The role of Quad Shot in palliative radiotherapy: narrative review of the evidence and applications in advanced head and neck cancer
Introduction
Palliative radiotherapy (RT) is the criterion standard for management of unresectable, recurrent, and metastatic head and neck cancers (HNCs) when curative intent is not feasible. The primary goals of RT are to alleviate symptoms (e.g., pain, dysphagia, bleeding, and airway obstruction), improve quality of life (QOL), and achieve local disease control, while minimizing treatment-related toxicity. Various RT schedules have been developed, ranging from short, hypofractionated regimens to longer, conventionally fractionated courses. Among these, the Quad Shot (QS) regimen, which delivers 14.0 to 14.8 Gy in 4 fractions over 2 days, with the option to repeat every 3 to 4 weeks for 3 to 4 cycles, has emerged as a promising approach because of its short treatment duration, rapid symptom relief, and repeatability. Our review provides a detailed examination of the QS regimen in managing advanced, recurrent, or metastatic HNCs, comparing it with other standard palliative RT schedules in terms of efficacy, toxicity, treatment duration, and patient convenience. We also discuss ongoing research and future directions. We present this article in accordance with the Narrative Review reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-25-80/rc).
Methods
We performed a narrative review of published literature on QS and other palliative RT regimens for HNC in accordance with Table 1. A comprehensive search was performed in the PubMed database for English-language articles published up to April 1, 2025. Search terms included combinations of the following keywords: “Quad Shot”, “palliative radiation therapy”, “head and neck cancer”, “hypofractionated radiotherapy”, and “short-course head and neck radiation”. Studies evaluating symptom relief, tumor response, toxicity profiles, and treatment logistics were included. Both prospective and retrospective studies were considered. Exclusion criteria included case reports and studies not focused on palliative RT regimens specifically for HNC. Twenty-two studies were included in this review.
Table 1
| Items | Specification |
|---|---|
| Date of search | April 1, 2025 |
| Database searched | PubMed |
| Search terms used | “Quad Shot”, “palliative radiation therapy”, “head and neck cancer”, “hypofractionated radiotherapy”, “short-course head and neck radiation” |
| Timeframe | Published up to April 1, 2025 |
| Inclusion and exclusion criteria | Inclusion: English language; studies evaluating symptom relief, toxicity profiles, treatment logistics |
| Excluded: Case reports | |
| Selection process | Conducted by first author D.J.C. and corresponding author A.L.H. |
N/A, not applicable.
Definition and historical context
The QS regimen is a hypofractionated palliative RT schedule that delivers a total dose of 14.0 to 14.8 Gy in 4 fractions over 2 consecutive days, with each fraction typically 3.5 to 3.7 Gy, administered twice daily with at least 6 hours between fractions. This cycle can be repeated every 3 to 4 weeks for up to 3 to 4 cycles, allowing for a cumulative dose of 42 to 56 Gy. The regimen was initially developed for pelvic malignancies as part of the Radiation Therapy Oncology Group 8502 trial, which demonstrated its feasibility and efficacy in providing symptom relief (1). While there have been other dose and fractionation scheduled utilized, QS has been associated with less treatment-induced toxicity and better treatment adherence (2). Its adaptation for HNC was driven by the need for short-course treatments that could rapidly relieve palliative symptoms in patients with advanced, recurrent, or metastatic disease, while balancing acute and late toxicities. Hypofractionated schedules like QS are thought to be especially useful for HNC, as they typically don’t reach the threshold dose to produce mucositis and the interval between the treatment courses is sufficient for depleted mucosal stem cells to repopulate before the next cycle (3).
Efficacy and outcomes of QS in HNCs
Several studies have evaluated symptom relief, tumor response, and toxicities of the QS regimen for palliative RT in HNC. In 2009, Ghoshal et al. (4) published a pilot study of 15 patients with inoperable or metastatic HNC. The regimen delivered 14 Gy in 4 fractions over 2 days, targeting the gross tumor volume with a 2-cm margin. In this study, 13 patients (86.7%) achieved over 50% tumor regression after the first cycle. All patients reported good symptom relief, with pain improving in 10 (66.7%) and swallowing improving in 5 (33.3%). Eleven patients (73.3%) required narcotics before treatment, while only 4 (26.7%) needed them after treatment. There were no grade 3 toxicities in this study. At 6 weeks, 10 patients (66.7%) had a partial response, 2 (13.3%) had static disease, and 3 (20.0%) had progressive disease, with a mean time to progression of 12 weeks (4). In 2019, a subsequent phase III randomized clinical trial compared the QS regimen to conventional hypofractionated palliative RT (30 Gy in 10 fractions) (5). Symptom relief was similar between the 2 schedules for pain (60.86% vs. 57.17%) and dysphagia (43.85% vs. 38.09%). Partial response and stable disease were seen in over 70% of patients in both groups. Treatment was well tolerated, with no patients experiencing grade 2 toxicity in the QS group (5).
Additional series have been published since the initial trials investigating the ideal radiation modality and patient population and confirming adequate results. In 2018, Ma et al. (6) published a series of 26 patients with recurrent or metastatic cancers treated with proton therapy using QS dosing. The overall palliative response was 73%, with no grade 3 to 5 toxicities observed. This response rate remained consistent even in patients who had received prior RT. In 2020, Fan et al. (7) published a series of 166 patients with prior HNC RT treated with the QS regimen with both proton and photon modalities. The overall response rate was 66%, and symptoms improved in 60% of patients. Predictors of palliative response included a greater than 2-year interval from prior RT and 3 to 4 QS cycles. The overall grade 3 toxicity rate was 10.8%, with no grade 4 or 5 toxicities observed. In 2024, Toya et al. (8) published a series of 105 patients using volumetric modulated arc therapy for incurable HNC. Tumor response was observed in 88% of patients, with a rate of grade 3+ toxicity of 2%. Receiving 3 QS cycles was an independent prognostic factor of better overall survival in this series (8).
As the QS regimen has demonstrated promising results with RT alone, improving outcomes with the addition of radiosensitizing chemotherapy has also been investigated. In 2017, Gamez et al. (9) published a study of 21 patients with newly diagnosed or recurrent HNC treated with the QS regimen with the addition of radiosensitizing chemotherapy. The agent selected was at the discretion of the medical oncologist, but most patients received carboplatin before the first fraction of each radiation cycle. An objective response to therapy was observed in 85.7% of patients, with 23.8% achieving a complete response. Palliation was achieved in 100% of patients (9).
Collectively, these studies demonstrate that QS is effective in providing rapid and durable symptom relief for patients with advanced HNC, with a favorable toxicity profile, especially when combined with immune checkpoint inhibitors (ICIs) for enhanced local control. Please note, while the studies generally demonstrate similar outcomes, there is some heterogeneity in the outcomes found in the aforementioned studies which could be attributed to the Common Terminology Criteria for Adverse Events toxicity guidelines used, different patient populations, variability in treatment approaches, selection biases, or statistical and methodologic differences.
Comparison overview of palliative regimens
While QS is an excellent option for palliative RT for HNC, many other regimens have been reported in both retrospective and prospective small phase 2 clinical trials (3,4,9-24) (Table 2). The treatment schedules in these studies include short courses, stereotactic body radiation therapy, and standard-length courses. Response rates, symptom relief, and toxicity profiles vary by treatment regimen. A summary of the dose and fractionation in these studies is shown in Table 2. Ultimately, QS offers effective, low-risk treatment of shorter duration, making it more convenient than other regimens and suitable for repeat administration. Regimens with higher total doses and conventional fractionation may provide better long-term control, particularly for large tumors; however, this comes with an increased risk of toxicity.
Table 2
| Regimen group | Studies | Gy per fraction | Responses | Key toxicities |
|---|---|---|---|---|
| Quad Shot regimens | ||||
| ~14.0–14.8 Gy in 4 fractions, twice a day for 2 days, repeated) | Paris et al. (22); Corry et al. (3); Carrascosa et al. (14); Lok et al. (19); Gamez et al. (9) | 3.5–3.7 | CR, 14–65%; PR, 47–71%; palliation, >66–85% | Primarily G1–2 |
| 40 Gy in 10 fractions, twice weekly | Das et al. (15) | 4.0 | 88% pain relief | 18% G3 mucositis |
| 20 Gy in 5 fractions | Mohanti et al. (20); Paliwal et al. (21) | 4.0 | CR, 7–62%; PR, 38–92%; palliation, >70%. Rapid relief, lower long-term control | High G3 mucositis (~39–64%) |
| 30 Gy in 10 fractions | Ghoshal et al. (4); Adlakha et al. (10) | 3.0 | CR, 26–100% [especially high symptom relief (4)]; 60–80% symptom relief | Moderate G2 mucositis (32–37%) |
| Very hypofractionated regimens (~5–6 Gy/fraction) | Porceddu et al. (23); Fortin et al. (16) | 5.0–6.0 | CR, 56%; PR, 95% (23); QOL improved, >58% (16) | G3 mucositis (13–26%); G3 dysphagia (11%) |
| SBRT regimens | Siddiqui et al. (24); Kawaguchi et al. (17); Khan et al. (18) | 5.6–8.0 (SBRT) | CR, 25–31%; PR, 19–67%; symptom palliation, 76–82% | Variable toxicity, some hospitalization |
| Conventional fractionation regimens (~2–3 Gy/fraction) | Agarwal et al. (11); Al-mamgani et al. (12); Bledsoe et al. (13) | 2.0–3.1 | CR, 10–60%; PR, 28–63% | Higher G3 mucositis, dermatitis; 42% feeding tube use (13) |
CR, complete remission; PR, partial remission; QOL, quality of life; SBRT, stereotactic body radiation therapy.
Randomized trials and additional regimens
Two randomized trials have compared different palliative regimens for HNC. In 2017, Soni et al. (25) compared 3 groups: the QS regimen, 50 Gy in 16 fractions, and 20 Gy in 5 fractions. The QS regimen had the best local control rate of 84%, with a 28% rate of grade III acute skin reaction and 36% rate of grade III mucosal reaction (25). In 2024, Puraiya et al. (26) compared 30 Gy in 10 fractions to the QS regimen. The treatment response of the QS regimen was 78.7% and only 61.2% in the 10-fraction arm. QOL was also better in the QS regimen after treatment (26).
Two other randomized trials included palliative regimens other than QS. In 2025, Mallick et al. (27) compared 20 Gy in 5 fractions to 30 Gy in 5 fractions delivered over 1 week. They found no benefit in the 30 Gy arm; however, it was well tolerated in terms of toxicity (27). In 2015, Nguyen et al. (28) published retrospective data on a different hypofractionated regimen, treating patients with 24 Gy in 3 fractions delivered once weekly. Their results were comparable to the QS regimen, with 82% of patients having at least a partial response, and the regimen was well tolerated (28).
Clinical examples
The clinical courses of 2 patients with HNC who provided consent to be included in this case report and were successfully treated with QS are outlined below. We discuss these not as high-level evidence of Mayo Clinic practice patterns, but rather to demonstrate the efficacy of the QS regimen in specific cases. The first patient was a 72-year-old man with history of severe dementia diagnosed with American Joint Committee on Cancer Eighth Edition stage T4N2 (laryngeal involvement with bilateral neck adenopathy), human papillomavirus-associated, p16 positive, squamous cell carcinoma of the base of the tongue. Given his advanced dementia and poor QOL, the patient and his family chose QS over a definitive course of RT. His pretreatment scope examination and sagittal computed tomography are shown in Figure 1A. He completed his first cycle of QS (14 Gy in 4 fractions), and reported improvement in swallowing and appetite at his palliative care clinic visit 1 month after treatment. He subsequently proceeded with the second cycle of QS (also 14 Gy in 4 fractions); posttreatment imaging one month after the second cycle demonstrated a complete radiographic response (Figure 1B).
The second patient was a 64-year-old woman with history of locally advanced lung cancer treated with chemoradiation, and terminal liver disease. She presented with otalgia, severe dysphagia, and right tongue pain, and was diagnosed with American Joint Committee on Cancer Eighth Edition stage cT2N1 (primary 2.1–4.0 cm and ipsilateral cervical lymph nodes ≤6 cm) squamous cell carcinoma of the right pyriform sinus. An image taken from her pretreatment scope examination is shown in Figure 2A. Given her poor performance status and short life expectancy, she chose treatment with QS palliative RT over total laryngectomy or high-dose curative-intent chemoradiation. She completed the first cycle (14 Gy in 4 fractions) with minimal toxicity, and reported substantial improvement in tongue pain, throat pain, and dysphagia at 2-week posttreatment follow-up. Nasopharyngoscopic examination demonstrated a significant treatment response (Figure 2B). She proceeded with the second cycle of QS, with follow-up examinations in our palliative care clinic demonstrating prolonged complete response and no associated toxicities or persistent symptoms. She remained symptom- and disease-free for an additional year and a half before she died due to complications from hepatic dysfunction.
Patient selection
Careful selection of patients to receive QS treatment is crucial. Candidates for QS fall into two categories: those with metastatic, unresectable, and recurrent disease and those with potentially curative disease who cannot tolerate definitive treatment due to comorbid conditions, poor life expectancy, or excessive toxicity from the location and extent of disease. In the second category, curative treatment would diminish the patient’s QOL. Patients in this category are candidates for reirradiation, as they have previously received RT, have locally recurred, and do not have salvage surgical options for curative-intent therapy. Given the high toxicities and likelihood of radioresistance, QS balances locoregional control to reduce disease burden and improve symptoms without negatively impacting QOL by subjecting these patients to prolonged courses of RT. The criteria for patient selection are presented in Table 3. These criteria are not meant to be general recommendations and are only mentioned to discuss our institutional practice patterns.
Table 3
| Clinical scenario | Patient characteristics | Rationale for Quad Shot | Therapeutic goal |
|---|---|---|---|
| Metastatic, recurrent, or curative cases with significant comorbid conditions/poor prognosis | Metastatic or locally recurrent disease | Conventional or curative-intent RT may cause excessive toxicity | Palliative local control to relieve symptoms and preserve QOL |
| Poor performance status (e.g., ECOG ≥3) | Palliative but needs durable local control | ||
| Significant comorbid conditions (e.g., cardiac, pulmonary) | Balances tumor control with QOL | ||
| Poor life expectancy (<6–12 months) | |||
| Tumor location/extent causing high expected toxicity from standard RT | |||
| Reirradiation in previously treated patients without surgical salvage options | Prior full-course radiation to the same area with no feasible surgical salvage options | Full reirradiation not feasible due to toxicity | Curative or durable disease control with palliative approach |
| Recurrent or persistent disease in previously irradiated field | Quad Shot offers local control with minimal toxicity and allows repeat cycles if well tolerated | Minimize toxicity | |
| Symptomatic disease impacting function (e.g., pain, bleeding, obstruction) | Maximize symptom relief |
ECOG, Eastern Cooperative Oncology Group; QOL, quality of life; RT, radiation therapy.
Target definitions and normal tissue constraints
Given that QS is typically reserved for palliative cases, the RT target usually includes the gross tumor volume with a 3-mm isotropic margin to generate the planning target volume, prescribed as 14 Gy in 4 fractions. Elective nodal irradiation is generally not used but may be included in select cases at the physician’s discretion, delivered as 56 Gy to high-risk areas and 40 to 48 Gy to standard-risk areas. If there are 2 volumes, this is administered using a simultaneous integrated boost approach. Elective nodal irradiation is considered when the expected benefit in locoregional control outweighs potential negative impacts to QOL, particularly in patients with a high risk of subclinical disease. It is rarely used in the setting of reirradiation. There is no routine replanning for optimizing clinical and logistic workflow and patient convenience; instead, replanning is adaptive based on cone beam computed tomography results. Summaries of target volume delineation and normal tissue constraints are presented in Tables 4,5. Similar to Table 3, the volumes and normal tissue constraints discussed in Tables 4,5 are not meant to be general recommendations and are only mentioned to discuss our institutional practice patterns.
Table 4
| Elective volume included | Volume definitions | Dose/fractionation | Notes |
|---|---|---|---|
| No | GTV = radiographic and clinical gross disease | 14 Gy in 4 fractions | Typically, no elective nodal volumes; used for symptom control and QOL preservation |
| PTV = GTV + 3-mm isotropic margin | |||
| Yes | GTV and PTV defined as above | GTV (high-risk): 56 Gy (3.5 Gy/fraction) | If elective nodal volume is included, treated with SIB approach |
| CTV = GTV + elective nodal regions based on clinician discretion | Elective (standard-risk): 40–48 Gy (2.5–3 Gy/fraction) | ||
| PTV = CTV + 3-mm isotropic margin |
CTV, clinical target volume; GTV, gross tumor volume; PTV, planning target volume; QOL, quality of life; SIB, simultaneous integrated boost.
Table 5
| Organ at risk | Life expectancy ≤6 months | Life expectancy >6 months |
|---|---|---|
| Brain | – | V4700cGy <1 cc (priority 2) |
| Brainstem | Max <3,000 cGy (priority 1) | V4300cGy <0.03 cc (priority 1) |
| Max <5,000 cGy (priority 2) | ||
| Brainstem + 3-mm margin | – | V4400cGy <0.03 cc (priority 1) |
| Mean <2,900 cGy (priority 2) | ||
| Brachial plexus (L/R) | – | V4900cGy <0.01 cc (priority 3) |
| Cerebellum | – | V4000cGy <10% (priority 3) |
| Temporal lobe (L/R) | – | V5400cGy <2 cc (priority 2) |
| Spinal cord | Max <3,000 cGy (priority 1) | V3600cGy <0.01 cc (priority 1) |
| Max <5,000 cGy (priority 2) | ||
| Spinal cord + 5-mm margin | – | V4000cGy <0.03 cc (priority 1) |
| Mean <2,200 cGy (priority 2) | ||
| Parotid (total) | Mean <2,000 cGy (priority 1) | Mean <2,200 cGy (priority 2) |
| V2500cGy <50% (priority 2) | ||
| Parotid (L/R) | – | Mean <2,200 cGy (priority 2) |
| V2500cGy <50% (priority 2) | ||
| Submandibular (L/R) | – | Mean <3,200 cGy (priority 2) |
| Pharyngeal constrictors | – | Mean <4,300 cGy (priority 2) |
| Superior/middle/inferior pharyngeal constrictor | – | Mean <4,000 cGy (priority 2) |
| Oral cavity | – | D0.03cc <105% (priority 2) |
| Mean <2,600 cGy (priority 3) | ||
| Cochlea (L/R) | – | Mean <2,900 cGy (priority 2) |
| Larynx | – | Mean <3,300 cGy (priority 2) |
| Esophagus | – | Mean <2,800 cGy (priority 3) |
| Optic chiasm | – | V4000cGy <0.01 cc (priority 1) |
| Optic nerve (L/R) | – | V4000cGy <0.01 cc (priority 1) |
| Mandible | – | V5400cGy <0.03 cc (priority 2) |
| V5400cGy <6.5% (priority 2) | ||
| Eyes (L/R) | – | V4000cGy <0.1 cc (priority 2) |
| Lacrimal gland (L/R) | – | Mean <900 cGy (priority 2) |
| Lens (L/R) | – | V300cGy <0.03 cc (priority 2) |
| Thyroid | – | Mean <3,200 cGy (priority 3) |
| Tubarial salivary gland (L/R) | – | Mean <3,200 cGy (priority 2) |
–, not applicable; L, left; Max, maximum; R, right.
Toxicity and tolerance monitoring in the palliative care clinic
At our institution, an advanced practice provider-led palliative care clinic plays a central role in coordinating QS for patients with complex needs (29). A physician conducts an initial assessment to determine candidacy for QS, after which a comprehensive plan is established that typically involves a total dose of 56 Gy delivered in 4 cycles. The entire course is planned upfront to optimize dosimetric planning and ensure consistent setup using immobilization devices, such as masks, which are maintained throughout treatment. Each cycle is spaced approximately 3 to 4 weeks apart, allowing time for symptom evaluation and recovery. Patients are closely monitored with management and follow-up visits before and after initiation of each cycle, ensuring adverse effects are promptly addressed.
Toxicity from QS is generally mild and well-tolerated, though location and tumor burden can influence the adverse effect profile, with delayed symptoms emerging 1 to 2 weeks after treatment. These symptoms generally self-resolve or are managed with supportive medication, such as gabapentin, nonsteroidal anti-inflammatory drugs, acetaminophen, or opioids, when necessary. However, due to the often-fragile clinical status of this population, structured and proactive toxicity assessment is essential. Toxicity monitoring in a palliative care setting centers on symptom control, QOL, and maintaining function, unlike standard oncology workflows that may emphasize radiologic or pathologic response. This patient-centered approach requires close coordination across disciplines and frequent reassessment to ensure therapeutic benefit without compromising the patient’s well-being.
Future directions
The QS literature and applications continue to evolve. For example, the combination of ICIs and QS is currently being investigated. In 2024, Upadhyay et al. (30) published a study of 70 patients with recurrent and metastatic HNC treated with QS with or without concurrent ICIs. Local control was significantly higher with concurrent ICIs (85% vs. 63% at 12 months); 23% of patients experienced grade 3 toxicities, which was similar between the 2 groups (30).
In addition to combining QS with ICIs, other areas of development within RT could improve palliative treatment of HNC. Minibeam RT is a new technique that delivers submillimeter-wide regions of high and low doses throughout a tumor by using clinical orthovoltage units and a tungsten collimator with submillimeter slits placed on the tumor’s surface. In 2024, Grams et al. (31) described 2 patients treated with minibeam RT; both experienced prompt improvement in symptoms and tumor response.
Furthermore, an ongoing phase II study (PULS-Pal, NCT06572423) is evaluating personalized ultrafractionated stereotactic adaptive RT for palliative HNC treatment (32). Forty-three patients will receive an 11-Gy fraction of RT every 2 weeks for a total of 5 fractions (55 Gy). This will be the first prospective study of PULSAR with HyperArc software (Varian Medical Systems, Inc.) for HNC, with the goal of improving local tumor management compared to controls in patients undergoing palliative RT (32).
Memorial Sloan Kettering Cancer Center is also conducting a phase II clinical trial studying proton reirradiation for HNC treatment (NCT03217188), directly comparing conventionally fractionated full-dose reirradiation to hypofractionated palliative reirradiation (i.e., QS) (33).
Finally, reirradiation with carbon ion therapy is being considered for HNC treatment, as it is hypofractionated with high linear energy transfer. A large retrospective study of 229 patients who underwent carbon ion reirradiation for recurrent HNC suggested it is a feasible and effective treatment option with acceptable toxicity and local control (34).
Conclusions
Palliative RT is an essential component in the management of advanced, recurrent, and metastatic HNCs, providing symptom relief and improved QOL for patients who are not candidates for curative treatment. The QS regimen has emerged as a highly effective and well-tolerated option within palliative RT, providing rapid palliation with minimal toxicity and logistical advantages due to its short treatment duration and repeatable design. Comparative studies consistently show that QS achieves symptom control and tumor responses comparable to traditional and hypofractionated regimens, often with acceptable rates of high-grade toxicity. Despite the considerable amount of data demonstrating the efficacy of the QS regimen, there are limitations. For example, the majority of the evidence is not randomized phase III data, which can lead to selection bias, heterogeneity in retrospective toxicity analysis, and publication bias.
Recent innovations, including proton therapy, volumetric modulated arc therapy, radiosensitizing chemotherapy, and combination therapy with ICIs, have further expanded the versatility and efficacy of the QS regimen. Upcoming research exploring novel techniques, such as minibeam RT and personalized ultrafractionated regimens (e.g., PULS-Pal), underscores an ongoing commitment to improving palliative care outcomes. As the field of palliative RT evolves, the QS regimen remains a cornerstone strategy, balancing effective tumor control, symptom relief, and patient-centered care.
Acknowledgments
None.
Footnote
Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-25-80/rc
Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-25-80/prf
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-25-80/coif). S.H.P. reports payment from Galera Therapeutics—single advisory board meeting. The other authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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