A phase II study of personalized ultrafractionated stereotactic adaptive radiotherapy for palliative head and neck cancer treatment (PULS-Pal): a single-arm clinical trial protocol

A phase II study of personalized ultrafractionated stereotactic adaptive radiotherapy for palliative head and neck cancer treatment (PULS-Pal): a single-arm clinical trial protocol | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol A phase II study of personalized ultrafractionated stereotactic adaptive radiotherapy for palliative head and neck cancer treatment (PULS-Pal): a single-arm clinical trial protocol P. Travis Courtney, Milisuryani Santoso, Ricky R. Savjani, Vishruth Reddy, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4988211/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Dec, 2024 Read the published version in BMC Cancer → Version 1 posted 9 You are reading this latest preprint version Abstract Background: Many patients with head and neck cancer will not be candidates for standard of care definitive treatments though often require palliative treatments given the frequent symptoms associated with head and neck cancer. While existing palliative radiotherapy regimens can provide adequate symptom control, they have limitations particularly with respect to local control which is becoming more important as advances in systemic therapy are improving survival. Personalized ultrafractionated stereotactic adaptive radiotherapy (PULSAR) is a novel radiotherapy regimen which leverages advances in radiotherapy treatment technology and extended interfraction intervals to enable adaptive radiotherapy and possible synergy with the immune system. Additionally, HyperArc© (Varian Medical Systems, Inc.) radiotherapy planning software allows for safe dose-escalation to head and neck tumors. Methods: This single-arm phase II study will prospectively evaluate PULSAR with HyperArc software for palliative treatment of head and neck cancer. Patients with de novo or recurrent, localized or metastatic, head and neck cancer who are ineligible for or decline standard of care definitive treatments are eligible for enrollment. Forty-three patients will receive an 11 Gray fraction of radiation every two weeks for a total of five fractions and dose of 55 Gy. Adaptive radiotherapy planning is permitted. A safety and feasibility evaluation will be performed after enrollment of the first fifteen patients whereby the trial will continue if less than five patients experience a CTCAEv5.0 grade 3 or higher toxicity definitely attributable to PULSAR during or within thirty days after its completion. The primary endpoint is one-year local head and neck tumor control. Secondary endpoints include safety, disease progression-free and overall survival, symptomatic impact, frequency of re-simulation and/or adaptive planning, and radiation dosimetry of PULSAR. Additionally, enrolled patients are permitted to receive immunotherapy during PULSAR, which may allow for the analysis of the safety and efficacy of this combination. Discussion: The PULS-Pal trial is the first prospective study of PULSAR with HyperArc software for head and neck cancer. We hypothesize that this radiotherapy regimen will lead to improved local tumor control compared with historical controls in patients undergoing palliative radiotherapy for head and neck cancer. Trial Registration: Clinicaltrials.gov identifier: NCT06572423. Date of registration: August 28 th , 2024. https://clinicaltrials.gov/study/NCT06572423. head and neck cancer stereotactic body radiotherapy (SBRT) personalized ultrafractionated stereotactic adaptive radiotherapy (PULSAR) palliative radiotherapy Figures Figure 1 Figure 2 Background A significant proportion of patients with de novo or recurrent head and neck cancer (HNC) will not be candidates for standard of care definitive treatment(s) 1 – 3 , which includes a combination of surgery, radiation therapy, and/or systemic therapy, and in some cases, standard of care stereotactic body radiotherapy (SBRT). Common contraindications for standard definitive treatment for HNC include locally advanced disease not amenable to definitive treatment because of the anticipated morbidity with primary or salvage treatment, poor performance status, presence of metastatic disease, or patient treatment preferences 4 , 5 . In such cases, locoregional palliative radiation therapy is often utilized given the frequent accompanying symptoms of HNC such as pain or difficulty breathing or eating 6 , with the most common HNC palliative radiation therapy regimens being the RTOG-8502 regimen (“quad-shot”) 7 – 9 and SBRT 10 . While these current palliative radiation therapy options can provide adequate symptom improvement, there are some limitations with these regimens as well. With quad-shot, there are logistic challenges for both providers and patients given the twice-daily treatments, albeit for just two days total. Moreover, typically multiple cycles are needed to achieve maximal symptomatic benefit, although only about 50% of patients will be able to complete three or more cycles at which point the palliative response rate of this regimen is significantly increased 8 , 11 – 13 . Additionally, while newer radiation therapy techniques such as intensity modulated radiation therapy (IMRT) have been employed to enhance the quad-shot regimen, it represents an older radiation therapy practice which may not fully leverage more recent advances in radiation therapy technology. Regarding SBRT, there is the possibility for severe toxicity, minimization of which is important in the palliative setting, as well as efficacy concerns, particularly for larger tumors or in the re-irradiation setting 6 , 14 – 16 . However, a main limitation across all palliative radiation therapy regimens is suboptimal local control. Local tumor progression negatively impacts symptoms and possibly overall survival given the frequency at which locoregional tumor progression causes death in patients with HNC 17 – 19 . Prospective data of SBRT for unresectable head and neck cancer has demonstrated one year local control rates of 60% in the re-irradiation setting 20 . In the de novo setting, prospective data are limited and primarily consist of SBRT for early-stage glottis cancer, though in small, retrospective series predominantly for palliative purposes and/or for patients who are not candidates for standard of care definitive therapy, the reported one year local control rates range from 69–87% 21 . However, not all patients will be eligible for standard of care SBRT in the definitive or palliative setting, for example because of tumor size or location near the carotid artery 22 . In such cases, a variety of other radiation regimens are often used, such as quad-shot, which generally have lower and/or less durable local control rates 23 – 25 . The durability of symptom and local control in this patient population is becoming more important as advances in systemic therapy, particularly immunotherapy, are improving patient survival 26 – 29 . Personalized ultrafractionated stereotactic adaptive radiotherapy (PULSAR) is a novel radiation therapy regimen in which large radiation doses are delivered in “pulses” over extended interfraction intervals, with typically several days to multiple weeks between each radiation fraction 30 , 31 . The PULSAR technique is enabled by advances in SBRT and image-guided radiation therapy, and allows for possible adaptation of each subsequent fraction to the most current patient anatomy and tumor response. This not only permits adequate time passage for tumor shrinkage and subsequent adaptive radiation therapy re-planning to occur, but also a protracted SBRT course may be less toxic than the standard SBRT course typically delivered over 1–2 weeks given the additional time for normal tissue healing as well as smaller radiation fields with possible tumor shrinkage. To this end, the PULSAR paradigm may enable safer tumor dose escalation 32 . Similarly, advances in radiation planning and treatment delivery, specifically HyperArc© (Varian Medical Systems, Inc.) 33 technology, have permitted dose escalation with high conformity in HNC SBRT 15 , 34 . Dose escalation has been found to be associated with improved locoregional control in HNC 35 , 36 , and thus the combination of PULSAR with HyperArc technology may further improve the therapeutic ratio of palliative radiation therapy in this patient population. Even more so, it has been suggested that there may be a synergism between PULSAR and immunotherapy, and further exploration of this relationship is warranted, particularly in the clinical setting 37 . With the increased use of immunotherapy in patients with recurrent, unresectable, or metastatic disease 38 , the potential complimentary relationship between PULSAR and immunotherapy may provide these patients with additional benefit. In this context, PULSAR is an appealing option for patients requiring palliative radiation therapy for HNC. Given the potential efficacy, safety, symptomatic, and logistical benefits of this radiation regimen, we hypothesize that PULSAR delivered with HyperArc technology will result in improved local control, reduced toxicity, and similar or improved symptom relief compared with existing palliative radiation regimens in patients with de novo or recurrent HNC who are not candidates for standard of care definitive treatment(s), including standard of care SBRT. To test this hypothesis, we will conduct a prospective clinical trial of PULSAR in this patient population. Because PULSAR is a newer technique, it has not yet been comprehensively studied, particularly in combination with HyperArc technology. To our knowledge, there are currently nine early phase clinical trials prospectively evaluating PULSAR in some capacity (NCT 04677413, 04779489, 04786093, 04889066, 05021237, 05846646, 05846659, 06044857, 06359275), none of which are in HNC. Thus, validation of its safety and feasibility is first required prior to larger-scale prospective studies of efficacy in HNC. Herein, we propose an early safety and feasibility study of palliative PULSAR delivered with HyperArc technology in patients with de novo or recurrent, localized or metastatic HNC who are ineligible for or decline standard of care definitive treatment(s). HyperArc radiation technology is a commercial tool that provides automated non-coplanar volumetric modulated arc therapy (VMAT) treatment planning. It was initially developed for intracranial stereotactic radiosurgery; however, it can be adapted for the treatment of HNC, and our institution has evaluated HyperArc technology in HNC dosimetrically and prospectively with encouraging results 15 , 34 . From a treatment planning perspective, HyperArc allows for target dose escalation, which as noted above is correlated with improved locoregional control, while maintaining minimal head and neck organs-at-risk doses compared with more conventional VMAT SBRT 34 . From a clinical perspective, our institution recently completed patient accrual for a phase II trial of HyperArc SBRT to 55 Gray in five every other day fractions for definitive treatment in previously radiated patients with recurrent HNC (NCT03892720). The initial report of this study found this intervention to be feasible, safe, and well tolerated with minimal treatment-related toxicity and favorable quality of life metrics. Additionally, unpublished analysis of this study found a one year local control rate of 85%, which is higher than existing prospective data of SBRT for recurrent, previously radiated HNC reporting a one year local rate of 60% 20 . These findings support the rationale for using HyperArc treatment planning technology in this study. Methods/Design Study Design This is a single-center (UCLA), single-arm, prospective phase II study with a safety lead-in. 43 subjects are planned. Each subject will receive the same PULSAR radiation therapy course as described below. The first 15 enrolled patients will be evaluated in the safety lead-in portion. If 5 or more of these 15 patients experience CTCAE v5.0 grade 3 or higher definitely attributable to the intervention during or within 30 days after completion of PULSAR, the study will be stopped for safety concerns; otherwise, the study will proceed, and those initial 15 patients will be included in the 43 subject sample. The trial schema is shown in Fig. 1 . Ethics Approval This study is approved by the Institutional Review Board (IRB) of the University of California, Los Angeles (UCLA IRB #24–000663), and is registered at the U.S. National Institutes of Health (clinicaltrials.gov) # NCT06572423. The current protocol is version 1.5. This manuscript adheres to the guidelines and methodology outlined in the SPIRIT checklist. Aims Primary Aim To evaluate the 1-year local tumor control of PULSAR for patients with de novo or recurrent, localized or metastatic head and neck cancer who are ineligible for or decline standard of care treatment(s), including standard of care SBRT. Secondary Aims Secondary Aim 1 To evaluate the safety and toxicity of PULSAR as local treatment for patients with de novo or recurrent, localized or metastatic head and neck cancer who are ineligible for or decline standard of care definitive treatment(s). Secondary Aim 2 To evaluate the 1-year disease progression-free (PFS) and overall survival (OS) of patients with de novo or recurrent, localized or metastatic head and neck cancer who are ineligible for or decline standard of care treatment(s) who receive PULSAR. Secondary Aim 3 To evaluate the symptomatic impact of PULSAR as local treatment for patients with de novo or recurrent, localized or metastatic head and neck cancer who are ineligible for or decline standard of care definitive treatment(s). Secondary Aim 4 To determine the frequency of re-simulation and/or adaptive planning required with PULSAR. Secondary Aim 5 To evaluate standard of care tumor and organs-at-risk (OARs) dosimetry with PULSAR. Secondary Aim 6 To evaluate the safety and efficacy of combination PULSAR and immunotherapy in enrolled patients receiving immunotherapy. Patient Selection Study Population Patients with a diagnosis of primary or recurrent head and neck cancer who are ineligible for or decline standard of care definitive (i.e., curative) treatment(s), including standard of care stereotactic body radiation therapy (SBRT). Reasons for ineligibility for standard of care definitive treatments include locally advanced disease not amenable to standard definitive treatment(s) (e.g., due to the anticipated morbidity associated with definitive treatment), presence of metastatic disease, and medical comorbidities and/or poor performance status that preclude definitive treatment. Additionally, patients with primary or recurrent localized head and neck cancer who are candidates for but decline standard of care definitive treatment(s) will be eligible for enrollment. Inclusion Criteria ≥ 18 years old. Diagnosis of primary or recurrent, localized or metastatic (AJCC 8th Edition stages I-IV) head and neck cancer. In primary diagnosis cases, pathologic confirmation is required. In recurrent and/or metastatic diagnosis cases, pathologic confirmation is not required if not beneficial to the patient as standard of care, and diagnosis can be assumed based on clinical and/or radiographic evidence. Ineligible for or declines standard of care definitive treatment(s), which will be documented in the patient’s trial screening progress note in their electronic medical record by the treating physician. Measurable disease within the head and/or neck clinically and/or on imaging studies (CT, PET, MRI) within 30 days from date of enrollment. Patient maximum tumor(s) or tumor bed in postoperative patients diameter must be less than 10cm. In a woman of childbearing potential, a negative serum or urine pregnancy test within 1 week of treatment start must be documented. Women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; or abstinence) for duration of study participation and for up to 4 weeks following the study treatment. Patients with a tracheostomy and/or a percutaneous endoscopic gastrostomy tube are eligible for inclusion. Exclusion Criteria Pregnant or breast-feeding. More than 1 prior radiation treatment course directed to the treatment area over the patient’s lifetime. In patients who have received 1 prior radiation treatment course directed to the treatment area, that prior radiation treatment course must have concluded at least 6 months prior to trial enrollment. Any comorbidity or condition which would limit full compliance with the protocol. Registration and Enrollment Process General Guidelines Patients with primary or de novo, localized or metastatic, HNC who are not eligible for or decline standard of care definitive treatment(s) will be informed of this clinical trial if eligible. The decision to participate will be voluntary. Eligible patients who decide not to participate will be offered alternative palliative radiation therapy regimens, systemic therapy (per their medical oncologist), alternative clinical trials, or palliative/hospice care. Information regarding this research study will be included on the UCLA Health Clinical Trials webpage and Clinicaltrials.gov. Registration Process When feasible, an informed consent form in the patient’s preferred language will be given to the patient, or surrogate or legal-authorized representative when applicable, for review. Consent will be obtained after a clear and thorough discussion between the patient, or surrogate or legal-authorized representative when applicable, and the study investigator in clinic in the patient’s preferred language, utilizing a certified interpreter when necessary. To register a patient, the research coordinator will obtain or collect: (1) confirmation of diagnosis of HNC per inclusion criteria above; (2) signed informed consent form; (3) signed HIPAA authorization form. The informed consent form is provided in the Supplemental Material. Pretreatment Evaluations Upon confirmation of eligibility and enrollment in the study, the following will be obtained prior to treatment (if not already performed): Medical history and clinical examination including weight and ECOG Performance Status Serum creatinine/estimated GFR within 60 days of CT simulation University of Washington Quality of Life (UW-QoL) and Functional Assessment of Cancer Therapy Head and Neck (FACT-H&N) validated questionnaire For patients who have received and/or are currently receiving cancer-directed treatment(s), evaluation for existing treatment-related toxicities as measured by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0), as this version is currently implemented in our institution’s electronic medical record system which allows for easier and more consistent data documentation and recording. Additional pretreatment studies including blood tests, imaging, and pathologic evaluation of tumor tissue for Human Papillomavirus and/or p16 positivity may be obtained per standard of care guidelines and/or the patient’s treatment team’s discretion. Intervention Radiation Simulation After confirmation of eligibility, enrolled patients will undergo radiation CT simulation and planning per standard of care. IV contrast will be administered with CT simulation at the treating physician’s discretion though is not required. A thermoplastic face mask will be used for immobilization. HyperArc technology will be used for treatment planning given prior internal validation of its superiority as above. Radiation Planning For unresectable patients, the treating physician will delineate the gross tumor volume (GTV). For resected patients, a clinical target volume (CTV) will be delineated. The target will include the preoperative tumor volume with up to 5mm expansion for microscopic disease, with considerations for postoperative anatomical changes. Relevant previously obtained imaging studies may be fused to the CT simulation images as deemed necessary by the treating physician to further delineate the GTV or CTV. The GTV or CTV will be expanded by 3–5 mm for treatment setup error. This expansion will comprise the planning target volume (PTV). The dose will be prescribed to cover at least 95% of the PTV unless under-dosing of the PTV is required to meet constraints to OARs. Delineation of normal structures will be performed, including but not limited to: larynx, spinal cord, mandible, brainstem, skin, oral cavity, and parotid gland. OAR Dose Constraints No Prior Radiation Therapy to Tumor/Tumor Bed Site will use max dose point constraints (defined as dose to 0.035 cm 3 ) from the AAPM Task Group 101 Report 39 . Prior Radiation Therapy to Tumor/Tumor Bed Site (Reirradiation) will use the following max dose point constraints (defined as dose to 0.035 cm 3 ) 15 Larynx: ≤ 20 Gy Spinal cord: ≤ 8 Gy Mandible: ≤ 30 Gy Brainstem: ≤ 8 Gy Skin: Dmax < 39.5Gy PULSAR Treatment Daily cone-beam CT will be obtained prior to radiation delivery to verify anatomic location and stability. Treatment will consist of 6, 10, or 15 MV photons directed at the PTV using HyperArc’s automated non-coplanar VMAT technique. Patients will receive a total of 55 Gray in 5 fractions (biological effective dose with alpha/beta of 10: 115.5 Gray) to the PTV. Patients will receive each 11 Gray fraction of radiation every 14 +/-10 days. Treatment will be terminated early in cases of intolerable treatment-related toxicity, altered clinical context, or the patient declines further treatment. Adaptive Radiation Planning It is possible that patients will experience anatomical and/or tumor changes during the radiation therapy course such that patient alignment for radiation therapy is no longer optimized to the original CT simulation and radiation plan. In such cases where it is determined that adaptive planning is needed, we will abort planned radiation therapy and immediately perform re-simulation and re-planning if the anatomic change is significant enough to put adjacent normal tissue at significant risk; otherwise, we will re-plan with the next fraction of radiation to minimize treatment delays. This will be determined by the treating physician through standard of care clinical criteria and procedures. For patients who undergo re-simulation and re-planning, an extended window of 14 + 21/-10 days from most recent radiation therapy fraction to receive the next radiation therapy fraction to accommodate re-simulation scheduling and re-planning time. The frequency of re-simulation and adaptive planning as well as associated changes in dosimetry will be measured and documented. Patient Follow-up Symptomatic response will be assessed through subjective patient report and completion of the UW-QoL and FACT-H&N questionnaires ( Supplemental Material ). Treatment-related toxicity during and after completion of PULSAR will be measured according to the CTCAE v5.0. Local tumor response will be assessed clinically and/or radiographically (e.g., by CT, PET, MRI), as applicable. Patient follow-up will be measured starting from the time of trial enrollment. Patient clinical assessments during PULSAR will occur within 7 days of each radiation treatment and consist of brief history, physical exam, and assessment of treatment-related toxicity. After receipt of the last PULSAR fraction, patients will be assessed clinically at 1 month +/- 28 days, 3 months +/- 28 days, 6 months +/- 28 days, 12 months +/- 28 days, 18 months +/- 28 days, and 24 months +/- 28 days post-treatment. These follow-up visits will consist of a history and physical exam, completion of the UW-QoL and FACT-H&N questionnaires, and measurement of toxicity. Surveillance imaging will be obtained per standard of care. Patients who experience disease progression will receive standard of care treatment(s) at the discretion of the treating physician. Patient enrollment, treatment, and follow-up is shown in Fig. 2 . Adverse Experience Reporting and Documentation Adverse Events An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a patient administered a pharmaceutical product and that does not necessarily have a causal relationship with the treatment. An AE is therefore any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the administration of an investigational product, whether or not related to that investigational product. An unexpected AE is one of a type not identified in nature, severity, or frequency in the current Investigator’s Brochure or of greater severity or frequency than expected based on the information in the Investigator’s Brochure. The Investigator will probe, via discussion with the subject, for the occurrence of AEs during each subject visit and record the information in the site’s source documents. Adverse events will be recorded in the case report form (CRF). Adverse events will be described by duration (start and stop dates and times), severity, outcome, treatment and relation to study intervention, and the cause. All adverse events should be treated appropriately. Such treatment may include changes in study intervention including possible interruption or discontinuation, starting or stopping concomitant treatments, changes in the frequency or nature of assessments, hospitalization, or any other medically required intervention. An assessment should be made at each visit (or more frequently, if necessary) of any changes in its severity, its suspected relationship to the study intervention, any of the interventions required to treat it, and its outcome. AE Evaluation An investigator who is a qualified physician will evaluate all AEs. At each visit, the investigator will determine whether any AEs have occurred by evaluating the participant. Adverse events may be directly observed (through physical examination, laboratory test, or other assessments), reported spontaneously by the participant or by non-directive questioning of the participant at each study visit. The investigator must assess all AEs to determine: The severity grade according to CTCAE v5.0. If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, life-threatening and death (grades 1–5, respectively) will be used; Its relationship to the study intervention (related; probably-related; possibly-related; unlikely-related; not related); Its duration (start and end dates or if continuing at final exam); Action taken (none required; intervention not administered; dose reduced; dose delayed/interrupted; intervention discontinued); Treatment of adverse event (none required; medication given; procedure/surgery; other); Whether it constitutes a serious adverse event (SAE); and, Outcome (resolved; resolved with sequelae; persists, death; unknown). The investigator’s assessment must be clearly documented in the study site’s source documentation with the investigator’s signature. AE Severity The National Cancer Institute’s CTCAE v5.0 should be used to assess and grade AE severity, including laboratory abnormalities judged to be clinically significant. If the AE is not covered in the CTCAE, the guidelines shown in Table 1 below should be used to grade severity. It should be pointed out that the term “severe” is a measure of intensity and that a severe AE is not necessarily serious. Table 1 AE Severity Grading Severity (Toxicity Grade) Description Mild (1) Transient or mild discomfort; no limitation in activity; no medical intervention or therapy required. The subject may be aware of the sign or symptom but tolerates it reasonably well. Moderate (2) Mild to moderate limitation in activity, no or minimal medical intervention/therapy required. Severe (3) Marked limitation in activity, medical intervention/therapy required, hospitalizations possible. Life-threatening (4) The subject is at risk of death due to the adverse experience as it occurred. This does not refer to an experience that hypothetically might have caused death if it were more severe. AE Relationship to the Study Intervention The relationship of an AE to the study intervention should be assessed by an investigator using the following guidelines in Table 2. The causality assessment must be made based on the available information and can be updated as new information becomes available. Table 2 AE Relationship to Study Intervention Relationship to Intervention Comment Definitely Previously known toxicity of the intervention; or an event that follows a reasonable temporal sequence from administration of the intervention; that follows a known or expected response pattern to the suspected intervention; that is confirmed by stopping or reducing the dosage of the intervention; and that is not explained by any other reasonable hypothesis. Probably An event that follows a reasonable temporal sequence from administration of the intervention; that follows a known or expected response pattern to the suspected intervention; that is confirmed by stopping or reducing the dosage of the intervention; and that is unlikely to be explained by the known characteristics of the subject’s clinical state or by other interventions. Possibly An event that follows a reasonable temporal sequence from administration of the intervention; that follows a known or expected response pattern to that suspected intervention; but that could readily have been produced by a number of other factors. Not Related/ Unlikely Related An event that can be determined with certainty to have no relationship to the study intervention. AE Action Taken Regarding Study Intervention Where necessary the intervention name will be included in the source documenting the event. None required : No change in study intervention. Intervention not administered : The study intervention was held. Dose reduced : The study intervention was modified. Dose delayed/interrupted : The study intervention was temporarily stopped. Intervention discontinued : The study intervention was permanently stopped. Treatment of the AE None : No treatment was required. Medication required : Prescription and/or over-the-counter medication was required to treat the AE. Procedure/Surgery : Medical procedure was required to treat the AE. Other : to be specified in the source documents. AE Outcome Resolved : The participant fully recovered from the AE with no residual effect observed. Resolved with Sequelae : The residual effects of the AE are still present and observable. Include sequelae/residual effects. Persists : The AE itself is still present and observable. Death : Death should be used when death is a direct outcome of the AE. Unknown : Information unavailable Serious Adverse Event (SAE) An SAE is any untoward medical occurrence that at any dose: Results in death, Is life-threatening, that is, places the participant at immediate risk of death from the event as it occurred. This definition does not include a reaction that, had it occurred in a more severe form, might have caused death; Requires inpatient hospitalization or prolongation of existing hospitalization, unless hospitalization is for: Routine treatment or monitoring of the studied indication, not associated with any deterioration in condition; Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under study and has not worsened since signing the informed consent; Social reasons and respite care in the absence of any deterioration in the participant’s general condition; Results in persistent or significant disability/incapacity; Is a congenital anomaly/birth defect; or Is an important medical event. Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require intervention to prevent one of the other outcomes listed in the definition above. Examples include allergic bronchospasm, convulsions, and blood dyscrasias or development of drug dependency or drug abuse. Note • Procedures are not AEs or SAEs, but the reason for the procedure may be an AE or SAE. Pre-planned (prior to signing the informed consent form [ICF]) procedures or treatments requiring hospitalizations for pre-existing conditions that do not worsen in severity are not SAEs. For events that are serious due to hospitalization, the reason for hospitalization must be reported as the SAE (diagnosis or symptom requiring hospitalization). For deaths, the underlying or immediate cause of death should always be reported as an SAE. Any serious, untoward event that may occur subsequent to the reporting period that the investigator assesses as related to study intervention should also be reported and managed as an SAE. Unlike routine safety assessments, SAEs are monitored continuously and have special reporting requirements. All serious or intervention-related AEs ongoing at the end of treatment visit will be followed until resolution or until the condition is considered chronic/stable by the investigator. AE and SAE Reporting All AEs and SAEs that occur between study enrollment and 6 months after completion of the intervention, will be reported in the eCRF and all SAEs will be reported in the Clinical Research Management System (CRMS) (OnCore). After 6 months after completion of the intervention, only AEs and SAEs suspected to be related to the intervention will be reported. All events (serious and non-serious) must be reported with investigator’s assessment of the event’s seriousness, severity, and causality to the study intervention. A detailed narrative summarizing the course of the event, including its evaluation, treatment, and outcome should be provided. Specific or estimated dates of event onset, treatment, and resolution should be included when available. Medical history, concomitant medications, and laboratory data that are relevant to the event should also be summarized in the narrative. For fatal events, the narrative should state whether an autopsy was or will be performed, and include the results if available. Source documents (including medical reports) will be retained at the study site and should not be submitted to the Sponsor for SAE reporting purposes. Disease progression/worsening of disease will not be recorded as an AE on the Adverse Event eCRF. However, events associated with disease progression may be recorded as AEs. Death due to disease progression should be recorded on the Death eCRF. The study teams must report all SAEs to the JCCC DSMB in a timely manner. Regardless of relationship and expectedness of the event to the study intervention, the PI or their delegate must report the SAE within 10 business days of awareness. In the event of a participant death, the PI or their delegate must report the event within 2 business days of awareness. The SAE submission must note the date of awareness in the event narrative. To report the SAEs to the JCCC DSMB, the study team enters the SAE information into OnCore, the CRMS. The CRMS generates and sends notifications regarding the submission to the JCCC DSMB administrative team and the study team. Study teams without access to OnCore, may complete the SAE submission form manually and submit it to the JCCC DSMB administrative staff, who will enter the SAE into OnCore on their behalf. The CRMS generates reports for full JCCC DSMB review. The PI is also responsible for reporting any serious adverse event (SAE) to the sponsor, and any appropriate agency, according to the agency requirements. These include, but are not limited to: UCLA IRB; FDA; and NCI, if it is an NCI sponsored trial. The collection period for all SAEs will begin after informed consent is obtained and end after procedures for the final study visit have been completed. Any SAEs experienced after this period should only be reported to the Sponsor if the investigator suspects a causal relationship to the study intervention. In accordance with the standard operating procedures and policies of the local Institutional Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report SAEs to the IRB/IEC when applicable. DSMB Review of AEs and SAEs The JCCC DSMB reviews all AEs as part of the summary report review performed quarterly, semi-annually or annually based on the risk level assigned to the study and in accordance with the JCCC Data and Safety Monitoring Plan. The DSMB reviews each SAE monthly and determines if the event(s) warrants modifications to the protocol to ensure subject safety. In their review, the DMSB considers prior occurrences of similar toxicity with the intervention under study, as well as the severity of the event and the likelihood of relation to the study intervention or investigational product. The DSMB may recommend no changes to the study if the event is expected or related to other causes such as underlying disease. To assist discussions and decisions, the DSMB may request the expert advice of another clinical researcher with national experience. Data Safety, Collection, Retention, and Monitoring Monitoring The JCCC Office of Regulatory Compliance (ORC) will perform monitoring and auditing activities in accordance with the JCCC Data and Safety Monitoring Plan (DSMP). Data Safety Monitoring The JCCC DSMB will serve as the DSMB to review data relating to safety and efficacy, to conduct and review interim analyses, and to ensure the continued scientific validity and merit of the study, according to the JCCC DSMP. There will be quarterly, semi-annually or annual interim review(s) conducted by the DSMB based on the risk level assigned to the study for the purpose of monitoring study conduct and assessing participant safety. Risk level 1 studies are the highest risk and are reviewed quarterly; Risk Level 2 studies are intermediate risk and are reviewed semi-annually; Risk Level 3 studies are the lowest risk and are reviewed annually. Further details regarding the timing and content of the interim reviews via summary reports are included in the JCCC DSMP. Data Management The radiation oncology research staff will be responsible for the database records of study patients. The data will be kept on the research staff computer, under password protection, with the patient information de-identified (study patients will be referred by their coded study number). A chart with all the relevant research patient information will be maintained for each patient by the research coordinator and will be filed in a locked cabinet. Only the research team (study staff, investigators, and project supporting staff) will have the password and key to the data from the study patients. Confidentiality Study data will be maintained in password protected computer files. Only research personnel will have access to this information. All identifiers will be removed. The patient’s name or other public identifiers will not be included in any information shared with other investigators. The master key that will identify specific study patients to their coded study number will be kept in a separate password protected file on the research staff computer. Only the study staff and the principal investigator will know the password to this file. Statistical Methods and Considerations General All analyses will be descriptive and will be presented by treatment period and overall as appropriate. Data collected in this study will be presented using summary tables and patient data listings. Continuous variables will be summarized using descriptive statistics, specifically the mean, median, standard deviation, minimum, and maximum. Categorical variables will be summarized by frequencies and percentages. Safety Lead-In/Interim Analysis The study includes a safety lead-in portion, with formal evaluation on enrollment of the 15th subject. The trial will be stopped if 5 or more patients in the safety lead-in portion experience a serious adverse event, defined as a CTCAE v5.0 grade 3 or higher definitely attributable to the intervention during or within 30 days after completion of PULSAR. Sample Size Determination Prospective data of SBRT for unresectable head and neck cancer has demonstrated 1 year local control rates of 60% in the re-irradiation setting 20 . In the de novo setting, prospective data are limited and primarily consist of SBRT for early-stage glottis cancer, though in small, retrospective series predominantly for palliative purposes and/or for patients who are not candidates for standard of care definitive therapy, the reported 1 year local control rates range from 69–87% 21 . However, in the palliative setting or patients unfit for definitive therapy, a variety of other radiation regimens are often used, such as the “Quad-Shot” regimen, which generally have lower and/or less durable local control rates 23 – 25 . From these data, we estimate the historic control group 1 year local control rate to be 65%. For the study group, unpublished analysis of a recently closed phase II trial at UCLA of dose-escalated SBRT to 55 Gray for treatment of previously radiated, recurrent head and neck cancer demonstrated a 1 year local control rate of 85% (NCT 03892720). We therefore hypothesize that patients enrolled in this trial will have a similar 1 year local control rate. A sample size of 38 patients will achieve 80% power to detect a 20% difference in the 1 year local control rate between PULSAR (85%) and historic control (65%), using a two-sided one-sample exact binomial test, at 0.05 significance level. Considering that some patients may become ineligible/drop out after enrollment, the target sample size is determined to be at least 43 patients. The 15 patients in the safety lead-in portion will be included in the sample should the study proceed past this portion. Patient Accrual and Study Duration We used an institutional database of patients with HNC and departmental treatment records to retrospectively approximate the number of patients that would have been eligible for this trial. Taking into account errors in electronic medical record documentation and coding 40 , 41 , we estimate that approximately 120–170 eligible patients were seen in our department over the past five years, roughly equating to two to three eligible patients monthly. These numbers are in line with or even slightly lower than what we have seen clinically recently, particularly as the COVID pandemic has subsided and more patients are being seen in our department. Additionally, our department’s recently closed phase II study of definitive HyperArc SBRT in patients with recurrent, previously radiated HNC enrolled and treated the first fifteen patients in one year 15 . The patient population in this recently closed phase II trial is much narrower than that in the proposed study, so we anticipate similar if not faster enrollment with this proposed study compared with the recently closed phase II trial. As such, we anticipate enrollment of two to four patients monthly and that it will take approximately 1 year to complete the safety lead-in portion and 4 years to complete the study. Study-related data will be stored after completion of the clinical portion of the study to be used in the exploratory portion of the study, as needed. Populations for Analyses Full Analysis Set (FAS) All efficacy analyses will be performed on the Full Analysis Set (FAS) following the Intent-To-Treat (ITT) principle. Patients who were enrolled but did not receive study treatment are included in the FAS population. Evaluable Analysis Set (EAS) A subset of the full analysis set (FAS), the evaluable analysis set is defined as those treated patients who are evaluable (i.e. compliant with treatment and without any major protocol deviations that may impact primary efficacy analysis). The EAS will be used for supportive analyses of the efficacy endpoints. Safety Analysis Set (SAS) All patients who received at least 1 fraction of radiation and for whom any valid post-baseline safety data are available will be included in the safety analysis set. When assessing safety and tolerability, summaries will be produced based on the safety analysis set. Patients are analyzed according to the actual treatment received. Study Endpoints Primary Endpoint The primary endpoint is local control rate of the treated tumor target at 1 year, as measured from the date of enrollment. Local control will be evaluated by radiographic and/or clinical assessment as applicable. Participants who experience death or are lost to follow-up prior to 1 year will be assessed by their last radiographic/clinical evaluation. Secondary Endpoints Measurement of grade 3 or higher treatment-related toxicity during or within 24 months after completion of PULSAR, according to the CTCAE v5.0. Disease progression free survival (PFS), defined as the time from enrollment to the first objectively documented disease progression, either in or out of the treated field per radiographic and/or clinical evaluation, or death due to any cause. Participants who experience death or are lost to follow-up prior to 1 year will be assessed by their last radiographic/clinical evaluation. Overall survival (OS), defined as the time between enrollment and death of any cause. Participants who are lost to follow-up prior to 1 year will be censored at the date of their last documentation in the medical record system. Impact of PULSAR on symptoms/quality of life as measured by the UW-QoL and FACT-H&N validated questionnaires. Measurement of the frequency of re-simulation and/or adaptive planning required with PULSAR. Evaluation of the standard of care tumor and OAR dosimetry with PULSAR. Evaluation of the safety and efficacy of combination PULSAR and immunotherapy in enrolled patients receiving immunotherapy will be descriptive and exploratory. Statistical Analysis Plan Demographics and Baseline Characteristics Demographic data, medical history, other baseline characteristics, and concomitant disease will be summarized. To determine whether the criteria for study conduct are met, corresponding tables and listings will be provided. These will include an assessment of protocol deviations, study treatment accountability, and other data that may impact the general conduct of the study. The analysis sets FAS, EAS, SAS will be used. Efficacy Analyses Primary endpoint: Primary endpoint analyses will be performed on patients included in analysis sets FAS and EAS across the whole cohort, as well as separate analyses stratifying patients by Human Papillomavirus/p16 status. For the primary endpoint, we will calculate the percentage and construct 95% exact confidence interval for local control rate. Additionally, Kaplan-Meier method and cumulative incidence functions considering distant progression or death as a competing risk will be used to provide estimates of the local control at 1-year, median local control, and cumulative incidence of local control at 1-year, with corresponding 95% confidence intervals. Secondary Endpoints: Secondary endpoint analyses will be performed on patients included in analysis sets FAS and EAS across the whole cohort, as well as separate analyses stratifying patients by Human Papillomavirus/p16 status. For the secondary endpoints of PFS and OS, Kaplan-Meier method and cumulative incidence curves treating death as a competing risk will be used to provide estimates of the PFS/OS at 1-year, median PFS/OS, and cumulative incidence of PFS/OS at 1-year. Corresponding 95% confidence intervals will also be presented. Safety Analyses Safety analyses will be performed for patients included in analysis set SAS. Percentage of patients with acute or chronic grade 3 or higher treatment-related toxicity, incidence of AEs, clinical laboratory information, vital signs, ECOG performance status, and weight, will be tabulated and summarized. Incidence of AEs will be summarized overall and with separate summaries for SAEs, AEs leading to discontinuation, AEs leading to death, etc. The overall safety and tolerability will be assessed throughout the study period. All AE data will be listed individually by patient identifier. Symptom/Quality of Life Analyses Analysis of data related to the symptom/quality of life impact of PULSAR using the UW-QoL and FACT-H&N validated questionnaires will be primarily descriptive and exploratory. Descriptive/Exploratory Analyses Analysis of data related to the frequency of re-simulation and/or adaptive planning required with PULSAR; standard of care tumor and OAR dosimetry with PULSAR; and the safety and efficacy of combination PULSAR and immunotherapy in enrolled patients receiving immunotherapy will be descriptive and exploratory. Dissemination Policies Protocol Modifications Important protocol modifications will be communicated to relevant parties including investigators, the UCLA IRB, trial participants, journal, and regulators by standard methods of communications. Trial Results The investigators will communicate trial results to participants, healthcare professionals, the public, and other relevant groups via publication. Data Public access to the full protocol and statistical code will be granted. Discussion This study has significance across a wide-range of clinical situations. In regards to the enrolled patient population, there is a need for more optimal palliative treatments, especially as longevity is improved from advances in other treatment modalities, particularly systemic therapy. As such, if the safety and efficacy of PULSAR is confirmed, it may supplant existing palliative radiation therapy regimens for HNC and become more common in clinical practice. Furthermore, there are limited prospective clinical data evaluating the PULSAR regimen, and this study will provide guidance on the logistics, workflow, safety, and efficacy of PULSAR with HyperArc technology so that it may be studied and utilized further in HNC and/or in other cancer sites. Similarly, given the interest in the combination of PULSAR and immunotherapy, this study could provide early, hypothesis generating data on this combination treatment, laying the groundwork for future studies. Ultimately, we anticipate that this study will provide important, early data on this promising new radiotherapy paradigm. Abbreviations AAPM American Association of Physicists in Medicine AE Adverse Event AJCC American Joint Committee on Cancer CRF Case Report Form CRMS Clinical Research Management System CT Computed Tomography CTCAE Common Terminology Criteria for Adverse Events CTV Clinical Target Volume DSMB Data Safety and Monitoring Board DSMP Data Safety and Monitoring Plan EAS Evaluable Analysis Set ECOG Eastern Cooperative Oncology Group FACT H&N–Functional Assessment of Cancer Therapy Head and Neck FAS Full Analysis Set ICF Informed Consent Form ITT Intent–to–Treat GFR Glomerular Filtration Rate GTV Gross Tumor Volume IEC Independent Ethics Committee IMRT Intensity Modulated Radiation Therapy IRB Institutional Review Board JCCC Jonsson Comprehensive Cancer Center MRI Magnetic Resonance Imaging HIPAA Health Insurance Portability and Accountability Act MV Megavoltage OAR Organ–at–Risk ORC Office of Regulatory Compliance PET Positron Emission Tomography PI Principal Investigator PTV Planning Target Volume PULSAR Personalized Ultrafractionated Stereotactic Adaptive Radiothearpy SAE Serious Adverse Event SAS Safety Analysis Set SBRT Stereotactic Body Radiotherapy HNC Head and Neck Cancer SPIRIT Standard Protocol Items: Recommendations for Interventional Trials PFS Progression–Free Survival OS Overall Survival UCLA University of California, Los Angeles UW QoL–University of Washington Quality of Life VMAT Volumetric Modulated Arc Therapy WOCBP Women of Child Bearing Potential Declarations Ethics Approval and Consent to Participate: This study is approved by the Institutional Review Board (IRB) of the University of California, Los Angeles (UCLA IRB #24-000663), and is registered at the U.S. National Institutes of Health (clinicaltrials.gov) # NCT06572423. The current protocol is version 1.5. Consent for Publication: This manuscript does not include details, images, or videos relating to an individual person. Availability of Data and Materials: All data generated or analyzed during this study are included in this published article [and its supplementary information files]. Competing Interests : Dr. Ricky Savjani reports research grant support from BrainLab, Varian Medical Systems, and StratPharma, all unrelated to the submitted work. Dr. Minsong Cao reports personal fees from Varian Medical Systems unrelated to the submitted work. There are no other competing interests. Funding : This is an investigator initiated trial funded by Varian Medical Systems, Inc. The funder had no role in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication, including whether they will have ultimate authority over any of these activities. Authors' Contributions : Study Conception: PTC and RKC Initial Study Design: PTC and RKC Revising of Study Design and Protocol: PTC, MS, RRS, VR, CP, TVB, DOC, DT, RKC Study Coordination and Acquisition of Data: PTC, MS, CP Drafting of Manuscript: TC and RKC Substantial Revising of Manuscript: PTC, MS, RRS, VR, CP, TVB, DOC, DT, RKC All authors have reviewed and approve of the materials contained herein. Acknowledgements : We would like to acknowledge the patients who will enroll on this study to further the cause of medical science. References Bishnoi R, Bennett J, Reisman DN. Palliative treatment of patients with inoperable locally advanced, recurrent or metastatic head and neck squamous cell cancer, using a low-dose and personalized chemotherapeutic regimen. Oncol Lett. 2017;13(6):4633–40. 10.3892/ol.2017.6068 . Roland NJ, Bradley PJ. The role of surgery in the palliation of head and neck cancer. Curr Opin Otolaryngol Head Neck Surg. 2014;22(2):101–8. 10.1097/MOO.0000000000000031 . 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Radiat Oncol Lond Engl. 2023;18(1):166. 10.1186/s13014-023-02342-0 . Vargo JA, Ferris RL, Ohr J, et al. A prospective phase 2 trial of reirradiation with stereotactic body radiation therapy plus cetuximab in patients with previously irradiated recurrent squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 2015;91(3):480–8. 10.1016/j.ijrobp.2014.11.023 . Swain M, Ghosh-Laskar S. Stereotactic body radiotherapy (SBRT) for primary non-metastatic head and neck cancer: When less is enough. Oral Oncol. 2021;116:105265. 10.1016/j.oraloncology.2021.105265 . Grimm J, Vargo JA, Mavroidis P, et al. Initial Data Pooling for Radiation Dose-Volume Tolerance for Carotid Artery Blowout and Other Bleeding Events in Hypofractionated Head and Neck Retreatments. Int J Radiat Oncol Biol Phys. 2021;110(1):147–59. 10.1016/j.ijrobp.2020.12.037 . Soni A, Kaushal V, Verma M, Dhull AK, Atri R, Dhankhar R. 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Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. J Clin Oncol Off J Am Soc Clin Oncol. 2023;41(4):790–802. 10.1200/JCO.21.02508 . Chow LQM, Haddad R, Gupta S, et al. Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(32):3838–45. 10.1200/JCO.2016.68.1478 . Cohen EEW, Soulières D, Le Tourneau C, et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet Lond Engl. 2019;393(10167):156–67. 10.1016/S0140-6736(18)31999-8 . Timmerman R. Beyond Fractionation: PULSAR as Novel Radiotherapy Paradigm. Oncol Times. 2021;43(24):117–17. 10.1097/01.COT.0000805556.39152.17 . Tubin S, Vozenin MC, Prezado Y, et al. Novel unconventional radiotherapy techniques: Current status and future perspectives - Report from the 2nd international radiation oncology online seminar. Clin Transl Radiat Oncol. 2023;40:100605. 10.1016/j.ctro.2023.100605 . Rahimian J, Bhattasali O, Girvigian MR. Adaptive Dose-Staged Stereotactic Ablative Body Radiotherapy for Treatment of Large Central NSCLC Lung Tumors: A Dosimetric Simulation Study. ASTRO 2023 65th Annu Meet . 2023;117(2, Supplement):e709. 10.1016/j.ijrobp.2023.06.2204 Varian. HyperArc. https://www.varian.com/products/radiotherapy/treatment-planning/hyperarc Woods K, Chin RK, Cook KA, et al. Automated Non-Coplanar VMAT for Dose Escalation in Recurrent Head and Neck Cancer Patients. Cancers. 2021;13(8):1910. 10.3390/cancers13081910 . Rwigema MJC, Vargo AJ, Clump AD, Ferris LR, Ohr J, Heron ED. 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Stereotactic body radiation therapy: the report of AAPM Task Group 101. Med Phys. 2010;37(8):4078–101. 10.1118/1.3438081 . Hassett MJ. Usability Considerations in Oncology Electronic Medical Records. J Oncol Pract. 2017;13(8):539–41. 10.1200/JOP.2017.024745 . Khela H, Khalil J, Daxon N, et al. Real world challenges in maintaining data integrity in electronic health records in a cancer program. Tech Innov Patient Support Radiat Oncol. 2024;29:100233. 10.1016/j.tipsro.2023.100233 . Additional Declarations Competing interest reported. Dr. Ricky Savjani reports research grant support from BrainLab, Varian Medical Systems, and StratPharma, all unrelated to the submitted work. Dr. Minsong Cao reports personal fees from Varian Medical Systems unrelated to the submitted work. There are no other competing interests. Supplementary Files PULSPalSupplementalMaterial.docx PULSPalFootnotesforStudyCalendar.docx Cite Share Download PDF Status: Published Journal Publication published 21 Dec, 2024 Read the published version in BMC Cancer → Version 1 posted Editorial decision: Revision requested 03 Dec, 2024 Reviews received at journal 03 Dec, 2024 Reviews received at journal 01 Dec, 2024 Reviewers agreed at journal 24 Nov, 2024 Reviewers agreed at journal 22 Nov, 2024 Reviewers invited by journal 06 Sep, 2024 Editor assigned by journal 28 Aug, 2024 Submission checks completed at journal 28 Aug, 2024 First submitted to journal 28 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4988211","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":352536008,"identity":"6b0c34fb-7cf8-49cd-92b8-2d61d519705e","order_by":0,"name":"P. 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Vincent Basehart","email":"","orcid":"","institution":"University of California, Los Angeles","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"T.","middleName":"Vincent","lastName":"Basehart","suffix":""},{"id":352536017,"identity":"426e4721-7ef0-4206-89fb-d3c0313c4197","order_by":9,"name":"Dylan O’Connell","email":"","orcid":"","institution":"University of California, Los Angeles","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Dylan","middleName":"","lastName":"O’Connell","suffix":""},{"id":352536018,"identity":"3b77f9b6-7400-4e6c-a701-2a09ff3f08c9","order_by":10,"name":"Minsong Cao","email":"","orcid":"","institution":"University of California, Los Angeles","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Minsong","middleName":"","lastName":"Cao","suffix":""},{"id":352536019,"identity":"92f8366c-eb98-446c-b9dd-6903a5af94d5","order_by":11,"name":"Donatello Telesca","email":"","orcid":"","institution":"University of California, Los Angeles","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Donatello","middleName":"","lastName":"Telesca","suffix":""},{"id":352536020,"identity":"dc8e4fb0-7a18-4c8e-a166-52628c019020","order_by":12,"name":"Robert K. Chin","email":"","orcid":"","institution":"University of California, Los Angeles","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Robert","middleName":"K.","lastName":"Chin","suffix":""}],"badges":[],"createdAt":"2024-08-28 05:12:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4988211/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4988211/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12885-024-13303-5","type":"published","date":"2024-12-21T15:57:03+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":66868200,"identity":"140ed07a-0ce9-4329-8210-4ece3dfbbf04","added_by":"auto","created_at":"2024-10-17 09:23:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":129529,"visible":true,"origin":"","legend":"\u003cp\u003eThe trial schema\u003c/p\u003e","description":"","filename":"Figure1Schema2.png","url":"https://assets-eu.researchsquare.com/files/rs-4988211/v1/4c99f2ff4dd73ee6aa9f825f.png"},{"id":66868222,"identity":"ec9ef1f0-09e0-4962-9c52-93bdce277325","added_by":"auto","created_at":"2024-10-17 09:23:53","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":226563,"visible":true,"origin":"","legend":"\u003cp\u003ePatient enrollment, treatment, and follow-up\u003c/p\u003e","description":"","filename":"Figure2Calendar2.png","url":"https://assets-eu.researchsquare.com/files/rs-4988211/v1/11937abc22382cd7b51c9a99.png"},{"id":72201579,"identity":"ff5d60a6-f566-412c-8d61-8b63a34bea8f","added_by":"auto","created_at":"2024-12-23 16:08:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1172655,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4988211/v1/8fb682d4-73b1-46bc-9de2-8a7644620d72.pdf"},{"id":66868234,"identity":"066e73cb-6379-4984-a7b1-9b9feb789440","added_by":"auto","created_at":"2024-10-17 09:23:57","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":52271,"visible":true,"origin":"","legend":"","description":"","filename":"PULSPalSupplementalMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-4988211/v1/531f03a441488f75db16eac4.docx"},{"id":66868228,"identity":"d68a3e54-d85e-4ef1-934d-9446b38b09c5","added_by":"auto","created_at":"2024-10-17 09:23:55","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":12665,"visible":true,"origin":"","legend":"","description":"","filename":"PULSPalFootnotesforStudyCalendar.docx","url":"https://assets-eu.researchsquare.com/files/rs-4988211/v1/0cb4ff74bd10a62d063acbe4.docx"}],"financialInterests":"Competing interest reported. Dr. Ricky Savjani reports research grant support from BrainLab, Varian Medical Systems, and StratPharma, all unrelated to the submitted work. Dr. Minsong Cao reports personal fees from Varian Medical Systems unrelated to the submitted work. There are no other competing interests.","formattedTitle":"A phase II study of personalized ultrafractionated stereotactic adaptive radiotherapy for palliative head and neck cancer treatment (PULS-Pal): a single-arm clinical trial protocol","fulltext":[{"header":"Background","content":"\u003cp\u003eA significant proportion of patients with de novo or recurrent head and neck cancer (HNC) will not be candidates for standard of care definitive treatment(s)\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e, which includes a combination of surgery, radiation therapy, and/or systemic therapy, and in some cases, standard of care stereotactic body radiotherapy (SBRT). Common contraindications for standard definitive treatment for HNC include locally advanced disease not amenable to definitive treatment because of the anticipated morbidity with primary or salvage treatment, poor performance status, presence of metastatic disease, or patient treatment preferences\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. In such cases, locoregional palliative radiation therapy is often utilized given the frequent accompanying symptoms of HNC such as pain or difficulty breathing or eating\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e, with the most common HNC palliative radiation therapy regimens being the RTOG-8502 regimen (\u0026ldquo;quad-shot\u0026rdquo;)\u003csup\u003e\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e and SBRT\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. While these current palliative radiation therapy options can provide adequate symptom improvement, there are some limitations with these regimens as well.\u003c/p\u003e \u003cp\u003eWith quad-shot, there are logistic challenges for both providers and patients given the twice-daily treatments, albeit for just two days total. Moreover, typically multiple cycles are needed to achieve maximal symptomatic benefit, although only about 50% of patients will be able to complete three or more cycles at which point the palliative response rate of this regimen is significantly increased\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Additionally, while newer radiation therapy techniques such as intensity modulated radiation therapy (IMRT) have been employed to enhance the quad-shot regimen, it represents an older radiation therapy practice which may not fully leverage more recent advances in radiation therapy technology. Regarding SBRT, there is the possibility for severe toxicity, minimization of which is important in the palliative setting, as well as efficacy concerns, particularly for larger tumors or in the re-irradiation setting\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. However, a main limitation across all palliative radiation therapy regimens is suboptimal local control. Local tumor progression negatively impacts symptoms and possibly overall survival given the frequency at which locoregional tumor progression causes death in patients with HNC\u003csup\u003e\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eProspective data of SBRT for unresectable head and neck cancer has demonstrated one year local control rates of 60% in the re-irradiation setting\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. In the de novo setting, prospective data are limited and primarily consist of SBRT for early-stage glottis cancer, though in small, retrospective series predominantly for palliative purposes and/or for patients who are not candidates for standard of care definitive therapy, the reported one year local control rates range from 69\u0026ndash;87%\u003csup\u003e21\u003c/sup\u003e. However, not all patients will be eligible for standard of care SBRT in the definitive or palliative setting, for example because of tumor size or location near the carotid artery\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. In such cases, a variety of other radiation regimens are often used, such as quad-shot, which generally have lower and/or less durable local control rates\u003csup\u003e\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. The durability of symptom and local control in this patient population is becoming more important as advances in systemic therapy, particularly immunotherapy, are improving patient survival\u003csup\u003e\u003cspan additionalcitationids=\"CR27 CR28\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePersonalized ultrafractionated stereotactic adaptive radiotherapy (PULSAR) is a novel radiation therapy regimen in which large radiation doses are delivered in \u0026ldquo;pulses\u0026rdquo; over extended interfraction intervals, with typically several days to multiple weeks between each radiation fraction\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. The PULSAR technique is enabled by advances in SBRT and image-guided radiation therapy, and allows for possible adaptation of each subsequent fraction to the most current patient anatomy and tumor response. This not only permits adequate time passage for tumor shrinkage and subsequent adaptive radiation therapy re-planning to occur, but also a protracted SBRT course may be less toxic than the standard SBRT course typically delivered over 1\u0026ndash;2 weeks given the additional time for normal tissue healing as well as smaller radiation fields with possible tumor shrinkage. To this end, the PULSAR paradigm may enable safer tumor dose escalation\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Similarly, advances in radiation planning and treatment delivery, specifically HyperArc\u0026copy; (Varian Medical Systems, Inc.)\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e technology, have permitted dose escalation with high conformity in HNC SBRT\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. Dose escalation has been found to be associated with improved locoregional control in HNC\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e, and thus the combination of PULSAR with HyperArc technology may further improve the therapeutic ratio of palliative radiation therapy in this patient population. Even more so, it has been suggested that there may be a synergism between PULSAR and immunotherapy, and further exploration of this relationship is warranted, particularly in the clinical setting\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. With the increased use of immunotherapy in patients with recurrent, unresectable, or metastatic disease\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e, the potential complimentary relationship between PULSAR and immunotherapy may provide these patients with additional benefit.\u003c/p\u003e \u003cp\u003eIn this context, PULSAR is an appealing option for patients requiring palliative radiation therapy for HNC. Given the potential efficacy, safety, symptomatic, and logistical benefits of this radiation regimen, we hypothesize that PULSAR delivered with HyperArc technology will result in improved local control, reduced toxicity, and similar or improved symptom relief compared with existing palliative radiation regimens in patients with de novo or recurrent HNC who are not candidates for standard of care definitive treatment(s), including standard of care SBRT. To test this hypothesis, we will conduct a prospective clinical trial of PULSAR in this patient population. Because PULSAR is a newer technique, it has not yet been comprehensively studied, particularly in combination with HyperArc technology. To our knowledge, there are currently nine early phase clinical trials prospectively evaluating PULSAR in some capacity (NCT 04677413, 04779489, 04786093, 04889066, 05021237, 05846646, 05846659, 06044857, 06359275), none of which are in HNC. Thus, validation of its safety and feasibility is first required prior to larger-scale prospective studies of efficacy in HNC. Herein, we propose an early safety and feasibility study of palliative PULSAR delivered with HyperArc technology in patients with de novo or recurrent, localized or metastatic HNC who are ineligible for or decline standard of care definitive treatment(s).\u003c/p\u003e \u003cp\u003eHyperArc radiation technology is a commercial tool that provides automated non-coplanar volumetric modulated arc therapy (VMAT) treatment planning. It was initially developed for intracranial stereotactic radiosurgery; however, it can be adapted for the treatment of HNC, and our institution has evaluated HyperArc technology in HNC dosimetrically and prospectively with encouraging results\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. From a treatment planning perspective, HyperArc allows for target dose escalation, which as noted above is correlated with improved locoregional control, while maintaining minimal head and neck organs-at-risk doses compared with more conventional VMAT SBRT\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. From a clinical perspective, our institution recently completed patient accrual for a phase II trial of HyperArc SBRT to 55 Gray in five every other day fractions for definitive treatment in previously radiated patients with recurrent HNC (NCT03892720). The initial report of this study found this intervention to be feasible, safe, and well tolerated with minimal treatment-related toxicity and favorable quality of life metrics. Additionally, unpublished analysis of this study found a one year local control rate of 85%, which is higher than existing prospective data of SBRT for recurrent, previously radiated HNC reporting a one year local rate of 60%\u003csup\u003e20\u003c/sup\u003e. These findings support the rationale for using HyperArc treatment planning technology in this study.\u003c/p\u003e"},{"header":"Methods/Design","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThis is a single-center (UCLA), single-arm, prospective phase II study with a safety lead-in. 43 subjects are planned. Each subject will receive the same PULSAR radiation therapy course as described below. The first 15 enrolled patients will be evaluated in the safety lead-in portion. If 5 or more of these 15 patients experience CTCAE v5.0 grade 3 or higher definitely attributable to the intervention during or within 30 days after completion of PULSAR, the study will be stopped for safety concerns; otherwise, the study will proceed, and those initial 15 patients will be included in the 43 subject sample. The trial schema is shown in \u003cb\u003eFig.\u0026nbsp;1\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEthics Approval\u003c/h2\u003e \u003cp\u003e This study is approved by the Institutional Review Board (IRB) of the University of California, Los Angeles (UCLA IRB #24\u0026ndash;000663), and is registered at the U.S. National Institutes of Health (clinicaltrials.gov) # NCT06572423. The current protocol is version 1.5. This manuscript adheres to the guidelines and methodology outlined in the SPIRIT checklist.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eAims\u003c/h2\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003ePrimary Aim\u003c/h2\u003e \u003cp\u003eTo evaluate the 1-year local tumor control of PULSAR for patients with de novo or recurrent, localized or metastatic head and neck cancer who are ineligible for or decline standard of care treatment(s), including standard of care SBRT.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eSecondary Aims\u003c/h2\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003ch2\u003eSecondary Aim 1\u003c/h2\u003e \u003cp\u003eTo evaluate the safety and toxicity of PULSAR as local treatment for patients with de novo or recurrent, localized or metastatic head and neck cancer who are ineligible for or decline standard of care definitive treatment(s).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003eSecondary Aim 2\u003c/h2\u003e \u003cp\u003eTo evaluate the 1-year disease progression-free (PFS) and overall survival (OS) of patients with de novo or recurrent, localized or metastatic head and neck cancer who are ineligible for or decline standard of care treatment(s) who receive PULSAR.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003eSecondary Aim 3\u003c/h2\u003e \u003cp\u003eTo evaluate the symptomatic impact of PULSAR as local treatment for patients with de novo or recurrent, localized or metastatic head and neck cancer who are ineligible for or decline standard of care definitive treatment(s).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSecondary Aim 4\u003c/h2\u003e \u003cp\u003eTo determine the frequency of re-simulation and/or adaptive planning required with PULSAR.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSecondary Aim 5\u003c/h2\u003e \u003cp\u003eTo evaluate standard of care tumor and organs-at-risk (OARs) dosimetry with PULSAR.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSecondary Aim 6\u003c/h2\u003e \u003cp\u003eTo evaluate the safety and efficacy of combination PULSAR and immunotherapy in enrolled patients receiving immunotherapy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003ePatient Selection\u003c/h2\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003eStudy Population\u003c/h2\u003e \u003cp\u003ePatients with a diagnosis of primary or recurrent head and neck cancer who are ineligible for or decline standard of care definitive (i.e., curative) treatment(s), including standard of care stereotactic body radiation therapy (SBRT). Reasons for ineligibility for standard of care definitive treatments include locally advanced disease not amenable to standard definitive treatment(s) (e.g., due to the anticipated morbidity associated with definitive treatment), presence of metastatic disease, and medical comorbidities and/or poor performance status that preclude definitive treatment. Additionally, patients with primary or recurrent localized head and neck cancer who are candidates for but decline standard of care definitive treatment(s) will be eligible for enrollment.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eInclusion Criteria\u003c/span\u003e \u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e\u0026ge;\u0026thinsp;18 years old.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eDiagnosis of primary or recurrent, localized or metastatic (AJCC 8th Edition stages I-IV) head and neck cancer. In primary diagnosis cases, pathologic confirmation is required. In recurrent and/or metastatic diagnosis cases, pathologic confirmation is not required if not beneficial to the patient as standard of care, and diagnosis can be assumed based on clinical and/or radiographic evidence.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eIneligible for or declines standard of care definitive treatment(s), which will be documented in the patient\u0026rsquo;s trial screening progress note in their electronic medical record by the treating physician.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eMeasurable disease within the head and/or neck clinically and/or on imaging studies (CT, PET, MRI) within 30 days from date of enrollment.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePatient maximum tumor(s) or tumor bed in postoperative patients diameter must be less than 10cm.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eIn a woman of childbearing potential, a negative serum or urine pregnancy test within 1 week of treatment start must be documented. Women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; or abstinence) for duration of study participation and for up to 4 weeks following the study treatment.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePatients with a tracheostomy and/or a percutaneous endoscopic gastrostomy tube are eligible for inclusion.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eExclusion Criteria\u003c/span\u003e \u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePregnant or breast-feeding.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eMore than 1 prior radiation treatment course directed to the treatment area over the patient\u0026rsquo;s lifetime. In patients who have received 1 prior radiation treatment course directed to the treatment area, that prior radiation treatment course must have concluded at least 6 months prior to trial enrollment.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAny comorbidity or condition which would limit full compliance with the protocol.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eRegistration and Enrollment Process\u003c/h2\u003e \u003cdiv id=\"Sec17\" class=\"Section3\"\u003e \u003ch2\u003eGeneral Guidelines\u003c/h2\u003e \u003cp\u003ePatients with primary or de novo, localized or metastatic, HNC who are not eligible for or decline standard of care definitive treatment(s) will be informed of this clinical trial if eligible. The decision to participate will be voluntary. Eligible patients who decide not to participate will be offered alternative palliative radiation therapy regimens, systemic therapy (per their medical oncologist), alternative clinical trials, or palliative/hospice care. Information regarding this research study will be included on the UCLA Health Clinical Trials webpage and Clinicaltrials.gov.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eRegistration Process\u003c/h2\u003e \u003cp\u003eWhen feasible, an informed consent form in the patient\u0026rsquo;s preferred language will be given to the patient, or surrogate or legal-authorized representative when applicable, for review. Consent will be obtained after a clear and thorough discussion between the patient, or surrogate or legal-authorized representative when applicable, and the study investigator in clinic in the patient\u0026rsquo;s preferred language, utilizing a certified interpreter when necessary. To register a patient, the research coordinator will obtain or collect: (1) confirmation of diagnosis of HNC per inclusion criteria above; (2) signed informed consent form; (3) signed HIPAA authorization form. The informed consent form is provided in the \u003cb\u003eSupplemental Material.\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003ePretreatment Evaluations\u003c/h2\u003e \u003cp\u003eUpon confirmation of eligibility and enrollment in the study, the following will be obtained prior to treatment (if not already performed):\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eMedical history and clinical examination including weight and ECOG Performance Status\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eSerum creatinine/estimated GFR within 60 days of CT simulation\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eUniversity of Washington Quality of Life (UW-QoL) and Functional Assessment of Cancer Therapy Head and Neck (FACT-H\u0026amp;N) validated questionnaire\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eFor patients who have received and/or are currently receiving cancer-directed treatment(s), evaluation for existing treatment-related toxicities as measured by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0), as this version is currently implemented in our institution\u0026rsquo;s electronic medical record system which allows for easier and more consistent data documentation and recording.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003e Additional pretreatment studies including blood tests, imaging, and pathologic evaluation of tumor tissue for Human Papillomavirus and/or p16 positivity may be obtained per standard of care guidelines and/or the patient\u0026rsquo;s treatment team\u0026rsquo;s discretion.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eIntervention\u003c/h2\u003e \u003cdiv id=\"Sec21\" class=\"Section3\"\u003e \u003ch2\u003eRadiation Simulation\u003c/h2\u003e \u003cp\u003eAfter confirmation of eligibility, enrolled patients will undergo radiation CT simulation and planning per standard of care. IV contrast will be administered with CT simulation at the treating physician\u0026rsquo;s discretion though is not required. A thermoplastic face mask will be used for immobilization. HyperArc technology will be used for treatment planning given prior internal validation of its superiority as above.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eRadiation Planning\u003c/h2\u003e \u003cp\u003eFor unresectable patients, the treating physician will delineate the gross tumor volume (GTV). For resected patients, a clinical target volume (CTV) will be delineated. The target will include the preoperative tumor volume with up to 5mm expansion for microscopic disease, with considerations for postoperative anatomical changes. Relevant previously obtained imaging studies may be fused to the CT simulation images as deemed necessary by the treating physician to further delineate the GTV or CTV. The GTV or CTV will be expanded by 3\u0026ndash;5 mm for treatment setup error. This expansion will comprise the planning target volume (PTV). The dose will be prescribed to cover at least 95% of the PTV unless under-dosing of the PTV is required to meet constraints to OARs. Delineation of normal structures will be performed, including but not limited to: larynx, spinal cord, mandible, brainstem, skin, oral cavity, and parotid gland.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eOAR Dose Constraints\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eNo Prior Radiation Therapy to Tumor/Tumor Bed Site\u003c/strong\u003e \u003cp\u003ewill use max dose point constraints (defined as dose to 0.035 cm\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e) from the AAPM Task Group 101 Report\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003ePrior Radiation Therapy to Tumor/Tumor Bed Site (Reirradiation)\u003c/strong\u003e \u003cp\u003ewill use the following max dose point constraints (defined as dose to 0.035 cm\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eLarynx: \u0026le; 20 Gy\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSpinal cord: \u0026le; 8 Gy\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eMandible: \u0026le; 30 Gy\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eBrainstem: \u0026le; 8 Gy\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSkin: Dmax\u0026thinsp;\u0026lt;\u0026thinsp;39.5Gy\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003ePULSAR Treatment\u003c/h2\u003e \u003cp\u003eDaily cone-beam CT will be obtained prior to radiation delivery to verify anatomic location and stability. Treatment will consist of 6, 10, or 15 MV photons directed at the PTV using HyperArc\u0026rsquo;s automated non-coplanar VMAT technique. Patients will receive a total of 55 Gray in 5 fractions (biological effective dose with alpha/beta of 10: 115.5 Gray) to the PTV. Patients will receive each 11 Gray fraction of radiation every 14 +/-10 days. Treatment will be terminated early in cases of intolerable treatment-related toxicity, altered clinical context, or the patient declines further treatment.\u003c/p\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003eAdaptive Radiation Planning\u003c/h2\u003e \u003cp\u003eIt is possible that patients will experience anatomical and/or tumor changes during the radiation therapy course such that patient alignment for radiation therapy is no longer optimized to the original CT simulation and radiation plan. In such cases where it is determined that adaptive planning is needed, we will abort planned radiation therapy and immediately perform re-simulation and re-planning if the anatomic change is significant enough to put adjacent normal tissue at significant risk; otherwise, we will re-plan with the next fraction of radiation to minimize treatment delays. This will be determined by the treating physician through standard of care clinical criteria and procedures. For patients who undergo re-simulation and re-planning, an extended window of 14\u0026thinsp;+\u0026thinsp;21/-10 days from most recent radiation therapy fraction to receive the next radiation therapy fraction to accommodate re-simulation scheduling and re-planning time. The frequency of re-simulation and adaptive planning as well as associated changes in dosimetry will be measured and documented.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section3\"\u003e \u003ch2\u003ePatient Follow-up\u003c/h2\u003e \u003cp\u003eSymptomatic response will be assessed through subjective patient report and completion of the UW-QoL and FACT-H\u0026amp;N questionnaires (\u003cb\u003eSupplemental Material\u003c/b\u003e). Treatment-related toxicity during and after completion of PULSAR will be measured according to the CTCAE v5.0. Local tumor response will be assessed clinically and/or radiographically (e.g., by CT, PET, MRI), as applicable. Patient follow-up will be measured starting from the time of trial enrollment. Patient clinical assessments during PULSAR will occur within 7 days of each radiation treatment and consist of brief history, physical exam, and assessment of treatment-related toxicity. After receipt of the last PULSAR fraction, patients will be assessed clinically at 1 month +/- 28 days, 3 months +/- 28 days, 6 months +/- 28 days, 12 months +/- 28 days, 18 months +/- 28 days, and 24 months +/- 28 days post-treatment. These follow-up visits will consist of a history and physical exam, completion of the UW-QoL and FACT-H\u0026amp;N questionnaires, and measurement of toxicity. Surveillance imaging will be obtained per standard of care. Patients who experience disease progression will receive standard of care treatment(s) at the discretion of the treating physician. Patient enrollment, treatment, and follow-up is shown in \u003cb\u003eFig.\u0026nbsp;2\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section3\"\u003e \u003ch2\u003eAdverse Experience Reporting and Documentation\u003c/h2\u003e \u003cdiv id=\"Sec28\" class=\"Section4\"\u003e \u003ch2\u003eAdverse Events\u003c/h2\u003e \u003cp\u003eAn adverse event (AE) is any untoward medical occurrence in a clinical investigation of a patient administered a pharmaceutical product and that does not necessarily have a causal relationship with the treatment. An AE is therefore any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the administration of an investigational product, whether or not related to that investigational product. An unexpected AE is one of a type not identified in nature, severity, or frequency in the current Investigator\u0026rsquo;s Brochure or of greater severity or frequency than expected based on the information in the Investigator\u0026rsquo;s Brochure.\u003c/p\u003e \u003cp\u003eThe Investigator will probe, via discussion with the subject, for the occurrence of AEs during each subject visit and record the information in the site\u0026rsquo;s source documents. Adverse events will be recorded in the case report form (CRF). Adverse events will be described by duration (start and stop dates and times), severity, outcome, treatment and relation to study intervention, and the cause.\u003c/p\u003e \u003cp\u003eAll adverse events should be treated appropriately. Such treatment may include changes in study intervention including possible interruption or discontinuation, starting or stopping concomitant treatments, changes in the frequency or nature of assessments, hospitalization, or any other medically required intervention. An assessment should be made at each visit (or more frequently, if necessary) of any changes in its severity, its suspected relationship to the study intervention, any of the interventions required to treat it, and its outcome.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec29\" class=\"Section2\"\u003e \u003ch2\u003eAE Evaluation\u003c/h2\u003e \u003cp\u003eAn investigator who is a qualified physician will evaluate all AEs. At each visit, the investigator will determine whether any AEs have occurred by evaluating the participant. Adverse events may be directly observed (through physical examination, laboratory test, or other assessments), reported spontaneously by the participant or by non-directive questioning of the participant at each study visit. The investigator must assess all AEs to determine:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eThe severity grade according to CTCAE v5.0. If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, life-threatening and death (grades 1\u0026ndash;5, respectively) will be used;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIts relationship to the study intervention (related; probably-related; possibly-related;\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eunlikely-related; not related);\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e Its duration (start and end dates or if continuing at final exam);\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAction taken (none required; intervention not administered; dose reduced; dose delayed/interrupted; intervention discontinued);\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e Treatment of adverse event (none required; medication given; procedure/surgery; other);\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e Whether it constitutes a serious adverse event (SAE); and,\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e Outcome (resolved; resolved with sequelae; persists, death; unknown).\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eThe investigator\u0026rsquo;s assessment must be clearly documented in the study site\u0026rsquo;s source documentation with the investigator\u0026rsquo;s signature.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eAE Severity\u003c/h3\u003e\n\u003cp\u003eThe National Cancer Institute\u0026rsquo;s CTCAE v5.0 should be used to assess and grade AE severity, including laboratory abnormalities judged to be clinically significant. If the AE is not covered in the CTCAE, the guidelines shown in Table\u0026nbsp;1 below should be used to grade severity. It should be pointed out that the term \u0026ldquo;severe\u0026rdquo; is a measure of intensity and that a severe AE is not necessarily serious.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAE Severity Grading\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSeverity (Toxicity Grade)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDescription\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTransient or mild discomfort; no limitation in activity; no medical intervention or therapy required. The subject may be aware of the sign or symptom but tolerates it reasonably well.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMild to moderate limitation in activity, no or minimal medical intervention/therapy required.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMarked limitation in activity, medical intervention/therapy required, hospitalizations possible.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLife-threatening (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThe subject is at risk of death due to the adverse experience as it occurred. This does not refer to an experience that hypothetically might have caused death if it were more severe.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec31\" class=\"Section2\"\u003e \u003ch2\u003eAE Relationship to the Study Intervention\u003c/h2\u003e \u003cp\u003e The relationship of an AE to the study intervention should be assessed by an investigator using the following guidelines in Table\u0026nbsp;2. The causality assessment must be made based on the available information and can be updated as new information becomes available.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAE Relationship to Study Intervention\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelationship\u003c/p\u003e \u003cp\u003eto Intervention\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eComment\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDefinitely\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePreviously known toxicity of the intervention; or an event that follows a reasonable temporal sequence from administration of the intervention; that follows a known or expected response pattern to the suspected intervention; that is confirmed by stopping or reducing the dosage of the intervention; and that is not explained by any other reasonable hypothesis.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProbably\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAn event that follows a reasonable temporal sequence from administration of the intervention; that follows a known or expected response pattern to the suspected intervention; that is confirmed by stopping or reducing the dosage of the intervention; and that is unlikely to be explained by the known characteristics of the subject\u0026rsquo;s clinical state or by other interventions.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePossibly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAn event that follows a reasonable temporal sequence from administration of the intervention; that follows a known or expected response pattern to that suspected intervention; but that could readily have been produced by a number of other factors.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot Related/ Unlikely Related\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAn event that can be determined with certainty to have no relationship to the study intervention.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec32\" class=\"Section2\"\u003e \u003ch2\u003eAE Action Taken Regarding Study Intervention\u003c/h2\u003e \u003cp\u003eWhere necessary the intervention name will be included in the source documenting the event.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eNone required\u003c/b\u003e: No change in study intervention.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eIntervention not administered\u003c/b\u003e: The study intervention was held.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eDose reduced\u003c/b\u003e: The study intervention was modified.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eDose delayed/interrupted\u003c/b\u003e: The study intervention was temporarily stopped.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eIntervention discontinued\u003c/b\u003e: The study intervention was permanently stopped.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cdiv id=\"Sec33\" class=\"Section3\"\u003e \u003ch2\u003eTreatment of the AE\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eNone\u003c/b\u003e: No treatment was required.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eMedication required\u003c/b\u003e: Prescription and/or over-the-counter medication was required to treat the AE.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eProcedure/Surgery\u003c/b\u003e: Medical procedure was required to treat the AE.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eOther\u003c/b\u003e: to be specified in the source documents.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec34\" class=\"Section3\"\u003e \u003ch2\u003eAE Outcome\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eResolved\u003c/b\u003e: The participant fully recovered from the AE with no residual effect observed.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eResolved with Sequelae\u003c/b\u003e: The residual effects of the AE are still present and observable. Include sequelae/residual effects.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003ePersists\u003c/b\u003e: The AE itself is still present and observable.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eDeath\u003c/b\u003e: Death should be used when death is a direct outcome of the AE.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eUnknown\u003c/b\u003e: Information unavailable\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eSerious Adverse Event (SAE)\u003c/h3\u003e\n\u003cp\u003eAn SAE is any untoward medical occurrence that at any dose:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eResults in death,\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIs life-threatening, that is, places the participant at immediate risk of death from the event as it occurred. This definition does not include a reaction that, had it occurred in a more severe form, might have caused death;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eRequires inpatient hospitalization or prolongation of existing hospitalization, unless hospitalization is for:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eRoutine treatment or monitoring of the studied indication, not associated with any deterioration in condition;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eElective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under study and has not worsened since signing the informed consent;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eSocial reasons and respite care in the absence of any deterioration in the participant\u0026rsquo;s general condition;\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eResults in persistent or significant disability/incapacity;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIs a congenital anomaly/birth defect; or\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIs an important medical event.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eMedical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require intervention to prevent one of the other outcomes listed in the definition above. Examples include allergic bronchospasm, convulsions, and blood dyscrasias or development of drug dependency or drug abuse.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eNote\u003c/strong\u003e \u003cp\u003e\u0026bull; Procedures are not AEs or SAEs, but the reason for the procedure may be an AE or SAE.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003ePre-planned (prior to signing the informed consent form [ICF]) procedures or treatments requiring hospitalizations for pre-existing conditions that do not worsen in severity are not SAEs.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eFor events that are serious due to hospitalization, the reason for hospitalization must be reported as the SAE (diagnosis or symptom requiring hospitalization). For deaths, the underlying or immediate cause of death should always be reported as an SAE. Any serious, untoward event that may occur subsequent to the reporting period that the investigator assesses as related to study intervention should also be reported and managed as an SAE. Unlike routine safety assessments, SAEs are monitored continuously and have special reporting requirements. All serious or intervention-related AEs ongoing at the end of treatment visit will be followed until resolution or until the condition is considered chronic/stable by the investigator.\u003c/p\u003e\n\u003ch3\u003eAE and SAE Reporting\u003c/h3\u003e\n\u003cp\u003eAll AEs and SAEs that occur between study enrollment and 6 months after completion of the intervention, will be reported in the eCRF and all SAEs will be reported in the Clinical Research Management System (CRMS) (OnCore). After 6 months after completion of the intervention, only AEs and SAEs suspected to be related to the intervention will be reported.\u003c/p\u003e \u003cp\u003eAll events (serious and non-serious) must be reported with investigator\u0026rsquo;s assessment of the event\u0026rsquo;s seriousness, severity, and causality to the study intervention. A detailed narrative summarizing the course of the event, including its evaluation, treatment, and outcome should be provided. Specific or estimated dates of event onset, treatment, and resolution should be included when available. Medical history, concomitant medications, and laboratory data that are relevant to the event should also be summarized in the narrative. For fatal events, the narrative should state whether an autopsy was or will be performed, and include the results if available. Source documents (including medical reports) will be retained at the study site and should not be submitted to the Sponsor for SAE reporting purposes.\u003c/p\u003e \u003cp\u003eDisease progression/worsening of disease will not be recorded as an AE on the Adverse Event eCRF. However, events associated with disease progression may be recorded as AEs. Death due to disease progression should be recorded on the Death eCRF.\u003c/p\u003e \u003cp\u003eThe study teams must report all SAEs to the JCCC DSMB in a timely manner. Regardless of relationship and expectedness of the event to the study intervention, the PI or their delegate must report the SAE within 10 business days of awareness. In the event of a participant death, the PI or their delegate must report the event within 2 business days of awareness. The SAE submission must note the date of awareness in the event narrative.\u003c/p\u003e \u003cp\u003eTo report the SAEs to the JCCC DSMB, the study team enters the SAE information into OnCore, the CRMS. The CRMS generates and sends notifications regarding the submission to the JCCC DSMB administrative team and the study team. Study teams without access to OnCore, may complete the SAE submission form manually and submit it to the JCCC DSMB administrative staff, who will enter the SAE into OnCore on their behalf. The CRMS generates reports for full JCCC DSMB review.\u003c/p\u003e \u003cp\u003eThe PI is also responsible for reporting any serious adverse event (SAE) to the sponsor, and any appropriate agency, according to the agency requirements. These include, but are not limited to: UCLA IRB; FDA; and NCI, if it is an NCI sponsored trial.\u003c/p\u003e \u003cp\u003eThe collection period for all SAEs will begin after informed consent is obtained and end after procedures for the final study visit have been completed. Any SAEs experienced after this period should only be reported to the Sponsor if the investigator suspects a causal relationship to the study intervention.\u003c/p\u003e \u003cp\u003e In accordance with the standard operating procedures and policies of the local Institutional Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report SAEs to the IRB/IEC when applicable.\u003c/p\u003e \u003cdiv id=\"Sec37\" class=\"Section2\"\u003e \u003ch2\u003eDSMB Review of AEs and SAEs\u003c/h2\u003e \u003cp\u003e The JCCC DSMB reviews all AEs as part of the summary report review performed quarterly, semi-annually or annually based on the risk level assigned to the study and in accordance with the JCCC Data and Safety Monitoring Plan. The DSMB reviews each SAE monthly and determines if the event(s) warrants modifications to the protocol to ensure subject safety. In their review, the DMSB considers prior occurrences of similar toxicity with the intervention under study, as well as the severity of the event and the likelihood of relation to the study intervention or investigational product. The DSMB may recommend no changes to the study if the event is expected or related to other causes such as underlying disease. To assist discussions and decisions, the DSMB may request the expert advice of another clinical researcher with national experience.\u003c/p\u003e \u003cdiv id=\"Sec38\" class=\"Section3\"\u003e \u003ch2\u003eData Safety, Collection, Retention, and Monitoring\u003c/h2\u003e \u003c/div\u003e \u003cdiv id=\"Sec39\" class=\"Section3\"\u003e \u003ch2\u003eMonitoring\u003c/h2\u003e \u003cp\u003eThe JCCC Office of Regulatory Compliance (ORC) will perform monitoring and auditing activities in accordance with the JCCC Data and Safety Monitoring Plan (DSMP).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec40\" class=\"Section3\"\u003e \u003ch2\u003eData Safety Monitoring\u003c/h2\u003e \u003cp\u003eThe JCCC DSMB will serve as the DSMB to review data relating to safety and efficacy, to conduct and review interim analyses, and to ensure the continued scientific validity and merit of the study, according to the JCCC DSMP. There will be quarterly, semi-annually or annual interim review(s) conducted by the DSMB based on the risk level assigned to the study for the purpose of monitoring study conduct and assessing participant safety. Risk level 1 studies are the highest risk and are reviewed quarterly; Risk Level 2 studies are intermediate risk and are reviewed semi-annually; Risk Level 3 studies are the lowest risk and are reviewed annually. Further details regarding the timing and content of the interim reviews via summary reports are included in the JCCC DSMP.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eData Management\u003c/span\u003e \u003c/p\u003e \u003cp\u003eThe radiation oncology research staff will be responsible for the database records of study patients. The data will be kept on the research staff computer, under password protection, with the patient information de-identified (study patients will be referred by their coded study number). A chart with all the relevant research patient information will be maintained for each patient by the research coordinator and will be filed in a locked cabinet. Only the research team (study staff, investigators, and project supporting staff) will have the password and key to the data from the study patients.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eConfidentiality\u003c/span\u003e \u003c/p\u003e \u003cp\u003eStudy data will be maintained in password protected computer files. Only research personnel will have access to this information. All identifiers will be removed. The patient\u0026rsquo;s name or other public identifiers will not be included in any information shared with other investigators. The master key that will identify specific study patients to their coded study number will be kept in a separate password protected file on the research staff computer. Only the study staff and the principal investigator will know the password to this file.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eStatistical Methods and Considerations\u003c/span\u003e \u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eGeneral\u003c/span\u003e \u003c/p\u003e \u003cp\u003eAll analyses will be descriptive and will be presented by treatment period and overall as appropriate. Data collected in this study will be presented using summary tables and patient data listings. Continuous variables will be summarized using descriptive statistics, specifically the mean, median, standard deviation, minimum, and maximum. Categorical variables will be summarized by frequencies and percentages.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eSafety Lead-In/Interim Analysis\u003c/span\u003e \u003c/p\u003e \u003cp\u003eThe study includes a safety lead-in portion, with formal evaluation on enrollment of the 15th subject. The trial will be stopped if 5 or more patients in the safety lead-in portion experience a serious adverse event, defined as a CTCAE v5.0 grade 3 or higher definitely attributable to the intervention during or within 30 days after completion of PULSAR.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eSample Size Determination\u003c/span\u003e \u003c/p\u003e \u003cp\u003eProspective data of SBRT for unresectable head and neck cancer has demonstrated 1 year local control rates of 60% in the re-irradiation setting\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. In the de novo setting, prospective data are limited and primarily consist of SBRT for early-stage glottis cancer, though in small, retrospective series predominantly for palliative purposes and/or for patients who are not candidates for standard of care definitive therapy, the reported 1 year local control rates range from 69\u0026ndash;87%\u003csup\u003e21\u003c/sup\u003e. However, in the palliative setting or patients unfit for definitive therapy, a variety of other radiation regimens are often used, such as the \u0026ldquo;Quad-Shot\u0026rdquo; regimen, which generally have lower and/or less durable local control rates\u003csup\u003e\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. From these data, we estimate the historic control group 1 year local control rate to be 65%.\u003c/p\u003e \u003cp\u003eFor the study group, unpublished analysis of a recently closed phase II trial at UCLA of dose-escalated SBRT to 55 Gray for treatment of previously radiated, recurrent head and neck cancer demonstrated a 1 year local control rate of 85% (NCT 03892720). We therefore hypothesize that patients enrolled in this trial will have a similar 1 year local control rate. A sample size of 38 patients will achieve 80% power to detect a 20% difference in the 1 year local control rate between PULSAR (85%) and historic control (65%), using a two-sided one-sample exact binomial test, at 0.05 significance level. Considering that some patients may become ineligible/drop out after enrollment, the target sample size is determined to be at least 43 patients. The 15 patients in the safety lead-in portion will be included in the sample should the study proceed past this portion.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003ePatient Accrual and Study Duration\u003c/span\u003e \u003c/p\u003e \u003cp\u003eWe used an institutional database of patients with HNC and departmental treatment records to retrospectively approximate the number of patients that would have been eligible for this trial. Taking into account errors in electronic medical record documentation and coding\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, we estimate that approximately 120\u0026ndash;170 eligible patients were seen in our department over the past five years, roughly equating to two to three eligible patients monthly. These numbers are in line with or even slightly lower than what we have seen clinically recently, particularly as the COVID pandemic has subsided and more patients are being seen in our department. Additionally, our department\u0026rsquo;s recently closed phase II study of definitive HyperArc SBRT in patients with recurrent, previously radiated HNC enrolled and treated the first fifteen patients in one year\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. The patient population in this recently closed phase II trial is much narrower than that in the proposed study, so we anticipate similar if not faster enrollment with this proposed study compared with the recently closed phase II trial. As such, we anticipate enrollment of two to four patients monthly and that it will take approximately 1 year to complete the safety lead-in portion and 4 years to complete the study. Study-related data will be stored after completion of the clinical portion of the study to be used in the exploratory portion of the study, as needed.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003ePopulations for Analyses\u003c/span\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eFull Analysis Set (FAS)\u003c/h3\u003e\n\u003cp\u003eAll efficacy analyses will be performed on the Full Analysis Set (FAS) following the Intent-To-Treat (ITT) principle. Patients who were enrolled but did not receive study treatment are included in the FAS population.\u003c/p\u003e\n\u003ch3\u003eEvaluable Analysis Set (EAS)\u003c/h3\u003e\n\u003cp\u003eA subset of the full analysis set (FAS), the evaluable analysis set is defined as those treated patients who are evaluable (i.e. compliant with treatment and without any major protocol deviations that may impact primary efficacy analysis). The EAS will be used for supportive analyses of the efficacy endpoints.\u003c/p\u003e\n\u003ch3\u003eSafety Analysis Set (SAS)\u003c/h3\u003e\n\u003cp\u003eAll patients who received at least 1 fraction of radiation and for whom any valid post-baseline safety data are available will be included in the safety analysis set. When assessing safety and tolerability, summaries will be produced based on the safety analysis set. Patients are analyzed according to the actual treatment received.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eStudy Endpoints\u003c/span\u003e \u003c/p\u003e\n\u003ch3\u003ePrimary Endpoint\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint is local control rate of the treated tumor target at 1 year, as measured from the date of enrollment. Local control will be evaluated by radiographic and/or clinical assessment as applicable. Participants who experience death or are lost to follow-up prior to 1 year will be assessed by their last radiographic/clinical evaluation.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSecondary Endpoints\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eMeasurement of grade 3 or higher treatment-related toxicity during or within 24 months after completion of PULSAR, according to the CTCAE v5.0.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eDisease progression free survival (PFS), defined as the time from enrollment to the first objectively documented disease progression, either in or out of the treated field per radiographic and/or clinical evaluation, or death due to any cause. Participants who experience death or are lost to follow-up prior to 1 year will be assessed by their last radiographic/clinical evaluation.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eOverall survival (OS), defined as the time between enrollment and death of any cause. Participants who are lost to follow-up prior to 1 year will be censored at the date of their last documentation in the medical record system.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eImpact of PULSAR on symptoms/quality of life as measured by the UW-QoL and FACT-H\u0026amp;N validated questionnaires.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eMeasurement of the frequency of re-simulation and/or adaptive planning required with PULSAR.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eEvaluation of the standard of care tumor and OAR dosimetry with PULSAR.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eEvaluation of the safety and efficacy of combination PULSAR and immunotherapy in enrolled patients receiving immunotherapy will be descriptive and exploratory.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eStatistical Analysis Plan\u003c/span\u003e \u003c/p\u003e\n\u003ch3\u003eDemographics and Baseline Characteristics\u003c/h3\u003e\n\u003cp\u003eDemographic data, medical history, other baseline characteristics, and concomitant disease will be summarized. To determine whether the criteria for study conduct are met, corresponding tables and listings will be provided. These will include an assessment of protocol deviations, study treatment accountability, and other data that may impact the general conduct of the study. The analysis sets FAS, EAS, SAS will be used.\u003c/p\u003e \u003cp\u003e \u003cb\u003eEfficacy Analyses\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePrimary endpoint: Primary endpoint analyses will be performed on patients included in analysis sets FAS and EAS across the whole cohort, as well as separate analyses stratifying patients by Human Papillomavirus/p16 status. For the primary endpoint, we will calculate the percentage and construct 95% exact confidence interval for local control rate. Additionally, Kaplan-Meier method and cumulative incidence functions considering distant progression or death as a competing risk will be used to provide estimates of the local control at 1-year, median local control, and cumulative incidence of local control at 1-year, with corresponding 95% confidence intervals.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSecondary Endpoints: Secondary endpoint analyses will be performed on patients included in analysis sets FAS and EAS across the whole cohort, as well as separate analyses stratifying patients by Human Papillomavirus/p16 status. For the secondary endpoints of PFS and OS, Kaplan-Meier method and cumulative incidence curves treating death as a competing risk will be used to provide estimates of the PFS/OS at 1-year, median PFS/OS, and cumulative incidence of PFS/OS at 1-year. Corresponding 95% confidence intervals will also be presented.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eSafety Analyses\u003c/span\u003e \u003c/p\u003e \u003cp\u003eSafety analyses will be performed for patients included in analysis set SAS. Percentage of patients with acute or chronic grade 3 or higher treatment-related toxicity, incidence of AEs, clinical laboratory information, vital signs, ECOG performance status, and weight, will be tabulated and summarized. Incidence of AEs will be summarized overall and with separate summaries for SAEs, AEs leading to discontinuation, AEs leading to death, etc. The overall safety and tolerability will be assessed throughout the study period. All AE data will be listed individually by patient identifier.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eSymptom/Quality of Life Analyses\u003c/span\u003e \u003c/p\u003e \u003cp\u003eAnalysis of data related to the symptom/quality of life impact of PULSAR using the UW-QoL and FACT-H\u0026amp;N validated questionnaires will be primarily descriptive and exploratory.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eDescriptive/Exploratory Analyses\u003c/span\u003e \u003c/p\u003e \u003cp\u003eAnalysis of data related to the frequency of re-simulation and/or adaptive planning required with PULSAR; standard of care tumor and OAR dosimetry with PULSAR; and the safety and efficacy of combination PULSAR and immunotherapy in enrolled patients receiving immunotherapy will be descriptive and exploratory.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldItalicUnderline\" class=\"BoldItalicUnderline\" name=\"Emphasis\"\u003eDissemination Policies\u003c/span\u003e \u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eProtocol Modifications\u003c/span\u003e \u003c/p\u003e \u003cp\u003eImportant protocol modifications will be communicated to relevant parties including investigators, the UCLA IRB, trial participants, journal, and regulators by standard methods of communications.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eTrial Results\u003c/span\u003e \u003c/p\u003e \u003cp\u003eThe investigators will communicate trial results to participants, healthcare professionals, the public, and other relevant groups via publication.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eData\u003c/span\u003e \u003c/p\u003e \u003cp\u003ePublic access to the full protocol and statistical code will be granted.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study has significance across a wide-range of clinical situations. In regards to the enrolled patient population, there is a need for more optimal palliative treatments, especially as longevity is improved from advances in other treatment modalities, particularly systemic therapy. As such, if the safety and efficacy of PULSAR is confirmed, it may supplant existing palliative radiation therapy regimens for HNC and become more common in clinical practice. Furthermore, there are limited prospective clinical data evaluating the PULSAR regimen, and this study will provide guidance on the logistics, workflow, safety, and efficacy of PULSAR with HyperArc technology so that it may be studied and utilized further in HNC and/or in other cancer sites. Similarly, given the interest in the combination of PULSAR and immunotherapy, this study could provide early, hypothesis generating data on this combination treatment, laying the groundwork for future studies. Ultimately, we anticipate that this study will provide important, early data on this promising new radiotherapy paradigm.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAAPM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAmerican Association of Physicists in Medicine\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAdverse Event\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAJCC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAmerican Joint Committee on Cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCRF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCase Report Form\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCRMS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eClinical Research Management System\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eComputed Tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCTCAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCommon Terminology Criteria for Adverse Events\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCTV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eClinical Target Volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDSMB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eData Safety and Monitoring Board\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDSMP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eData Safety and Monitoring Plan\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEAS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEvaluable Analysis Set\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eECOG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEastern Cooperative Oncology Group\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFACT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eH\u0026amp;N\u0026ndash;Functional Assessment of Cancer Therapy Head and Neck\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFAS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFull Analysis Set\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInformed Consent Form\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eITT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntent\u0026ndash;to\u0026ndash;Treat\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGFR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGlomerular Filtration Rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGTV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGross Tumor Volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIEC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIndependent Ethics Committee\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIMRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntensity Modulated Radiation Therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIRB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInstitutional Review Board\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eJCCC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eJonsson Comprehensive Cancer Center\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMagnetic Resonance Imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHIPAA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHealth Insurance Portability and Accountability Act\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMegavoltage\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOAR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOrgan\u0026ndash;at\u0026ndash;Risk\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eORC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOffice of Regulatory Compliance\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePET\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePositron Emission Tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePrincipal Investigator\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePTV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePlanning Target Volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePULSAR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePersonalized Ultrafractionated Stereotactic Adaptive Radiothearpy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSerious Adverse Event\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSAS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSafety Analysis Set\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSBRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStereotactic Body Radiotherapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHNC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHead and Neck Cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSPIRIT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStandard Protocol Items: Recommendations for Interventional Trials\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePFS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eProgression\u0026ndash;Free Survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOverall Survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUCLA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eUniversity of California, Los Angeles\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUW\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eQoL\u0026ndash;University of Washington Quality of Life\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVMAT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eVolumetric Modulated Arc Therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWOCBP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWomen of Child Bearing Potential\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate:\u0026nbsp;\u003c/strong\u003eThis study is approved by the Institutional Review Board (IRB) of the University of California, Los Angeles (UCLA IRB #24-000663), and is registered at the U.S. National Institutes of Health (clinicaltrials.gov) # NCT06572423. The current protocol is version 1.5.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication:\u0026nbsp;\u003c/strong\u003eThis manuscript does not include details, images, or videos relating to an individual person.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials:\u0026nbsp;\u003c/strong\u003eAll data generated or analyzed during this study are included in this published article [and its supplementary information files].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e: Dr. Ricky Savjani reports research grant support from BrainLab, Varian Medical Systems, and StratPharma, all unrelated to the submitted work. Dr. Minsong Cao reports personal fees from Varian Medical Systems unrelated to the submitted work. There are no other competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: This is an investigator initiated trial funded by Varian Medical Systems, Inc. The funder had no role in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication, including whether they will have ultimate authority over any of these activities.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; Contributions\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eStudy Conception: PTC and RKC\u003c/p\u003e\n\u003cp\u003eInitial Study Design: PTC and RKC\u003c/p\u003e\n\u003cp\u003eRevising of Study Design and Protocol: PTC, MS, RRS, VR, CP, TVB, DOC, DT, RKC\u003c/p\u003e\n\u003cp\u003eStudy Coordination and Acquisition of Data: PTC, MS, CP\u003c/p\u003e\n\u003cp\u003eDrafting of Manuscript: TC and RKC\u003c/p\u003e\n\u003cp\u003eSubstantial Revising of Manuscript: PTC, MS, RRS, VR, CP, TVB, DOC, DT, RKC\u003c/p\u003e\n\u003cp\u003eAll authors have reviewed and approve of the materials contained herein.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: We would like to acknowledge the patients who will enroll on this study to further the cause of medical science.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBishnoi R, Bennett J, Reisman DN. Palliative treatment of patients with inoperable locally advanced, recurrent or metastatic head and neck squamous cell cancer, using a low-dose and personalized chemotherapeutic regimen. Oncol Lett. 2017;13(6):4633\u0026ndash;40. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3892/ol.2017.6068\u003c/span\u003e\u003cspan address=\"10.3892/ol.2017.6068\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoland NJ, Bradley PJ. The role of surgery in the palliation of head and neck cancer. 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Usability Considerations in Oncology Electronic Medical Records. J Oncol Pract. 2017;13(8):539\u0026ndash;41. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JOP.2017.024745\u003c/span\u003e\u003cspan address=\"10.1200/JOP.2017.024745\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhela H, Khalil J, Daxon N, et al. Real world challenges in maintaining data integrity in electronic health records in a cancer program. Tech Innov Patient Support Radiat Oncol. 2024;29:100233. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.tipsro.2023.100233\u003c/span\u003e\u003cspan address=\"10.1016/j.tipsro.2023.100233\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"head and neck cancer, stereotactic body radiotherapy (SBRT), personalized ultrafractionated stereotactic adaptive radiotherapy (PULSAR), palliative radiotherapy","lastPublishedDoi":"10.21203/rs.3.rs-4988211/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4988211/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eMany patients with head and neck cancer will not be candidates for standard of care definitive treatments though often require palliative treatments given the frequent symptoms associated with head and neck cancer. While existing palliative radiotherapy regimens can provide adequate symptom control, they have limitations particularly with respect to local control which is becoming more important as advances in systemic therapy are improving survival. Personalized ultrafractionated stereotactic adaptive radiotherapy (PULSAR) is a novel radiotherapy regimen which leverages advances in radiotherapy treatment technology and extended interfraction intervals to enable adaptive radiotherapy and possible synergy with the immune system. Additionally, HyperArc© (Varian Medical Systems, Inc.) radiotherapy planning software allows for safe dose-escalation to head and neck tumors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis single-arm phase II study will prospectively evaluate PULSAR with HyperArc software for palliative treatment of head and neck cancer. Patients with \u003cem\u003ede novo \u003c/em\u003eor recurrent, localized or metastatic, head and neck cancer who are ineligible for or decline standard of care definitive treatments are eligible for enrollment. Forty-three patients will receive an 11 Gray fraction of radiation every two weeks for a total of five fractions and dose of 55 Gy. Adaptive radiotherapy planning is permitted. A safety and feasibility evaluation will be performed after enrollment of the first fifteen patients whereby the trial will continue if less than five patients experience a CTCAEv5.0 grade 3 or higher toxicity definitely attributable to PULSAR during or within thirty days after its completion. The primary endpoint is one-year local head and neck tumor control. Secondary endpoints include safety, disease progression-free and overall survival, symptomatic impact, frequency of re-simulation and/or adaptive planning, and radiation dosimetry of PULSAR. Additionally, enrolled patients are permitted to receive immunotherapy during PULSAR, which may allow for the analysis of the safety and efficacy of this combination.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion: \u003c/strong\u003eThe PULS-Pal trial is the first prospective study of PULSAR with HyperArc software for head and neck cancer. We hypothesize that this radiotherapy regimen will lead to improved local tumor control compared with historical controls in patients undergoing palliative radiotherapy for head and neck cancer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Registration: \u003c/strong\u003eClinicaltrials.gov identifier: NCT06572423. Date of registration: August 28\u003csup\u003eth\u003c/sup\u003e, 2024. https://clinicaltrials.gov/study/NCT06572423.\u003c/p\u003e","manuscriptTitle":"A phase II study of personalized ultrafractionated stereotactic adaptive radiotherapy for palliative head and neck cancer treatment (PULS-Pal): a single-arm clinical trial protocol","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-17 09:23:09","doi":"10.21203/rs.3.rs-4988211/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-12-03T11:22:27+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-03T09:03:10+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-02T02:08:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"322930695807204270736063539222098918051","date":"2024-11-24T16:09:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"37371457630398134531134908448701293482","date":"2024-11-22T17:52:50+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-06T11:21:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-29T01:06:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-29T01:05:53+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2024-08-28T05:10:43+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"89c79363-c7e9-4e97-804a-3abe529b02a9","owner":[],"postedDate":"October 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-23T15:59:39+00:00","versionOfRecord":{"articleIdentity":"rs-4988211","link":"https://doi.org/10.1186/s12885-024-13303-5","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2024-12-21 15:57:03","publishedOnDateReadable":"December 21st, 2024"},"versionCreatedAt":"2024-10-17 09:23:09","video":"","vorDoi":"10.1186/s12885-024-13303-5","vorDoiUrl":"https://doi.org/10.1186/s12885-024-13303-5","workflowStages":[]},"version":"v1","identity":"rs-4988211","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4988211","identity":"rs-4988211","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}