-QUAD SHOT Palliative Radiotherapy – From Current Evidence to Future Perspectives

1. Introduction

Palliative radiotherapy has served as an effective treatment modality for approximately a century, addressing symptoms in patients with metastatic or advanced cancers. While no standardized protocol exists, short treatment courses are generally preferred for frail patients with significant symptoms, maximizing comfort for both patients and families. Recent advances in imaging, systemic therapies, and radiation delivery techniques including intensity-modulated radiotherapy (IMRT) and stereotactic approaches have expanded the role of palliative radiotherapy to include asymptomatic patients seeking improved long-term disease control, where longer fractionation schedules are typically employed.

Although prolonged fractionation was historically thought to enhance response duration, the RTOG 97-14 trial demonstrated equivalent efficacy between single 8 Gy fractions and 30 Gy delivered in 10 daily fractions, with complete or partial responses achieved in 66% of patients with bone metastases. Similarly, Arnalot and colleagues found no statistically significant differences in pain control at multiple time points (3, 12, 24, and 48 weeks) when comparing these regimens, with overall response rates of 75% versus 86% respectively [3,4].

The Trans-Tasman Radiation Oncology Group study of 270 patients with neuropathic pain from bone metastases compared single 8 Gy fractions to 20 Gy in 5 fractions. With median overall survival of 4.8 months, results favored the multi-fraction approach, showing overall response rates of 53% versus 63%, though complete response rates differed by only 1%.

Beyond these commonly used regimens, various alternative schedules have gained acceptance across different clinical scenarios. These include twice-weekly 8 Gy fractions for spinal cord compression (total 16 Gy), weekly 8.5 Gy fractions (total 17 Gy), and single 10 Gy fractions for gynecologic malignancies, which reduced vaginal bleeding in 90% of patients and achieved 22% complete tumor responses. For head and neck squamous cell carcinoma (HNSCC) unsuitable for curative treatment, the Christie regimen (50 Gy in 16 fractions of 3.125 Gy) has demonstrated favorable responses with acceptable toxicity in patients surviving beyond one year [5-8].

2. Aim of This Review

This review aims to comprehensively evaluate current evidence on the QUAD SHOT palliative radiotherapy regimen for advanced and metastatic malignancies, including its clinical efficacy, toxicity profile, application in elderly and frail populations, integration with modern radiation techniques, and emerging role in combination with immunotherapy. We critically assess the quality of existing evidence and identify areas requiring further investigation.

3. Methods

This narrative review was conducted in accordance with the SANRA (Scale for the Assessment of Narrative Review Articles) guidance for transparent reporting of narrative reviews.

Databases and timeframe:

We searched MEDLINE (via PubMed), Scopus, and the Cochrane Library for English-language articles published between January 2000 and February 2025. The ClinicalTrials.gov registry was additionally screened to identify ongoing or completed prospective trials. The reference lists of all included articles were hand-searched to identify further relevant studies (snowballing).

Search terms:

The primary search combined the terms (“QUAD SHOT” OR “quad-shot” OR “RTOG 8502” OR “RTOG 85-02”) AND (“radiotherapy” OR “palliative”). Secondary searches combined these with “IMRT,” “VMAT,” “proton,” “hypofractionation,” “geriatric,” “elderly,” “re-irradiation,” “immunotherapy,” “immune checkpoint inhibitor,” “PD-1,” “PD-L1,” and “CTLA-4” using the Boolean operators AND/OR.

Selection criteria:

Studies were eligible if they reported clinical outcomes (response, survival, symptom control, or toxicity) of a QUAD SHOT or QUAD SHOT-type regimen (approximately 14–14.8 Gy in four twice-daily fractions over two consecutive days, or close variants) in adult patients treated with palliative or re-irradiation intent. Prospective trials, retrospective cohorts, case series, and instructive case reports were all considered, given the limited evidence base. Articles were excluded if they were non-English, did not report extractable clinical outcomes, addressed unrelated fractionation schedules, or were available only as conference abstracts without sufficient methodological detail. Two reviewers screened titles and abstracts independently, and discrepancies were resolved by consensus. Because of the small number and methodological heterogeneity of eligible studies, a formal meta-analysis was not feasible; results are therefore synthesized narratively and summarized in Table 1.

Table 1. Summary of key studies of the QUAD SHOT regimen: study design, population, regimen, response/symptom control, survival or local control, and toxicity.

4. Historical Development and Initial Clinical Experience:

The Original QUAD SHOT Regimen:

The QUAD SHOT regimen was first formally described by Corry et al. in a phase II study (RTOG 8502) evaluating patients with incurable head and neck cancers unsuitable for definitive treatment due to locally advanced disease, recurrent tumors, metastatic spread, poor performance status, or prior therapy precluding further curative approaches. The protocol delivered a total dose of 14 Gy in four fractions administered twice daily with a minimum 6-hour interfraction interval over two consecutive days. In the absence of tumor progression, up to three treatment cycles could be administered at 4-week intervals.

Among 30 enrolled patients, 16 (53%) completed all three treatment cycles, with clinically meaningful palliative benefit observed in 11 (44%) cases. Quality of life was assessed using the EORTC QLQ-C30 questionnaire, demonstrating symptom improvement with minimal acute toxicity. Median overall survival was 5.7 months, with median progression-free survival of 3.1 months. This foundational study established QUAD SHOT as a feasible palliative approach characterized by good tolerability and rapid symptom relief [9].

Early Single-Institution Experiences:

A single-center study from India evaluated a modified QUAD SHOT regimen using 3.7 Gy per fraction, maintaining the twice-daily schedule over two consecutive days with 4-week intervals between cycles. The biological equivalent dose (BED) per cycle was calculated as 18.9 Gy (α/β=10 Gy) for tumor tissue and 30.38 Gy (α/β=3 Gy) for late-responding normal tissues. Over half of patients proceeded to a second treatment cycle. At 6-week follow-up, 66.67% demonstrated partial response, with median time to progression of 12 weeks. All reported toxicities (mucositis and dermatitis) were grade 2 or lower. The authors noted reductions in anxiety and analgesic requirements, though taste dysfunction occurred in 7 of 15 patients [10].

Population-Level Analysis:

Lorenz et al. queried the National Cancer Database (NCDB) for patients treated with 3.3–3.9 Gy per fraction delivered over 12-16 fractions, identifying 162 patients who received QUAD SHOT-type regimens. This represented approximately 7% of palliative treatments for both metastatic and locally advanced incurable cases. Median survival was 3.5 months, with 14% of patients alive at 1 year. Treatment completion rates were modest: 54% completed the first cycle, and only 28% completed all three cycles. Notably, the number of completed cycles correlated with overall survival. The authors observed an increasing trend in QUAD SHOT utilization between 2012 and 2014, suggesting growing recognition of this approach [11].

5. Clinical Efficacy Across Disease Sites:

Head and Neck Malignancies:

Head and neck cancers represent the most extensively studied indication for QUAD SHOT. Lok et al. retrospectively reviewed their institutional experience with the RTOG 8502 regimen, evaluating palliation (defined as symptom improvement and clinical/radiographic response) and toxicity per CTCAE v3.0 criteria. The cohort included patients aged 23-97 years (median 76 years), with over half presenting T4 tumors. Approximately 48% had undergone prior resection, 36% had received previous radiotherapy (median dose 68 Gy, range 30-70 Gy), and 61% had prior chemotherapy exposure. Common presenting symptoms included pain, bleeding, and dysphagia/odynophagia.

Palliative response was achieved in 75% of patients, with 36% completing all three cycles. Median overall survival was 6.27 months. Grade 3 toxicities (dermatitis and mucositis) occurred in only 5% of patients. Prior locoregional treatment and the number of completed QUAD SHOT cycles both correlated with palliative benefit, supporting the regimen’s effectiveness in both previously treated and treatment-naïve patients with advanced head and neck cancers [13, 16].

A randomized comparison evaluated 50 patients with Stage IVB and IVC disease, comparing QUAD SHOT (14 Gy in 4 fractions over 2 days) against conventional palliation (30 Gy in 10 daily fractions over 2 weeks). Response rates appeared similar between arms for pain (60.86% vs 57.17%), dysphagia (60.86% vs 52.17%), and hoarseness (43.85% vs 38.09%). Overall response rates exceeded 70% in both groups, with no grade 3 or higher toxicities reported in the QUAD SHOT arm. While these results suggest comparable efficacy with reduced treatment time, formal statistical testing of between-group differences was not explicitly reported [14].

Non-Melanoma Skin Cancer:

The application of volumetric modulated arc therapy (VMAT) for delivering QUAD SHOT to unresectable non-melanoma skin cancers of the head and neck demonstrated a 44% incidence of grade 2 acute toxicities, with no grade 3 or higher adverse events reported. This experience highlights the feasibility of using modern delivery techniques for complex anatomical sites while maintaining the favorable toxicity profile characteristic of this regimen [12].

Breast Cancer:

Limited but promising data exist for therapeutically neglected breast cancer. Kil et al. reported two cases of ulcerative, fungating breast tumors causing pain, bleeding, infection, and malodor treated with IMRT-delivered QUAD SHOT. Both patients experienced meaningful symptom improvement, with pain reduction from severe to mild and achievement of wound closure. These cases demonstrate potential utility in managing locally advanced breast cancer where systemic therapy alone provides insufficient local control [18].

Sarcomas:

Lee et al. presented experience with proton beam QUAD SHOT for recurrent and metastatic sarcomas in 28 patients, predominantly leiomyosarcomas and gastrointestinal stromal tumors (GISTs) with peritoneal and pelvic locations. The authors demonstrated that four QUAD SHOT cycles delivered via proton therapy could improve locoregional control. Though three cases of grade 3 toxicity occurred, the study established feasibility of extended treatment courses using proton delivery [19-20].

For previously irradiated head and neck cancers, QUAD SHOT using 3.7 Gy per fraction achieved 73% palliative response rates. Notably, despite 88% of patients having received prior radiotherapy, only grade 1 toxicity was observed in 58% of cases, with no grade 3-5 toxicities reported. This experience supports QUAD SHOT as a viable re-irradiation strategy with acceptable toxicity [19-20].

6. Modern Radiation Delivery Techniques:

IMRT and VMAT Applications:

The integration of intensity-modulated techniques has expanded QUAD SHOT applications by improving conformality and reducing normal tissue exposure. Toya et al. treated 34 patients with head and neck cancers using at least one cycle of RTOG 85-02 delivered via VMAT. The regimen employed 14.8 Gy per cycle in 4 fractions, with up to three cycles at 3–4 week intervals without concurrent chemotherapy. Favorable response was observed in 94% of patients overall, increasing to 100% among those receiving two cycles. Completion of all three cycles correlated with superior overall survival. Grade 2 toxicities occurred in 12% of patients, with no grade 3 or higher acute toxicity. These results demonstrate that modern delivery techniques can maintain or potentially improve the therapeutic ratio of QUAD SHOT compared to conventional delivery [17].

An 85-year-old patient with parotid squamous cell carcinoma and multiple comorbidities received IMRT-delivered QUAD SHOT for left facial pain palliation, completing three cycles at 4-week intervals. At 12-month follow-up, pain was completely controlled, with favorable late toxicity profile and delayed disease recurrence. This case exemplifies how IMRT can enable safe palliative treatment in elderly patients with significant comorbidities [15].

Proton Beam Therapy:

Proton therapy offers theoretical advantages for QUAD SHOT delivery through superior dose conformality and reduced integral dose to surrounding tissues. Ma et al. evaluated proton radiotherapy for recurrent or metastatic head and neck cancers, demonstrating feasibility of this approach and the potential for administering four treatment cycles rather than the standard three. While three cases experienced grade 3 toxicity, the overall toxicity profile remained acceptable, and the ability to deliver additional cycles may offer enhanced disease control in selected patients. The experience with proton QUAD SHOT for sarcomas further supports the utility of this modality for deep-seated tumors where conventional photon therapy would expose large volumes of normal tissue. These preliminary experiences suggest proton therapy may enable dose escalation or treatment intensification while maintaining acceptable toxicity, though comparative studies are needed to definitively establish clinical advantage [19].

7. Special Populations: Elderly and Frail Patients:

Elderly and medically frail patients represent an important target population for QUAD SHOT given the regimen’s short treatment duration and favorable toxicity profile. Multiple studies have specifically evaluated QUAD SHOT in geriatric oncology settings.

Kil et al. reported outcomes in 12 elderly patients (median age 77 years, range 49-95 years) with Karnofsky performance scores of 40-70 and diverse histologies including melanoma, papillary thyroid carcinoma, Ewing sarcoma, lung adenocarcinoma, and urothelial carcinoma. Treatment planning utilized 0.5–1 cm expansion from gross tumor volume (GTV) to planning target volume (PTV), with 3.5 Gy per fraction. Target coverage of 95–110% was acceptable, while spinal cord and neural structures were limited to 9 Gy per cycle. Eight patients (66.7%) completed all three cycles, with symptom relief typically observed 2-3 weeks after the first cycle. Complete responses were documented for hematuria, cellulitis, and limb edema. Target volume reduction was implemented for subsequent cycles when appropriate. No grade 3 or higher toxicities occurred, though 6 patients died before completing treatment due to disease progression [18].

A quasi-experimental study from Pakistan enrolled 40 elderly patients with inoperable cancer and WHO performance status of 2-3, excluding those with prior radiotherapy or second primary malignancies. Treatment was delivered using Cobalt-60, with 14 Gy per cycle in 4 fractions. Using a 10-point pain scale, mean scores decreased significantly from 8.04 to 4.32. The study concluded that QUAD SHOT provides effective palliation with favorable tolerability in elderly patients with advanced disease [16].

Across these geriatric-focused studies, common themes emerge: treatment completion rates of 60-70%, rapid symptom improvement within 2-3 weeks, predominantly low-grade toxicity, and correlation between number of completed cycles and overall survival. These consistent findings support QUAD SHOT as particularly well-suited for elderly and frail patients requiring effective palliation with minimal treatment burden.

8. Combination with Immunotherapy:

Biological Rationale:

Growing evidence supports combining radiotherapy with immunotherapy based on complex mechanisms involving immunogenic cell death, increased tumor antigen presentation, release of tumor neoantigens, and modulation of the tumor microenvironment (TME). Hypofractionated regimens may be particularly effective in this context due to their capacity to stimulate antitumor immune responses while potentially limiting treatment-related lymphopenia compared to protracted schedules.

The abscopal effect—systemic antitumor response following localized radiotherapy—has been documented in melanoma, lung cancer, and head and neck malignancies when radiotherapy is combined with immune checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4 pathways. Theoretical advantages of combining QUAD SHOT specifically with immunotherapy include: (1) the short treatment duration minimizes disruption of immunotherapy schedules; (2) hypofractionated dosing may enhance immunogenicity; and (3) the intermittent schedule allows immune system recovery between cycles [21-26].

Clinical Experience and Case Reports:

Higgins et al. reported a case series of anal mucosal melanoma treated with QUAD SHOT added to standard dual immunotherapy protocols. The approach was based on a prior case of locoregional anal carcinoma where QUAD SHOT provided effective pain palliation: the first cycle (14.8 Gy) reduced pain from 10/10 to 4/10, and the second cycle further decreased pain from 8/10 to 0/10. No acute toxicity was observed, though the patient died 15 weeks after radiotherapy initiation. While illustrative of potential benefit, these case reports provide only preliminary evidence requiring validation in larger cohorts [22].

Prospective Trials:

The WFBCCC 60320 trial (NCT04454489) represents a prospective evaluation of QUAD SHOT combined with PD-1 inhibition in advanced/recurrent head and neck squamous cell carcinoma. The protocol administers QUAD SHOT (14.8 Gy per cycle) before immunotherapy cycles 4, 8, and 13, evaluating overall survival, toxicity profile, and tumor response biomarkers from blood and saliva samples. This trial specifically aims to address the limitations of retrospective experiences by prospectively assessing efficacy, safety, and predictive markers. Results from this study will provide important data on the true clinical benefit of this combination approach [29].

Retrospective Comparative Data:

Upadhyay et al. retrospectively compared head and neck cancer patients receiving three or more QUAD SHOT cycles between 2017 and 2022, analyzing outcomes with QUAD SHOT alone versus concurrent immune checkpoint inhibition. The major difference was observed in 12-month local control: 85% with concurrent immunotherapy versus 63% with QUAD SHOT alone. Despite this local control improvement, no overall survival benefit was demonstrated for the combination. Grade 3 toxicity rates were identical at 23% in both groups. These results suggest potential local control benefits from combining QUAD SHOT with immunotherapy while maintaining acceptable toxicity. However, the authors appropriately noted that compared to historical cohorts, their patient population may have had better baseline prognosis, and the absence of randomization limits definitive conclusions. The lack of survival benefit despite improved local control may reflect the advanced disease stage and competing risks of distant progression in this population [29].

Critical Assessment:

While the biological rationale for combining QUAD SHOT with immunotherapy is compelling, current clinical evidence remains preliminary. Key limitations include: (1) predominance of retrospective analyses and case reports, (2) absence of randomized comparisons with appropriate control arms, (3) small sample sizes limiting statistical power, (4) potential selection bias in patient cohorts, and (5) lack of validated predictive biomarkers for patient selection.

The suggestion that this combination represents a “promising treatment option” must be tempered by acknowledgment that prospective validation is required before it can be considered standard practice. Ongoing trials such as NCT04454489 (ClinicalTrials.gov) are essential to definitively establish the role of this combination strategy.

9. Limitations of Current Evidence:

Study Design Considerations:

The available evidence supporting QUAD SHOT is predominantly derived from retrospective studies, small case series, and quasi-experimental designs. These study types are inherently subject to selection bias, confounding by indication, and limited generalizability. The historical cohort described by Corry et al., while foundational, included only 30 patients. Many subsequent reports describe single-institution experiences with similar sample sizes, limiting the ability to detect rare toxicities or define optimal patient selection criteria. Quasi-experimental studies, such as the Pakistani geriatric cohort, lack randomization and may not adequately control for confounding factors including performance status, disease burden, and concurrent supportive care measures. While such studies provide valuable preliminary data, they cannot establish causality or definitively demonstrate superiority over alternative regimens [9, 16].

Statistical Analysis Limitations:

Many published studies rely primarily on descriptive statistics (response rates, median survival, toxicity frequencies) without formal hypothesis testing. When comparisons are made between treatment approaches or patient subgroups, statistical significance is often not reported, making it unclear whether observed differences reflect true effects or random variation.

For example, the randomized comparison of QUAD SHOT versus 30 Gy in 10 fractions presented response rates without p-values or confidence intervals. Similarly, retrospective comparisons of QUAD SHOT with and without immunotherapy lack adjustment for potential confounders such as performance status, disease burden, and availability of subsequent therapies. Small sample sizes in many studies further limit statistical power—the ability to detect true differences when they exist. Studies with 12-40 patients, while clinically informative, cannot reliably detect modest but clinically meaningful differences in efficacy or toxicity. Reporting of effect sizes and confidence intervals would provide better context for interpreting results from small studies.

Absence of Prospective Randomized Trials:

No large-scale, prospective, randomized controlled trials comparing QUAD SHOT to standard palliative regimens have been published. Such trials would be essential to: (1) definitively establish relative efficacy compared to alternatives, (2) identify patient populations most likely to benefit, (3) determine optimal dosing and scheduling, (4) assess quality of life and patient-reported outcomes systematically, and (5) evaluate cost-effectiveness.

The lack of Level 1 evidence limits the ability to make strong treatment recommendations and may partially explain the relatively low utilization rates (7%) observed in the NCDB analysis [11].

Technical and Reporting Inconsistencies:

Published studies employ variable QUAD SHOT protocols, including: (1) dose per fraction: 3.3–3.7 Gy, (2) total dose per cycle: 13.2–14.8 Gy, (3) number of cycles: 1-4, (4) treatment planning techniques: 2D, 3D-conformal, IMRT, VMAT, protons, (5) interfraction intervals: minimum 6 hours (variably enforced), and (6) cycle intervals: 3–4 weeks.

This heterogeneity complicates cross-study comparisons and meta-analyses. Additionally, reporting of target volume delineation, normal tissue constraints, and treatment planning objectives varies considerably, making protocol replication challenging.

Generalizability Concerns:

Most published series originate from academic medical centers with expertise in palliative radiotherapy and access to advanced delivery techniques. It remains unclear whether reported outcomes and toxicity profiles are achievable in community settings with different resources, patient populations, and supportive care capabilities.

Geographic and healthcare system differences may also impact generalizability. Studies from different continents report variable completion rates and outcomes, potentially reflecting differences in patient selection, supportive care availability, or socioeconomic factors affecting treatment access and adherence.

10. Future Directions and Research Needs:

Prospective Trial Development:

Rigorous prospective studies are needed to establish the role of QUAD SHOT relative to other palliative regimens. Priority trial designs should include:

Phase II/III Randomized Comparisons: QUAD SHOT versus standard single or multi-fraction regimens, with primary endpoints including quality of life (using validated instruments), symptom control, treatment completion rates, and overall survival. Secondary endpoints should include healthcare utilization (hospitalizations, emergency department visits) and cost-effectiveness.

Biomarker-Driven Studies: Investigation of predictive markers for treatment response, including tumor mutational burden, PD-L1 expression, and immune microenvironment characteristics in the context of QUAD SHOT plus immunotherapy combinations.

Patient-Reported Outcome Research: Systematic assessment of patient preferences, symptom burden, and quality of life using validated PRO instruments throughout treatment and follow-up.

Technical Optimization:

Several technical questions warrant investigation:

Dose Escalation Studies: Given the favorable toxicity profile observed across multiple studies, investigation of dose-escalated regimens (e.g., 4.0 Gy × 4 fractions = 16 Gy per cycle) may be warranted for selected disease sites and volumes. Dose escalation using advanced techniques (IMRT, protons) could potentially improve local control while maintaining acceptable toxicity.

Optimal Fractionation: The optimal number of cycles (3 versus 4), cycle timing (3 versus 4-week intervals), and response-adapted approaches (additional cycles for responding patients) require systematic evaluation.

Re-irradiation Protocols: Given encouraging data in previously irradiated patients, formal study of QUAD SHOT re-irradiation protocols with standardized normal tissue constraints and cumulative dose tracking would inform safe practice.

Combination Strategy Refinement:

For QUAD SHOT-immunotherapy combinations, critical questions include: (1) optimal sequencing (radiotherapy before, during, or after immunotherapy initiation), (2) selection of immunotherapy agent(s) (single versus dual checkpoint blockade), (3) identification of patients most likely to benefit from combined modality treatment, (4) role of radiation field selection (target lesion only versus multiple lesions for enhanced abscopal effect), and (5) standardization initiatives.

Development of consensus guidelines for QUAD SHOT delivery would facilitate protocol consistency and outcome comparison across institutions. Such guidelines should address: (1) target volume definition principles, (2) normal tissue dose constraints by anatomical site, (3) treatment planning objectives and acceptability criteria, (4) quality assurance procedures, and (5) supportive care recommendations.

11. Conclusions

QUAD SHOT radiotherapy represents an effective and well-tolerated palliative treatment option for patients with advanced, recurrent, or metastatic malignancies. The regimen demonstrates particular utility in elderly and medically frail patients who require rapid symptom relief with minimal treatment burden. Consistent findings across multiple studies include high rates of symptom improvement, treatment completion rates of 50-70%, predominantly low-grade toxicity, and correlation between number of completed cycles and overall survival.

The integration of modern radiation delivery techniques including IMRT, VMAT, and proton therapy appears to maintain the favorable therapeutic ratio of QUAD SHOT through improved conformality and normal tissue sparing. These technical advances may, in principle, facilitate dose escalation, extended treatment courses beyond three cycles, and re-irradiation in previously treated patients, although such applications remain preliminary and require prospective validation before routine adoption.

Emerging data suggest potential synergy when combining QUAD SHOT with immune checkpoint inhibitors, supported by compelling biological rationale involving immunogenic cell death and tumor microenvironment modulation. However, current evidence for this combination remains largely preliminary, derived primarily from retrospective series and small prospective trials. The absence of randomized comparisons and formal statistical analyses limits definitive conclusions regarding clinical benefit, particularly for overall survival.

The current evidence base for QUAD SHOT is characterized by predominance of retrospective studies, small sample sizes, heterogeneous treatment protocols, and limited statistical rigor. While reported outcomes are consistently encouraging, these methodological limitations underscore the need for prospective randomized trials with standardized protocols, validated patient-reported outcome measures, and appropriate statistical analyses. Such studies are essential to definitively establish optimal patient selection, treatment parameters, and the role of combination approaches.

Despite these evidence limitations, QUAD SHOT’s rapid onset of palliation, short treatment duration, favorable toxicity profile, and compatibility with modern delivery techniques and immunotherapy schedules make it a valuable option in the palliative radiotherapy armamentarium. Future research should focus on prospective validation, technical optimization, combination strategy refinement, and development of consensus treatment guidelines to facilitate broader adoption and optimal utilization of this promising palliative approach.

Abbreviations

BED – biological equivalent dose

BID – twice daily

CR – complete response

CTCAE – Common Terminology Criteria for Adverse Events

CTLA-4 – cytotoxic T-lymphocyte-associated protein 4

EORTC QLQ-C30 – European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30

fx – fraction(s)

GIST – gastrointestinal stromal tumor

GTV – gross tumor volume

H&N – head and neck

HNSCC – head and neck squamous cell carcinoma

ICI – immune checkpoint inhibitor

IMRT – intensity-modulated radiotherapy

NCDB – National Cancer Database

ORR – overall response rate

OS – overall survival

PD-1 – programmed cell death protein 1

PD-L1 – programmed death-ligand 1

PFS – progression-free survival

PR – partial response

PRO – patient-reported outcome

PTV – planning target volume

QUAD SHOT – quasi-continuous hypofractionated palliative regimen (RTOG 8502)

RT – radiotherapy

RTOG – Radiation Therapy Oncology Group

SANRA – Scale for the Assessment of Narrative Review Articles

SCC – squamous cell carcinoma

TME – tumor microenvironment

TTP – time to progression

VMAT – volumetric modulated arc therapy

WHO – World Health Organization.

Statements

Funding. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflicts of Interest. The authors declare that they have no competing interests.

Ethics Approval and Consent to Participate. Not applicable. This article is a narrative review of previously published studies and did not involve any new studies of human or animal subjects performed by the authors; no ethics approval or patient consent was therefore required.

Author Contributions. C.C.M. and D.P.T.I. conceived and designed the review. C.C.M. and M.R. performed the literature search, study selection, and data extraction. C.C.M. and M.R. drafted the manuscript. D.P.T.I. provided critical revision for important intellectual content and supervised the work. All authors read and approved the final manuscript.

Data Availability Statement. Data sharing is not applicable to this article, as no new data were created or analyzed in this study. All data discussed are available in the cited published sources.

Acknowledgements. None.

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