of OC and OPx cancers treated with IMPT, and compare dosimetry and normal tissue complication probability (NTCP) of ≥ grade 3 mucositis for IMPT and HT.

Results – Twenty two patients, 77% males, 41% elderly and 73% OC subsite, were reviewed. With comparable target coverage, IMPT reduced mean dose and D32, D39, D45, D50 significantly, for both oral mucosa (OM) and spared oral mucosa (sOM). With IMPT, there was a 7% absolute and 16.5% relative reduction in NTCP for grade 3 mucositis for OM, compared to HT. IMPT further reduced NTCP for sOM and the benefit was maintained in OC, OPx subsites and elderly subgroup.

Acute toxicities, grade III dermatitis and mucositis, were noted in 50% and 45.5% patients, respectively, while 22.7% patients had grade 3 dysphagia. Compared with published data, hospital admission rate, median weight loss, feeding tube insertion, unplanned treatment gaps are less with IMPT. At median follow-up of 15 months, 81.8% are alive; 72.7%, alive without disease and 9%, alive with disease.

Conclusion: The dosimetric benefit of IMPT translates into NTCP reduction for Grade 3 mucositis compared to Helical Tomotherapy, for OPx and OC cancers and encourages the use of IMPT in their management.

Proton

NTCP

Mucositis

Oral Cavity

Oropharyngeal

Radiation induced oral mucositis (RIOM), is a troubling acute side effect of radiotherapy for head neck cancers(HNC), especially oral cavity(OC) and oropharyngeal(OPx)cancers. It occurs due to cellular depletion, loss of integrity of the mucosal barrier, inflammation, immune reaction and release of cytokines(1). Apart from patient related factors and concurrent systemic therapies, the radiation dose received by the oral mucosa (OM)is the most important factor in developing RIOM(2).

RIOM results in the requirement of analgesics including NSAIDs, opioids and gabapentinoids(3, 4). In addition, it results in decreased oral intake, weight loss, interruption or modification of treatment, and the risk of feeding-tube insertion. The risks of infection, antibiotic usage and hospitalization are also higher in patients with oral mucositis, as is the risk of aspiration pneumonia, hypothesized as the causative factor of toxic deaths due to mucositis dysphagia aspiration sepsis (MDAS) syndrome(5). The impact of RIOM is felt on many QOL domains including performance status, body-weight, pain, activity, recreation, swallowing, saliva, mood and anxiety(6).

While the potential of intensity modulated radiotherapy (IMRT) to reduce mucositis was recognized early, in 2001,dose constraints were first defined only in 2008 by Narayan et al(7). The validity of these were confirmed in a randomized setting(8). Additional dose constraints have been identified as significant(9, 10).Ascertaining a dose-volume-relationship has however been constrained by non-uniformity in delineation of the OM; the definition of OM proposed by Dean et al limits this variability(11).

Modern radiotherapy techniques viz., IMRT,VMAT and Helical Tomotherapy (HT) aim to reduce radiation dose received by organs at risk(OARs)to limit normal tissue complication probability (NTCP), and improve the therapeutic ratio(12, 13).Proton therapy (PT), with its particular physical characteristics, allows better sparing of OARs(14). The conformality and convenience afforded by pencil bean scanning (PBS) technique has led to an increase in application of PT in HNC, with benefits being noted in various patient groups. Langendijk et al have reported NTCP based plan comparisons to identify patients who will benefit with PT(15). The reduction in NTCP of oral mucositis and other side effects has been studied by Tambas et al in a dosimetric analysis; the authors noted a 5–10% benefit with PT in all HNC subsites, the highest in hypopharyngeal - laryngeal tumours(16).

Our study aims to quantify the reduction in pertinent oral mucosal dose parameters, as well as NTCP for grade 3RIOM, in OC and OPx cancer patients treated with PT compared IMRT plans. We have included parotid tumours, treated with adjuvant PT as OC lesions as their radiation treatment resembles unilateral OC irradiation and has previously been studied with oral cavity cancers (17). In addition, we report early toxicity and outcome data.

We report results of 22 consecutive patients of OC and OPx cancers treated with definitive or adjuvant (post-op) IMPT, from January 2019 to May 2020.Details of the planning process are documented in the Supplementary File. Primary and nodal clinical-target-volumes (CTVs) were delineated as previously reported(18, 19). While there are separate guidelines for delineation of oral cavity (20) and oral mucosal surface (11), we opted for the latter, as proposed by Dean et al(11)[Fig. 3, (Supplementary file)]. The mucosa overlapping with the CTV was excluded to the generate the spared oral mucosa(sOM). Dose constraints prescribed to this structure were similar to oral cavity constraints.

Comparative proton (IMPT) and photon plans were assessed for target coverage and OAR doses. The latter are generated using HT, prior to PT planning, as part of departmental policy.

Acute adverse events were recorded according to the RTOG grading. Grade of mucositis within the treatment volume and outside, as assessed on clinical examination, was recorded separately.

Using the same plans, NTCP of ≥ grade 3 mucositis for IMPT and HT plans was also calculated using following formula

NTCP Mucositis \(={\left(1+\left(\frac{D50}{D}\right)k\right)}^{-1}\), where D is mean dose, D50 is 51GyE and k =1. (9, 21)

Dosimetric data for all patients was collected and compiled using SPSS Software version 21, which was used for statistical analysis also. Dosimetric variables for OM and sOM for IMPT and HT plans were compared using paired t test; two tailed significance (p value) was calculated. (Fig. 4, (Supplementary file)).

Patient demographics including comorbidity index, frailty score and clinical details are summarized in Table 1. Median age of this population, comprising 22 patients, was 56 years (range 24–80 years);5 (23%) were female.

Table 1

– Demographics and salient clinical features
Age (Median)	56 Years ( 24–80) 9 (41%) were age >/= 65 years
Sex (M:F)	17:5 (77% : 23%)
aaCCI (Median)	6 (3–9)
cFS (Median)	3 (2–4)
Subsite	Oral Cavity – 16 (73%) Oropharynx – 6 (27%)
Histology	SCC – 18 (82%) MC – 2 (9%) ACC – 2 (9%)
Stage	II or III – 6 (27%) IVA - 11 (50%) IVB – 4 (18%) IVC - 1 (5%)
Radiation	Definitive – 8 (27%) Adjuvant – 16 (73%)
Concurrent Systemic therapy	Yes – 12 (55%) No – 10 (45%)
Systemic therapy agents	CDDP – 9 (75%) Nimotuzumab – 2 (17%) Pacli + Carbo – 1 (8%)
aaCCI – age adjusted Charlson’s Comorbidity Index, cFS – clinical Frailty scale, SCC – Squamous cell carcinoma, MC- Mucoepidermoid carcinoma, ACC – Adenoid cystic carcinoma, CDDP – Cisplatin, Pacli – Paclitaxane, Carbo – Carboplatin.

Nine (41%) patients were elderly, aged ≥ 65 years, all of whom had ≥ 1 comorbidity viz., diabetes, hypertension and, or hypothyroidism. Sixteen(73%) patients had OC cancer, while remaining 27% had OPx malignancies. The details of histology, subsite, indication and concurrent systemic treatment (CST)are detailed in Table 2.Two patients with OC cancer received definitive radiation due to unwillingness for surgery / inoperable disease and the rest received adjuvant radiation. Twelve (55%)patients received CST.

Table 2

– Dosimetry and dose reduction with intensity modulated proton therapy (IMPT)
	IMPT	IMRT	Average of % difference
HR PTV D95 (Avg)	97%	98%	NS
HR CTV D98 (Avg)	98%	100%	NS
LR PTV D95 (Avg)	97%	98%	NS
LR CTV D98 (Avg)	99%	100%	NS
Oral Mucosa D mean (Avg)	30.42 GyE	38.05 Gy	13.5% reduction
Spared oral mucosa D Mean (Avg)	19.17 GyE	32.16 Gy	38.6% reduction
Spinal Cord D Max (Avg)	19.64 GyE	35.76 Gy	44.4% reduction
Brainstem D Max (Avg)	25.86 GyE	42.03 Gy	36.7% reduction
C/L Parotid D mean (Avg)	20.56 GyE	25.26 Gy	28.3% reduction
HR PTV – High risk planning target volume, HR CTV – High risk clinical target volume, LR PTV – Low risk planning target volume, LR CTV – Low risk clinical target volume, D95 – Dose received by 95% of volume, D98 – Dose received by 98% of volume, Avg – Average, Max – Maximum, C/L – Contralateral, NS – Not Significant, Gy – Gray, GyE Gray equivalent

Treatment details and acute toxicities are summarized in Table 2. Dosimetric comparison between HT and PT plans with dose received by target volumes and OARs is summarized in Table 3.

Table 3

– NTCP of mucositis for oral mucosa and spared oral mucosa with benefit of IMPT
	NTCP for OM		Benefit of IMPT for OM Absolute % (Avg %)	NTCP for sOM		Benefit of IMPT for sOM Absolute % (Avg %)
	IMPT	HT	Benefit of IMPT for OM Absolute % (Avg %)	IMPT	HT	Benefit of IMPT for sOM Absolute % (Avg %)
Overall	38.5	45.5	7.0 (16.3)	24.5	41	16.5 (37)
OC	39.5	47	7.5 (26.5)	27.0	40.8	12.2 (34.5)
OPx	31.0	39.0	8.0 (31.3)	22.0	38.2	16.2 (43.4)
Unilateral RT	36.6	42.8	6.2 (27.7)	27.4	41.3	13.9 (34.8)
Bilateral RT	38.5	45.5	7.0 (24.4)	24.7	39.5	14.8 (38.2)
Elderly	36.5	44.5	8.0 (22.5)	26.3	39.8	13.5 (34.6)
NTCP – Normal tissue complication probability, OM – oral mucosa, sOM – spared oral mucosa, OC – Oral Cavity, OPx - Oropharynx, RT – Radiotherapy, IMPT – Intensity Modulated radiotherapy, HT – Helical Tomotherapy.

The coverage of the target volumes by 95% and 98% of the prescription dose was comparable in HT and IMPT plans, for HRCTV and LRCTV, respectively(Table 2).

The average sOM volume was 74% of total OM volume (range 43 to 100). Average of mean dose received by the OM was significantly less in IMPT plans (19.17GyE vs 30.42GyE), while it was further reduced for sOM (19.17GyE with IMPT Vs 32.16Gy). The volume of OM and sOM receiving 32GyE [V32], 39GyE [V39], 45GyE [V45], 50GyE [V50] and 55GyE [V55] were statistically significantly less in IMPT compared to HT plans [p < 0.05], again better for sOM compared to OM as noted in Table 2. The V60 was equivalent for both plans.

The dosimetric advantage of IMPT was maintained in other OARs.

NTCP for RIOM for both OM and sOM was significantly less with IMPT. With IMPT, NTCP for ≥ Grade 3 mucositis based on OM was38.5 compared to 45.5 with HT, 7% absolute difference, and an average 16.5% relative reduction. The reduction in absolute risk in NTCP for RIOM for OM was maintained in subgroup analysis, 7.5% in OC, 8% in OPx and elderly patients, 6.2% in unilateral radiation [RT]and 7% in bilateral RT. The relative benefit ranged from 22.5–31.3%, Fig. 2.IMPT further reduced NTCP for sOM compared to HT,[24.5 Vs 41, 16.6% absolute difference and an average37% reduction] and also in all subgroups mentioned above[Table 3].

Acute toxicities are summarized in Table 4. Grade 3dermatitis and mucositis were noted in 50% and 45.5% of total population, 11 and 10 patients respectively. Grade 2 mucositis or more was not noted outside the target volume as assessed on clinical examination. Five patients had grade 3 dysphagia, i.e.required feeding-tube insertion; during treatment in 3 and immediately after treatment completion in 2. All patients who required feeding-tube insertion were elderly with ≥ 1 comorbidity.

Table 4

– Acute toxicities and important parameters
Acute toxicities	Dermatitis	Grade 3–11 / 22 (50%)
	Mucositis (Within target)	Grade 3–10 / 22 (45.5%)
	Mucositis (Outside target)	Grade 2 or more – None
	Dysphagia	Grade 3–5/ 22 (22.7%)
Median Weight loss		2.8 Kg
NGT insertion		Yes 6/22, (27.3%) Avg duration of NGT 8 days (5–16 days)
Unplanned Treatment breaks		Yes 8/22, (36.4%) Avg treatment gap 1.2 days
Hospital admissions during treatment		Yes – 5/22, (22.7%) Avg duration of hospital admission 3.6 days (2–6 days)
Opioid analgesic requirement		Yes – 13/ 22 (59.1%)
OTT prolongation		Nil
Avg – Average, NGT – Naso-gastric tube, OTT – Overall treatment time.

Five patients required hospital admission during treatment, with an average hospital stay of 3 days. The median weight loss in this cohort was 3.8 Kg[1.4 to 9.1 Kg]. No patient lost ≥ 10% body weight. Though 8 patients had unplanned treatment gaps of one [6/8] or two [2/8] days, OTT was not prolonged; Treatment acceleration to 6 fractions per week was possible in the latter half of treatment in 7 patients,.

At median follow-up of 15 months, 18[81.8%] patients of this cohort were alive, 16[72.7%]were alive without disease while 2 [9%]were alive with disease. The cause of death was progressive local disease in 1 patient, local and distant progression in2 and metastatic disease in 1 patient.

We have demonstrated significant sparing of the oral mucosa in IMPT plans compared to HT plans, translating into significantly lower NTCP for RIOM in patients receiving radiation for OC and OPx cancers. We have also assessed control rates and acute toxicity in this group of patients treated with IMPT.

Oral mucosa delineation and dose response relationship

Development of RIOM is multifactorial and includes patient factors such as age, sex, comorbidities, immunity, radiosensitivity and treatment factors such as radiation dose, concurrent and, or neoadjuvant systemic therapy (1, 22–24). RIOM is limited to intermediate and high dose volumes of radiation, usually starting at a cumulative dose of 30Gy(10). Given its association with multiple side effects, conformal avoidance of the OM merits the same attention as the sparing of salivary and dysphagia associated structures. The benefit of sparing of OM has been demonstrated in a randomized trial, by Wang et al who treated tongue cancer patients with IMRT, and compared sparing the OM outside PTV in the study arm to a mean dose to 32Gy versus no constraint for this structure in the control arm. They noted significant reduction of Grade 2 and 3 mucositis on prescribing a constraint, which resulted in significantly reduced requirement of analgesics and intravenous antibiotics during treatment (8).

Estimation of the probability of oral mucositis on the basis of the dose received by the OM requires uniformity in delineation. The absence of this has been an issue while establishing a pertinent dose volume relationship. A number of groups have delineated the OC in total, and used it as a surrogate for the OM(20). The definition of OM proposed by Dean et al limits this variability by delineating a 3 mm thick oral mucosal surface over the palate, lip, bilateral gingiva [buccal, alveolar, lingual and gingiva proper], tongue and floor of mouth[FOM](11).Compared to delineation of the OC as an OAR, this mucosal surface volume ensures inclusion of palatal and buccal mucosal surfaces and exclusion of tongue and FOM musculature.

Using the guidelines proposed by Dean et al to delineate OM and then identifying sOM is relevant as different planning interventions and evaluation criteria are required for the OM versus sOM. The only intervention relevant for the OM within the PTV is avoiding hot spots, while the sOM can be prescribed stringent dose constraints. In this context, our average sOM volume, 75% of OM [Range 43% − 93%], allowed for sparing of a substantial part of oral mucosal surface.

A dose constraint for OM, RIOM being the endpoint, proposed by Narayan et al. was based on a prospective clinical study of 12 HNC patients. The authors noted that a cumulative dose of < 32 Gy and > 39Gy was associated with minimal acute mucositis and a longer duration of mucositis, respectively(7).

Following this, various authors have established dose response relationships and predictors for RIOM such as V30 more than 73%, D21 cc > 10.25 Gy / week and DMeanOM(8, 9, 25).Mazzola et al have studied the risk of ≥ Grade 2 mucositis and identified concurrent chemo-radiotherapy and certain dose parameters pertaining to both the total OM and the spared OM(26). The relevant parameters pertaining to ≥ Grade II and OM out of PTV were V45 > 40%, V50 > 30%, V55 > 20%. An extensive dose response correlation was also conducted by Bhide et al(27).

Protons, with their characteristic physical properties, deposit energy at a defined depth i.e., Bragg peak followed by a sharp dose fall off. The dose conformality and convenience of PBS PT allows better sparing of OARs compared to IMRT, and hence encourages its use in HNCs(17, 28–31). We have applied the same for the HNC cohort [OC and OPx]prevalent in our population.

Our findings summarized in Tables 2 and 3, showed significant reduction in the dose received by the OM and sOM at all dose points previously identified as significant, DMean, V32, V39, V45, V50, and V55 with PT[Fig. 2a, 2b, Fig. 5 (Supplementary file)]. This reduction ranges from 40–60% for the sOM and 16.9–28% for the OM as a whole. We have noted this reduction in patients treated for unilateral as well as bilateral targets, as well as for both, OC and OPx cancer patients. Romesser et al, have demonstrated a similar reduction of OC doses, with PT, in a non-randomized comparison of patients receiving unilateral radiotherapy, not ingsignificant reduction in oral mucositis and dysgeusia(17). Similarly, the clinical relevance of this dose reduction has been demonstrated for oropharyngeal cancers by Sharma et al, who reported better patient related outcomes measures[PROMs], pertaining to xerostomia and role function in patients treated with PT for post-op OPx cancers when compared with IMRT, even 12 months after treatment(30).

NTCP for Grade 3 mucositis

NTCP estimation isa tool predicting treatment induced toxicities. An ideal NTCP model should be sensitive to non-linear dose response relationships and multiple interplays between factors; it should be generalizable and should help in predicting various grades of complications at various time points(32).

The NTCP model-based approach was used by Langendijk et al to identify patients likely to benefit from reduction in NTCP for xerostomia, dysphagia and risk of tube feeding insertion and maximum benefit noted in locally advanced nasopharyngeal and OPx cancers(16). OC cancers constituted 6% patients in this analysis(16). Our study illustrates the advantage of proton therapy for cancers prevalent in our population i.e., OC and OPx cancers, and focusses on another clinically relevant endpoint, RIOM.

We have used the NTCP model for oral mucositis proposed by Bhide et al. Classified as TRIPOD 4b (TRIPOD criteria – Transparent reporting of multivariate prediction model for individual prognosis or diagnosis), i.e., this model has been validated in an external cohort, though with some caveats, as noted below (34). This model was created on patients of laryngeal and hypopharyngeal cancers treated in the setting of induction and concurrent chemotherapy[CCT], dose escalation and altered fractionation. It has then been validated by Sharabiani et al, in a cohort treated in a DAHANCA trial for laryngeal and oropharyngeal cancers with standard fractionation and CCT, with or without nimorazole, with acceptable concordance with a Brier score of0.67(33). Subsequently, this has been validated for proton therapy by Blanchard et al with acceptable concordance, albeit with a 0.17 difference in AUC between the proton cohort and the cross validated photon cohort, underlining the importance of validation when applying the model across techniques 3dCRT, IMRT and PT(34, 35).

We have calculated NTCP of oral mucositis for the OM and sOM for both IMPT and HT plans. The average absolute difference in NTCP of mucositis [ΔNTCP] for OM was 11.05%, a 20.4% benefit over IMRT, while for ΔNTCP sOM was 14.9%, a 37.3% benefit of IMPT over IMRT[Fig. 2A].The NTCP advantage was maintained for IMPT for both OM and sOM for unilateral and bilateral irradiation, OC and OPx cancers and in elderly patients [Figure 2B], conclusively demonstrating the advantage of proton therapy.

In our cohort, as summarized in Table 3, 50% and 45.5% patients developed grade 3 dermatitis and mucositis, respectively. We prospectively recorded the location of mucositis within and outside the target as based on clinical examination and noted the absence of mucositis outside the target in most patients. On comparison with calculated NTCP results for PT for OM,38.5%and sOM, 24.5%, we noted a higher incidence of grade 3 oral mucositis (45.5%) entirely within the target volume and none outside. The discordance in calculated NTCP for OM and the actual results can be attributed to use of CST, associated comorbidities, especially diabetes-mellitus and connective tissue disorders, age, immunity, individual radiosensitivity and possible different biological effects of protons; none of these is factored into current NTCP models for mucositis. Blanchard et al have commented on this discrepancy between calculated NTCP and actual complications, within their group, though maintaining the validity of using NTCP calculation for comparison of plans. However, as noted below, the tolerance of treatment was better than historical and contemporary cohorts.

Our tube [NGT]insertion approach was reactive and required in,27.3% patients, exclusively in the elderly with comorbidities, age being a known risk factor(36). This compares favorably, at 11–33% rate of reactive, rather than prophylactic, tube placement rates noted in studies on IMRT (36, 37).The duration of tube feeding is remarkably short at an average 8 days [range 5–16]. Beadle et al, reporting on a large SEER-Medicare database have noted a median duration of 100 days, following reactive tube placement.

In a systematic review of 33 randomized trials in HNC, Trotti et al have noted an average hospital admission duration of 35–42 days; in our cohort it was average 3.6 days [Range 2–6], none for mucositis(38).The median weight loss 2.8 Kg [1.5 to 6.8], with no patient losing > 10%,compared to 17% reported noted by Trotti etal. The average unplanned treatment gap was 1.2 days, all patients, including the elderly, completing treatment without prolongation of OTT. At a median follow up of 12 months, 18/22 [ 82%] patients of our cohort, comprising 73% patients with Stage IV disease and 41% elderly with comorbidities, were alive.

The limitation of our study is its preliminary nature; validation in a larger, more diverse population, as well as correlation with QOL, will reinforce the benefit of proton therapy in these head neck subsites. We noted a discrepancy between calculated and actual NTCP for mucositis, though the latter was confined within the target. NTCP models for mucositis require to be more broad-based, incorporating multiple factors noted above.

Our results demonstrate the importance of radiation techniques in improving of the tolerance of radiation and the benefit of modern proton therapy in OC and OPx patients, the former especially relevant in South Asia, and not so far addressed in reference to proton therapy. Improved tolerance of treatment, even with > 40% population being elderly, reinforces the impact of sparing of oral mucosa by proton therapy.

In conclusion, NTCP for mucositis is significantly less with IMPT for OC and OPx cancers, in all age groups. The acute toxicity profile of our patients encourages use of this modality for improving the therapeutic ratio of HNC treatment.

Patient consent statement:

The work described has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. Due consent process has been taken as per institutional protocols.

Ethical Approval and Consent to participate: As per institutional protocol

Consent for publication: As per institutional protocol

Availability of supporting data: Data will be made available upon request

Competing interests: None

Funding: No funding was received

Authors' contributions: Dr. Sapna Nangia- Conceptualization, Data curation, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing.

Dr. Utpal Gaikwad-Data curation, Formal Analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing – original draft, Writing – review and editing.

Dr. Noufal M P-Data curation, Investigation, Methodology, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing.

Mayur Sawant-Data curation, Investigation, Methodology, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing.

Manoj Wakde-Data curation, Investigation, Methodology, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing.

Dr. Ashwathy Mathew- Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing.

Dr. Srinivas Chilukuri- Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing.

Dr. Dayananda Sharma- Data curation, Investigation, Methodology, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing.

Dr. Rakesh Jalali- Data curation, Investigation, Methodology, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing.

Acknowledgements: We would like to acknowledge all head and neck cancer management team members and all our patients

Data sharing: The data has not been deposited in a repository at present but is available for scrutiny by reviewers, if required.

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Proton therapy & oral mucositis in oral&oropharyngeal cancers: outcomes, dosimetric&NTCP benefit

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