A Prospective Study of Daily Adaptive Radiotherapy to Better Organ-at-Risk Doses in Head and Neck Cancer (DARTBOARD)

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ClinicalTrials.gov Identifier: NCT04883281

Recruitment Status : Recruiting

First Posted : May 12, 2021

Last Update Posted : March 9, 2022

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Sponsor:

Information provided by (Responsible Party):

David Sher, University of Texas Southwestern Medical Center

Study Description

Brief Summary:

Varian Medical Systems has recently deployed a completely novel radiation treatment system called EthosTM, a first-of-its-kind system that allows for daily adapative radiotherapy (DART), such that the treatment for that day can be created on-the-fly based on the patient's current positioning and anatomy. This system is commercially-available and FDA-approved, and UTSW Radiation Oncology has installed two such units. The ability to adjust the dose delivery every day means both that adaptive therapy is possible with every fraction and that the PTV margin can be dramatically reduced/eliminated, since investigators are treating for that day's patient setup. Investigators are therefore proposing a randomized trial using DART with near marginless (ML) setup margins (a 1 mm margin will be retained for intrafractional motion).

Condition or disease	Intervention/treatment	Phase
Head and Neck Cancer	Radiation: Intensity modulated radiation therapy (IMRT) with or without chemotherapy Drug: cisplatin, cetuximab, or carboplatin-paclitaxel	Phase 2

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Detailed Description:

IMRT with daily cone-beam computed tomography (CBCT) set up is the current recommended radiation technique for head and neck squamous cell carcinoma. The conformality of IMRT has made it possible to reduce dose to normal tissues, but it also predisposes the treatments to drastic delivered dose deviations due to changes in the patient (e.g. weight loss, muscle atrophy, or normal tissue edema) or in the tumor (e.g. treatment response or treatment related edema). These changes can create poor coverage and/or cold spots in the tumor and increased coverage and/or hot spots in the normal organs at risk. Image guidance with CBCTs can help reduce set up error between treatments, but image guidance can't adjust for these patient or tumor changes.

Adaptive radiotherapy (ART) is the process of replanning the patient's radiation plan by adjusting the target structures, organs at risk structures, and optimal radiation delivery during the radiation therapy course. ART allows treating physicians to account for all the patient or tumor changes that can't be currently resolved with image guidance. Previously, ART was a prohibitively resource and time-consuming process that could only be performed once or twice during a conventional 6.5 to 7-week head and neck radiation treatment course in select patients with substantial structural changes. However, with the recent advent of adaptive software, ART can now be performed on a daily basis.

The data on the possible advantages of ART in head and neck cancer is still limited to small, mostly pre-clinical studies. In a feasibility study, five patients with locally advanced HPV-positive oropharynx cancer undergoing definitive chemoradiation underwent an MRI every two weeks during their treatment. The results showed an average decrease in the primary tumor GTV volume of 44%, 90%, and 100% and an average decrease in the nodal GTV volume of 25%, 60%, and 80% by at weeks 2, 4, and 6 weeks, respectively. Another similar study on eight patients saw an average 70% GTV volume reduction by week 6.

In addition to tumor coverage, parotid glands are of particular interest in ART because of their radiosensitivity and association with xerostomia and decreased quality of life. Toxicity of salivary glands are related to dose as a continuous variable, so even modest decreases in dose can have a clinical impact. The average volume of the parotids has been reported to decrease as much as 14.7%, 37%, and 48% by the end of weeks 2, 4, and 7. The parotid glands also appear to shift superiorly and medially during treatment. Feasibility ART studies have shown that the dose to the parotid may decrease by as much as 5.5 Gy with ART. Therefore ART holds the promise of preserving the expected dose distribution to salivary OARs, improving long-term patient outcomes.

The ability to ensure coverage of the target structures and proper avoidance of organs at risk on a daily basis also greatly improves the confidence of the daily set-up and targeting. Current recommended radial PTV margins with daily CBCT are 3-5 mm, with even larger margins recommended for patients at risk of larger inter-fraction variability. These PTV margins are built to ensure the disease is not missed by the treatment due to daily setup error. However, these margins also significantly increase the irradiated volume, since the volume increases exponentially with each additional millimeter. Therefore, decreasing margins, even by a few millimeters, can results in large changes in treatment volume and improvement in toxicity.

In a retrospective Danish analysis of patients treated with 5 mm versus 3 mm PTV margins, Navran et al. noted that acute grade 3 toxicity (65% vs 53.8%, p = 0.008) and late grade 3 dysphagia (20.4% vs 11.1%, p = 0.012) were significantly lower in the smaller margin group. There were no differences in disease outcomes between the two groups. In a retrospective study analyzing the benefit of changing the margin on gross disease from 8 mm to 5 mm, just a 3 mm difference, Samuels et al. found that plans with the smaller PTV margin had a clinically meaningful improvement in the normal tissue complication probability for the ipsilateral parotid gland and contralateral submandibular gland when compared to conventional PTV margin plans. In fact, 40% of patients would have theoretically experienced an improvement in the function of both of these glands, just by modestly shrinking the PTV.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	50 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	DARTBOARD: A Prospective Randomized Phase II Study of Daily Adaptive Radiotherapy to Better Organ-at-Risk Doses in Head and Neck Cancer
Actual Study Start Date :	February 23, 2022
Estimated Primary Completion Date :	December 15, 2023
Estimated Study Completion Date :	December 15, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Head and Neck Cancer

Drug Information available for: Cetuximab

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Involved Nodal Radiotherapy with conventional margins w or w/o chemotherapy If a patient loses a significant amount of weight on treatment, or the tumor contour changes substantially, repeat CT simulation and re-planning is allowed in the CM arm. However, the gross tumor volume may not be reduced due to tumor shrinkage. The original extent of disease must be included in the replanned GTV.	Radiation: Intensity modulated radiation therapy (IMRT) with or without chemotherapy Intensity modulated radiation therapy (IMRT) with or without chemotherapy (if given, either cisplatin, cetuximab, or carboplatin-paclitaxel) Drug: cisplatin, cetuximab, or carboplatin-paclitaxel chemotherapy (if given, either cisplatin, cetuximab, or carboplatin-paclitaxel)
Experimental: Involved Nodal Radiotherapy with marginless Daily Adaptive Radiotherapy w or w/o chemotherapy Patients in the ML/DART Arm will have their radiation plan adapted with every fraction. The adaptation process will be performed automatically on the Varian Ethos adaptive therapy software under the supervision of the treating physician.	Radiation: Intensity modulated radiation therapy (IMRT) with or without chemotherapy Intensity modulated radiation therapy (IMRT) with or without chemotherapy (if given, either cisplatin, cetuximab, or carboplatin-paclitaxel) Drug: cisplatin, cetuximab, or carboplatin-paclitaxel chemotherapy (if given, either cisplatin, cetuximab, or carboplatin-paclitaxel)

Arm

Intervention/treatment

Active Comparator: Involved Nodal Radiotherapy with conventional margins w or w/o chemotherapy

If a patient loses a significant amount of weight on treatment, or the tumor contour changes substantially, repeat CT simulation and re-planning is allowed in the CM arm. However, the gross tumor volume may not be reduced due to tumor shrinkage. The original extent of disease must be included in the replanned GTV.

Radiation: Intensity modulated radiation therapy (IMRT) with or without chemotherapy

Intensity modulated radiation therapy (IMRT) with or without chemotherapy (if given, either cisplatin, cetuximab, or carboplatin-paclitaxel)

Drug: cisplatin, cetuximab, or carboplatin-paclitaxel

chemotherapy (if given, either cisplatin, cetuximab, or carboplatin-paclitaxel)

Experimental: Involved Nodal Radiotherapy with marginless Daily Adaptive Radiotherapy w or w/o chemotherapy

Patients in the ML/DART Arm will have their radiation plan adapted with every fraction. The adaptation process will be performed automatically on the Varian Ethos adaptive therapy software under the supervision of the treating physician.

Radiation: Intensity modulated radiation therapy (IMRT) with or without chemotherapy

Intensity modulated radiation therapy (IMRT) with or without chemotherapy (if given, either cisplatin, cetuximab, or carboplatin-paclitaxel)

Drug: cisplatin, cetuximab, or carboplatin-paclitaxel

chemotherapy (if given, either cisplatin, cetuximab, or carboplatin-paclitaxel)

Outcome Measures

Primary Outcome Measures :

Xerostomia Questionnaire (XQ) [ Time Frame: 1 year ]
1-year score on the Xerostomia Questionnaire (XQ)

Secondary Outcome Measures :

Patient reported outcome [ Time Frame: 1 year ]
Patient Reported Outcomes (PRO): European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-30). Score ranges 0-100. Higher the score better the outcome.
Pain and senses score [ Time Frame: 1 year ]
European Organization for the Research and Treatment of Cancer quality of life questionnaire EORTC HN 35. Score range 0-100. Lower scores are better.
Composite Score [ Time Frame: 1 year ]
MD Anderson Dysphagia Inventory (MDADI) questionnaire. score ranges 0-100. Higher score is better.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Pathologically-proven diagnosis of squamous cell carcinoma of the oropharynx, larynx, or hypopharynx.
clinically or radiographically evident measurable disease at the primary site and/or nodal stations
diagnostic or therapeutic transoral resection for a T1-2 tonsil or base of tongue cancer.
Clinical stage I-IVB (AJCC, 7th edition); stages I-II glottic cancer are excluded
Age ≥ 18 years.
ECOG Performance Status 0-2
All men, as well as women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study treatment, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
Negative serum or urine pregnancy test
Neck CT and/or neck MRI, and PET-CT (at least skull-to-thigh).
Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

Distant metastasis.
Inability to undergo PET-CT.
Stage I and II glottic carcinoma.
Gross total excision of both the primary and nodal disease.
Synchronous non-skin cancer primaries outside of the oropharynx, larynx, and hypopharynx except for low- and intermediate-risk prostate cancer and synchronous well-differentiated thyroid cancer
Prior invasive malignancy with an expected disease-free interval of less than 3 years.
Prior systemic chemotherapy for the study cancer;
Prior radiotherapy to the region of the study cancer that would result in overlap of radiation fields.
Subjects may not be receiving any other investigational agents.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to the chemotherapy agents in this study (if necessary).
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations
pregnant or nursing women
History of severe immunosuppression, including HIV, and organ or autologous or allogeneic stem cell transplant.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04883281

Contacts

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Contact: Kajal Desai	2146458525	Kajal.Desai@UTSouthwestern.edu
Contact: Sarah Neufeld	2146458525	Sarah.Neufeld@UTSouthwestern.edu

Locations

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United States, Texas
University of Texas Southwestern Medical Center	Recruiting
Dallas, Texas, United States, 75390
Contact: David Sher, MD 214-645-8525 david.sher@utsouthwestern.edu
Contact: Sarah Neufeld sarah.hardee@utsouthwestern.edu

Sponsors and Collaborators

University of Texas Southwestern Medical Center

More Information

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Responsible Party:	David Sher, Professor, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier:	NCT04883281
Other Study ID Numbers:	STU-2021-0401
First Posted:	May 12, 2021 Key Record Dates
Last Update Posted:	March 9, 2022
Last Verified:	February 2022

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Studies a U.S. FDA-regulated Drug Product:	No
Studies a U.S. FDA-regulated Device Product:	No

Additional relevant MeSH terms:

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Head and Neck Neoplasms Neoplasms by Site Neoplasms Paclitaxel Carboplatin Cetuximab Antineoplastic Agents, Phytogenic	Antineoplastic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action Antineoplastic Agents, Immunological

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