Safety and Symptom Relief of a Modified QUAD-SHOT Regimen in Head and Neck Cancer: A Single-Center Retrospective Study

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However, the optimal schedule balancing safety and efficacy remains unclear. This study aimed to evaluate the safety and symptom relief of modified QUAD-SHOT (mQUAD) regimens by comparing four cycles (QUAD4), three cycles combined with intra-arterial chemotherapy (QUAD3 + IAC), and the standard three-cycle regimen (QUAD3). Methods We retrospectively analyzed 25 patients treated at the University of the Ryukyus Hospital between April 2012 and March 2023: six received QUAD3, five received QUAD3 + IAC, and 14 received QUAD4. Primary endpoints were acute or late adverse events and symptom relief. Toxicities were graded using the Common Terminology Criteria for Adverse Events v5.0. Results No grade ≥ 3 acute adverse events occurred in QUAD3 or QUAD4, while two grade 3–4 hematologic adverse events were observed in the QUAD3 + IAC group. All these patients recovered with conservative management. Symptom relief was attained in 4 out of 5 (80%) individuals in QUAD3, 3 out of 4 (75%) in QUAD3 + IAC, and 11 out of 12 (92%) in QUAD4. Although no significant differences were noted among the three groups, the QUAD4 cohort demonstrated a higher rate of symptom relief. Conclusions Among the mQUAD regimens, QUAD4 demonstrated the same level of safety as QUAD3. QUAD4 showed a higher symptom relief rate without severe toxicity, suggesting its feasibility as a palliative option. However, the occurrence of severe hematological toxicity in QUAD3 + IAC highlights the need for careful patient selection and monitoring. Head and Neck Cancer Palliative radiotherapy Hypofractionated radiotherapy QUAD-SHOT Intra-arterial chemotherapy Figures Figure 1 Figure 2 Background The utilization of radical treatments such as surgery and chemoradiotherapy for patients with head and neck cancer poses significant challenges, mainly due to factors like age, performance status (PS), distant metastasis, and potential complications. Despite undergoing curative treatment, local and regional recurrences have been documented at a rate of 11–53% [ 1 – 6 ]. Furthermore, the management of recurrent cases is complicated by the patient's deteriorating general condition and the limited availability of additional treatment options due to prior therapies. In such scenarios, radiation therapy (RT) is employed to alleviate symptoms such as pain, bleeding, dysphagia, and airway constriction caused by the tumor. In the 1980s, the Radiation Therapy Oncology Group (RTOG) introduced the “QUAD-SHOT regimen,” a palliative hypofractionated RT approach [ 7 ]. This regimen entails administering 3.5–3.7 Gy twice daily over two days per cycle, totaling 14–14.4 Gy. The standard protocol consists of three cycles repeated every three to six weeks, resulting in a total of 42–43.2 Gy/12 fr (QUAD3) [ 7 , 8 ]. Initially designed for treating pelvic malignant tumors, the QUAD-SHOT regimen has garnered broad acceptance as a palliative RT strategy for head and neck cancer due to its proven safety and efficacy [ 8 – 15 ]. Although QUAD3 can achieve a favorable treatment response, the optimal number of QUAD-SHOT cycles remains unclear. New treatment methods are being developed to identify the appropriate number of cycles to enhance efficacy and safety. Lok et al. [ 9 ] demonstrated that receiving four or more QUAD-SHOT cycles was significantly associated with a palliative response, leading to symptom improvement in 89% of patients. In this cohort, which included patients receiving four or more QUAD-SHOT cycles, acute toxicities comprised an overall grade 2 rate of 28% and grade 3 mucositis or dermatitis in 5% of patients, with no acute events of grade 4 or higher; late events of grade 3 or higher were not observed. Additionally, various chemotherapy regimens are under investigation as adjuvant therapies to enhance the efficacy of the QUAD-SHOT regimens. Carrascosa et al. [ 10 ] documented improved outcomes with paclitaxel, showing symptomatic improvement in 89.5% of patients without any grade 2 or higher late adverse events. Gamez et al. [ 11 ] found that all patients treated with carboplatin or cetuximab experienced symptomatic improvement, with 34.8% encountering grade 2 acute adverse events and no grade 3 or higher events. In RTOG 8502 [ 7 , 8 ], 8.5% of patients experienced acute grade 2 mucositis, with no cases of grade 3 or higher, and 28.5% had late grade 2 or lower salivary gland toxicities. Notably, the use of multiple QUAD-SHOT cycles or systemic chemotherapy could potentially enhance therapeutic efficacy but also increase toxicities. Several regimens combining RT with intra-arterial chemotherapy (IAC) have been documented [ 16 – 19 ]. Among these, docetaxel plus nedaplatin- and carboplatin-based regimens do not necessitate prophylactic hydration and carry a low risk of nephrotoxicity. Furthermore, these regimens have shown high therapeutic efficacy in patients with large tumors and bulky disease [ 17 – 19 ]. Further improvements in treatment efficacy, without escalating toxicity, are still needed. In this context, our institution has implemented the use of standard QUAD3 plus an additional one cycle (QUAD4) or combined with ultra-selective IAC injection (QUAD3 + IAC) for patients with head and neck cancer. We defined “modified QUAD-SHOT (mQUAD)” as the collective term for QUAD4 and QUAD3 + IAC. This study was conducted to evaluate the safety and efficacy of mQUAD and to provide insights into palliative RT options for head and neck malignancies. Methods Patients We retrospectively reviewed patients with head and neck cancer who underwent palliative treatment with the QUAD3 or mQUAD at the University of the Ryukyus Hospital between April 2012 and March 2023. For each patient, the indications for each treatment regimen were determined by a Cancer Board consisting mainly of otolaryngologists and radiation oncologists. The decision to extend the QUAD-SHOT regimen to QUAD4 and incorporate QUAD3 + IAC was based on institutional policy. In general, if the patient’s condition was acceptable, QUAD4 was administered. IAC was administered at the physician’s discretion when the patient demonstrated good PS (0–1), had a bulky tumor, and maintained adequate organ function. Radiation therapy The patients were simulated using computed tomography (CT) with a dedicated thermoplastic head and neck mask for immobilization (Bluebag™, Elekta AB, Stockholm, Sweden). The gross tumor volume (GTV) and clinical target volume (CTV) were determined by the attending radiation oncologist based on the patient’s condition and tumor status. Planning target volume (PTV) margins of 5 mm were added to compensate for the setup errors. CT simulation was performed for each cycle, and adaptive treatment planning was performed if the target or body contour changed. The treatment plans included three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT). The decision to use 3D-CRT or IMRT was made on a case-by-case basis, depending on the morphological complexity and location of the PTV and organs at risk. RT was administered according to the QUAD-SHOT regimen, consisting of two daily fractions of 3.5 Gy separated by at least six hours, for two consecutive days, totaling 14 Gy over four fractions per cycle. Each QUAD-SHOT cycle was principally scheduled at four-week intervals, with variations ranging from three to six weeks, based on patient convenience or other clinical considerations. RT was performed using a linear accelerator system (TrueBeam; Varian Medical Systems, Palo Alto, CA, USA) and a helical tomotherapy platform (Radixact; Accuray Incorporated, Sunnyvale, CA, USA). Concomitant intra-arterial chemotherapy IAC was administered three times concurrently with each QUAD-SHOT cycle. Carboplatin (AUC 3) was administered for non-tongue oral cancers, whereas nedaplatin (80 mg/m 2 ) and docetaxel (60 mg/m 2 ) were administered for other head and neck cancers. If the patient's condition worsened, the chemotherapy dose was reduced, or IAC was suspended. Before arteriography, systemic heparin (700 units per 10 kg of body weight) was administered to prevent clot formation. An additional 500 units were injected intravenously once every hour during the procedure. A 5-Fr catheter and coaxially placed 2.0-Fr microcatheter were used to selectively catheterize the arteries supplying the tumor. Intraoperative cone-beam CT was performed to identify all tumor-feeding arteries and determine the anticancer agent dose for each vessel. Doses were determined according to the percentage of the tumor volume supplied by the target artery, which was measured intraoperatively using angiography-assisted cone-beam CT as a proportion of the total tumor volume. Before IAC, contrast medium was infused into the target artery using a syringe driver. The maximum flow rate at which there was no extra overflow of the contrast medium from the target artery was confirmed fluoroscopically; this rate of contrast medium infusion was considered the optimal infusion rate of the anticancer agents. Evaluation The primary endpoints were adverse events and symptom relief rates compared with mQUAD and QUAD3. Toxicities were scored according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Acute adverse events were defined as toxicities occurring up to three months after treatment completion, and late adverse events were defined as toxicities occurring more than three months after treatment completion. Symptom relief was evaluated through physician interviews during routine clinical visits. Pain relief was assessed retrospectively from electronic medical records. Baseline pain status was defined as the most recent clinical assessment documented within 7 days prior to the start of each QUAD-SHOT cycle, including assessments performed on the day of treatment initiation. Post-treatment pain status was evaluated at the first follow-up visit approximately 1–2 weeks after completion of each cycle. Because standardized patient-reported outcome instruments or validated symptom scales were not routinely used during the study period, pain relief was operationally defined using a pre-specified chart-based algorithm incorporating symptom descriptions and analgesic changes. Pain response was categorized as: (1) improved, documented subjective pain improvement and/or reduction in analgesic requirement; (2) stable, no clear change in pain with stable analgesic use; or (3) worsened, documented pain aggravation and/or escalation of analgesics. Analgesic use was reviewed during the assessment window and classified as escalation/de-escalation (including initiation of opioids, dose increase, addition of adjuvant analgesics, or increased dosing frequency). Given the palliative intent of the QUAD-SHOT regimen and the limited overall survival observed in previous studies, which typically ranged from approximately four to seven months [ 8 , 9 , 11 , 14 , 15 ], short- to mid-term treatment outcomes were considered particularly important in this study. Among these, local control (LC) was selected as a clinically relevant metric because it influences symptom relief and quality of life. Accordingly, six-month LC, defined as freedom from in-field local progression at six months after the start of RT, was adopted as a meaningful and practical measure for evaluating the mid-term efficacy of treatment in this patient population. Local progression was determined based on either clinically apparent tumor growth on physical examination or radiological evidence of progressive disease (PD) on CT or magnetic resonance imaging (MRI), as assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. As secondary endpoints, we also evaluated six-month LC and complete response (CR) and partial response (PR) rates. Tumor response was evaluated according to RECIST version 1.1, using CT or MRI scans obtained before treatment, and those showing the best overall response in terms of tumor size after treatment. CR and PR were defined as tumor responses. Furthermore, we investigated whether the patients’ medical background, tumor size, and tumor stage were associated with the safety and efficacy of mQUAD. PS was assessed using the Eastern Cooperative Oncology Group (ECOG) scale. Statistical analysis Patient characteristics, including age and CTV, were compared across the three treatment groups using the Kruskal–Wallis test. Associations between clinical factors and primary and secondary endpoints were evaluated using Fisher’s exact test. The relationship between symptom relief and CTV was examined using univariate logistic regression. For the secondary endpoint, six-month LC was derived as the complement of the cumulative incidence of in-field local failure at six months using competing-risk methods; death without prior in-field progression was treated as a competing event. Between-group comparisons were performed using Gray’s test, and adjusted effects were obtained from the Fine–Gray sub-distribution hazard models (two-sided 95% confidence intervals reported). All statistical analyses were performed using the EZR ver. 1.61 (Saitama Medical Centre, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of the R Commander designed to add statistical functions frequently used in biostatistics [ 20 ]. Statistical significance was set at p < 0.05. Use of large language models in manuscript preparation During the preparation of this manuscript, LLM (ChatGPT, OpenAI) was used solely for language editing and stylistic improvements in the selected paragraphs. No sections involving the generation, analysis, or interpretation of the research data were produced using generative AI. All the scientific content was created and verified by the authors. Furthermore, no figures or visual data were generated or modified using generative AI or machine learning-based image enhancement tools. Results Patient and treatment characteristics Palliative RT was administered to 110 patients with head and neck cancer during the study period, of whom 42 received the QUAD-SHOT regimen. The analysis involved 25 patients, excluding 17 who completed only one or two cycles of the QUAD-SHOT regimen. Among these 17 patients, treatment was discontinued due to patient refusal in six cases, clinical deterioration in seven cases, and a history of prior irradiation in two cases, despite experiencing only mild adverse events. Out of the 25 analyzed patients, six received QUAD3, five received QUAD3 + IAC, and 14 received QUAD4. A flow diagram illustrating the patient selection process is presented in Fig. 1 . The patient characteristics are summarized in Table 1 . The median patient age was 82 years (range: 50–91 years). Most patients had an ECOG PS of 1 (11 patients), followed by PS 0 and PS 2 (six patients each). Histology revealed squamous cell carcinoma in 23 (92%) patients, adenocarcinoma in one patient, and sebaceous cancer in one patient. Fifteen patients had primary tumors, and 10 patients had recurrent tumors. Among those with primary tumors, 13 were classified as having clinical stage III–IV disease. Two patients had clinical stage II disease; one declined long-term RT, while the other received the QUAD-SHOT regimen because definitive RT was deemed infeasible owing to severe aortic stenosis. Concomitant chemotherapy was administered to five patients, all of whom were in the QUAD3 + IAC group. None of the patients underwent systemic chemotherapy. Three patients received a regimen of nedaplatin and docetaxel, and two patients received carboplatin. Sixteen (73%) patients were treated with IMRT. Three patients received both 3D-CRT and IMRT during the treatment period to account for potential changes in tumor shape as the tumor shrank and to minimize the risk of overdose to adjacent normal organs. There were no statistically significant differences in baseline characteristics, including age, ECOG PS, tumor site, histology, clinical stage, CTV volume, or radiotherapy technique, among the three treatment groups. The median follow-up period for all patients was 251 days (range: 68–1301 days). Table 1 Comparison of patient and treatment characteristics among treatment groups (n = 25) Factors QUAD3 (n = 6) QUAD3 + IAC (n = 5) QUAD4 (n = 14) p-value Age, median (range), years 84 (75–91) 73 (50–86) 82 (56–91) 0.179† Gender 0.844‡ Male 5 3 10 Female 1 2 4 ECOG PS 0.262‡(0–1 vs 2–3) 0 1 3 2 1 3 2 6 2 2 0 4 3 0 0 2 4 0 0 0 Tumor site 0.907‡ Nasal cavity and paranasal sinus 0 0 1 Oral cavity 4 4 5 Oropharynx 1 1 5 Larynx 1 0 2 Skin 0 0 1 Histology > 0.99‡ Squamous cell carcinoma 6 5 13 Others§ 0 0 2 Clinical stage II 0 0 2 III 2 0 0 IVA 0 0 4 IVB 0 0 5 IVC 0 2 0 Recurrence 4 3 3 CTV (ml) 180 (26–467) 138 (43–586) 196 (33–426) 0.891† Radiotherapy technique 0.558‡ 3D-CRT 2 2 2 IMRT 4 2 10 Both 0 1 2 †Kruskal–Wallis test for non-parametric continuous variables ‡Fisher’s exact test for categorical variables §Adenocarcinoma and sebaceous cancer CTV, clinical target volume; ECOG PS, Eastern Cooperative Oncology Group Performance Status; IMRT, intensity-modulated radiation therapy; QUAD3, three cycles of the QUAD-SHOT regimen; QUAD3 + IAC, QUAD3 with intra-arterial chemotherapy; QUAD4, four cycles of the QUAD-SHOT regimen; 3D-CRT, three-dimensional conformal radiation therapy. Toxicity The adverse events in each group are presented in Table 2 . No acute grade 3 or higher adverse events were noted in QUAD3, while grade 2 mucositis occurred in two cases. In the QUAD3 + IAC group, grade 4 neutropenia was observed in one case, grade 3 anemia in one case, and grade 2 mucositis in two cases. Acute adverse events of grade 3 or higher were observed in patients receiving the nedaplatin and docetaxel regimens. No hematologic adverse events were detected in patients treated with the carboplatin regimens. Neutropenia improved following the administration of granulocyte colony-stimulating factor, while anemia improved with observation. In QUAD4, no acute grade 3 adverse events were observed, and grade 2 adverse events were noted in three cases, including dermatitis, mucositis, dacryoadenitis, and anorexia. No statistically significant differences in acute adverse events were observed between the groups (QUAD3 vs. QUAD3 + IAC, p = 0.182; QUAD3 vs. QUAD4, p > 0.99). No late adverse events were observed for QUAD3 or QUAD4. In the case of soft palate cancer with mandibular invasion in QUAD3 + IAC, grade 3 mandibular osteonecrosis was observed 3 years and 2 months after the completion of RT. Table 2 Toxicity of the QUAD-SHOT regimens (n = 25) Factors n Toxicity Grade 1 Grade 2 Grade 3 Grade 4 n % n % n % n % QUAD3 6 1 17 2 33 0 0 QUAD3 + IAC 5 1 20 2 40 1 20 1 20 QUAD4 14 2 14 4 29 0 0 0 Total 25 4 16 8 32 1 4 1 4 QUAD3, three cycles of the QUAD-SHOT regimen; QUAD3 + IAC, QUAD3 with intra-arterial chemotherapy; QUAD4, four cycles of the QUAD-SHOT regimen. Symptom relief A total of 21 patients were symptomatic, presenting with pain at 16 sites, bleeding, and exudate at four sites, and dysphagia at two sites. The rates of symptom relief for each group are detailed in Table 3 . Symptom relief was achieved in four of five patients (80%) in the QUAD3 group, three of four patients (75%) in the QUAD3 + IAC group, and 11 of 12 patients (92%) in the QUAD4 group. No statistically significant differences were observed between the groups (QUAD3 vs. QUAD3 + IAC, p > 0.99; QUAD3 vs. QUAD4, p = 0.515). Overall, symptom relief was achieved in 18 (86%) patients. Specifically, pain relief was achieved in 14 of 16 sites, while bleeding and exudate improved in all four sites, and dysphagia improved in one of two patients. No significant association was observed between symptom relief and CTV (odds ratio [OR], 0.999; 95% confidence interval [CI], 0.991–1.01; p = 0.686). Furthermore, no significant association was found between symptom relief and either histological type (p > 0.99) or performance status (0–1 vs. ≥ 2; p > 0.99). Table 3 Symptom relief of the QUAD-SHOT regimens (n = 21) Factors n Symptom relief n % QUAD3 5 4 80 QUAD3 + IAC 4 3 75 QUAD4 12 11 92 Total 21 18 86 QUAD3, three cycles of the QUAD-SHOT regimen; QUAD3 + IAC, QUAD3 with intra-arterial chemotherapy; QUAD4, four cycles of the QUAD-SHOT regimen. Tumor response The tumor responses in each group are presented in Table 4 . The CR and PR rates were 83.3% in QUAD3, 60% in QUAD3 + IAC, and 77% in QUAD4. Fisher’s exact test indicated no statistically significant differences between the groups (QUAD3 vs. QUAD3 + IAC, p = 0.545; QUAD3 vs. QUAD4, p > 0.99). Table 4 CR and PR rates of the QUAD-SHOT regimens (n = 24*) Factors n CR PR SD PD CR and PR rates QUAD3 6 1 4 1 0 83.3% QUAD3 + IAC 5 2 1 2 0 60% QUAD4 13 2 8 3 0 77% * One case involving an indeterminate skin lesion was excluded from the table because the degree of reduction could not be assessed accurately. CR, complete response; PD, progressive disease; PR, partial response; QUAD3, three cycles of the QUAD-SHOT regimen; QUAD3 + IAC, QUAD3 with intra-arterial chemotherapy; QUAD4, four cycles of the QUAD-SHOT regimen; SD, stable disease. Local control Six-month LC was calculated as 66.7% (95% CI: 29.6%–96.8%) in the QUAD3 group (n = 6), 40.0% (95% CI: 9.2–93.3%) in the QUAD3 + IAC group (n = 5), and 77.1% (95% CI: 51.6%–95.1%) in the QUAD4 group (n = 14) (p = 0.791, based on the overall Gray test). The CIs were broad due to the limited sample size, and no statistically significant differences were observed among the groups. The cumulative incidence curves are depicted in Fig. 2 . Discussion Palliative RT is a crucial treatment option for patients with head and neck cancer who are not eligible for curative treatment. This study assessed the safety and efficacy of two modified treatment regimens: QUAD4, comprising four cycles of the standard QUAD-SHOT regimen, and QUAD3 + IAC, which incorporates IAC into three cycles of the standard regimen. There was no significant increase in adverse events with QUAD4 compared to QUAD3. No acute adverse events of grade 3 or higher were noted, indicating the safety and feasibility of QUAD4 as a treatment option. In the QUAD4 group, the symptom relief rate was 92%, and the CR and PR rate was 77%, showing favorable outcomes consistent with previously reported data. However, no statistically significant differences were found between QUAD4 and QUAD3 regarding symptom relief, CR, and PR rates. Additionally, the six-month LC rate was slightly higher in the QUAD4 group than in the QUAD3 and QUAD3 + IAC groups, although this difference was not statistically significant. Lok et al. [ 9 ] demonstrated improved overall survival with an increased number of treatment cycles, suggesting that extending treatment to four cycles could improve symptom palliation and local control. While QUAD4 is not currently considered more effective than QUAD3, adding a fourth cycle may offer a potentially beneficial treatment approach in cases where the response to QUAD3 is insufficient or in instances of recurrence after three cycles. In the QUAD3 + IAC group, hematological adverse events of grade 3 or higher were observed. Although all patients showed improvement with conservative management, the results raise safety concerns regarding this treatment approach. There were no significant differences in symptom relief, CR, and PR rates, as well as in the six-month LC, indicating the need for careful consideration of indications for IAC combined therapy. Previous studies have shown that combining IAC with RT leads to better therapeutic outcomes compared to standard irradiation for bulky diseases [ 16 – 19 ]. Incorporating IAC into the QUAD-SHOT regimen could enhance symptom palliation in such scenarios, warranting clinical trials focusing on these specific disease types. This study had several limitations. First, it is a retrospective, single-institution analysis with a small sample size. Selection bias may have influenced the results and analysis due to variations in patient characteristics, such as disease stage and concomitant therapies. Patients with a poor response after QUAD3 may have transitioned to QUAD4, potentially impacting the LC outcomes. Second, symptom relief—particularly pain relief—was not assessed using standardized patient-reported outcome measures or validated symptom scales, because these instruments were not routinely collected during the study period. Although we applied a pre-specified chart-based definition incorporating physician-documented symptoms and analgesic changes, this approach is subject to documentation variability and potential misclassification. The safety profile of QUAD4 was comparable to that of QUAD3, with no severe acute adverse events. Although a numerically higher symptom relief rate was observed in the QUAD4 group, the difference was not statistically significant. These findings suggest that extending the treatment to four cycles can be considered without compromising patient safety; however, larger prospective studies are warranted to determine whether this approach provides a true clinical benefit in symptom control. Conclusion Among the mQUAD regimens, QUAD4 demonstrated comparable safety to the standard QUAD3 regimen. QUAD4 exhibited a higher rate of symptom relief without severe toxicity, indicating its potential as a palliative option. However, the presence of significant hematological toxicity in QUAD3 + IAC highlights the importance of meticulous patient selection and monitoring. Abbreviations 3D-CRT Three-dimensional conformal radiation therapy CR Complete response CT Computed tomography CTCAE Common Terminology Criteria for Adverse Events CTV Clinical target volume ECOG PS Eastern Cooperative Oncology Group performance status GTV Gross tumor volume IAC Intra-arterial chemotherapy IMRT Intensity-modulated radiation therapy LLMs Large language models LC Local control mQUAD Modified QUAD-SHOT MRI Magnetic resonance imaging PD Progressive disease PR Partial response PS Performance status PTV Planning target volume QUAD3 Three cycles of the QUAD-SHOT regimen QUAD3 + IAC QUAD3 with intra-arterial chemotherapy QUAD4 Four cycles of the QUAD-SHOT regimen RECIST Response Evaluation Criteria in Solid Tumors RT Radiation therapy RTOG Radiation Therapy Oncology Group SD Stable disease Declarations Clinical trial number: not applicable. Ethic s approval and consent to participate : This study was approved by the Institutional Review Board of the University of the Ryukyus (approval no. 23-2130-00-00-00) and was conducted in accordance with the principles of the Declaration of Helsinki. Owing to the retrospective design of the study, the requirement for informed consent was waived, and an opt-out approach was employed by providing information on the institutional website in accordance with ethical guidelines. C onsent for publication : Not applicable. Availability of d ata and m aterial s : The datasets generated and/or analyzed in the current study are available from the corresponding author upon reasonable request. Co mpeting i nterest s : The authors declare that they have no competing interests. Funding: This research received no specific grants from any funding agency. Authors’ contributions: Wataru Yamagata: Conceptualization, methodology, data curation, formal analysis, and writing—original draft. Takuro Ariga: Writing—review and editing. Joichi Heianna: Writing—review and editing. Hitoshi Maemoto: Writing—review and editing. Shota Kinjo: Investigation. Yuka Ota: Investigation. Mayako Zaha: Investigation. Akihiro Nishie: Supervision and writing—review and editing. All authors read and approved the final manuscript. Acknowledgements: We would like to thank Editage (www.editage.com) for English language editing. References Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003;349:2091–8. https://doi.org/10.1056/NEJMoa031317 . Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre JL, Greiner RH, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350:1945–52. https://doi.org/10.1056/NEJMoa032641 . 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Dose-finding and efficacy confirmation trial of the superselective intra-arterial infusion of cisplatin and concomitant radiation therapy for locally advanced maxillary sinus cancer (JCOG1212): results of the efficacy confirmation phase in patients with T4aN0M0. Int J Radiat Oncol Biol Phys. 2024;118:1271–81. https://doi.org/10.1016/j.ijrobp.2023.11.031 . Heianna J, Makino W, Hirakawa H, Yamashita Y, Tomita H, Murayama S. Therapeutic efficacy of intra-arterial docetaxel and nedaplatin infusion concomitant with radiotherapy for T4 maxillary sinus squamous cell carcinoma. Int J Oral Maxillofac Surg. 2022;51:1123–30. https://doi.org/10.1016/j.ijom.2021.12.006 . Heianna J, Makino W, Hirakawa H, Agena S, Tomita H, Ariga T, et al. Therapeutic efficacy of selective intra-arterial chemoradiotherapy with docetaxel and nedaplatin for fixed bulky nodal disease in head and neck cancer of unknown primary. Eur Arch Otorhinolaryngol. 2022;279:3105–13. https://doi.org/10.1007/s00405-021-07121-9 . Bertino G, Occhini A, Falco CE, Porta C, Corbella F, Colombo S, et al. Concurrent intra-arterial carboplatin administration and radiation therapy for the treatment of advanced head and neck squamous cell carcinoma: short term results. BMC Cancer. 2009;9:313. https://doi.org/10.1186/1471-2407-9-313 . Kanda Y. Investigation of the freely available easy-to-use software EZR for medical statistics. Bone Marrow Transpl. 2013;48:452–8. https://doi.org/10.1038/bmt.2012.244 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 17 May, 2026 Reviewers agreed at journal 21 Apr, 2026 Reviewers invited by journal 19 Apr, 2026 Editor assigned by journal 11 Mar, 2026 Submission checks completed at journal 11 Mar, 2026 First submitted to journal 09 Mar, 2026 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-9073888","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":627997377,"identity":"541cf076-ca39-4c87-b440-114746f0bd1d","order_by":0,"name":"Wataru Yamagata","email":"data:image/png;base64,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","orcid":"","institution":"University of the Ryukyus","correspondingAuthor":true,"prefix":"","firstName":"Wataru","middleName":"","lastName":"Yamagata","suffix":""},{"id":627997379,"identity":"ab2140de-70ef-4e5f-ac6b-686872d1f672","order_by":1,"name":"Takuro Ariga","email":"","orcid":"","institution":"Nakagami Hospital","correspondingAuthor":false,"prefix":"","firstName":"Takuro","middleName":"","lastName":"Ariga","suffix":""},{"id":627997381,"identity":"b2e9fb9c-e9c1-4e86-ae06-4048a2327bc9","order_by":2,"name":"Joichi Heianna","email":"","orcid":"","institution":"Nanbu Tokushukai Hospital","correspondingAuthor":false,"prefix":"","firstName":"Joichi","middleName":"","lastName":"Heianna","suffix":""},{"id":627997383,"identity":"1db04fc7-c9fc-4132-b815-9cefe3d8c674","order_by":3,"name":"Hitoshi Maemoto","email":"","orcid":"","institution":"University of the Ryukyus","correspondingAuthor":false,"prefix":"","firstName":"Hitoshi","middleName":"","lastName":"Maemoto","suffix":""},{"id":627997387,"identity":"dba2dc1b-0675-4a00-8c00-f7a2d193a37d","order_by":4,"name":"Shota Kinjo","email":"","orcid":"","institution":"Nanbu Tokushukai Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shota","middleName":"","lastName":"Kinjo","suffix":""},{"id":627997389,"identity":"75385cb2-8f7b-479a-bce1-dad6a27b99ee","order_by":5,"name":"Yuka Ota","email":"","orcid":"","institution":"University of the Ryukyus","correspondingAuthor":false,"prefix":"","firstName":"Yuka","middleName":"","lastName":"Ota","suffix":""},{"id":627997390,"identity":"30bf7085-d0da-4b6f-8273-53179e38fb08","order_by":6,"name":"Mayako Zaha","email":"","orcid":"","institution":"Naha City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mayako","middleName":"","lastName":"Zaha","suffix":""},{"id":627997392,"identity":"86d655d8-8268-46c7-bf6e-85464a365869","order_by":7,"name":"Akihiro Nishie","email":"","orcid":"","institution":"University of the Ryukyus","correspondingAuthor":false,"prefix":"","firstName":"Akihiro","middleName":"","lastName":"Nishie","suffix":""}],"badges":[],"createdAt":"2026-03-09 13:54:55","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9073888/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9073888/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107917996,"identity":"912c5521-a937-4e40-a764-e40c43a0b202","added_by":"auto","created_at":"2026-04-27 14:27:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":180902,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of palliative radiotherapy regimens in patients with head and neck cancer. Flow diagram showing the number of patients who received QUAD-SHOT (n = 42) and other regimens (n = 68). The numbers of patients who completed ≥3 cycles or 1–2 cycles are shown. Subgroups of QUAD-SHOT including QUAD3 (n = 6), QUAD3+IAC (n = 5), and QUAD4 (n = 14) are also presented.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-9073888/v1/96a54945ec219ce7211c63ea.png"},{"id":107917953,"identity":"b8a361dd-cd3d-44e5-b38f-14d2a036bd0e","added_by":"auto","created_at":"2026-04-27 14:26:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":119915,"visible":true,"origin":"","legend":"\u003cp\u003eLocal control in patients receiving QUAD3, QUAD3+IAC and QUAD4. Cumulative incidence curves of in-field local failure are shown for patients treated with QUAD3, QUAD3+IAC, and QUAD4. The comparison of local control among these groups was not statistically significant (p = 0.791). Numbers at risk are indicated below the x-axis.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-9073888/v1/a12de83d2b3ba0edce36fdcb.png"},{"id":108007475,"identity":"ccc6f259-f4b5-44c4-af5a-9369a4b771e2","added_by":"auto","created_at":"2026-04-28 13:00:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":627778,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9073888/v1/20e50a96-1c70-4ff7-b10e-d24bf7fb94dc.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eSafety and Symptom Relief of a Modified QUAD-SHOT Regimen in Head and Neck Cancer: A Single-Center Retrospective Study\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eThe utilization of radical treatments such as surgery and chemoradiotherapy for patients with head and neck cancer poses significant challenges, mainly due to factors like age, performance status (PS), distant metastasis, and potential complications. Despite undergoing curative treatment, local and regional recurrences have been documented at a rate of 11\u0026ndash;53% [\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Furthermore, the management of recurrent cases is complicated by the patient's deteriorating general condition and the limited availability of additional treatment options due to prior therapies. In such scenarios, radiation therapy (RT) is employed to alleviate symptoms such as pain, bleeding, dysphagia, and airway constriction caused by the tumor. In the 1980s, the Radiation Therapy Oncology Group (RTOG) introduced the \u0026ldquo;QUAD-SHOT regimen,\u0026rdquo; a palliative hypofractionated RT approach [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This regimen entails administering 3.5\u0026ndash;3.7 Gy twice daily over two days per cycle, totaling 14\u0026ndash;14.4 Gy. The standard protocol consists of three cycles repeated every three to six weeks, resulting in a total of 42\u0026ndash;43.2 Gy/12 fr (QUAD3) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Initially designed for treating pelvic malignant tumors, the QUAD-SHOT regimen has garnered broad acceptance as a palliative RT strategy for head and neck cancer due to its proven safety and efficacy [\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12 CR13 CR14\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough QUAD3 can achieve a favorable treatment response, the optimal number of QUAD-SHOT cycles remains unclear. New treatment methods are being developed to identify the appropriate number of cycles to enhance efficacy and safety. Lok et al. [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] demonstrated that receiving four or more QUAD-SHOT cycles was significantly associated with a palliative response, leading to symptom improvement in 89% of patients. In this cohort, which included patients receiving four or more QUAD-SHOT cycles, acute toxicities comprised an overall grade 2 rate of 28% and grade 3 mucositis or dermatitis in 5% of patients, with no acute events of grade 4 or higher; late events of grade 3 or higher were not observed.\u003c/p\u003e \u003cp\u003eAdditionally, various chemotherapy regimens are under investigation as adjuvant therapies to enhance the efficacy of the QUAD-SHOT regimens. Carrascosa et al. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] documented improved outcomes with paclitaxel, showing symptomatic improvement in 89.5% of patients without any grade 2 or higher late adverse events. Gamez et al. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] found that all patients treated with carboplatin or cetuximab experienced symptomatic improvement, with 34.8% encountering grade 2 acute adverse events and no grade 3 or higher events. In RTOG 8502 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], 8.5% of patients experienced acute grade 2 mucositis, with no cases of grade 3 or higher, and 28.5% had late grade 2 or lower salivary gland toxicities. Notably, the use of multiple QUAD-SHOT cycles or systemic chemotherapy could potentially enhance therapeutic efficacy but also increase toxicities. Several regimens combining RT with intra-arterial chemotherapy (IAC) have been documented [\u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Among these, docetaxel plus nedaplatin- and carboplatin-based regimens do not necessitate prophylactic hydration and carry a low risk of nephrotoxicity. Furthermore, these regimens have shown high therapeutic efficacy in patients with large tumors and bulky disease [\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurther improvements in treatment efficacy, without escalating toxicity, are still needed. In this context, our institution has implemented the use of standard QUAD3 plus an additional one cycle (QUAD4) or combined with ultra-selective IAC injection (QUAD3\u0026thinsp;+\u0026thinsp;IAC) for patients with head and neck cancer. We defined \u0026ldquo;modified QUAD-SHOT (mQUAD)\u0026rdquo; as the collective term for QUAD4 and QUAD3\u0026thinsp;+\u0026thinsp;IAC. This study was conducted to evaluate the safety and efficacy of mQUAD and to provide insights into palliative RT options for head and neck malignancies.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003e We retrospectively reviewed patients with head and neck cancer who underwent palliative treatment with the QUAD3 or mQUAD at the University of the Ryukyus Hospital between April 2012 and March 2023. For each patient, the indications for each treatment regimen were determined by a Cancer Board consisting mainly of otolaryngologists and radiation oncologists. The decision to extend the QUAD-SHOT regimen to QUAD4 and incorporate QUAD3\u0026thinsp;+\u0026thinsp;IAC was based on institutional policy. In general, if the patient\u0026rsquo;s condition was acceptable, QUAD4 was administered. IAC was administered at the physician\u0026rsquo;s discretion when the patient demonstrated good PS (0\u0026ndash;1), had a bulky tumor, and maintained adequate organ function.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRadiation therapy\u003c/h3\u003e\n\u003cp\u003eThe patients were simulated using computed tomography (CT) with a dedicated thermoplastic head and neck mask for immobilization (Bluebag\u0026trade;, Elekta AB, Stockholm, Sweden). The gross tumor volume (GTV) and clinical target volume (CTV) were determined by the attending radiation oncologist based on the patient\u0026rsquo;s condition and tumor status. Planning target volume (PTV) margins of 5 mm were added to compensate for the setup errors. CT simulation was performed for each cycle, and adaptive treatment planning was performed if the target or body contour changed. The treatment plans included three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT). The decision to use 3D-CRT or IMRT was made on a case-by-case basis, depending on the morphological complexity and location of the PTV and organs at risk. RT was administered according to the QUAD-SHOT regimen, consisting of two daily fractions of 3.5 Gy separated by at least six hours, for two consecutive days, totaling 14 Gy over four fractions per cycle. Each QUAD-SHOT cycle was principally scheduled at four-week intervals, with variations ranging from three to six weeks, based on patient convenience or other clinical considerations. RT was performed using a linear accelerator system (TrueBeam; Varian Medical Systems, Palo Alto, CA, USA) and a helical tomotherapy platform (Radixact; Accuray Incorporated, Sunnyvale, CA, USA).\u003c/p\u003e\n\u003ch3\u003eConcomitant intra-arterial chemotherapy\u003c/h3\u003e\n\u003cp\u003eIAC was administered three times concurrently with each QUAD-SHOT cycle. Carboplatin (AUC 3) was administered for non-tongue oral cancers, whereas nedaplatin (80 mg/m\u003csup\u003e2\u003c/sup\u003e) and docetaxel (60 mg/m\u003csup\u003e2\u003c/sup\u003e) were administered for other head and neck cancers. If the patient's condition worsened, the chemotherapy dose was reduced, or IAC was suspended. Before arteriography, systemic heparin (700 units per 10 kg of body weight) was administered to prevent clot formation. An additional 500 units were injected intravenously once every hour during the procedure. A 5-Fr catheter and coaxially placed 2.0-Fr microcatheter were used to selectively catheterize the arteries supplying the tumor. Intraoperative cone-beam CT was performed to identify all tumor-feeding arteries and determine the anticancer agent dose for each vessel. Doses were determined according to the percentage of the tumor volume supplied by the target artery, which was measured intraoperatively using angiography-assisted cone-beam CT as a proportion of the total tumor volume. Before IAC, contrast medium was infused into the target artery using a syringe driver. The maximum flow rate at which there was no extra overflow of the contrast medium from the target artery was confirmed fluoroscopically; this rate of contrast medium infusion was considered the optimal infusion rate of the anticancer agents.\u003c/p\u003e\n\u003ch3\u003eEvaluation\u003c/h3\u003e\n\u003cp\u003eThe primary endpoints were adverse events and symptom relief rates compared with mQUAD and QUAD3. Toxicities were scored according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Acute adverse events were defined as toxicities occurring up to three months after treatment completion, and late adverse events were defined as toxicities occurring more than three months after treatment completion. Symptom relief was evaluated through physician interviews during routine clinical visits. Pain relief was assessed retrospectively from electronic medical records. Baseline pain status was defined as the most recent clinical assessment documented within 7 days prior to the start of each QUAD-SHOT cycle, including assessments performed on the day of treatment initiation. Post-treatment pain status was evaluated at the first follow-up visit approximately 1\u0026ndash;2 weeks after completion of each cycle. Because standardized patient-reported outcome instruments or validated symptom scales were not routinely used during the study period, pain relief was operationally defined using a pre-specified chart-based algorithm incorporating symptom descriptions and analgesic changes. Pain response was categorized as: (1) improved, documented subjective pain improvement and/or reduction in analgesic requirement; (2) stable, no clear change in pain with stable analgesic use; or (3) worsened, documented pain aggravation and/or escalation of analgesics. Analgesic use was reviewed during the assessment window and classified as escalation/de-escalation (including initiation of opioids, dose increase, addition of adjuvant analgesics, or increased dosing frequency).\u003c/p\u003e \u003cp\u003eGiven the palliative intent of the QUAD-SHOT regimen and the limited overall survival observed in previous studies, which typically ranged from approximately four to seven months [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], short- to mid-term treatment outcomes were considered particularly important in this study. Among these, local control (LC) was selected as a clinically relevant metric because it influences symptom relief and quality of life. Accordingly, six-month LC, defined as freedom from in-field local progression at six months after the start of RT, was adopted as a meaningful and practical measure for evaluating the mid-term efficacy of treatment in this patient population. Local progression was determined based on either clinically apparent tumor growth on physical examination or radiological evidence of progressive disease (PD) on CT or magnetic resonance imaging (MRI), as assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.\u003c/p\u003e \u003cp\u003eAs secondary endpoints, we also evaluated six-month LC and complete response (CR) and partial response (PR) rates. Tumor response was evaluated according to RECIST version 1.1, using CT or MRI scans obtained before treatment, and those showing the best overall response in terms of tumor size after treatment. CR and PR were defined as tumor responses. Furthermore, we investigated whether the patients\u0026rsquo; medical background, tumor size, and tumor stage were associated with the safety and efficacy of mQUAD. PS was assessed using the Eastern Cooperative Oncology Group (ECOG) scale.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003ePatient characteristics, including age and CTV, were compared across the three treatment groups using the Kruskal\u0026ndash;Wallis test. Associations between clinical factors and primary and secondary endpoints were evaluated using Fisher\u0026rsquo;s exact test. The relationship between symptom relief and CTV was examined using univariate logistic regression. For the secondary endpoint, six-month LC was derived as the complement of the cumulative incidence of in-field local failure at six months using competing-risk methods; death without prior in-field progression was treated as a competing event. Between-group comparisons were performed using Gray\u0026rsquo;s test, and adjusted effects were obtained from the Fine\u0026ndash;Gray sub-distribution hazard models (two-sided 95% confidence intervals reported).\u003c/p\u003e \u003cp\u003eAll statistical analyses were performed using the EZR ver. 1.61 (Saitama Medical Centre, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of the R Commander designed to add statistical functions frequently used in biostatistics [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eUse of large language models in manuscript preparation\u003c/h2\u003e \u003cp\u003eDuring the preparation of this manuscript, LLM (ChatGPT, OpenAI) was used solely for language editing and stylistic improvements in the selected paragraphs. No sections involving the generation, analysis, or interpretation of the research data were produced using generative AI. All the scientific content was created and verified by the authors. Furthermore, no figures or visual data were generated or modified using generative AI or machine learning-based image enhancement tools.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003ePatient and treatment characteristics\u003c/h2\u003e \u003cp\u003ePalliative RT was administered to 110 patients with head and neck cancer during the study period, of whom 42 received the QUAD-SHOT regimen. The analysis involved 25 patients, excluding 17 who completed only one or two cycles of the QUAD-SHOT regimen. Among these 17 patients, treatment was discontinued due to patient refusal in six cases, clinical deterioration in seven cases, and a history of prior irradiation in two cases, despite experiencing only mild adverse events. Out of the 25 analyzed patients, six received QUAD3, five received QUAD3\u0026thinsp;+\u0026thinsp;IAC, and 14 received QUAD4. A flow diagram illustrating the patient selection process is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe patient characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median patient age was 82 years (range: 50\u0026ndash;91 years). Most patients had an ECOG PS of 1 (11 patients), followed by PS 0 and PS 2 (six patients each). Histology revealed squamous cell carcinoma in 23 (92%) patients, adenocarcinoma in one patient, and sebaceous cancer in one patient. Fifteen patients had primary tumors, and 10 patients had recurrent tumors. Among those with primary tumors, 13 were classified as having clinical stage III\u0026ndash;IV disease. Two patients had clinical stage II disease; one declined long-term RT, while the other received the QUAD-SHOT regimen because definitive RT was deemed infeasible owing to severe aortic stenosis. Concomitant chemotherapy was administered to five patients, all of whom were in the QUAD3\u0026thinsp;+\u0026thinsp;IAC group. None of the patients underwent systemic chemotherapy. Three patients received a regimen of nedaplatin and docetaxel, and two patients received carboplatin. Sixteen (73%) patients were treated with IMRT. Three patients received both 3D-CRT and IMRT during the treatment period to account for potential changes in tumor shape as the tumor shrank and to minimize the risk of overdose to adjacent normal organs. There were no statistically significant differences in baseline characteristics, including age, ECOG PS, tumor site, histology, clinical stage, CTV volume, or radiotherapy technique, among the three treatment groups. The median follow-up period for all patients was 251 days (range: 68\u0026ndash;1301 days).\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\u003eComparison of patient and treatment characteristics among treatment groups (n\u0026thinsp;=\u0026thinsp;25)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFactors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eQUAD3 (n\u0026thinsp;=\u0026thinsp;6)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eQUAD3\u0026thinsp;+\u0026thinsp;IAC (n\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eQUAD4 (n\u0026thinsp;=\u0026thinsp;14)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, median (range), years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e84 (75\u0026ndash;91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73 (50\u0026ndash;86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e82 (56\u0026ndash;91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.179\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.844\u0026Dagger;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.262\u0026Dagger;(0\u0026ndash;1 vs 2\u0026ndash;3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor site\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.907\u0026Dagger;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNasal cavity and paranasal sinus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOral cavity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOropharynx\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLarynx\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u0026Dagger;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u0026sect;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIVA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIVB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIVC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCTV (ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e180 (26\u0026ndash;467)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e138 (43\u0026ndash;586)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e196 (33\u0026ndash;426)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.891\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiotherapy technique\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.558\u0026Dagger;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3D-CRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIMRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBoth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u0026dagger;Kruskal\u0026ndash;Wallis test for non-parametric continuous variables\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u0026Dagger;Fisher\u0026rsquo;s exact test for categorical variables\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u0026sect;Adenocarcinoma and sebaceous cancer\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eCTV, clinical target volume; ECOG PS, Eastern Cooperative Oncology Group Performance Status; IMRT, intensity-modulated radiation therapy; QUAD3, three cycles of the QUAD-SHOT regimen; QUAD3\u0026thinsp;+\u0026thinsp;IAC, QUAD3 with intra-arterial chemotherapy; QUAD4, four cycles of the QUAD-SHOT regimen; 3D-CRT, three-dimensional conformal radiation therapy.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eToxicity\u003c/h2\u003e \u003cp\u003eThe adverse events in each group are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. No acute grade 3 or higher adverse events were noted in QUAD3, while grade 2 mucositis occurred in two cases. In the QUAD3\u0026thinsp;+\u0026thinsp;IAC group, grade 4 neutropenia was observed in one case, grade 3 anemia in one case, and grade 2 mucositis in two cases. Acute adverse events of grade 3 or higher were observed in patients receiving the nedaplatin and docetaxel regimens. No hematologic adverse events were detected in patients treated with the carboplatin regimens. Neutropenia improved following the administration of granulocyte colony-stimulating factor, while anemia improved with observation. In QUAD4, no acute grade 3 adverse events were observed, and grade 2 adverse events were noted in three cases, including dermatitis, mucositis, dacryoadenitis, and anorexia. No statistically significant differences in acute adverse events were observed between the groups (QUAD3 vs. QUAD3\u0026thinsp;+\u0026thinsp;IAC, p\u0026thinsp;=\u0026thinsp;0.182; QUAD3 vs. QUAD4, p\u0026thinsp;\u0026gt;\u0026thinsp;0.99). No late adverse events were observed for QUAD3 or QUAD4. In the case of soft palate cancer with mandibular invasion in QUAD3\u0026thinsp;+\u0026thinsp;IAC, grade 3 mandibular osteonecrosis was observed 3 years and 2 months after the completion of RT.\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\u003eToxicity of the QUAD-SHOT regimens (n\u0026thinsp;=\u0026thinsp;25)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFactors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"8\" nameend=\"c10\" namest=\"c3\"\u003e \u003cp\u003eToxicity\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eGrade 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eGrade 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eGrade 3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eGrade 4\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQUAD3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQUAD3\u0026thinsp;+\u0026thinsp;IAC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQUAD4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eQUAD3, three cycles of the QUAD-SHOT regimen; QUAD3\u0026thinsp;+\u0026thinsp;IAC, QUAD3 with intra-arterial chemotherapy; QUAD4, four cycles of the QUAD-SHOT regimen.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSymptom relief\u003c/h2\u003e \u003cp\u003eA total of 21 patients were symptomatic, presenting with pain at 16 sites, bleeding, and exudate at four sites, and dysphagia at two sites. The rates of symptom relief for each group are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Symptom relief was achieved in four of five patients (80%) in the QUAD3 group, three of four patients (75%) in the QUAD3\u0026thinsp;+\u0026thinsp;IAC group, and 11 of 12 patients (92%) in the QUAD4 group. No statistically significant differences were observed between the groups (QUAD3 vs. QUAD3\u0026thinsp;+\u0026thinsp;IAC, p\u0026thinsp;\u0026gt;\u0026thinsp;0.99; QUAD3 vs. QUAD4, p\u0026thinsp;=\u0026thinsp;0.515). Overall, symptom relief was achieved in 18 (86%) patients. Specifically, pain relief was achieved in 14 of 16 sites, while bleeding and exudate improved in all four sites, and dysphagia improved in one of two patients. No significant association was observed between symptom relief and CTV (odds ratio [OR], 0.999; 95% confidence interval [CI], 0.991\u0026ndash;1.01; p\u0026thinsp;=\u0026thinsp;0.686). Furthermore, no significant association was found between symptom relief and either histological type (p\u0026thinsp;\u0026gt;\u0026thinsp;0.99) or performance status (0\u0026ndash;1 vs. \u0026ge; 2; p\u0026thinsp;\u0026gt;\u0026thinsp;0.99).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSymptom relief of the QUAD-SHOT regimens (n\u0026thinsp;=\u0026thinsp;21)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFactors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eSymptom relief\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQUAD3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQUAD3\u0026thinsp;+\u0026thinsp;IAC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQUAD4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eQUAD3, three cycles of the QUAD-SHOT regimen; QUAD3\u0026thinsp;+\u0026thinsp;IAC, QUAD3 with intra-arterial chemotherapy; QUAD4, four cycles of the QUAD-SHOT regimen.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eTumor response\u003c/h2\u003e \u003cp\u003eThe tumor responses in each group are presented in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. The CR and PR rates were 83.3% in QUAD3, 60% in QUAD3\u0026thinsp;+\u0026thinsp;IAC, and 77% in QUAD4. Fisher\u0026rsquo;s exact test indicated no statistically significant differences between the groups (QUAD3 vs. QUAD3\u0026thinsp;+\u0026thinsp;IAC, p\u0026thinsp;=\u0026thinsp;0.545; QUAD3 vs. QUAD4, p\u0026thinsp;\u0026gt;\u0026thinsp;0.99).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCR and PR rates of the QUAD-SHOT regimens (n\u0026thinsp;=\u0026thinsp;24*)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFactors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCR and PR rates\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQUAD3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e83.3%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQUAD3\u0026thinsp;+\u0026thinsp;IAC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e60%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQUAD4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e77%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e* One case involving an indeterminate skin lesion was excluded from the table because the degree of reduction could not be assessed accurately.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eCR, complete response; PD, progressive disease; PR, partial response; QUAD3, three cycles of the QUAD-SHOT regimen; QUAD3\u0026thinsp;+\u0026thinsp;IAC, QUAD3 with intra-arterial chemotherapy; QUAD4, four cycles of the QUAD-SHOT regimen; SD, stable disease.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eLocal control\u003c/h2\u003e \u003cp\u003eSix-month LC was calculated as 66.7% (95% CI: 29.6%\u0026ndash;96.8%) in the QUAD3 group (n\u0026thinsp;=\u0026thinsp;6), 40.0% (95% CI: 9.2\u0026ndash;93.3%) in the QUAD3\u0026thinsp;+\u0026thinsp;IAC group (n\u0026thinsp;=\u0026thinsp;5), and 77.1% (95% CI: 51.6%\u0026ndash;95.1%) in the QUAD4 group (n\u0026thinsp;=\u0026thinsp;14) (p\u0026thinsp;=\u0026thinsp;0.791, based on the overall Gray test). The CIs were broad due to the limited sample size, and no statistically significant differences were observed among the groups. The cumulative incidence curves are depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003ePalliative RT is a crucial treatment option for patients with head and neck cancer who are not eligible for curative treatment. This study assessed the safety and efficacy of two modified treatment regimens: QUAD4, comprising four cycles of the standard QUAD-SHOT regimen, and QUAD3\u0026thinsp;+\u0026thinsp;IAC, which incorporates IAC into three cycles of the standard regimen. There was no significant increase in adverse events with QUAD4 compared to QUAD3. No acute adverse events of grade 3 or higher were noted, indicating the safety and feasibility of QUAD4 as a treatment option. In the QUAD4 group, the symptom relief rate was 92%, and the CR and PR rate was 77%, showing favorable outcomes consistent with previously reported data. However, no statistically significant differences were found between QUAD4 and QUAD3 regarding symptom relief, CR, and PR rates. Additionally, the six-month LC rate was slightly higher in the QUAD4 group than in the QUAD3 and QUAD3\u0026thinsp;+\u0026thinsp;IAC groups, although this difference was not statistically significant. Lok et al. [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] demonstrated improved overall survival with an increased number of treatment cycles, suggesting that extending treatment to four cycles could improve symptom palliation and local control. While QUAD4 is not currently considered more effective than QUAD3, adding a fourth cycle may offer a potentially beneficial treatment approach in cases where the response to QUAD3 is insufficient or in instances of recurrence after three cycles.\u003c/p\u003e \u003cp\u003eIn the QUAD3\u0026thinsp;+\u0026thinsp;IAC group, hematological adverse events of grade 3 or higher were observed. Although all patients showed improvement with conservative management, the results raise safety concerns regarding this treatment approach. There were no significant differences in symptom relief, CR, and PR rates, as well as in the six-month LC, indicating the need for careful consideration of indications for IAC combined therapy. Previous studies have shown that combining IAC with RT leads to better therapeutic outcomes compared to standard irradiation for bulky diseases [\u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Incorporating IAC into the QUAD-SHOT regimen could enhance symptom palliation in such scenarios, warranting clinical trials focusing on these specific disease types.\u003c/p\u003e \u003cp\u003eThis study had several limitations. First, it is a retrospective, single-institution analysis with a small sample size. Selection bias may have influenced the results and analysis due to variations in patient characteristics, such as disease stage and concomitant therapies. Patients with a poor response after QUAD3 may have transitioned to QUAD4, potentially impacting the LC outcomes. Second, symptom relief\u0026mdash;particularly pain relief\u0026mdash;was not assessed using standardized patient-reported outcome measures or validated symptom scales, because these instruments were not routinely collected during the study period. Although we applied a pre-specified chart-based definition incorporating physician-documented symptoms and analgesic changes, this approach is subject to documentation variability and potential misclassification. The safety profile of QUAD4 was comparable to that of QUAD3, with no severe acute adverse events. Although a numerically higher symptom relief rate was observed in the QUAD4 group, the difference was not statistically significant. These findings suggest that extending the treatment to four cycles can be considered without compromising patient safety; however, larger prospective studies are warranted to determine whether this approach provides a true clinical benefit in symptom control.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAmong the mQUAD regimens, QUAD4 demonstrated comparable safety to the standard QUAD3 regimen. QUAD4 exhibited a higher rate of symptom relief without severe toxicity, indicating its potential as a palliative option. However, the presence of significant hematological toxicity in QUAD3\u0026thinsp;+\u0026thinsp;IAC highlights the importance of meticulous patient selection and monitoring.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e3D-CRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eThree-dimensional conformal radiation therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eComplete response\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\"\u003eECOG PS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEastern Cooperative Oncology Group performance status\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\"\u003eIAC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntra-arterial chemotherapy\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\"\u003eLLMs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLarge language models\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLocal control\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003emQUAD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eModified QUAD-SHOT\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\"\u003ePD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eProgressive disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePartial response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePerformance status\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\"\u003eQUAD3\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eThree cycles of the QUAD-SHOT regimen\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eQUAD3\u0026thinsp;+\u0026thinsp;IAC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eQUAD3 with intra-arterial chemotherapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eQUAD4\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFour cycles of the QUAD-SHOT regimen\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRECIST\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eResponse Evaluation Criteria in Solid Tumors\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRadiation therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRTOG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRadiation Therapy Oncology Group\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStable disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eClinical trial number:\u003c/strong\u003e not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthic\u003c/strong\u003e\u003cstrong\u003es approval and consent to participate\u003c/strong\u003e\u003cstrong\u003e: \u003c/strong\u003eThis study was approved by the Institutional Review Board of the University of the Ryukyus (approval no. 23-2130-00-00-00) and was conducted in accordance with the principles of the Declaration of Helsinki. Owing to the retrospective design of the study, the requirement for informed consent was waived, and an opt-out approach was employed by providing information on the institutional website in accordance with ethical guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC\u003c/strong\u003e\u003cstrong\u003eonsent for publication\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of \u003c/strong\u003e\u003cstrong\u003ed\u003c/strong\u003e\u003cstrong\u003eata and \u003c/strong\u003e\u003cstrong\u003em\u003c/strong\u003e\u003cstrong\u003eaterial\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e The datasets generated and/or analyzed in the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCo\u003c/strong\u003e\u003cstrong\u003empeting\u003c/strong\u003e\u003cstrong\u003ei\u003c/strong\u003e\u003cstrong\u003enterest\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This research received no specific grants from any funding agency.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u003c/strong\u003e Wataru Yamagata: Conceptualization, methodology, data curation, formal analysis, and writing\u0026mdash;original draft. Takuro Ariga: Writing\u0026mdash;review and editing. Joichi Heianna: Writing\u0026mdash;review and editing. Hitoshi Maemoto: Writing\u0026mdash;review and editing. Shota Kinjo: Investigation. Yuka Ota: Investigation. Mayako Zaha: Investigation. Akihiro Nishie: Supervision and writing\u0026mdash;review and editing. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e We would like to thank Editage (www.editage.com) for English language editing.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eForastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. 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Eur Arch Otorhinolaryngol. 2022;279:3105\u0026ndash;13. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00405-021-07121-9\u003c/span\u003e\u003cspan address=\"10.1007/s00405-021-07121-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBertino G, Occhini A, Falco CE, Porta C, Corbella F, Colombo S, et al. Concurrent intra-arterial carboplatin administration and radiation therapy for the treatment of advanced head and neck squamous cell carcinoma: short term results. BMC Cancer. 2009;9:313. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/1471-2407-9-313\u003c/span\u003e\u003cspan address=\"10.1186/1471-2407-9-313\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKanda Y. Investigation of the freely available easy-to-use software EZR for medical statistics. Bone Marrow Transpl. 2013;48:452\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/bmt.2012.244\u003c/span\u003e\u003cspan address=\"10.1038/bmt.2012.244\" 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":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"radiation-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"raon","sideBox":"Learn more about [Radiation Oncology](http://ro-journal.biomedcentral.com/)","snPcode":"13014","submissionUrl":"https://submission.nature.com/new-submission/13014/3","title":"Radiation Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Head and Neck Cancer, Palliative radiotherapy, Hypofractionated radiotherapy, QUAD-SHOT, Intra-arterial chemotherapy","lastPublishedDoi":"10.21203/rs.3.rs-9073888/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9073888/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe QUAD-SHOT regimen is a palliative radiation therapy approach for patients with advanced head and neck cancers. However, the optimal schedule balancing safety and efficacy remains unclear. This study aimed to evaluate the safety and symptom relief of modified QUAD-SHOT (mQUAD) regimens by comparing four cycles (QUAD4), three cycles combined with intra-arterial chemotherapy (QUAD3\u0026thinsp;+\u0026thinsp;IAC), and the standard three-cycle regimen (QUAD3).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe retrospectively analyzed 25 patients treated at the University of the Ryukyus Hospital between April 2012 and March 2023: six received QUAD3, five received QUAD3\u0026thinsp;+\u0026thinsp;IAC, and 14 received QUAD4. Primary endpoints were acute or late adverse events and symptom relief. Toxicities were graded using the Common Terminology Criteria for Adverse Events v5.0.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eNo grade\u0026thinsp;\u0026ge;\u0026thinsp;3 acute adverse events occurred in QUAD3 or QUAD4, while two grade 3\u0026ndash;4 hematologic adverse events were observed in the QUAD3\u0026thinsp;+\u0026thinsp;IAC group. All these patients recovered with conservative management. Symptom relief was attained in 4 out of 5 (80%) individuals in QUAD3, 3 out of 4 (75%) in QUAD3\u0026thinsp;+\u0026thinsp;IAC, and 11 out of 12 (92%) in QUAD4. Although no significant differences were noted among the three groups, the QUAD4 cohort demonstrated a higher rate of symptom relief.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eAmong the mQUAD regimens, QUAD4 demonstrated the same level of safety as QUAD3. QUAD4 showed a higher symptom relief rate without severe toxicity, suggesting its feasibility as a palliative option. However, the occurrence of severe hematological toxicity in QUAD3\u0026thinsp;+\u0026thinsp;IAC highlights the need for careful patient selection and monitoring.\u003c/p\u003e","manuscriptTitle":"Safety and Symptom Relief of a Modified QUAD-SHOT Regimen in Head and Neck Cancer: A Single-Center Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-27 14:25:33","doi":"10.21203/rs.3.rs-9073888/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-05-17T11:00:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"25330284709705372204029660104661128004","date":"2026-04-22T02:31:39+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-19T20:42:40+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-11T14:07:17+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-11T14:07:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"Radiation Oncology","date":"2026-03-09T13:45:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"radiation-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"raon","sideBox":"Learn more about [Radiation Oncology](http://ro-journal.biomedcentral.com/)","snPcode":"13014","submissionUrl":"https://submission.nature.com/new-submission/13014/3","title":"Radiation Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"92d37b75-21d0-4e58-aecd-e408a37d1fcc","owner":[],"postedDate":"April 27th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-17T11:00:00+00:00","index":17,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-27T14:25:38+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-27 14:25:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9073888","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9073888","identity":"rs-9073888","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}