Efficacy and safety of diffusing alpha-emitter radiation therapy (DaRT) for head and neck cancer recurrence after radiotherapy

Efficacy and safety of diffusing alpha-emitter radiation therapy (DaRT) for head and neck cancer recurrence after radiotherapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and safety of diffusing alpha-emitter radiation therapy (DaRT) for head and neck cancer recurrence after radiotherapy Ryo-ichi Yoshimura, Kazuma Toda, Hiroshi Watanabe, Masahiko Miura, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5335358/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Feb, 2025 Read the published version in International Journal of Clinical Oncology → Version 1 posted 5 You are reading this latest preprint version Abstract Background To evaluate the efficacy and safety of diffusing alpha-emitter radiation therapy (DaRT) for recurrent head and neck cancer (rHNC) after radiotherapy. Methods This study was a multicenter prospective clinical trial. Eligibility criteria included all patients with biopsy-proven rHNC, history of radiotherapy. The efficacy of DaRT was evaluated in terms of tumor shrinkage after 10 weeks of DaRT seed implantation. To assess safety of DaRT, radioactivity levels in blood and urine were measured, and incidence and grade of adverse events (AEs) were evaluated. Results Between 2019 and 2021, DaRT was performed in 11 patients and completed in 10 patients with 11 tumors. The tumor sites included the tongue (n = 3), buccal mucosa (2), lips (2), floor of the mouth (1), soft palate (1), nose (1), and subcutaneous layer (1). Nine tumors were confirmed to be squamous cell carcinoma, and the remaining two tumors were basal cell carcinoma and neuroblastoma. Complete response (CR) and partial response (PR) were observed in three and six patients, respectively. The response rate was 81.8%. The maximum average radioactivity levels in blood and urine were 42.5 Bq/cm 3 and 8.4 Bq/cm 3 , respectively, on the second day after implantation. Forty AEs were observed in all 11 patients; they included 22 Grade 1 AEs, 16 Grade 2, and two Grade 3 (hypertension and seed remnants). Conclusion The initial response of rHNC after radiotherapy to DaRT was favorable, and the incidence and grade of AEs were acceptable, as compared to existing therapies. alpha-emitter radiation therapy recurrent head and neck cancer response rate adverse event Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Radiotherapy with or without concurrent chemotherapy has been established as the primary treatment for various subsites and stages of head and neck cancer (HNC). However, the incidence of relapse is reported in 15–50% of patients [ 1 , 2 ]. Although salvage surgery is considered to be the best possible curative treatment for these patients, most recurrences are inoperable, given the infiltrative property of recurrent tumors and the comorbidity or poor performance status of pretreated patients [ 1 ]. Re-irradiation is a therapeutic alternative for patients who are not candidates for surgical treatment, but severe toxicity was reported in 18–75% of patients [ 1 , 3 ]. Chemotherapy with cisplatin or cisplatin in combination with other anticancer agents has been used to treat patients with recurrent and/or metastatic HNC, and response rates have been high with improvement in overall survival compared to best supportive care [ 4 , 5 ]. Moreover, the combination of chemotherapy (cisplatin and fluorouracil) and monoclonal antibody therapy (cetuximab) significantly improved overall survival with an absolute advantage of 2.6 months in comparison with chemotherapy alone (7.4 months). This combination therapy has become the standard of care for recurrent head and neck cancer (rHNC). However, due to higher incidence of grade 3–4 toxicities (82%), administration of this regimen has not been indicated for all of these patients [ 4 , 6 ]. Immune checkpoint inhibitors have demonstrated the potential to control cancer by immune activation, but the clinical trials using pembrolizumab or nivolumab for the treatment of patients with recurrent and/or metastatic head and neck squamous cell carcinoma (SCC) showed that the overall response rates were 13–18% and grade 3–4 adverse events (AEs) were reported in 9–15% [ 4 , 7 – 9 ]. These results seem to indicate that the response rate for rHNC has been improved, but is still low, and can only be applied to a limited number of patients in light of expected AEs. As a result, many patients with rHNC continue to suffer from various symptoms but have no effective treatment options in practice. Diffusing alpha-emitter radiation therapy (DaRT) is a novel method for the delivery of alpha particles to solid tumors. The DaRT seed consists of a biocompatible, inert, and metallic scaffold with low activity of 224 Ra. Once inside the tumor, the seeds are designed to continuously release 220 Rn atoms by recoil into the tumor tissue. 220 Rn, a noble gas, diffuses freely as a free atom into surrounding tumor tissues, decaying by alpha emission up to 2–3 mm away from the seed’s surface. This emission is followed by additional alpha emissions by 216 Po at the same location and by alpha-emitting daughters of 212 Pb- 212 Bi and 212 Po. The decay chain continues until the formation of stable 208 Pb, while 212 Pb atoms entering the bloodstream are sequestered by red blood cells [ 10 – 12 ]. The therapeutic potential of alpha particles in the treatment of cancer has long been recognized because of its high linear energy transfer and short range, which minimize damage to the surrounding area. It is considered to have a high biological effect on recurrent tumors after radiotherapy. The efficacy of DaRT has been proven in a series of preclinical studies on tumors with different histologic features [ 11 – 15 ]. The seeds used in this novel therapy were produced by Alpha Tau Medical, Ltd. and, at the time this article was written, branded in regions outside of Japan as “Alpha DaRT™” technology. In this multicenter clinical trial, we evaluated the efficacy and safety of DaRT in patients with rHNC after radiotherapy. Patients and Methods Study design and patients This study was an open-label, single-arm, multicenter, prospective clinical trial. The study was conducted in accordance with the principles of the Declaration of Helsinki, international ethical guidelines of Council for International Organizations of Medical Sciences, and guidelines of Good Clinical Practice. The study protocol, informed consent form, and other relevant documents were approved by the institutional review boards and independent ethics committees of the participating hospitals, including National Cancer Center Hospital, Tohoku University Hospital, and Tokyo Medical and Dental University Hospital. All patients enrolled in this trial provided written informed consent before protocol therapy was initiated. This study included patients with biopsy-proven rHNC and a history of radiotherapy, non-response or non-adherence to medical therapy, and no other treatment options. Eligibility criteria were as follows: patients with a tumor size of ≤ 5 cm in the longest diameter, age of ≥ 18 years with an Eastern Cooperative Oncology Group Performance Status Scale of ≤ 2, a life expectancy of > 6 months, stable vital signs, platelet count of ≥ 100,000/mm 3 , prothrombin time of ≤ 1.8, written informed consent, and target tumor assessable on revised Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients were excluded, if they had ongoing treatment with immunosuppressant medications (including corticosteroids), history of allergy to anesthesia or other drugs, metastases requiring treatment, ongoing treatment with chemotherapy, immunotherapy or molecular targeting agents in the past 30 days, treatment with immune checkpoint inhibitors in the past 2 months, enrollment in another clinical trial in the past 30 days, pregnancy or lactation, or unwillingness to sign a consent form. Treatment procedure The DaRT seeds were administered using an applicator produced by Alpha Tau Medical, Ltd. (Jerusalem, Israel). Each seed consisted of a 10-mm long and 0.7-mm diameter 316LVM stainless steel tube with 224 Ra fixed to its surface with a radioactivity of 2 µCi (74 kBq). Up to six seeds were linearly threaded on a single monofilament suture, sealed in glycerine, and contained within an applicator needle [ 15 ]. First, the applicator insertion method and DaRT placement were simulated based on tumor images used for planning. The applicators were inserted into the tumor to geometrically cover the tumor with DaRT seeds at ≤ 5-mm intervals. With this insertion method, tumors could receive a minimal total dose of approximately 10 Gy by alpha-emitter radiation. This technique which results in tumor destruction has been previously demonstrated [ 11 – 14 ]. Planning included maintaining a distance of 10-mm from the major blood vessels. If tumor thickness exceeded 5 mm, multi-layer applicator insertions were planned. The number of applicators and DaRT seeds per applicator were calculated and ordered, as required by the treatment plan. According to the pre-treatment plan, DaRT seeds were inserted under local anesthesia at participating institutions on an inpatient basis. After DaRT placement, head and neck CT was used to assess final DaRT positions within the tumor for treatment quality assurance. The seeds were removed 14–21 days after implantation. Evaluation Assuming a threshold response rate of 30% and expected response rate of 70% with DaRT for locally rHNC, the number of lesions for analysis was set at 10. This is per the modified full analysis set (mFAS) method. This method includes only the patients who received treatment. The primary endpoint of this study was efficacy of DaRT as determined by response rate at 10 weeks from insertion using RECIST criteria ver1.1. Tumor size was measured directly using digital calipers or CT images, and the same measurement method was used to evaluate response in the same cases. The secondary endpoint of the study was safety of DaRT. The incidence and grade of AEs were evaluated during the observation period according to the Common Terminology Criteria for Adverse Events (CTCAE) ver5.0/ Medical Dictionary for Regulatory Activities (MedDRA) ver20.1. Additionally, radioactivity levels in the blood and urine were measured the day before insertion and on days 2, 4, and 14 after DaRT placement. These evaluations were performed by the investigators and determined at a central case review meeting. Results Patient registration Between June 2019 and December 2021, 15 patients with 16 tumors were enrolled in this study. However, four patients were excluded before treatment. The reasons for exclusion included maximum tumor diameter above 5 cm in one patient, quick progression of tumor growth with possible yield of size beyond the acceptance criteria by the start of treatment in two, and difficulty to insert treatment device (as determined by screening test) in one. The remaining 11 patients underwent the treatment procedure and were included in the full analysis set (FAS) for safety evaluation. However, one of the patients in the FAS developed severe hypertension due to patient’s anxiety during the implantation procedure, forcing the investigators to halt the implantation midway through the procedure. Therefore, DaRT seed implantation was completed in 10 patients with 11 lesions, and they constituted the mFAS for efficacy evaluation. The characteristics of the 10 patients were shown in Table 1 . Seven patients had 14 cancers in their previous medical history, and had completed treatment for these previous cancers. The 11 tumor sites treated in this study included the tongue (n = 3), buccal mucosa (2), lip (2), floor of the mouth (1), soft palate (1), nose (1), and subcutaneous layer of the head (1). Nine tumors were SCCs, one tumor was a basal cell carcinoma of the nose, and the other was a subcutaneous neuroblastoma. They all had been irradiated by conventional radiotherapy techniques, using X-ray or electron beam, intensity-modulated radiotherapy (IMRT), brachytherapy, or the combination of X-ray radiotherapy and brachytherapy. The mean volume of 11 tumors was 783 mm 3 (range: 141–1920 mm 3 ). An average of 25.6 seeds (range: 6–83) were implanted, and the treatment duration was 14 days in all 11 lesions. Radioactivity in blood and urine Radioactivity levels in blood and urine were evaluated in 10 patients in the mFAS. Outlier levels of radioactivity in blood and urine were reported in each case, and these were considered to be measurement errors and excluded from the evaluation. The average levels of radioactivity in blood were 34.7 Bq/cm 3 (maximum, 106 Bq/cm 3 ) on day 1, 42.5 Bq/cm 3 (maximum, 128) on day 2, 34.0 Bq/cm 3 (maximum, 105) on day 4, and 5.0 Bq/cm 3 (maximum, 16.9) on day 14. The average levels of radioactivity in urine were 6.6 Bq/cm 3 (maximum, 16 Bq/cm 3 ) on day 1, 8.4 Bq/cm 3 (maximum, 20) on day 2, 5.1 Bq/cm 3 (maximum, 14.6) on day 4, and 0.9 Bq/cm 3 (maximum, 2) on day 14. The radioactivity levels in both blood and urine were highest on day 2, and they decreased to about 10% of those levels on day 14. A strong correlation existed between the number of seeds and radioactivity level in blood during the entire period, with coefficients of determination (R 2 ) of 0.96, 0.98, 0.96, and 0.94 on days 1, 2, 4, and 14, respectively. The correlation between the number of seeds and radioactivity level in urine was weaker than that in blood, with R 2 of 0.88, 0.61, 0.18, and 0.93 on days 1, 2, 4, and 14, respectively. Daily changes in radioactivity levels in blood and urine for the equivalent of one implanted seed are shown in Figs. 1 a and 1 b. Tumor response Complete response (CR, Fig. 2 ), partial response (PR, Fig. 3 ), stable disease (SD), and progressive disease (PD) were observed in 27.3% (n = 3), 54.5% (6), 9.1% (1), and 9.1% (1) of the lesions, respectively (Fig. 4 a). The response (CR or PR) rate for all 11 lesions after 10 weeks was 81.8% (95% CI: 48.2–97.7%). The spider plot in Fig. 4 b shows the time course of the tumor diameter rate. The average percentage changes were + 0.37% (range: 0 to + 4.1) at week 1, − 5.2% (–24 to 0) at week 2, − 8.9% (–67 to + 8.3) at week 3, − 12.1% (–67 to 0) at week 4, − 51.4% (–100 to 0) at week 10, and − 54.8% (–100 to 0) at week 12. The lesion evaluated as SD was a subcutaneous recurrence of olfactory neuroblastoma of the head (Patient No. 3). Its lesion volume was reduced by about 70% (440/1620 mm 3 ), but the maximum diameter of the lesion, the baseline, was reduced by only 21% (5/24 mm). Therefore, the tumor was rated as SD. The second lesion, treated in a tongue cancer patient (Patient No. 6), was evaluated as PD. At week 10, the target tumor size was unchanged from baseline, but a new, untreated lesion was found in close proximity, resulting in PD based on assessment criteria. AE causally related to DaRT Altogether, 40 AEs were reported in all 11 patients in the FAS. Among the AEs, 22, 16, and two AEs were Grades 1, 2, and 3, respectively (Table 2 ). AEs related to application and device insertion were the most common, occurring as 27 AEs in nine patients. However, none of them were Grade 3 or higher. They occurred immediately or early after initiation of treatment and recovered early after the seeds were removed. Grade 3 hypertension due to patient anxiety was reported in a 79-year-old woman during the seed implantation procedure; therefore, the procedure had to be halted. The treatment was discontinued, and all implanted seeds were left behind (Grade 2 foreign body) and removed the next day. The remaining seed, a Grade 3 foreign body related to treatment procedure, was observed in Patient No. 7. Additionally, a suture remnant, a Grade 1 foreign body, was observed in this patient who had 30 DaRT seeds inserted into his 1271 mm 3 tumor. At the time of seed removal on day 14, the two seeds remained in the tongue after the suture was pulled out. During the same procedure, in another suture, two seeds detached from the suture and fell off, leaving the suture and clip in the tongue. The two remaining seeds were finally retrieved from the tongue ulcer site on week 12, and the remaining suture and clip were removed at the surgery on week 19. Discussion Popovtzer et al. [ 15 ] treated 31 SCC lesions in the skin and head and neck with DaRT and reported a 100% response rate (78.6% in CR and 21.4% in PR). Additionally, D’Andrea et al. [ 16 ] treated 10 patients with recurrent or unresectable SCC or basal cell carcinoma of the skin with DaRT and reported a 100% CR. In our study, the response rate of DaRT for rHNC was 81.8% (27.3% in CR and 54.5% in PR). DaRT was shown to be highly effective in treating localized cancer lesions, which are conventionally difficult to treat. Popovtzer et al. [ 15 ] evaluated the effect of DaRT 6 weeks after treatment and reported a good prognosis in the case of CR, whereas D’Andrea et al. [ 16 ] reported no relapse in all cases of CR 12 and 24 weeks after treatment. In our study, most of SCC lesions showed significant changes from week 4 to week 10, with no changes occurring after week 10. Whereas in non-SCC cases, the tumors continued to shrink after week 10. SCC may respond quickly to DaRT, and evaluation within 10 weeks would be prognostic. However, in our study, the CR rate was lower than those reported by Popovtzer et al. [ 15 ] and D’Andrea et al. [ 16 ]. Like our study, these studies also used RECIST ver1.1 for the evaluation. The tumors treated in our study were not larger than those in both studies, nor did we implant fewer seeds. The tumor sites reported by Popovtzer et al. were the skin (39%), ear (23%), lip (16%), tongue (10%), nose (6%), and parotid (6%), whereas D’Andrea et al. reported only cutaneous tumors. In our study, 55% of the tumors were observed in the oral cavity, and all 11 lesions previously underwent radiotherapy of approximately 50Gy or more. Therefore, they were considered to be resistant to radiotherapy, and due to the narrow space in the oral cavity and the hardness of tissues after radiotherapy, implantation of seeds in the oral cavity was challenging for us unfamiliar with existing devices. Since a high-dose region of DaRT does not diffuse much beyond 2–3 mm from the seed, the seed spatial arrangement has a strong influence on treatment effect. The CR rate must be lower in the oral cavity than on the other body surfaces because of the difficulty of seed spacing according to treatment plan. Improved insertion techniques and devices could enhance the effectiveness of treatment. The radioactivity level in blood was proportional to the number of seeds implanted from day 0 to day 14 of DaRT. The highest level of radioactivity was recorded on the second day of treatment (consistent with the buildup of 212 Pb, as described in [ 12 ]). Additionally, urine radioactivity peaked on day 2 but did not show a strong proportional relationship with the number of seeds. This finding was due to the fact that radioactivity was measured per 1 cm 3 , and radioactivity level in urine is thought to be related to the total urine volume. The decrease of activity over time after the maximum value at day two is consistent with the exponential decay of 224 Ra (with all its short-lived progeny in secular equilibrium) [ 12 ]. Popovtzer et al. [ 15 ] reported no measurable radioactivity in the blood and urine 30 days after treatment (consistent with the expectation after ~ 8 half-lives of 224 Ra). Re-irradiation is a therapeutic alternative for patients who are not candidates for surgery, but a high incidence (8.7–48%) of severe AEs such as radionecrosis, dysphagia requiring feeding tube placement, trismus, and carotid artery blowout is often reported, even with IMRT, stereotactic body irradiation, and heavy particles [ 1 , 3 ]. In our study on DaRT, 18% (2/11) of the patients had Grade 3 AEs, but they were not caused by alpha radiotherapy but by the treatment procedure. Popovtzer et al. [ 15 ] and D’Andrea et al. [ 16 ] reported no grade 3 or higher AEs and no device-related severe AEs. Additionally, our study showed that DaRT did not cause severe mucositis or osteoradionecrosis, which are commonly observed with X-ray irradiation or gamma-ray brachytherapy. The AEs experienced in this study led to improvements in the connection between the seed and suture. Future development of treatment procedures and device applicators could further enhance and broaden DaRT’s application in the oral cavity tumor treatment. Due to the small number of patients and short period of follow-up in our study, the effect of DaRT on long-term local control, survival, and AEs could not be determined. However, this study showed that the initial response to DaRT by rHNC after radiotherapy was favorable, with acceptable grade and incidence of AEs. Data from a longer term assessment of DaRT by Popovtzer et al. support a favorable safety profile [ 17 ]. Declarations Data availability The data presented in this article cannot be shared publicly to protect the privacy of the individuals who participated in the study. Proposals should be directed to the corresponding author. Conflict of Interests Ryo-ichi Yoshimura served as an advisory role to HekaBio K.K.; Kazuma Toda received a research funding from HekaBio K.K.; Masahiko Miura served as an advisory role to HekaBio K.K.; Naoya Murakami received honoraria from Elekta K.K., Chiyoda Technol, Teleflex, and Bayer Japan, and a research funding from Elekta K.K.; Keiichi Jingu received honoraria from Novartis pharma K.K. and a research funding from Elekta K.K.; Jun Itami received honoraria from HekaBio K.K. and a research funding from Teleflex; Hiroshi Watanabe, Ryoichi Notake, Hiroshi Igaki, Satoshi Nakamura, Rei Umezawa, and Noriyuki Kadoya have no conflict of interest. Funding This study was supported by Alpha Tau Medical, Ltd. (Jerusalem, Israel) in partnership with HekaBio K.K. (Tokyo, Japan). Acknowledgements The authors would like to thank all patients and their families for participating in this study. The authors would also like to thank the following individuals who played a role in the management of this study and/or support of the publications: Atsushi Kaida and Hitomi Nojima (Department of Dental Radiology and Radiation Oncology, Institute of Science Tokyo); Hiroyuki Okamoto (Division of Radiation Safety and Quality Assurance, National Cancer Center Hospital); Tomonori Goka (Department of Radiological Technology, National Cancer Center Hospital); Kotaro Iijima (Department of Radiation Oncology, Juntendo University Hospital); Kiyokazu Sato and Hiroyasu Kodama (Department of Radiation Technology, Tohoku University Hospital). We also thank Takashi Uno (Diagnostic Radiology and Radiation Oncology, Chiba University), Yasuo Yoshioka (Department of Radiation Oncology, Cancer Institute Hospital), and Koji Konishi (Department of Radiation Oncology, Osaka International Cancer Institute Hospital) for their support as members of the Efficacy and Safety Assessment Committee. References Svajdova M, Dubinsky P, Kazda T (2021) Radical external beam re-irradiation in the treatment of recurrent head and neck cancer: critical review. Head Neck 43:354–366 Elbers JBW, Al-Mamgani A, van den Brekel MWM, Jozwiak K, de Boer JP, Lohuis PJFM, Willems SM, Verheiji M, Zuur CL (2019) Salvage surgery for recurrence after radiotherapy for squamous cell carcinoma of the head and neck. 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Int J Radiat Oncol Biol Phys 106:571–578 D’Andrea MA, VanderWalde NA, Ballo MT, Patra P, Cohen GN, Damato AL, Barker CA (2023) Feasibility and safety of diffusing alpha-emitter radiation therapy for recurrent or unresectable skin cancers. JAMA Netw Open 6(5):e2312824 Popovtzer A, Mizrachi A, D’Andrea MA, VanderWalde NA, Kurman N, Rosenfeld E, Ben-Hur Ran, Bellia SR, Feliciani G, Silvern D, Sarnelli A, Ballo MT, Patra P, Cohen GN, Damato AL, Shkedy Y, Den RB, Barker CA, Charas T, Hirshoren N (2024) Extended Follow-Up Outcomes from Pooled Prospective Studies Evaluating Efficacy of Interstitial Alpha Radionuclide Treatment for Skin and Head and Neck Cancers. Cancers 16:2312 Tables Table 1 Characteristics Patient /Tumor No Age Sex PS History of cancer Site of tumor Histology Previous treatment Stage Tumor size Long/short/depth (mm) Volume (mm 2 ) No. of seed Result 1 84 M 0 Lung ca. Laryngeal ca. Nose Basal cell carcinoma RT: Electron 65Gy r2 22/ 21/ 8 1920 83 PR 2 62 M 0 Esophageal ca. Gastric ca. Soft palate SCC Anticancer agent RT: X-ray 60Gy r4 21/ 10/ 3 500 13 CR 3 66 M 0 None Head Subcutaneous Neuroblastoma Anticancer agent Surgery RT: X-ray 30Gy, Electron 30Gy - 24/ 18/ 7 1620 28 SD 4 82 F 0 None Buccal mucosa SCC Anticancer agent, RT: Au-BT 67Gy r1 20/ 16/ 3 753 12 PR 5 73 M 0 Lung ca. Bladder ca. Tongue SCC RT: X-ray 30Gy Cs-BT 60Gy Au-BT 85Gy, 77Gy r1 10/ 6/ 3 141 6 CR 6 45 M 0 None Tongue SCC Anticancer agent Surgery RT: Ir-BT 70Gy Au-BT 162Gy r1 12/ 10/ 3 319 12 PD 7 72 M 0 Tongue ca. Tongue SCC Surgery RT: Ir-BT 70Gy r3 30/ 18/ 3 1271 30 PR 8 81 M 1 Oropharyngeal ca. Buccal mucosa SCC Anticancer agent RT: X-ray 65Gy r1 12/ 8/ 4 201 11 PR 9 76 M 1 Esophageal ca. Prostate ca. Gastric ca. Floor of the mouth SCC RT: X-ray 70Gy r2 25/ 15/ 8 1200 45 CR 10 74 F 1 Hypopharyngeal ca. Esophageal ca. Lower lip SCC Surgery, RT: X-ray 48Gy r1 15/ 8/ 5 370 20 PR 11 Upper lip SCC Surgery RT: X-ray 48Gy r1 20/ 7/ 4 320 22 PR Abbreviations: PS, performance status; ca., cancer; RT, radiotherapy; Au-BT, brachytherapy using Au-198 grains; Cs-BT, brachytherapy using Cs-137 needles; Ir-BT, brachytherapy using Ir-192 hair and single pins Table 2. Adverse events in 11 patients All grades Grade 1 Grade 2 Grade 3 Days from implantation to onset Range (median) Days of symptomatic period Range (median) Total 40 22 16 2 0–27 (1) 1–128 (17) Blood and lymphatic system disorders Anemia 1 1 0 0 1 83 Vascular disorders Hypertension 2 1 0 1 0 1 Respiratory, thoracic and mediastinal disorders Nasal obstruction 2 2 0 0 3, 22 3, 7 Gastrointestinal disorder Pharyngodynia 1 0 1 0 1 1 General disorders and administration site conditions Application site inflammation Application site pain Medical device site abscess Medical device site erythema Medical device site hemorrhage Medical device site edema Medical device site pain Medical device site scab Medical device site swelling Medical device site ulcer Pain 2 1 1 2 1 1 9 1 6 3 1 0 1 1 2 1 1 3 1 5 0 0 2 0 0 0 0 0 6 0 1 3 1 0 0 0 0 0 0 0 0 0 0 0 1 0 11 1, 14 0 10 0–20 (0) 6 0–7 (1) 14–27 (14) 0 19, 81 30 16 8, 127 15 4 1–128 (19) 1 3–109 (20) 15–55 (16) 81 Injury, poisoning and procedural complications Foreign body 3 1 1 1 14, 14 N.A. Procedural site pain 1 1 0 0 20 7 Radiation mucositis 1 0 1 0 3 17 Investigations Creatinine increased 1 1 0 0 7 15 Cite Share Download PDF Status: Published Journal Publication published 19 Feb, 2025 Read the published version in International Journal of Clinical Oncology → Version 1 posted Editorial decision: Major revisions 27 Nov, 2024 Reviewers agreed at journal 29 Oct, 2024 Reviewers invited by journal 29 Oct, 2024 Editor assigned by journal 26 Oct, 2024 First submitted to journal 25 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Yoshimura","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxElEQVRIiWNgGAWjYBADxn4gIQFmNRCrZWYbyVo2HINqIQgMzp9O+3Rzj53s5vvdiTcYauwYmGcTsMbgRu7m2TnPko23HePdbMFwLJmBcc4BQlp4NzPnHGBOBGrZJsHAdoCBcUYCIYedBWmpT9zcBtLyjxgtB3JBWg4nbmADamFsI0KL5A2wluPGM47lbrZI7EvmIegXPojDqmX7m89uvPHhm52cIaEQU0AxEugkHsMZ+HUwyGMYKU9chI6CUTAKRsEIAgD+REkFI6gNiwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-9435-1503","institution":"Institute of Science Tokyo","correspondingAuthor":true,"prefix":"","firstName":"Ryo-ichi","middleName":"","lastName":"Yoshimura","suffix":""},{"id":371549007,"identity":"ddefbe25-406c-47ab-994f-619c4dc98ef8","order_by":1,"name":"Kazuma Toda","email":"","orcid":"","institution":"Japanese Red Cross Musashino Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kazuma","middleName":"","lastName":"Toda","suffix":""},{"id":371549008,"identity":"1a5db323-a95d-4c8c-bece-5041ce36e92d","order_by":2,"name":"Hiroshi Watanabe","email":"","orcid":"","institution":"Institute of Science Tokyo","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Watanabe","suffix":""},{"id":371549009,"identity":"c0bf8b74-0fe1-4875-ac9a-da4f46589a53","order_by":3,"name":"Masahiko Miura","email":"","orcid":"","institution":"Institute of Science Tokyo","correspondingAuthor":false,"prefix":"","firstName":"Masahiko","middleName":"","lastName":"Miura","suffix":""},{"id":371549010,"identity":"3f7d04ab-3c07-433d-b8b0-815f9b3f4977","order_by":4,"name":"Ryoichi Notake","email":"","orcid":"","institution":"Institute of Science Tokyo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ryoichi","middleName":"","lastName":"Notake","suffix":""},{"id":371549011,"identity":"2d33a10e-3970-44da-9cf5-2a37e12806db","order_by":5,"name":"Naoya Murakami","email":"","orcid":"","institution":"Juntendo University Hospital: Juntendo Daigaku Igakubu Fuzoku Juntendo Iin","correspondingAuthor":false,"prefix":"","firstName":"Naoya","middleName":"","lastName":"Murakami","suffix":""},{"id":371549012,"identity":"098f6bfe-642f-4402-8916-aaa654dc3062","order_by":6,"name":"Hiroshi Igaki","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Igaki","suffix":""},{"id":371549013,"identity":"6aa30057-244e-4d9c-a5f5-92f5077b70cb","order_by":7,"name":"Satoshi Nakamura","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Nakamura","suffix":""},{"id":371549014,"identity":"cca4446c-ac51-49d1-ad79-7490acf2e43d","order_by":8,"name":"Rei Umezawa","email":"","orcid":"","institution":"Tohoku University: Tohoku Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Rei","middleName":"","lastName":"Umezawa","suffix":""},{"id":371549015,"identity":"cec2d687-8b86-4cf4-b083-60836007393b","order_by":9,"name":"Noriyuki Kadoya","email":"","orcid":"","institution":"Tohoku University: Tohoku Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Noriyuki","middleName":"","lastName":"Kadoya","suffix":""},{"id":371549016,"identity":"0fab3491-1553-4a66-b92b-4edd4dccd28e","order_by":10,"name":"Keiichi Jingu","email":"","orcid":"","institution":"Tohoku University: Tohoku Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Keiichi","middleName":"","lastName":"Jingu","suffix":""},{"id":371549017,"identity":"d6c0cacc-3936-449a-8b71-361072eaab83","order_by":11,"name":"Jun Itami","email":"","orcid":"","institution":"Shin-Matsudo Central General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Itami","suffix":""}],"badges":[],"createdAt":"2024-10-26 03:44:53","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5335358/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5335358/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10147-025-02720-6","type":"published","date":"2025-02-19T15:57:20+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":69360046,"identity":"910a6d2d-b6f6-4821-982a-bd4ca556a3bc","added_by":"auto","created_at":"2024-11-19 14:14:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":23960,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Daily change in blood radioactivity concentration per seed (Mean ± SD); (b) Daily change in urinary radioactivity concentration per seed (Mean ± SD)\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5335358/v1/bbfc067612e8e8e89b5a1240.png"},{"id":69360047,"identity":"4249f79c-e5c7-4f41-a765-3ae8e4a3d64a","added_by":"auto","created_at":"2024-11-19 14:14:05","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":847107,"visible":true,"origin":"","legend":"\u003cp\u003eClinical course of Patient No. 5 with recurrent tongue SCC after brachytherapy treated with DaRT: (a) A tumor before treatment with size of 10 mm x 6 mm x 3 mm; (b) MRI coronal section showing tumor (arrow); (c) State of six DaRT seeds implanted in a single plane; (d) Sagittal reconstruction CT image of inserted DaRT seeds; (e) No change was observed until 4 weeks after initiation of treatment, but the tumor disappeared after 10 weeks of treatment.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5335358/v1/2eda07e84b05f3ddbfffa046.png"},{"id":69360048,"identity":"da654f1a-83ae-4615-b99f-3ca03f4d3508","added_by":"auto","created_at":"2024-11-19 14:14:05","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":665027,"visible":true,"origin":"","legend":"\u003cp\u003eClinical course of Patient No. 8 with papillary SCC of buccal mucosa after radiotherapy. (a) A tumor before treatment with size of 12 mm x 8 mm x 4 mm. (b) State of 11 DaRT seeds implanted in a single plane. (c) Coronal reconstruction CT image of inserted DaRT seeds; (d) Mucositis appeared 1 weeks after seed removal. (e) Mucosal erosion 12 weeks after treatment. Biopsy showed no malignancy.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5335358/v1/1fa6292cda31524c3ddf55b2.png"},{"id":69358462,"identity":"ed358d6b-c065-410f-a665-d0b1bbdc00ff","added_by":"auto","created_at":"2024-11-19 14:06:05","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":49635,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Reduction rate of tumor size after 10 weeks of treatment; (b) Time course of the reduction rate of tumor size.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5335358/v1/57a9cfeef812a62238af3ec9.png"},{"id":77052726,"identity":"161278ea-a7fc-4608-b541-2871d4068b7d","added_by":"auto","created_at":"2025-02-24 16:24:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2269790,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5335358/v1/911b0b59-4d46-48f5-8c3b-3cd240512933.pdf"}],"financialInterests":"","formattedTitle":"Efficacy and safety of diffusing alpha-emitter radiation therapy (DaRT) for head and neck cancer recurrence after radiotherapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRadiotherapy with or without concurrent chemotherapy has been established as the primary treatment for various subsites and stages of head and neck cancer (HNC). However, the incidence of relapse is reported in 15\u0026ndash;50% of patients [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Although salvage surgery is considered to be the best possible curative treatment for these patients, most recurrences are inoperable, given the infiltrative property of recurrent tumors and the comorbidity or poor performance status of pretreated patients [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Re-irradiation is a therapeutic alternative for patients who are not candidates for surgical treatment, but severe toxicity was reported in 18\u0026ndash;75% of patients [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Chemotherapy with cisplatin or cisplatin in combination with other anticancer agents has been used to treat patients with recurrent and/or metastatic HNC, and response rates have been high with improvement in overall survival compared to best supportive care [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Moreover, the combination of chemotherapy (cisplatin and fluorouracil) and monoclonal antibody therapy (cetuximab) significantly improved overall survival with an absolute advantage of 2.6 months in comparison with chemotherapy alone (7.4 months). This combination therapy has become the standard of care for recurrent head and neck cancer (rHNC). However, due to higher incidence of grade 3\u0026ndash;4 toxicities (82%), administration of this regimen has not been indicated for all of these patients [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Immune checkpoint inhibitors have demonstrated the potential to control cancer by immune activation, but the clinical trials using pembrolizumab or nivolumab for the treatment of patients with recurrent and/or metastatic head and neck squamous cell carcinoma (SCC) showed that the overall response rates were 13\u0026ndash;18% and grade 3\u0026ndash;4 adverse events (AEs) were reported in 9\u0026ndash;15% [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. These results seem to indicate that the response rate for rHNC has been improved, but is still low, and can only be applied to a limited number of patients in light of expected AEs. As a result, many patients with rHNC continue to suffer from various symptoms but have no effective treatment options in practice.\u003c/p\u003e \u003cp\u003eDiffusing alpha-emitter radiation therapy (DaRT) is a novel method for the delivery of alpha particles to solid tumors. The DaRT seed consists of a biocompatible, inert, and metallic scaffold with low activity of \u003csup\u003e224\u003c/sup\u003eRa. Once inside the tumor, the seeds are designed to continuously release \u003csup\u003e220\u003c/sup\u003eRn atoms by recoil into the tumor tissue. \u003csup\u003e220\u003c/sup\u003eRn, a noble gas, diffuses freely as a free atom into surrounding tumor tissues, decaying by alpha emission up to 2\u0026ndash;3 mm away from the seed\u0026rsquo;s surface. This emission is followed by additional alpha emissions by \u003csup\u003e216\u003c/sup\u003ePo at the same location and by alpha-emitting daughters of \u003csup\u003e212\u003c/sup\u003ePb-\u003csup\u003e212\u003c/sup\u003eBi and \u003csup\u003e212\u003c/sup\u003ePo. The decay chain continues until the formation of stable \u003csup\u003e208\u003c/sup\u003ePb, while \u003csup\u003e212\u003c/sup\u003ePb atoms entering the bloodstream are sequestered by red blood cells [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The therapeutic potential of alpha particles in the treatment of cancer has long been recognized because of its high linear energy transfer and short range, which minimize damage to the surrounding area. It is considered to have a high biological effect on recurrent tumors after radiotherapy. The efficacy of DaRT has been proven in a series of preclinical studies on tumors with different histologic features [\u003cspan additionalcitationids=\"CR12 CR13 CR14\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The seeds used in this novel therapy were produced by Alpha Tau Medical, Ltd. and, at the time this article was written, branded in regions outside of Japan as \u0026ldquo;Alpha DaRT\u0026trade;\u0026rdquo; technology.\u003c/p\u003e \u003cp\u003eIn this multicenter clinical trial, we evaluated the efficacy and safety of DaRT in patients with rHNC after radiotherapy.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and patients\u003c/h2\u003e \u003cp\u003eThis study was an open-label, single-arm, multicenter, prospective clinical trial. The study was conducted in accordance with the principles of the Declaration of Helsinki, international ethical guidelines of Council for International Organizations of Medical Sciences, and guidelines of Good Clinical Practice. The study protocol, informed consent form, and other relevant documents were approved by the institutional review boards and independent ethics committees of the participating hospitals, including National Cancer Center Hospital, Tohoku University Hospital, and Tokyo Medical and Dental University Hospital. All patients enrolled in this trial provided written informed consent before protocol therapy was initiated.\u003c/p\u003e \u003cp\u003eThis study included patients with biopsy-proven rHNC and a history of radiotherapy, non-response or non-adherence to medical therapy, and no other treatment options. Eligibility criteria were as follows: patients with a tumor size of \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;5 cm in the longest diameter, age of \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;18 years with an Eastern Cooperative Oncology Group Performance Status Scale of \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;2, a life expectancy of \u0026gt;\u0026thinsp;6 months, stable vital signs, platelet count of \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;100,000/mm\u003csup\u003e3\u003c/sup\u003e, prothrombin time of \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;1.8, written informed consent, and target tumor assessable on revised Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.\u003c/p\u003e \u003cp\u003ePatients were excluded, if they had ongoing treatment with immunosuppressant medications (including corticosteroids), history of allergy to anesthesia or other drugs, metastases requiring treatment, ongoing treatment with chemotherapy, immunotherapy or molecular targeting agents in the past 30 days, treatment with immune checkpoint inhibitors in the past 2 months, enrollment in another clinical trial in the past 30 days, pregnancy or lactation, or unwillingness to sign a consent form.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTreatment procedure\u003c/h3\u003e\n\u003cp\u003eThe DaRT seeds were administered using an applicator produced by Alpha Tau Medical, Ltd. (Jerusalem, Israel). Each seed consisted of a 10-mm long and 0.7-mm diameter 316LVM stainless steel tube with \u003csup\u003e224\u003c/sup\u003eRa fixed to its surface with a radioactivity of 2 \u0026micro;Ci (74 kBq). Up to six seeds were linearly threaded on a single monofilament suture, sealed in glycerine, and contained within an applicator needle [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFirst, the applicator insertion method and DaRT placement were simulated based on tumor images used for planning. The applicators were inserted into the tumor to geometrically cover the tumor with DaRT seeds at \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;5-mm intervals. With this insertion method, tumors could receive a minimal total dose of approximately 10 Gy by alpha-emitter radiation. This technique which results in tumor destruction has been previously demonstrated [\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Planning included maintaining a distance of 10-mm from the major blood vessels. If tumor thickness exceeded 5 mm, multi-layer applicator insertions were planned. The number of applicators and DaRT seeds per applicator were calculated and ordered, as required by the treatment plan.\u003c/p\u003e \u003cp\u003eAccording to the pre-treatment plan, DaRT seeds were inserted under local anesthesia at participating institutions on an inpatient basis. After DaRT placement, head and neck CT was used to assess final DaRT positions within the tumor for treatment quality assurance. The seeds were removed 14\u0026ndash;21 days after implantation.\u003c/p\u003e\n\u003ch3\u003eEvaluation\u003c/h3\u003e\n\u003cp\u003eAssuming a threshold response rate of 30% and expected response rate of 70% with DaRT for locally rHNC, the number of lesions for analysis was set at 10. This is per the modified full analysis set (mFAS) method. This method includes only the patients who received treatment.\u003c/p\u003e \u003cp\u003eThe primary endpoint of this study was efficacy of DaRT as determined by response rate at 10 weeks from insertion using RECIST criteria ver1.1. Tumor size was measured directly using digital calipers or CT images, and the same measurement method was used to evaluate response in the same cases.\u003c/p\u003e \u003cp\u003eThe secondary endpoint of the study was safety of DaRT. The incidence and grade of AEs were evaluated during the observation period according to the Common Terminology Criteria for Adverse Events (CTCAE) ver5.0/ Medical Dictionary for Regulatory Activities (MedDRA) ver20.1. Additionally, radioactivity levels in the blood and urine were measured the day before insertion and on days 2, 4, and 14 after DaRT placement.\u003c/p\u003e \u003cp\u003eThese evaluations were performed by the investigators and determined at a central case review meeting.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003ePatient registration\u003c/h2\u003e \u003cp\u003eBetween June 2019 and December 2021, 15 patients with 16 tumors were enrolled in this study. However, four patients were excluded before treatment. The reasons for exclusion included maximum tumor diameter above 5 cm in one patient, quick progression of tumor growth with possible yield of size beyond the acceptance criteria by the start of treatment in two, and difficulty to insert treatment device (as determined by screening test) in one. The remaining 11 patients underwent the treatment procedure and were included in the full analysis set (FAS) for safety evaluation.\u003c/p\u003e \u003cp\u003eHowever, one of the patients in the FAS developed severe hypertension due to patient\u0026rsquo;s anxiety during the implantation procedure, forcing the investigators to halt the implantation midway through the procedure. Therefore, DaRT seed implantation was completed in 10 patients with 11 lesions, and they constituted the mFAS for efficacy evaluation.\u003c/p\u003e \u003cp\u003eThe characteristics of the 10 patients were shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Seven patients had 14 cancers in their previous medical history, and had completed treatment for these previous cancers. The 11 tumor sites treated in this study included the tongue (n\u0026thinsp;=\u0026thinsp;3), buccal mucosa (2), lip (2), floor of the mouth (1), soft palate (1), nose (1), and subcutaneous layer of the head (1). Nine tumors were SCCs, one tumor was a basal cell carcinoma of the nose, and the other was a subcutaneous neuroblastoma. They all had been irradiated by conventional radiotherapy techniques, using X-ray or electron beam, intensity-modulated radiotherapy (IMRT), brachytherapy, or the combination of X-ray radiotherapy and brachytherapy. The mean volume of 11 tumors was 783 mm\u003csup\u003e3\u003c/sup\u003e (range: 141\u0026ndash;1920 mm\u003csup\u003e3\u003c/sup\u003e). An average of 25.6 seeds (range: 6\u0026ndash;83) were implanted, and the treatment duration was 14 days in all 11 lesions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eRadioactivity in blood and urine\u003c/h2\u003e \u003cp\u003eRadioactivity levels in blood and urine were evaluated in 10 patients in the mFAS. Outlier levels of radioactivity in blood and urine were reported in each case, and these were considered to be measurement errors and excluded from the evaluation.\u003c/p\u003e \u003cp\u003eThe average levels of radioactivity in blood were 34.7 Bq/cm\u003csup\u003e3\u003c/sup\u003e (maximum, 106 Bq/cm\u003csup\u003e3\u003c/sup\u003e) on day 1, 42.5 Bq/cm\u003csup\u003e3\u003c/sup\u003e (maximum, 128) on day 2, 34.0 Bq/cm\u003csup\u003e3\u003c/sup\u003e (maximum, 105) on day 4, and 5.0 Bq/cm\u003csup\u003e3\u003c/sup\u003e (maximum, 16.9) on day 14. The average levels of radioactivity in urine were 6.6 Bq/cm\u003csup\u003e3\u003c/sup\u003e (maximum, 16 Bq/cm\u003csup\u003e3\u003c/sup\u003e) on day 1, 8.4 Bq/cm\u003csup\u003e3\u003c/sup\u003e (maximum, 20) on day 2, 5.1 Bq/cm\u003csup\u003e3\u003c/sup\u003e (maximum, 14.6) on day 4, and 0.9 Bq/cm\u003csup\u003e3\u003c/sup\u003e (maximum, 2) on day 14. The radioactivity levels in both blood and urine were highest on day 2, and they decreased to about 10% of those levels on day 14.\u003c/p\u003e \u003cp\u003eA strong correlation existed between the number of seeds and radioactivity level in blood during the entire period, with coefficients of determination (R\u003csup\u003e2\u003c/sup\u003e) of 0.96, 0.98, 0.96, and 0.94 on days 1, 2, 4, and 14, respectively. The correlation between the number of seeds and radioactivity level in urine was weaker than that in blood, with R\u003csup\u003e2\u003c/sup\u003e of 0.88, 0.61, 0.18, and 0.93 on days 1, 2, 4, and 14, respectively. Daily changes in radioactivity levels in blood and urine for the equivalent of one implanted seed are shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e1\u003c/span\u003ea and \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e1\u003c/span\u003eb.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTumor response\u003c/h3\u003e\n\u003cp\u003eComplete response (CR, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), partial response (PR, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), stable disease (SD), and progressive disease (PD) were observed in 27.3% (n\u0026thinsp;=\u0026thinsp;3), 54.5% (6), 9.1% (1), and 9.1% (1) of the lesions, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e4\u003c/span\u003ea). The response (CR or PR) rate for all 11 lesions after 10 weeks was 81.8% (95% CI: 48.2\u0026ndash;97.7%).\u003c/p\u003e \u003cp\u003eThe spider plot in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e4\u003c/span\u003eb shows the time course of the tumor diameter rate. The average percentage changes were +\u0026thinsp;0.37% (range: 0 to +\u0026thinsp;4.1) at week 1, \u0026minus;\u0026thinsp;5.2% (\u0026ndash;24 to 0) at week 2, \u0026minus;\u0026thinsp;8.9% (\u0026ndash;67 to +\u0026thinsp;8.3) at week 3, \u0026minus;\u0026thinsp;12.1% (\u0026ndash;67 to 0) at week 4, \u0026minus;\u0026thinsp;51.4% (\u0026ndash;100 to 0) at week 10, and \u0026minus;\u0026thinsp;54.8% (\u0026ndash;100 to 0) at week 12.\u003c/p\u003e \u003cp\u003eThe lesion evaluated as SD was a subcutaneous recurrence of olfactory neuroblastoma of the head (Patient No. 3). Its lesion volume was reduced by about 70% (440/1620 mm\u003csup\u003e3\u003c/sup\u003e), but the maximum diameter of the lesion, the baseline, was reduced by only 21% (5/24 mm). Therefore, the tumor was rated as SD. The second lesion, treated in a tongue cancer patient (Patient No. 6), was evaluated as PD. At week 10, the target tumor size was unchanged from baseline, but a new, untreated lesion was found in close proximity, resulting in PD based on assessment criteria.\u003c/p\u003e\n\u003ch3\u003eAE causally related to DaRT\u003c/h3\u003e\n\u003cp\u003eAltogether, 40 AEs were reported in all 11 patients in the FAS. Among the AEs, 22, 16, and two AEs were Grades 1, 2, and 3, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). AEs related to application and device insertion were the most common, occurring as 27 AEs in nine patients. However, none of them were Grade 3 or higher. They occurred immediately or early after initiation of treatment and recovered early after the seeds were removed.\u003c/p\u003e \u003cp\u003eGrade 3 hypertension due to patient anxiety was reported in a 79-year-old woman during the seed implantation procedure; therefore, the procedure had to be halted. The treatment was discontinued, and all implanted seeds were left behind (Grade 2 foreign body) and removed the next day. The remaining seed, a Grade 3 foreign body related to treatment procedure, was observed in Patient No. 7. Additionally, a suture remnant, a Grade 1 foreign body, was observed in this patient who had 30 DaRT seeds inserted into his 1271 mm\u003csup\u003e3\u003c/sup\u003e tumor. At the time of seed removal on day 14, the two seeds remained in the tongue after the suture was pulled out. During the same procedure, in another suture, two seeds detached from the suture and fell off, leaving the suture and clip in the tongue. The two remaining seeds were finally retrieved from the tongue ulcer site on week 12, and the remaining suture and clip were removed at the surgery on week 19.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePopovtzer et al. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] treated 31 SCC lesions in the skin and head and neck with DaRT and reported a 100% response rate (78.6% in CR and 21.4% in PR). Additionally, D\u0026rsquo;Andrea et al. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] treated 10 patients with recurrent or unresectable SCC or basal cell carcinoma of the skin with DaRT and reported a 100% CR. In our study, the response rate of DaRT for rHNC was 81.8% (27.3% in CR and 54.5% in PR). DaRT was shown to be highly effective in treating localized cancer lesions, which are conventionally difficult to treat.\u003c/p\u003e \u003cp\u003ePopovtzer et al. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] evaluated the effect of DaRT 6 weeks after treatment and reported a good prognosis in the case of CR, whereas D\u0026rsquo;Andrea et al. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] reported no relapse in all cases of CR 12 and 24 weeks after treatment. In our study, most of SCC lesions showed significant changes from week 4 to week 10, with no changes occurring after week 10. Whereas in non-SCC cases, the tumors continued to shrink after week 10. SCC may respond quickly to DaRT, and evaluation within 10 weeks would be prognostic. However, in our study, the CR rate was lower than those reported by Popovtzer et al. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and D\u0026rsquo;Andrea et al. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Like our study, these studies also used RECIST ver1.1 for the evaluation. The tumors treated in our study were not larger than those in both studies, nor did we implant fewer seeds. The tumor sites reported by Popovtzer et al. were the skin (39%), ear (23%), lip (16%), tongue (10%), nose (6%), and parotid (6%), whereas D\u0026rsquo;Andrea et al. reported only cutaneous tumors. In our study, 55% of the tumors were observed in the oral cavity, and all 11 lesions previously underwent radiotherapy of approximately 50Gy or more. Therefore, they were considered to be resistant to radiotherapy, and due to the narrow space in the oral cavity and the hardness of tissues after radiotherapy, implantation of seeds in the oral cavity was challenging for us unfamiliar with existing devices. Since a high-dose region of DaRT does not diffuse much beyond 2\u0026ndash;3 mm from the seed, the seed spatial arrangement has a strong influence on treatment effect. The CR rate must be lower in the oral cavity than on the other body surfaces because of the difficulty of seed spacing according to treatment plan. Improved insertion techniques and devices could enhance the effectiveness of treatment.\u003c/p\u003e \u003cp\u003eThe radioactivity level in blood was proportional to the number of seeds implanted from day 0 to day 14 of DaRT. The highest level of radioactivity was recorded on the second day of treatment (consistent with the buildup of \u003csup\u003e212\u003c/sup\u003ePb, as described in [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]). Additionally, urine radioactivity peaked on day 2 but did not show a strong proportional relationship with the number of seeds. This finding was due to the fact that radioactivity was measured per 1 cm\u003csup\u003e3\u003c/sup\u003e, and radioactivity level in urine is thought to be related to the total urine volume. The decrease of activity over time after the maximum value at day two is consistent with the exponential decay of \u003csup\u003e224\u003c/sup\u003eRa (with all its short-lived progeny in secular equilibrium) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Popovtzer et al. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] reported no measurable radioactivity in the blood and urine 30 days after treatment (consistent with the expectation after ~\u0026thinsp;8 half-lives of \u003csup\u003e224\u003c/sup\u003eRa).\u003c/p\u003e \u003cp\u003eRe-irradiation is a therapeutic alternative for patients who are not candidates for surgery, but a high incidence (8.7\u0026ndash;48%) of severe AEs such as radionecrosis, dysphagia requiring feeding tube placement, trismus, and carotid artery blowout is often reported, even with IMRT, stereotactic body irradiation, and heavy particles [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In our study on DaRT, 18% (2/11) of the patients had Grade 3 AEs, but they were not caused by alpha radiotherapy but by the treatment procedure. Popovtzer et al. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and D\u0026rsquo;Andrea et al. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] reported no grade 3 or higher AEs and no device-related severe AEs. Additionally, our study showed that DaRT did not cause severe mucositis or osteoradionecrosis, which are commonly observed with X-ray irradiation or gamma-ray brachytherapy. The AEs experienced in this study led to improvements in the connection between the seed and suture. Future development of treatment procedures and device applicators could further enhance and broaden DaRT\u0026rsquo;s application in the oral cavity tumor treatment.\u003c/p\u003e \u003cp\u003eDue to the small number of patients and short period of follow-up in our study, the effect of DaRT on long-term local control, survival, and AEs could not be determined. However, this study showed that the initial response to DaRT by rHNC after radiotherapy was favorable, with acceptable grade and incidence of AEs. Data from a longer term assessment of DaRT by Popovtzer et al. support a favorable safety profile [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e"},{"header":"Declarations","content":" \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eData availability\u003c/h2\u003e \u003cp\u003eThe data presented in this article cannot be shared publicly to protect the privacy of the individuals who participated in the study. Proposals should be directed to the corresponding author.\u003c/p\u003e \u003c/div\u003e\u003cp\u003e \u003cstrong\u003eConflict of Interests\u003c/strong\u003e \u003cp\u003eRyo-ichi Yoshimura served as an advisory role to HekaBio K.K.; Kazuma Toda received a research funding from HekaBio K.K.; Masahiko Miura served as an advisory role to HekaBio K.K.; Naoya Murakami received honoraria from Elekta K.K., Chiyoda Technol, Teleflex, and Bayer Japan, and a research funding from Elekta K.K.; Keiichi Jingu received honoraria from Novartis pharma K.K. and a research funding from Elekta K.K.; Jun Itami received honoraria from HekaBio K.K. and a research funding from Teleflex; Hiroshi Watanabe, Ryoichi Notake, Hiroshi Igaki, Satoshi Nakamura, Rei Umezawa, and Noriyuki Kadoya have no conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis study was supported by Alpha Tau Medical, Ltd. (Jerusalem, Israel) in partnership with HekaBio K.K. (Tokyo, Japan).\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThe authors would like to thank all patients and their families for participating in this study. The authors would also like to thank the following individuals who played a role in the management of this study and/or support of the publications: Atsushi Kaida and Hitomi Nojima (Department of Dental Radiology and Radiation Oncology, Institute of Science Tokyo); Hiroyuki Okamoto (Division of Radiation Safety and Quality Assurance, National Cancer Center Hospital); Tomonori Goka (Department of Radiological Technology, National Cancer Center Hospital); Kotaro Iijima (Department of Radiation Oncology, Juntendo University Hospital); Kiyokazu Sato and Hiroyasu Kodama (Department of Radiation Technology, Tohoku University Hospital). We also thank Takashi Uno (Diagnostic Radiology and Radiation Oncology, Chiba University), Yasuo Yoshioka (Department of Radiation Oncology, Cancer Institute Hospital), and Koji Konishi (Department of Radiation Oncology, Osaka International Cancer Institute Hospital) for their support as members of the Efficacy and Safety Assessment Committee.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSvajdova M, Dubinsky P, Kazda T (2021) Radical external beam re-irradiation in the treatment of recurrent head and neck cancer: critical review. Head Neck 43:354\u0026ndash;366\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eElbers JBW, Al-Mamgani A, van den Brekel MWM, Jozwiak K, de Boer JP, Lohuis PJFM, Willems SM, Verheiji M, Zuur CL (2019) Salvage surgery for recurrence after radiotherapy for squamous cell carcinoma of the head and neck. Otolaryngol Head Neck Surg 160:1023\u0026ndash;1033\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDionisi F, Fiorica F, D\u0026rsquo;Angelo E, Maddalo M, Giacomelli I, Tornari E, Rosca A, Vigo F, Romanello D, Cianchetti M, Tommasino F, Massaccesi M, Orlandi E (2019) Organs at risk\u0026rsquo;s tolerance and dose limits for head and neck cancer reiiradiation: a literature review. Oral Oncol 98:35\u0026ndash;47\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuidi A, Codeca C, Ferrari D (2018) Chemotherapy and immunotherapy for recurrent and metastatic head and neck cancer: a systematic review. Med Oncol 35:37\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThe Liverpool Head and Neck Oncology Group (1990) A phase III randomized trial of cistplatinum, methotrextate, cisplatinum\u0026thinsp;+\u0026thinsp;methotrexate and cisplatinum\u0026thinsp;+\u0026thinsp;5-FU in end stage squamous carcinoma of the head and neck. Br J Cancer 61:311\u0026ndash;315\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVermorken JB, Mesia R, Rivera F, Remenar E, Kawecky A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116\u0026ndash;1127\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSciwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, Heath K, McClanahan T, Lunceford J, Gause C, Cheng JD, Chow LQ (2016) Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase Ib trial. Lancet Oncol 17(7):956\u0026ndash;965\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChow LQ, Haddad R, Gupta S, Mahipal A, Mehra R, Tahara M, Berger R, Eder JP, Burtness B, Lee SH, Keam B, Kang H, Muro K, Weiss J, Geva R, Lin CC, Chung HC, Meister A, Dolled-Filhart M, Pathiraja K, Cheng JD, Seiwert TY (2016) Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol 34(32):3838\u0026ndash;3845\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerris RL, Blumenschein G, Fayette JJ, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Docampo LCI, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML (2016) Nivolumab for recurrent squamous cell carcinoma of the head and neck. N Engl J Med 375(19):1856\u0026ndash;1867\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArazi L, Cooks T, Schmidt M, Keisari Y, Kelson I (2007) Treatment of solid tumors by interstitial release of recoiling short-lived alpha emitters. Phys Med Biol 52:5025\u0026ndash;5042\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCooks T, Arazi L, Schmidt M, Marchak G, Kelson I, Keisari Y (2008) Growth retardation and destruction of experimental squamous cell carcinoma by interstitial radioactive wires releasing diffusing alpha-emitting atoms. Int J Cancer 122:1657\u0026ndash;1664\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArazi L, Cooks T, Schmidt M, Keisari Y, Kelson I (2010) The treatment of solid tumors by alpha emitters released from (224) Ra-loaded sources-internal dosimetry analysis. Phys Med Biol 55:120\u0026ndash;1218\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHorev-Drori G, Cooks T, Bittan H, Lazarov E, Schmidt M, Arazi L, Efrati M, Kelson I, Keisari Y (2012) Local control of experimental malignant pancreatic tumors by treatment with a combination of chemotherapy and intratumoral (224) Radium-loaded wires releasing alpha-emitting atoms. Transl Res 159:32\u0026ndash;41\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eConfino H, Schmidt M, Efrati M, Hochman I, Umansky V, Kelson I, Keisari Y (2016) Inhibition of mouse breast adenocarcinoma growth by ablation with intratumoral alpha-irradiation combined with inhibitors of immunosuppression and CpG. Cancer Immunol Immunother 65:1149\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePopovtzer A, Rosenfeld E, Mizrachi A, Bellia SR, Ben-Hur R, Feliciani G, Sarnelli A, Arazi L, Deutsh L, Kelson I, Keisari Y (2020) Initial safety and tumor control results from a first-in-human multicenter prospective trial evaluating a novel alpha-emitting radionuclide for the treatment squamous cell carcinomas of the skin and head and neck. Int J Radiat Oncol Biol Phys 106:571\u0026ndash;578\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eD\u0026rsquo;Andrea MA, VanderWalde NA, Ballo MT, Patra P, Cohen GN, Damato AL, Barker CA (2023) Feasibility and safety of diffusing alpha-emitter radiation therapy for recurrent or unresectable skin cancers. JAMA Netw Open 6(5):e2312824\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePopovtzer A, Mizrachi A, D\u0026rsquo;Andrea MA, VanderWalde NA, Kurman N, Rosenfeld E, Ben-Hur Ran, Bellia SR, Feliciani G, Silvern D, Sarnelli A, Ballo MT, Patra P, Cohen GN, Damato AL, Shkedy Y, Den RB, Barker CA, Charas T, Hirshoren N (2024) Extended Follow-Up Outcomes from Pooled Prospective Studies Evaluating Efficacy of Interstitial Alpha Radionuclide Treatment for Skin and Head and Neck Cancers. Cancers 16:2312\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 Characteristics\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 6.42648%;\"\u003e\n \u003cp\u003ePatient\u003c/p\u003e\n \u003cp\u003e/Tumor No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.64752%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.72639%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ePS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.9503%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eHistory of cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.853%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eSite of tumor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0029%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eHistology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8267%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ePrevious treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eStage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.703%;\"\u003e\n \u003cp\u003eTumor size Long/short/depth (mm)\u003c/p\u003e\n \u003cp\u003eVolume (mm\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNo. of seed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eResult\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 6.42648%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003e84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.64752%;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.72639%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.9503%;\"\u003e\n \u003cp\u003eLung ca.\u003cbr\u003e\u0026nbsp;Laryngeal ca.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.853%;\"\u003e\n \u003cp\u003eNose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0029%;\"\u003e\n \u003cp\u003eBasal cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8267%;\"\u003e\n \u003cp\u003eRT: Electron 65Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003er2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.703%;\"\u003e\n \u003cp\u003e22/ 21/ 8\u003c/p\u003e\n \u003cp\u003e1920\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003e83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 6.42648%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.64752%;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.72639%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.9503%;\"\u003e\n \u003cp\u003eEsophageal ca.\u003cbr\u003e\u0026nbsp;Gastric ca.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.853%;\"\u003e\n \u003cp\u003eSoft palate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0029%;\"\u003e\n \u003cp\u003eSCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8267%;\"\u003e\n \u003cp\u003eAnticancer agent\u003c/p\u003e\n \u003cp\u003eRT: X-ray 60Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003er4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.703%;\"\u003e\n \u003cp\u003e21/ 10/ 3\u003c/p\u003e\n \u003cp\u003e500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 6.42648%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.64752%;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.72639%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.9503%;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.853%;\"\u003e\n \u003cp\u003eHead Subcutaneous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0029%;\"\u003e\n \u003cp\u003eNeuroblastoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8267%;\"\u003e\n \u003cp\u003eAnticancer agent Surgery\u003c/p\u003e\n \u003cp\u003eRT: X-ray 30Gy, Electron 30Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.703%;\"\u003e\n \u003cp\u003e24/ 18/ 7\u003c/p\u003e\n \u003cp\u003e1620\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 6.42648%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003e82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.64752%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.72639%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.9503%;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.853%;\"\u003e\n \u003cp\u003eBuccal mucosa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0029%;\"\u003e\n \u003cp\u003eSCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8267%;\"\u003e\n \u003cp\u003eAnticancer agent,\u003c/p\u003e\n \u003cp\u003eRT: Au-BT 67Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003er1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.703%;\"\u003e\n \u003cp\u003e20/ 16/ 3\u003c/p\u003e\n \u003cp\u003e753\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 6.42648%;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.64752%;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.72639%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.9503%;\"\u003e\n \u003cp\u003eLung ca.\u003cbr\u003e\u0026nbsp;Bladder ca.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.853%;\"\u003e\n \u003cp\u003eTongue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0029%;\"\u003e\n \u003cp\u003eSCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8267%;\"\u003e\n \u003cp\u003eRT: X-ray 30Gy\u003c/p\u003e\n \u003cp\u003eCs-BT 60Gy\u003c/p\u003e\n \u003cp\u003eAu-BT 85Gy, 77Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003er1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.703%;\"\u003e\n \u003cp\u003e10/ 6/ 3\u003c/p\u003e\n \u003cp\u003e141\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 6.42648%;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.64752%;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.72639%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.9503%;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.853%;\"\u003e\n \u003cp\u003eTongue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0029%;\"\u003e\n \u003cp\u003eSCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8267%;\"\u003e\n \u003cp\u003eAnticancer agent Surgery\u003c/p\u003e\n \u003cp\u003eRT: Ir-BT 70Gy\u003c/p\u003e\n \u003cp\u003eAu-BT 162Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003er1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.703%;\"\u003e\n \u003cp\u003e12/ 10/ 3\u003c/p\u003e\n \u003cp\u003e319\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 6.42648%;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.64752%;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.72639%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.9503%;\"\u003e\n \u003cp\u003eTongue ca.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.853%;\"\u003e\n \u003cp\u003eTongue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0029%;\"\u003e\n \u003cp\u003eSCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8267%;\"\u003e\n \u003cp\u003eSurgery\u003c/p\u003e\n \u003cp\u003eRT: Ir-BT 70Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003er3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.703%;\"\u003e\n \u003cp\u003e30/ 18/ 3\u003c/p\u003e\n \u003cp\u003e1271\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 6.42648%;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003e81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.64752%;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.72639%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.9503%;\"\u003e\n \u003cp\u003eOropharyngeal ca.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.853%;\"\u003e\n \u003cp\u003eBuccal mucosa\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0029%;\"\u003e\n \u003cp\u003eSCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8267%;\"\u003e\n \u003cp\u003eAnticancer agent\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eRT: X-ray 65Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003er1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.703%;\"\u003e\n \u003cp\u003e12/ 8/ 4\u003c/p\u003e\n \u003cp\u003e201\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 6.42648%;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003e76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.64752%;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.72639%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.9503%;\"\u003e\n \u003cp\u003eEsophageal ca.\u003cbr\u003e\u0026nbsp;Prostate ca.\u003cbr\u003e\u0026nbsp;Gastric ca.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.853%;\"\u003e\n \u003cp\u003eFloor of the mouth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0029%;\"\u003e\n \u003cp\u003eSCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8267%;\"\u003e\n \u003cp\u003eRT: X-ray 70Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003er2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.703%;\"\u003e\n \u003cp\u003e25/ 15/ 8\u003c/p\u003e\n \u003cp\u003e1200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 6.42648%;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003e74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.64752%;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.72639%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.9503%;\"\u003e\n \u003cp\u003eHypopharyngeal ca.\u003cbr\u003e\u0026nbsp;Esophageal ca.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.853%;\"\u003e\n \u003cp\u003eLower lip\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0029%;\"\u003e\n \u003cp\u003eSCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8267%;\"\u003e\n \u003cp\u003eSurgery,\u003c/p\u003e\n \u003cp\u003eRT: X-ray 48Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003er1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.703%;\"\u003e\n \u003cp\u003e15/ 8/ 5\u003c/p\u003e\n \u003cp\u003e370\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 6.42648%;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.64752%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 2.72639%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.9503%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.853%;\"\u003e\n \u003cp\u003eUpper lip\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0029%;\"\u003e\n \u003cp\u003eSCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.8267%;\"\u003e\n \u003cp\u003eSurgery\u003c/p\u003e\n \u003cp\u003eRT: X-ray 48Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 4.57644%;\"\u003e\n \u003cp\u003er1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.703%;\"\u003e\n \u003cp\u003e20/ 7/ 4\u003c/p\u003e\n \u003cp\u003e320\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.3554%;\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: PS, performance status; ca., cancer; RT, radiotherapy; Au-BT, brachytherapy using Au-198 grains; Cs-BT, brachytherapy using Cs-137 needles; Ir-BT, brachytherapy using Ir-192 hair and single pins\u003c/p\u003e\n\u003cp\u003eTable 2. Adverse events in 11 patients\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.163%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.808%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eAll grades\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.697%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eGrade\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.4058%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eGrade\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.423%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eGrade\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.7291%;\"\u003e\n \u003cp\u003eDays from implantation to onset\u003c/p\u003e\n \u003cp\u003eRange (median)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7075%;\"\u003e\n \u003cp\u003eDays of symptomatic period\u003c/p\u003e\n \u003cp\u003eRange (median)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.163%;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.808%;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.697%;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.4058%;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.423%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.7291%;\"\u003e\n \u003cp\u003e0\u0026ndash;27 (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7075%;\"\u003e\n \u003cp\u003e1\u0026ndash;128 (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 30.9555%;\"\u003e\n \u003cp\u003e\u003cem\u003eBlood and lymphatic system disorders\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.163%;\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.808%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.697%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.4058%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.423%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.7291%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7075%;\"\u003e\n \u003cp\u003e83\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 30.9555%;\"\u003e\n \u003cp\u003e\u003cem\u003eVascular disorders\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.163%;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.808%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.697%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.4058%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.423%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.7291%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7075%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 30.9555%;\"\u003e\n \u003cp\u003e\u003cem\u003eRespiratory, thoracic and mediastinal disorders\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.163%;\"\u003e\n \u003cp\u003eNasal obstruction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.808%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.697%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.4058%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.423%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.7291%;\"\u003e\n \u003cp\u003e3, 22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7075%;\"\u003e\n \u003cp\u003e3, 7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 30.9555%;\"\u003e\n \u003cp\u003e\u003cem\u003eGastrointestinal disorder\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.163%;\"\u003e\n \u003cp\u003ePharyngodynia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.808%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.697%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.4058%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.423%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.7291%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7075%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 30.9555%;\"\u003e\n \u003cp\u003e\u003cem\u003eGeneral disorders and administration site conditions\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.163%;\"\u003e\n \u003cp\u003eApplication site inflammation\u003c/p\u003e\n \u003cp\u003eApplication site pain\u003c/p\u003e\n \u003cp\u003eMedical device site abscess\u003c/p\u003e\n \u003cp\u003eMedical device site erythema\u003c/p\u003e\n \u003cp\u003eMedical device site hemorrhage\u003c/p\u003e\n \u003cp\u003eMedical device site edema\u003c/p\u003e\n \u003cp\u003eMedical device site pain\u003c/p\u003e\n \u003cp\u003eMedical device site scab\u003c/p\u003e\n \u003cp\u003eMedical device site swelling\u003c/p\u003e\n \u003cp\u003eMedical device site ulcer\u003c/p\u003e\n \u003cp\u003ePain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.808%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.697%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.4058%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.423%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.7291%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003cp\u003e1, 14\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e0\u0026ndash;20 (0)\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e0\u0026ndash;7 (1)\u003c/p\u003e\n \u003cp\u003e14\u0026ndash;27 (14)\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7075%;\"\u003e\n \u003cp\u003e19, 81\u003c/p\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003cp\u003e8, 127\u003c/p\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e1\u0026ndash;128 (19)\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e3\u0026ndash;109 (20)\u003c/p\u003e\n \u003cp\u003e15\u0026ndash;55 (16)\u003c/p\u003e\n \u003cp\u003e81\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 30.9555%;\"\u003e\n \u003cp\u003e\u003cem\u003eInjury, poisoning and procedural complications\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.163%;\"\u003e\n \u003cp\u003eForeign body\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.808%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.697%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.4058%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.423%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.7291%;\"\u003e\n \u003cp\u003e14, 14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7075%;\"\u003e\n \u003cp\u003eN.A.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.163%;\"\u003e\n \u003cp\u003eProcedural site pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.808%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.697%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.4058%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.423%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.7291%;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7075%;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.163%;\"\u003e\n \u003cp\u003eRadiation mucositis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.808%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.697%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.4058%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.423%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.7291%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7075%;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 30.9555%;\"\u003e\n \u003cp\u003e\u003cem\u003eInvestigations\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.163%;\"\u003e\n \u003cp\u003eCreatinine increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.808%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.697%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.4058%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.423%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.7291%;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.7075%;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"alpha-emitter radiation therapy, recurrent head and neck cancer, response rate, adverse event","lastPublishedDoi":"10.21203/rs.3.rs-5335358/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5335358/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eTo evaluate the efficacy and safety of diffusing alpha-emitter radiation therapy (DaRT) for recurrent head and neck cancer (rHNC) after radiotherapy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study was a multicenter prospective clinical trial. Eligibility criteria included all patients with biopsy-proven rHNC, history of radiotherapy. The efficacy of DaRT was evaluated in terms of tumor shrinkage after 10 weeks of DaRT seed implantation. To assess safety of DaRT, radioactivity levels in blood and urine were measured, and incidence and grade of adverse events (AEs) were evaluated.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eBetween 2019 and 2021, DaRT was performed in 11 patients and completed in 10 patients with 11 tumors. The tumor sites included the tongue (n\u0026thinsp;=\u0026thinsp;3), buccal mucosa (2), lips (2), floor of the mouth (1), soft palate (1), nose (1), and subcutaneous layer (1). Nine tumors were confirmed to be squamous cell carcinoma, and the remaining two tumors were basal cell carcinoma and neuroblastoma. Complete response (CR) and partial response (PR) were observed in three and six patients, respectively. The response rate was 81.8%. The maximum average radioactivity levels in blood and urine were 42.5 Bq/cm\u003csup\u003e3\u003c/sup\u003e and 8.4 Bq/cm\u003csup\u003e3\u003c/sup\u003e, respectively, on the second day after implantation. Forty AEs were observed in all 11 patients; they included 22 Grade 1 AEs, 16 Grade 2, and two Grade 3 (hypertension and seed remnants).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe initial response of rHNC after radiotherapy to DaRT was favorable, and the incidence and grade of AEs were acceptable, as compared to existing therapies.\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of diffusing alpha-emitter radiation therapy (DaRT) for head and neck cancer recurrence after radiotherapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-19 14:06:00","doi":"10.21203/rs.3.rs-5335358/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2024-11-27T21:43:28+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-10-29T05:45:27+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-29T05:08:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-26T04:27:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2024-10-25T23:42:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"2f1597ab-d20b-462a-b2c3-738238906d3b","owner":[],"postedDate":"November 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-02-24T16:05:30+00:00","versionOfRecord":{"articleIdentity":"rs-5335358","link":"https://doi.org/10.1007/s10147-025-02720-6","journal":{"identity":"international-journal-of-clinical-oncology","isVorOnly":false,"title":"International Journal of Clinical Oncology"},"publishedOn":"2025-02-19 15:57:20","publishedOnDateReadable":"February 19th, 2025"},"versionCreatedAt":"2024-11-19 14:06:00","video":"","vorDoi":"10.1007/s10147-025-02720-6","vorDoiUrl":"https://doi.org/10.1007/s10147-025-02720-6","workflowStages":[]},"version":"v1","identity":"rs-5335358","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5335358","identity":"rs-5335358","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}