Reducing Salivary Toxicity with Adaptive Radiotherapy (ReSTART): A Randomized Controlled Trial comparing conventional IMRT to adaptive IMRT in head and neck Squamous Cell Carcinomas

doi:10.21203/rs.3.rs-3225340/v1

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Study protocol

Reducing Salivary Toxicity with Adaptive Radiotherapy (ReSTART): A Randomized Controlled Trial comparing conventional IMRT to adaptive IMRT in head and neck Squamous Cell Carcinomas

https://doi.org/10.21203/rs.3.rs-3225340/v1

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published 29 Feb, 2024

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Objectives:

The utility of Adaptive Radiation Therapy (ART) in Head and Neck Squamous Cell Carcinoma (HNSCC) remains to be ascertained. While multiple retrospective and single-arm prospective studies have demonstrated its efficacy in decreasing parotid doses and reducing xerostomia, there is a lack of adequate randomized evidence.

Methods and Analysis:

ReSTART is an ongoing phase III randomized trial of patients with previously untreated, locally advanced HNSCC of the oropharynx, larynx, and hypopharynx. Patients are randomized in a 1:1 ratio to the standard Intensity Modulated Radiation Therapy (IMRT) arm {Planning Target Volume (PTV) margin 5 mm} vs. ART arm (standard IMRT with a PTV margin 3 mm, two planned adaptive planning at 10^th and 20^th fractions). The stratification factors include the primary site and nodal stage. The RT dose prescribed is 66Gy in 30 fractions for high-risk PTV and 54Gy in 30 fractions for low-risk PTV over five weeks, along with concurrent chemotherapy.

The primary endpoint is to compare salivary toxicity between arms using salivary scintigraphy 12 months’ post-radiation. To detect a 25% improvement in the primary endpoint at 12 months in the ART arm with a two-sided 5% alpha value and a power of 80% (and 10% attrition ratio), a sample size of 130 patients is required (65 patients in each arm). The secondary endpoints include acute and late toxicities, locoregional control, disease-free survival, overall survival, quality of life, and xerostomia scores between the two arms.

Discussion:

The ReSTART trial aims to answer an important question in Radiation Therapy for HNSCC, particularly in a resource-limited setting. The uniqueness of this trial, compared to other ongoing randomized trials, includes the PTV margins and the xerostomia assessment by scintigraphy at 12 months as the primary endpoint.

Ethics and dissemination:

This trial was approved by the Institutional Ethical Committee of Tata Memorial Hospital, Mumbai, on 3^rd February 2017.

Trial Registration Number:

The trial is prospectively registered with the Clinical Trial Registry of India (CTRI) (Reg no: CTRI/2018/08/ 015531).

Definitive (chemo) radiation, i.e., radical Radiation Therapy (RT) with or without concurrent systemic chemotherapy, is the standard of care in the non-surgical management of head & neck squamous cell carcinoma (HNSCC) (1). Over the past 20 years, RT for HNSCC has transitioned from 2D to 3D-conformal radiotherapy (3D-CRT) to intensity-modulated radiation therapy (IMRT), improving the toxicity profile and, perhaps, locoregional control rates (2). In particular, IMRT, with its improved conformality over 2D & 3D-CRT, has reduced late Xerostomia and Dysphagia (3, 4). It may also improve the Quality of life (QOL) without compromising local control and overall survival (5, 6).

The role of Image Guided Radiation therapy (IGRT), in combination with IMRT, has grown exponentially in the past decade. IGRT minimizes uncertainties of undertreating target volumes and over-treating adjacent organs-at-risk (OARs) and may also reduce treatment-related toxicities by reducing the Clinical Target Volume (CTV) to Planning Target Volume (PTV) (7, 8, 9).

However, other uncertainties like target volume delineation, daily setup variations, and internal organ motion remain concerning when utilizing precision techniques like IMRT/ IGRT (10). Many patients experience volumetric and spatial changes in the target volumes and OARs during treatment. This is due to some combination of treatment response, weight loss, inflammation, muscle atrophy, and radiation effects on normal tissue and tumor (11). These geographical and volumetric alterations result in overdosing of normal tissues and underdosing or marginal geographical misses of target volumes during treatment in a significant proportion of patients.

A possible solution to account for these changes is adaptive Radiation Therapy (ART). ART is a closed feedback loop radiation process where treatment is adapted to account for internal anatomical or biological changes. Based on some previous studies, approx. 21 to 65% of all head & neck cancer patients may be benefitted dosimetrically from ART (12, 13). Several studies have reported the dosimetric advantages of adaptive re-planning for patients with HNSCC (14, 15). Schwartz et al. conducted a prospective study of ART in 22 patients with HNSCC and noted that the mean parotid sparing was improved with ART by 3.9% on the ipsilateral side and by 2.8% on the contralateral side (16). Few published non-randomized series have also shown a significantly higher locoregional control in the adaptive group than the non-adaptive group in head and neck cancer. Still, no significant difference was noted in overall survival (17, 18). Despite these advantages, one of the biggest obstacles for routine adaptation of ART is manually re-simulating, re-contour & re-plan patients, especially in resource-limited centers. Also, optimal triggering factors must be identified to maximize efficacy and utility, including the exact timing, frequency, and ideal candidates for implementing ART.

There is limited randomized evidence to date to demonstrate the clinical benefit of ART in routine clinical practice. The results from the recently published ARTIX trial raise further questions about the routine utility of ART in the clinics for all patients (19). At least four more randomized trials are looking at the clinical utility of Adaptive Radiotherapy (20, 21, 22, 23). ReSTART (Reducing Salivary Toxicity with Adaptive Radiotherapy) is an ongoing study to evaluate the efficacy of ART in reducing Xerostomia in patients with HNSCC. Here, we describe the study protocol of this randomized trial.

Ethical Approval: This ongoing study is approved by the Institutional Ethical Committee of Tata Memorial Hospital, Mumbai, on 03.02.2017 (TMC IRB Project No: 29093). This trial is prospectively registered with the Clinical Trial Registry of India (CTRI) (Reg no: CTRI/2018/08/ 015531).

Design: This is a single institutional, prospective, parallel design, open-label, two-arm randomized controlled trial with a superiority design conducted in India for HNSCC who are planned treatment with curative intent definitive Chemoradiation.

Patients are stratified by

Primary site: Oropharynx or Other Head and Neck Cancer (Larynx or Hypopharynx)
Nodal Status: N0 or N+

Randomization: Randomization is done in a ratio of 1:1 by stratified block randomization with a block size of 4. The two study groups are:

Control Arm (Arm A): Standard IMRT Radiotherapy schedule
Experimental Arm (Arm B): Adaptive Radiotherapy (ART) with margin reduction.

Inclusion & Exclusion Criteria:

The trial includes

Biopsy proven Squamous Cell Carcinoma of the Oropharynx, Larynx, and Hypopharynx
AJCC (8^th edition) Stage cT1-4a N0-3 M0
Patients older than 18 years but less than 70 years
Good performance status (Karnofsky Performance Status 70)
Patients willing & reliable for follow up
Nutritional & Physical conditions of patients compatible with definitive Chemoradiation
Signed study-specific consent forms

The exclusion criteria are

Stage cT1-2N0M0 vocal cord cancers,
Patients with a history of surgery for primary disease or node in the neck region;
Patients with distant metastasis
Patients with a previous history of radiation for head & neck cancer;
Patients with a diagnosis of other histology other than SCC;
Patients receiving neoadjuvant chemotherapy
Patients with diagnosed cases of nasopharyngeal and paranasal sinus cancer;
Previous history of malignancy within five years;
Pregnancy or lactating woman
Active untreated infection, which interferes with the completion of treatment;

Patient & Public Involvement: All patients are served a patient information sheet. Patients are randomized to either of the two arms after willingly consenting and understanding all the aspects of participating in the trial.

Treatment Details:

Baseline Evaluation: The baseline evaluation includes a complete history and physical examination, comprehensive dental and nutritional assessment, and complete blood investigations, (complete blood hemogram, renal function tests, serum electrolytes, and liver function tests) for assessing the suitability of systemic therapy. Contrast-enhanced Magnetic Resonance Imaging (CE-MRI) scan for the local extent of the disease, and a Positron Emission Tomography-Contrast Enhanced Computerized Tomography (PET-CECT) scan of the whole body to rule out any distant metastasis are advised for all patients as part of the staging workup. After clinical staging & confirmation of diagnosis, the treatment plan is decided in a multi-disciplinary tumor board.

After consenting, all patients undergo a salivary scintigraphy scan for baseline salivary function. European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and HN35 (QLQC30 & HN35) and Xerostomia questionnaires are also filled up at baseline.

Simulation & Contours: A CECT scan (2.5 mm slice thickness) is taken by positioning the patient supine on a flat table couch with a base plate and headrest with arms by the side and using a 4-point head-neck thermoplastic mask. Fiducials are placed at Glabella and two lateral temporal ones, one on each side. Diagnostic MRI & PET CECT scans are co-registered with the planning CECT scan. Gross Tumor Volume (GTV) is delineated from clinical information and with the help of diagnostic scans. A CTV-primary of 5 mm (including regions with a high risk of subclinical spread) is generated around the GTV for potential microscopic disease. The high-risk nodal CTV volume includes the entire involved nodal level after generating a 5 mm margin around the lymph node. In low-risk nodal CTV volume, uninvolved lymph nodal levels are contoured (24, 25).

Intervention: In the standard arm, IMRT group, per existing institutional practice, a PTV margin of 5 mm is generated for high-risk and low-risk PTV. The setup verification is done using Electronic Portal Imaging Device (EPID) or Cone Beam CT (CBCT) in the first three fractions and weekly after that as per institutional practice or maybe more often if necessary. In the standard arm, re-planning may be undertaken if significant weight loss or tumor shrinkage affects the fixation of the thermoplastic mold.

In the study arm, ART group, a PTV margin of 3 mm is used for primary disease and involved nodal level & a PTV margin of 5 mm is used for other prophylactic levels of the neck nodes. Daily image guidance using kilo-voltage (KV) CBCT is done. The adaptive scan is taken two times at pre-specified intervals during treatment, once at the 10^th fraction and another at the 20^th fraction of radiation. The re-planning scans are taken per the same protocol as the baseline scan. After taking the planning scan, deformable image registration, contour propagation, adaptive re-planning, and deformable dose accumulation are carried out. The new plan is implemented for the remaining radiation dose.

Radiotherapy & Chemotherapy Details: Definitive radiotherapy is planned to use a simultaneous integrated boost (SIB) technique as per institutional protocol. Our treatment protocol is described in detail in some of our previously reported studies (26). High-risk volume is planned with a modest hypofractionation (220cGy) for a total dose of 66Gy in 30 fractions over six weeks, whereas low-risk elective volumes are treated with a 180cGy per fraction for a total dose of 54Gy in 30 fractions over six weeks.

All patients in both arms receive cisplatin-based chemotherapy in a concurrent setting if fit for the same, along with standard antiemetic and hydration. If unfit, cisplatin is replaced by cetuximab, Nimotuzumab, carboplatin or docetaxel-based chemotherapy weekly as per institutional practice.

RT Plan: The RT plan is evaluated according to ICRU 83 and QUANTEC guidelines (27, 28). This is shown in Table 1.

Review: During treatment, acute toxicity is assessed weekly using Radiation Therapy Oncology Group (RTOG) and Common Terminology Criteria for Adverse Events (CTCAE) scales. All patients are monitored regularly with weekly blood investigations, e.g., complete blood count, renal function tests, and serum electrolytes, before every cycle of systemic therapy. At the end of treatment, EORTC QLQ C30 and HN35, and Xerostomia questionnaires are filled.

Follow-up: After completion of treatment, all patients are followed up with a response PET CT scan 10-12 weeks after completion of treatment and repeated thereafter in case of any suspicion of recurrence. The follow-up schedule is clinical evaluation every 3–4 months till the first two years, six months thereafter till five years, and then annually. Clinical evaluation and toxicity assessment are done at each follow-up visit. QOL and Xerostomia questionnaires are filled up every six months during follow-up. Salivary scintigraphy is advised after three months, six months, and 12 months of completion of treatment, then annually till three years after completion of treatment.

Endpoints & Statistics: The primary objective of this study is to compare salivary toxicity after 12 months post-radiation. The salivary function at 12 months is determined by the ratio of salivary excretion fraction (SEF) at 12 months after treatment compared to the baseline SEF (pre-treatment) x 100%. The primary efficacy analysis will be an intention-to-treat analysis.

The alternative hypothesis of this study is that the patients in the study arm would have lower rates of salivary toxicity at 12 months post-radiation compared to IMRT with a 25% superiority margin (40% SEF ratio in the IMRT arm and a 65% SEF ratio in the ART arm. This assumption of 40% SEF in the IMRT arm one year after completion of radiotherapy is based on the results of a study published by the same institute (29).

The secondary endpoints are to compare acute/late toxicities, locoregional control (LRC), disease-free survival (DFS), overall survival (OS), response rates, QOL and xerostomia score between the two arms.

OS is defined from the date of randomization to the date of death due to disease or any cause. Similarly, DFS is the time interval from randomization to recurrence, progression, or death due to any reason. LRC is defined as the interval from the date of randomization to the date of local or regional recurrence or progression. The response is measured using the Response Evaluation Criteria in Solid Tumors (RECIST Vr1.1).

The Mann-Whitney U test or Chi-square test (or equivalent parametric test)s will be used to compare the toxicity and Quality of life between the two arms. Kaplan Meier method will be used to estimate the survival endpoints in the two arms. Survival will be compared between the two groups by log-rank test. Schoenfeld residuals will be used to test the assumption of proportional hazards between the arms. If assumptions are met, a Cox proportional model will be used for multivariable analysis. A p-value of 0.05 will be considered statistically significant. All statistics will be done on R version 2020 (https://www.R-project.org/.) and SPSS version 24 (IBM Corp. Released 2016. IBM SPSS statistics for Windows, Version 24.0. Armork, NY: IBM Corp).

Sample size Estimation: To detect a difference in the primary endpoint of salivary toxicity at 12 months (40% in the IMRT arm and 65% in the ART arm) with a two-sided 5% alpha value and a power of 80% with a 10% attrition ratio, a sample size of 130 patients is required. This amounts to 65 patients in each arm (1:1 randomization).

The planned accrual period for this study is four years, along with a minimum of 1 year for outcome measures.

ART is an approach to account for the anatomical or biological changes during treatment, such as tumor response and normal tissue shrinkage. Several studies have reported on the dosimetric advantages of ART for patients with HNSCC (shown in Table 2). Hansen et al. performed midcourse repeat CT imaging and subsequent re-planning of 13 patients with HNSCC. This study noted an increased dose to normal structures and decreased target volume coverage if the original plan was continued without adapting (30). Schwartz et al. conducted a prospective study of ART and noted a decrease in the ipsilateral and contralateral parotid mean dose (16). The mean dose reduction in parotid glands ranged from 0.6% to 10% (31, 32, 33, 34). However, this reduced mean dose to the parotid glands did not reflect in clinical outcomes like xerostomia. Few studies have also found that ART was useful in decreasing the maximum dose of the spinal cord (31, 32, 35). Some of the reported prospective and retrospective series which have observed the clinical efficacy of ART, are shown in Table 3. Although comparative data are very limited, two published prospective studies from the Chinese group – Yang et al. and Chen et al., showed a statistically significant locoregional control rate at two years in adaptive radiotherapy than in the non-adaptive group but no benefit in overall survival (17, 18). Yang et al. also found a clinically significant improvement in most QOL scales, including global QOL, two functional scales (role & social functioning), and four symptom scales (dyspnea, appetite, constipation & diarrhea) with adaptive radiotherapy (17). The usefulness of adaptive radiotherapy in pediatric head and neck cancer was also demonstrated by S Laskar et al. (36).

Although the theoretical advantages of clinical outcomes have been established in multiple studies, there is no consensus on the appropriate timing for ART during radiotherapy. Many centers perform adaptive re-planning based on clinical characteristics, such as weight loss, tumor shrinkage, mask fitting, and patient setup changes (37). Other approaches suggest performing ART at pre-planned regular intervals, e.g., every ten fractions, as reductions in target and parotid volumes are most pronounced in the first or second weeks (38, 39). In a study assessing the timing of ART scans in 13 patients with oropharyngeal cancer receiving definitive radiotherapy, most of the benefit appeared within the first two weeks, with the author recommending ART at weeks 1, 2, and 5 (40). In a separate study of 19 patients with nasopharyngeal cancer, the authors recommended ART at fractions 5 and 15, as significant dosimetric variations were noted at these time points (39). In a retrospective institutional study, Chen et al. found some triggering factors for ART, e.g., significant weight loss, ill-fitting immobilization mask, or significant shrinkage of palpable disease (18). Therefore, the optimal timing, frequency & triggering factors remain to be determined.

Some of the upcoming prospective trials attempt to assess the benefit of Xerostomia reduction by using MRI/PET CT imaging, and weekly plan adaption for HNSCC (20, 21, 22) is ongoing. DARTBOARD is one where daily ART will be assessed for better organ sparing. The patient accrual is still going (20).

Few prospective randomized studies comparing ART with IMRT technique in head & neck cancer are ongoing. In the recently published ARTIX study (19), no significant benefit of stimulated salivary flow (primary endpoint) and patient-reported Xerostomia at 12 months were seen in the adaptive group. However, ART improved the excretory function of parotid glands (as assessed by scintigraphy) from 41 to 48 at 12 months without compromising local control & overall survival. Interestingly, in the ReSTART trial, the primary endpoint is the scintigraphy assessment of Xerostomia. While there is no consensus on the most appropriate endpoint for xerostomia assessment, there is likely a discordance between the results of various assessment modalities.

Another possible hypothesis for the ARTIX study results was the CTV to PTV expansion of 5 mm. In the ReSTART trial, we have used a CTV to PTV expansion of 3 mm with daily image guidance in the ART arm. Van Asselen et al. showed approx. 20% reduction of normal tissue complication probability, with respect to salivary sparing, by reduction of PTV margin from 6 mm to 3 mm (41). The safety of PTV reduction of less than 5 mm was also demonstrated by Allen et al. (42). In the setting of daily IGRT, the reduction of PTV margin to 3 mm appears to be adequate and safe with no increase in locoregional failures among patients treated with IMRT in HNSCC (43, 44, 45). Hence, we hope the combination of ART and reduced PTV margins can impact Xerostomia in the ReSTART trial.

The strength of the ReSTART study lies in the uniform inclusion criteria using a standard treatment protocol. This approach is more pragmatic in limited resource & high burden centers. In addition, we will also be assessing the safety of this approach, including any changes in the doses to target and other OARs.

The accrual is currently ongoing in the ReSTART trial, and we hope to answer a few of these relevant clinical questions in head and neck cancer radiotherapy with this trial.

3D CRT 3D- Conformal Radiotherapy

ART Adaptive Radiotherapy

CECT Contrast Enhancing Computed Tomography

CTV Clinical Target Volume

CTRI Clinical Trial Registry - India

DFS Disease Free Survival

EORTC European Organization for Research and Treatment of Cancer

EPID Electronic Portal Imaging Devices

GTV Gross Tumor Volume

HNSCC Head & Neck Squamous Cell Carcinoma

IMRT Intensity Modulated Radiotherapy

KV CBCT Kilo-Voltage Cone Beam Computed Tomography

MRI Magnetic Resonance Imaging

OAR Organs at Risk

PTV Planning Target Volume

QLQ Quality of Life Questionnaires

QOL Quality of Life

RECIST Vr1.1 Response Evaluation Criteria in Solid Tumors Version 1.1

SCC Squamous Cell Carcinoma

SEF Salivary Excretion Fraction

Ethics approval and consent to participate: Not applicable

Consent for publication: Not applicable

Availability of data and materials: Not applicable

Competing interests: None

Funding: This study is funded by an intramural grant from Tata Memorial Centre, Mumbai (TRAC/3852).

Authors' contributions SGL, VM, and SLS conceptualized the trial. SGL, SS, AK, AS, SM, SK and FK are involved in patient accrual and study procedures. The manuscript is drafted by SGL, SS, AK, and AS. All authors approved the final manuscript.

Acknowledgments: none

Authors' information (optional): Not applicable

Funding: This study is funded by an intramural grant from Tata Memorial Centre, Mumbai (TRAC/3852). No industry or pharmaceutical support has been received.

Patient Data Confidentiality: All study-related information is stored securely. All participant information is stored in an area with controlled access. All records that contain names or other personal identifiers, such as locator forms and informed consent forms, are kept separately from study records identified by study number. All local databases are secured with password-protected access systems. Forms, lists, logbooks, appointment books, and any other listings that link participant ID numbers to other identifying information are stored in a locked file in an area with limited access. Only the principal investigator and/ or study team members can access all study-related information.

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Table 1: Plan Evaluation and Dose Constraints

Plan Evaluation as per ICRU 83
Target Structures	D95%	Dnear-min or D98%	Dnear-max or D2%	Median absorbed dose or D50%		Mean absorbed dose
PTV_66/30	95% of planned absorbed dose	90% of planned absorbed dose	107%of planned absorbed dose	66 Gy		-
PTV_54/30	95% of planned absorbed dose	90% of planned absorbed dose	107%of planned absorbed dose	54 Gy		-
Structures	Dose Constraints		Structures		Dose Constraints
Spinal Cord	Dmax < 45 Gy		Contralateral Submandibular Gland		Dmean < 39 Gy
Brainstem	Dmax < 50 Gy		Glottic Larynx		Dmean < 40 Gy
Oral Cavity	Dmean < 40 Gy for uninvolved oral cavity		Supraglottic Larynx		Dmean < 40 Gy
Parotid Glands	Dmean < 26 Gy in ipsilateral glands		Temporal lobe B/L		Dmax < 70 Gy
Optic Nerve B/L	Dmax < 54 Gy		DARS		Dmean < 50 Gy
Optic Chiasma	Dmax < 54 Gy		Superior Pharyngeal Constrictors		Dmean < 60 Gy V55 < 70%
Parotid Glands	Dmean < 20 Gy in contralateral glands		Middle Pharyngeal Constrictors		Dmean < 60 Gy V55 < 70%

ICRU = International Commission on Radiation Units and Measurements, PTV = Planning Target Volume, DARS = Dysphagia and Aspiration related Structures

Table 2: Dosimetric Benefits of ART in Patients with Head & Neck Cancer

Author (year)	No of Patients	Timing of ART	Dmean of Parotid Glands	Dmax of Spinal Cord	Dosimetric benefits of PTV
Zhao et al 2011 (14)	33	15^th fractions	Decrease mean dose	-	-
Capelle et al 2012 (31)	20	3^rd week	- 0.6 Gy	- 0.6 Gy	+ 0.5 Gy (D1%)
Duma et al 2012 (32)	11	16^th fractions	No variation	- 0.14 Gy	-
Jansen et al 2012 (33)	15	8^th and 18^th fractions	CL: - 11.5%	-	Improvement of coverage by 8%
Schwartz et al 2013 (16)	22	16^th and 22^nd fractions	- 0.7%	-	Increase coverage and dose homogeneity
Castelli et al 2015 (34)	15	Weekly	- 3.8 Gy	-	-
Dewan et al 2016 (35)	30	40 Gy	IL: - 6 Gy CL: - 2.2 Gy	- 66 Gy	More uniform coverage Decrease V110% by 2

ART = Adaptive Radiotherapy, CL = Contralateral, IL = Ipsilateral,

Table 3: Clinical Benefits of ART in Patients with Head & Neck Cancer

Author (year)	No of Patients	Tumor site	Timing of ART	FU	LRC	OS	Other Outcomes
Schwartz et al 2012 (16)	22 ART	OPX	16^th & 22^nd fractions	31	2 yrs LRC: 95%	-	Full functional recovery of speech & eating at 20 m
Kataria et al 2016 (38)	36 ART	LAHNC	54 Gy		-	2 yrs OS: 75%	Gr II mucositis, xerostomia < 8% in ART
Yang et al 2013 (17)	86 ART vs 43 No ART	NPC	15^th & 25^th fractions	29	2 yrs LRC: 97.2% vs 82.2% (p = 0.04)	2 yrs OS: 89.8% vs 82.2% (p = 0.47)	Improvement of QOL with ART
Chen et al 2014 (18)	51 ART vs 266 No ART	LAHNC	40 Gy	30	2 yrs LRC: 88% vs 79% (p = 0.01)	2 yrs OS: 73% vs 79% (p = 0.55)	Gr III toxicity less in ART
Zhao et al 2011 (14)	33 ART vs 66 No ART	NPC	15^th +/- 5^th fractions	38	3 yrs LRC: 72.7% vs 68.1% (p = 0.3)	-	Less Xerostomia and mucositis in ART for N2 & N3 patients

OPX = Oropharynx, LAHNC = Locally advanced head and neck cancer, NPC = Nasopharyngeal cancer, ART = Adaptive Radiotherapy, LRC = Locoregional Control, OS = Overall Survival;

Table 4: Ongoing Trials

Trials	Description	Eligible	Status
MARTHA trial (21)	Prospective trial of MRI-guided IGRT with daily MRI imaging and weekly plan adaption with objective of evaluating Xerostomia by LENTSOMA & salivary flow measurement	Stage II-IVA HNC receiving EBRT	Not recruiting
C-ART 2 trial (23)	Randomized phase II trial randomizing participants to adaptive dose-painting-by-numbers or to standard radiation	SCC of oral cavity, oropharynx, larynx & hypopharynx	Active
MR-ADAPTOR (22)	Phase II trial using weekly MRI imaging to assess treatment response & guide dose de-intensification by reducing 69.96 Gy PTV volume as the tumor shrinks.	p16 (+), cT1-2N0-2b Oropharynx Cancer	Recruiting
ReSTART	Prospective randomised trial of reducing salivary toxicity with adaptive radiotherapy	Stage cT1-4N0-3M0 Oropharynx, Larynx & Hypopharynx	Recruiting

HNC = Head and Neck cancer, SCC = Squamous Cell Carcinoma, MRI = Magnetic Resonance Imaging, IGRT = Image Guided Radiotherapy, EBRT = External Beam Radiotherapy

No competing interests reported.

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Reducing Salivary Toxicity with Adaptive Radiotherapy (ReSTART): A Randomized Controlled Trial comparing conventional IMRT to adaptive IMRT in head and neck Squamous Cell Carcinomas

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