A Japanese multi-institutional phase II study of moderate hypofractionated intensity-modulated radiotherapy with image-guided technique for prostate cancer.

BACKGROUND: The aim of this multi-institutional phase II study was to confirm the safety and the potential efficacy of moderately hypofractionated intensity-modulated radiotherapy (IMRT) with prostate-based image-guidance for Japanese patients. METHODS: Patients with low- or intermediate-risk localized prostate cancer were eligible. Patients with a part of high risk (having only one of the following factors, cT3a, 20 < PSA ≤ 30, or GS = 8 or 9) were also included. Hypofractionated IMRT using daily image-guided technique with prostate matching was performed with a total dose of 70 Gy in 28 fractions. Neoadjuvant hormonal therapy for 4-8 months was mandatory for patients with intermediate or high-risk prostate cancer. RESULTS: From 20 institutions, 134 patients enrolled. The median follow-up was 5.16 years (range, 1.43-6.47 years). The number of patients with low, intermediate, and high-risk prostate cancer was 20, 80, and 34, respectively. The 5-year overall, biochemical failure-free, and clinical failure-free survival was 94.5%, 96.0%, and 99.2%, respectively. The 5-year biochemical failure-free survival for patients with low-, intermediate-, and high-risk disease was 94.1%, 97.4%, and 93.9%, respectively. The incidences of grade 2 gastrointestinal (GI) and genitourinary (GU) late toxicities at 5 years were 5.3% and 5.3%, respectively. There are no acute or late toxicities ≥ grade 3. Of 124 patients who were followed for up to 5 years, the grade 2 late GU or GI toxicities were 10.5% (90% confidence intervals, 6.3-16.2%, p = 0.0958). CONCLUSION: The safety and efficacy of moderately hypofractionated IMRT with prostate-based image-guidance was confirmed among Japanese patients with prostate cancer.

Gynecological technical notes for appropriate spacer injections.

BACKGROUND: Despite its efficacy, if adherence to dose constraints for surrounding normal tissues proves unattainable, the risk of late radiation-related adverse events after primary radiotherapy involving brachytherapy remains a noteworthy concern. Some studies suggest that similar to prostate radiotherapy, spacers may potentially reduce doses to surrounding healthy rectal or bladder tissues. However, guidance on spacer injections for gynecologic brachytherapy is scarce, and the optimal anatomical location for spacer placement remains undefined. We discuss maximizing the effects of spacers from an anatomical perspective. FINDINGS: As vesicovaginal and rectovaginal septa form part of the endopelvic fascia and are not uniform tissues, spacer injection resistance varies. In pelvic organ prolapse surgery, saline is injected into the anterior and posterior vaginal walls as a spacer, and the vagina, vesicovaginal septum, and bladder can be fluidly dissected. Relatively firm vesicovaginal septum tissue is used as a reconstructive organ, whereas rectovaginal septum tissue is less dense. Cervical cancer is invasive, involving surrounding fascia and ligaments. Ideally, the vesicovaginal and rectovaginal septa should be resected in radical hysterectomy. Here, spacer adaptation and the technical details of injection are described. When using ultrasound guidance for spacer injection, the target site should be adequately magnified, and the spacer ideally injected into the incision layer during radical hysterectomy. Finally, posthysterectomy, the intestinal tract may adhere to the vaginal cuffs. Therefore, artificial ascites may be useful; however, the spread depends on perioperative manipulation. CONCLUSIONS: Anatomical and surgical viewpoints are advantageous for safe, therapeutic, and replicable spacer injection administration.

Acral cutaneous malignant melanoma treated with linear accelerator-based boron neutron capture therapy system: a case report of first patient.

This study reports the first patient treatment for cutaneous malignant melanoma using a linear accelerator-based boron neutron capture therapy (BNCT) system. A single-center open-label phase I clinical trial had been conducted using the system since November 2019. A patient with a localized node-negative acral malignant melanoma and the largest diameter of the tumor ≤ 15 cm who refused primary surgery and chemotherapy was enrolled. After administering boronophenylalanine (BPA), a single treatment of BNCT with the maximum dose of 18 Gy-Eq delivered to the skin was performed. The safety and efficacy of the accelerator-based BNCT system for treating localized cutaneous malignant melanoma were evaluated. The first patient with cutaneous malignant melanoma in situ on the second finger of the left hand did not develop dose-limiting toxicity in the clinical trial. After BNCT, the treatment efficacy was gradually observed, and the patient achieved PR within 6 months and CR within 12 months. Moreover, during the follow-up period of 12 months after BNCT, the patient did not exhibit a recurrence without any treatment-related grade 2 or higher adverse events. Although grade 1 adverse events of dermatitis, dry skin, skin hyperpigmentation, edema, nausea, and aching pain were noted in the patient, those adverse events were relieved without any treatment. This case report shows that the accelerator-based BNCT may become a promising treatment modality for cutaneous malignant melanoma. We expect further clinical trials to reveal the efficacy and safety of the accelerator-based BNCT for cutaneous malignant melanoma.

Assessment of intrafractional motion of the cervix-uterus by MR-guided radiotherapy system†.

The uterus is known as one of the moving organs. We evaluated the movement of the uterus during irradiation and the effects of changes in the surrounding organs using a magnetic resonance (MR)-guided radiotherapy system. Seven patients with cervical cancer underwent pre- and posttreatment MR imaging to assess changes in the positioning of the uterus and cervix as well as the alterations in bladder and rectal volume. The study revealed that the movements of the uterus were greater than that of the cervix and showed a tendency to correlate with the bladder rather than the rectum. We also examined whether intrafractional motion could lead to insufficient dose coverage of the clinical target volume (CTV), specifically focusing on the D98% of the CTV in the uterine body and cervix. The impact of intrafractional motion on the D98% varied among patients, with one out of the seven patients experiencing an average dosimetric change of -2.6 Gy in the uterus, although larger planning target volume margins of 1.5 cm were applied, therefore, indicating the need for individualized optimal margins in each case. Online adaptive radiotherapy offers the advantage of modifying the treatment plan when irradiating moving organs, such as the uterus. However, it should be noted that this approach may result in longer overall treatment times compared with the traditional methods. Therefore, we must carefully consider the influence of intrafractional organ motions when opting for such a treatment.

Treatment planning comparison of high-dose-rate brachytherapy vs. robotic and conventional stereotactic body radiotherapy for ultrahypofractionated treatment of prostate cancer.

Background and purpose: Ultrahypofractionated radiation therapy is increasingly used in the treatment of prostate cancer. High-dose-rate brachytherapy (HDR-BT) and stereotactic body radiotherapy (SBRT) are representative methods of ultrahypofractionation. This study was performed to compare clinically applied treatment plans for patients who had been treated using HDR-BT vs. conventional or robotic SBRT. Materials and methods: Calculated dose-volume indices between HDR-BT without a perirectal spacer (n = 20), robotic SBRT without a spacer (n = 40), and conventional (non-robotic) SBRT with a spacer (n = 40) were compared. Percentages against the prescription dose regarding the planning target volume (PTV), bladder, rectum, and urethra were statistically compared. Results: The D50% of the PTV with HDR-BT (140.5% ± 4.9%) was significantly higher than that with robotic or conventional SBRT (116.2% ± 1.6%, 101.0% ± 0.4%, p < 0.01). The D2cm3 of the bladder with HDR-BT (65.6% ± 6.4%) was significantly lower than those with SBRT (105.3% ± 2.9%, 98.0% ± 1.3%, p < 0.01). The D2cm3 of the rectum with HDR-BT (60.6% ± 6.2%) was also significantly lower than those with SBRT (85.1% ± 8.8%, 70.4% ± 9.6%, p < 0.01). By contrast, the D0.1cm3 of the urethra with HDR-BT (117.1% ± 3.6%) was significantly higher than those with SBRT (100.2% ± 0.7%, 104.5% ± 0.6%, p < 0.01). Conclusions: HDR-BT could administer a higher dose to the PTV and a lower dose to the bladder and rectum, at the cost of a slightly higher dose to the urethra compared with SBRT.

HDR-brachytherapy for accelerated partial breast irradiation: Long-term experience from a Japanese institution.

Purpose: We investigated the long-term oncological outcome of high-dose-rate (HDR) multicatheter interstitial brachytherapy (MIB) for adjuvant accelerated partial breast irradiation (APBI) after breast conserving surgery in Japanese patients. Material and methods: Between June 2002 and October 2011, 86 breast cancer patients were treated at National Hospital Organization Osaka National Hospital (trial number of the local institutional review board, 0329). Median age was 48 years (range, 26-73 years). Eighty patients had invasive and 6 patients non-invasive ductal carcinoma. Tumor stage distribution was pT0 in 2, pTis in 6, pT1 in 55, pT2 in 22, and pT3 in one patient, respectively. Twenty-seven patients had close/positive resection margins. Total physical HDR dose was 36-42 Gy in 6-7 fractions. Results: At a median follow-up of 119 months (range, 13-189 months), the 10-year local control (LC) and overall survival rate was 93% and 88%, respectively. Concerning the 2009 Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology risk stratification scheme, the 10-year LC rate was 100%, 100%, and 91% for patients considered as low-risk, intermediate-risk, and high-risk, respectively. According to the 2018 American Brachytherapy Society risk stratification scheme, the 10-year LC rate was 100% and 90% for patients 'acceptable' and 'unacceptable' for APBI, respectively. Wound complications were observed in 7 patients (8%). Risk factors for wound complications were the omission of prophylactic antibiotics during MIB, open cavity implantation, and V100 ≥ 190 cc. No grade ≥ 3 late complications (CTCVE version 4.0) were observed. Conclusions: Adjuvant APBI using MIB is associated with favorable long-term oncological outcomes in Japanese patients for low-risk, intermediate-risk, and acceptable groups of patients.

Hands-on seminar for image-guided adaptive brachytherapy and intracavitary/interstitial brachytherapy for uterine cervical cancer.

OBJECTIVE: Compared with the implementation speed of image-guided adaptive brachytherapy for uterine cervical cancer, that of intracavitary and interstitial brachytherapy is slow, possible because it requires more invasive procedure of inserting needles directly into tumours. To accelerate the implementation speed of intracavitary and interstitial brachytherapy, a first hands-on seminar for image-guided adaptive brachytherapy and intracavitary and interstitial brachytherapy for uterine cervical cancer was held on 26 November 2022, supported by Japanese Society for Radiology and Oncology. This article deals with this hands-on seminar and difference of degree of confidence of participants in starting intracavitary and interstitial brachytherapy before and after the seminar. METHODS: The seminar consisted of lectures regarding intracavitary and interstitial brachytherapy in the morning and hands-on practice of needle insertion and contouring, as well as dose calculation practice using the radiation treatment system in the evening. Prior to and following the seminar, participants completed a questionnaire asking about their level of confidence in performing intracavitary and interstitial brachytherapy, expressed between 0 and 10 (the higher the number, the stronger the confidence). RESULTS: A total of 15 physicians, six medical physicists and eight radiation technologists from 11 institutions attended the meeting. The median level of confidence before and after the seminar was 3 (range, 0-6) and 5.5 (range, 3-7), respectively, and a statistically significant improvement was observed (P<0.001). CONCLUSION: It was suggested that the hands-on seminar on intracavitary and interstitial brachytherapy for locally advanced uterine cervical cancer improved the level of confidence of the attendees and propelled their motivation, through which it is expected that the implementation of intracavitary and interstitial brachytherapy will be accelerated.

Impact of interstitial lung abnormality on survival after adjuvant durvalumab with chemoradiotherapy for locally advanced non-small cell lung cancer.

INTRODUCTION: Concurrent chemoradiotherapy (CCRT) has been the standard of care for patients with locally advanced non-small cell lung cancer (LA-NSCLC). BACKGROUND AND PURPOSE: The results of the PACIFIC trial established the use of consolidative durvalumab after concurrent chemoradiotherapy (CCRT) as the standard of care for patients with locally advanced non-small cell lung cancer (LA-NSCLC). A subgroup analysis of the PACIFIC trial reported a better progression-free survival (PFS) in Asians. Although real-world data on LA-NSCLC patients who received CCRT plus durvalumab have been reported, there have been few large-scale reports on Asians. In this study, we investigated prognostic factors in the largest real-world data set in Asia of only Japanese LA-NSCLC patients treated with CCRT plus durvalumab. MATERIALS AND METHODS: One hundred and thirteen LA-NSCLC patients who received definitive CCRT and consolidative durvalumab at our institution between May 2018 and April 2021 were analyzed. Overall survival (OS), cause-specific survival (CSS), PFS, distant metastasis-free survival (DMFS), and in-field progression-free survival (IFPFS) were investigated as treatment outcomes using competing risk analyses. RESULTS: During a median follow-up of 24 months (range, 5-47) after the initiation of durvalumab therapy, 31 patients died, of whom 23 died of lung cancer. In the multivariate analysis, the pretreatment factors that correlated with OS were ILA scores, adenocarcinoma, and performance status at the initiation of durvalumab. Furthermore, ILA score and programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 1 % were significantly correlated with CSS, and PD-L1 TPS ≥ 1 % was significantly correlated with PFS and IFPFS. CONCLUSION: Pretreatment ILA, adenocarcinoma, and performance status may have an impact on OS of LA-NSCLC patients receiving CCRT plus durvalumab.

Phase I/II prospective clinical trial for the hybrid of intracavitary and interstitial brachytherapy for locally advanced uterine cervical cancer.

OBJECTIVE: The purposes of this trial were to demonstrate the feasibility and effectiveness of the hybrid of intracavitary and interstitial brachytherapy (HBT) for locally advanced cervical cancer patients in the phase I/II prospective clinical trial. METHODS: Patients with FIGO stage IB2-IVA uterine cervical cancer pretreatment width of which was ≥5 cm measured by magnetic resonance imaging were eligible for this clinical trial. The protocol therapy included 30-30.6 Gy in 15-17 fractions of whole pelvic radiotherapy concurrent with weekly CDDP, followed by 24 Gy in 4 fractions of HBT and pelvic radiotherapy with a central shield up to 50-50.4 Gy in 25-28 fractions. The primary endpoint of phase II part was 2-year pelvic progression-free survival (PPFS) rate higher than historical control of 64%. RESULTS: Between October 2015 and October 2019, 73 patients were enrolled in the initial registration and 52 patients proceeded to the secondary registration. With the median follow-up period of 37.3 months (range, 13.9-52.9 months), the 2- PPFS was 80.7% (90% confidence interval [CI]=69.7%-88%). Because the lower range of 90% CI of 2-year PPFS was 69.7%, which was higher than the historical control ICBT data of 64%, therefore, the primary endpoint of this study was met. CONCLUSION: The effectiveness of HBT were demonstrated by a prospective clinical study. Because the dose goal determined in the protocol was lower than 85 Gy, there is room in improvement for local control. A higher dose might have been needed for tumors with poor responses.

Clinical significance of local control of primary tumour in definitive radiotherapy for scalp angiosarcomas.

INTRODUCTION: Scalp angiosarcoma is a rare and aggressive cancer. Definitive radiotherapy is a treatment option for localised scalp angiosarcoma patients. Although definitive surgical resection reportedly prolongs overall survival (OS), whether initial local treatment effect affects OS when definitive radiotherapy is administered is unclear. Therefore, this study analysed whether local recurrence within 6 months of irradiation correlates with OS and cancer-specific survival (CSS). Furthermore, how local control affects patients' quality of life was investigated. MATERIALS AND METHODS: Thirty-one localised scalp angiosarcoma patients who had received definitive radiotherapy at our institution between October 2010 and July 2021 were analysed retrospectively. The most commonly used dose fractionation was 70 Gy in 35 fractions (83.9%). Local recurrence within 6 months of radiotherapy and other clinical factors were examined in univariate and subsequent multivariate analyses for correlation with OS and CSS. RESULTS: The median follow-up period was 16 months (range, 6-45 months). Local recurrence was detected in 16 patients (51.6%), 12 of whom had recurrence within 6 months. In multivariate analyses, the presence of local recurrence within 6 months of radiotherapy was significantly associated with OS and CSS (p = 0.003, 0.0001, respectively). Ten of the 16 patients with local recurrence had severe symptoms such as bleeding, pain, difficulty opening the eye and malodour. CONCLUSIONS: The initial local treatment effect was significantly associated with OS and CSS after definitive radiotherapy. Furthermore, local recurrence after radiotherapy resulted in a variety of symptoms, including bleeding and pain, which reduced the patient's quality of life.

Planning study: prone versus supine position for stereotactic body radiotherapy in prostate by CyberKnife.

This study aimed to clarify the differences in radiotherapy dose characteristics and delivery efficiency between the supine and prone positions in patients with prostate cancer using the CyberKnife. The planning computed tomography (CT) and delineations of the prone position were obtained by rotating the supine CT images with delineations of 180° using image processing software. The optimization parameters for planning target volume (PTV) and organs at risk (OARs) were based on the prone position. The optimization parameters determined for the prone position were applied to the supine position for optimization and dose calculation. The dosimetric characteristics of the PTV and OARs, and delivery efficiency were compared between the two different patient positions. The plans in the prone position resulted in better PTV conformity index (nCI), rectum V90%, V80%, V75%, V50% and bladder V50%. A significant difference was observed in treatment time and depth along the central axis (dCAX) between the two plans. The mean treatment time per fraction and dCAX for the supine and prone positions were 20.9 ± 1.7 min versus 19.8 ± 1.3 min (P = 0.019) and 151.1 ± 33.6 mm versus 233.2 ± 8.8 mm (P < 0.001), respectively. In this study the prone position was found to improve dosimetric characteristics and delivery efficiency compared with the supine position during prostate cancer treatment with the CyberKnife.

Hydrogel spacer injection to the meso-sigmoid to protect the sigmoid colon in cervical cancer brachytherapy: A technical report.

Purpose: The use of a hydrogel spacer inserted into recto-vaginal fossa is a valuable strategy to mitigate radiation exposure to the rectum during radiation therapy for female pelvic malignancies. However, when the sigmoid colon is in proximity to the cervix, radiation exposure to the sigmoid colon cannot be adequately mitigated with a hydrogel spacer injected into the recto-vaginal fossa. Here, we presented a case, in which a hydrogel spacer was injected into the meso-sigmoid to protect the sigmoid colon. Material and methods: A 73-year-old female diagnosed with T3b stage IIIC2r uterine cervical cancer (FIGO 2018) underwent high-dose-rate interstitial brachytherapy consisting of 24 Gy in 4 fractions, following concurrent chemoradiotherapy with external beam radiation therapy of 50 Gy in 25 fractions of whole pelvic radiation therapy. In the initial brachytherapy, the sigmoid colon was in close contact with the uterine cervix. In the second brachytherapy, attempts to create a space between the sigmoid colon and uterine cervix using injected artificial ascites were unsuccessful due to rapid absorption of fluid. In the third and fourth brachytherapy fractions, 5 mL of hydrogel was injected into the meso-sigmoid through a pouch of Douglas under trans-rectal ultrasonography guidance. Dose ratio of sigmoid colon D2cc and high-risk clinical target volume (HR-CTV) D90 of each brachytherapy were evaluated. Results: Dose ratio of the sigmoid colon D2cc to HR-CTV D90 was 1.03, 0.43, 0.56, and 0.47 in each respective brachytherapy session, indicating dose escalation to HR-CTV whilst achieving acceptable sigmoid dose with hydrogel spacer injected into the meso-sigmoid. Conclusions: The dose ratio of the sigmoid colon to HR-CTV D90 was decreased by introducing a hydrogel spacer into the meso-sigmoid. In cases where the sigmoid colon is in proximity to the cervical tumor, this novel technique can be considered to achieve better clinical outcomes.

Clinical impact of p16 positivity in nasopharyngeal carcinoma.

Purpose: The clinical characteristics and prognosis of HPV-related nasopharyngeal cancer (NPC) remain controversial. The relationship between p16 status and outcome was retrospectively investigated in the NPC patients. Materials and Methods: Between May 2009 and May 2019, 81 NPC patients who received definitive radiation therapy, in a hospital in Japan, were identified and the prognosis was investigated. p16, p53, and Epstein-Barr virus (EBV) status were assessed. Also, circumferential tumor extent in the nasopharyngeal cavity was assessed on a 5-point scale. Results: Nine and 72 patients were p16-positive and p16-negative, respectively. Fewer patients were EBV-encoded RNA in situ hybridization (EBER-ISH)-positive in the p16-positive group than in the p16-negative group (p < .01). Seventy-five patients were nonkeratinizing NPCs, and six patients were keratinizing NPCs. There were two p16-positive patients among the keratinizing NPCs.The mean circumferential tumor extent scores of 16-positive and p16-negative NPCs were 4.2 and 3.2, respectively with a statistically significant difference (p = .02). Two-year progression-free survival (PFS) of p16-positive and p16-negative patients undergoing chemoradiation therapy were 100% and 69%, respectively (p = .13). Conclusion: In this study conducted in Japan, p16-positive NPC patients are minor but not very low, and the proportion of keratinizing NPCs was small. p16-positive NPCs were seen both in keratinizing and nonkeratinizing NPCs. P16-positive NPC had a tendency of better PFS than p16-negative NPC. This better prognosis might be due to the higher radiosensitivity of the p16-positive cell. Additionally, p16-positive NPCs seemed to spread more extensively in circumference along the nasopharyngeal mucosa than p16-negative NPCs.

Circulating microRNA profiling for prediction of oncological outcomes in prostate cancer patients following radical prostatectomy.

BACKGROUND: Although radical prostatectomy is associated with good long-term oncological outcomes, approximately 30% of patients present biochemical recurrence, whereupon salvage treatments are required. Identification of novel molecular biomarkers to predict cancer behavior is clinically important. Here, we developed a novel microRNA (miRNA)-based prognostic model for patients who underwent radical prostatectomy. METHODS: We retrospectively investigated the clinical records of 295 patients who underwent radical prostatectomy between 2009 and 2017. We randomly assigned these cases into training or validation sets. The prognostic model was constructed using Fisher linear discriminant analysis in the training set, and we evaluated its performance in the validation set. RESULTS: Overall, 72 patients had biochemical recurrence. A prediction model was constructed using a combination of three miRNAs (miR-3147, miR-4513, and miR-4728-5p) and two pathological factors (pathological T stage and Gleason score). In the validation set, the predictive performance of the model was confirmed to be accurate (area under the receiver operating characteristic curve: 0.80; sensitivity: 0.78; specificity: 0.76). Additionally, Kaplan-Meier analysis revealed that the patients with a low prediction index had significantly longer recurrence-free survival than those with a high index (p < 0.001). CONCLUSIONS: Circulating miRNA profiles can provide information to predict recurrence after prostatectomy. Our model may be helpful for physicians to decide follow-up strategies for patients.

Practical guidelines of online MR-guided adaptive radiotherapy.

The first magnetic resonance (MR)-guided radiotherapy system in Japan was installed in May 2017. Implementation of online MR-guided adaptive radiotherapy (MRgART) began in February 2018. Online MRgART offers greater treatment accuracy owing to the high soft-tissue contrast in MR-images (MRI), compared to that in X-ray imaging. The Japanese Society for Magnetic Resonance in Medicine (JSMRM), Japan Society of Medical Physics (JSMP), Japan Radiological Society (JRS), Japanese Society of Radiological Technology (JSRT), and Japanese Society for Radiation Oncology (JASTRO) jointly established the comprehensive practical guidelines for online MRgART. These guidelines propose the essential requirements for clinical implementation of online MRgART with respect to equipment, personnel, institutional environment, practice guidance, and quality assurance/quality control (QA/QC). The minimum requirements for related equipment and QA/QC tools, recommendations for safe operation of MRI system, and the implementation system are described. The accuracy of monitor chamber and detector in dose measurements should be confirmed because of the presence of magnetic field. The ionization chamber should be MR-compatible. Non-MR-compatible devices should be used in an area that is not affected by the static magnetic field (outside the five Gauss line), and their operation should be checked to ensure that they do not affect the MR image quality. Dose verification should be performed using an independent dose verification system that has been confirmed to be reliable through commissioning. This guideline proposes the checklists to ensure the safety of online MRgART. Successful clinical implementation of online MRgART requires close collaboration between physician, radiological technologist, nurse, and medical physicist.

Effect of Hyaluronate Acid Injection on Dose-Volume Parameters in Brachytherapy for Cervical Cancer.

Purpose: Hyaluronate gel has been injected as a spacer into the rectovaginal fossa and vesicouterine fossa during brachytherapy for patients with cervical cancer at our institution. The effect of hyaluronate gel injection (HGI) on dose-volume parameters was investigated in this study. Methods and Materials: Between July 2008 to January 2020, a total of 104 patients (non-HGI group: 52 patients; HGI group: 52 patients) who underwent curative radiation therapy for cervical cancer were selected. The total doses of external beam radiation therapy and brachytherapy for high-risk clinical target volume (CTVHR) D90, bladder D2cc, and rectal D2cc were converted to the equivalent dose in 2 Gy fractions (EQD2) and were analyzed for association with HGI. Results: Median CTVHR D90 (EQD2) in the non-HGI group was 76.0 Gy (63.7-99.5 Gy), and in the HGI group it was 79.4 Gy (52.6-97.5 Gy) (P = .017). The median bladder D2cc and rectal D2cc (EQD2) were 62.9 Gy and 56.0 Gy in the non-HGI group and 63.7 Gy and 54.8 Gy in the HGI group, which had no significant difference. Conclusions: In cases with HGI, a significant CTVHR D90 dose increase was obtained with sufficient bladder and rectal doses suppression.

Salvage image-guided freehand interstitial brachytherapy for pelvic sidewall recurrence after hysterectomy for uterine malignancies.

PURPOSE: Pelvic sidewall recurrence after hysterectomy for uterine malignances has a poor prognosis, and the salvage therapy for this type of recurrence is still challenging. The purpose of this study was to investigate the efficacy of freehand high-dose-rate interstitial brachytherapy (HDR-ISBT) through the perineum using transrectal ultrasonography for this disease. METHODS AND MATERIALS: We retrospectively evaluated 42 patients with pelvic sidewall recurrence after hysterectomy for uterine cervical and endometrial cancers. We investigated patients' characteristics, the 2-year local control and survival rates, and late adverse events of the rectum and bladder. RESULTS: The 2-year overall survival, local control, and progression-free survival rates were 73.7% (95% confidence interval [CI], 60.8-89.3%), 69.4% (95% CI, 55.4-80.1%), and 37.3% (95% CI, 24.6-56.5%), respectively. In Cox multivariate analysis, tumor size at recurrence (<45 mm vs. ≥45 mm) (p = 0.04) and disease-free periods after hysterectomy (<10 months vs. ≥10 months) (p < 0.01) were significant prognostic factors for overall survival. Lymph node metastasis at recurrence (p < 0.01) was also a significant prognostic factor for progression-free survival. Three patients experienced Grade 3-4 late proctitis (7%). CONCLUSIONS: Transperineal freehand salvage HDR-ISBT using transrectal ultrasonography was demonstrated to be a curative treatment option for patients with pelvic sidewall recurrence following hysterectomy. Based on the findings of this study, we emphasize the importance of HDR-ISBT for pelvic sidewall recurrence.

Non-Robustness of Ang's Risk Classification in Human Papillomavirus-Related Oropharyngeal Squamous Cell Carcinoma in Japanese Patients.

BACKGROUND: Validity of the risk classification by Ang for human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) remains to be studied in the patients treated by modalities other than chemoradiotherapy and in Japanese patients. MATERIALS AND METHODS: Between 2010 and 2018, 122 patients with HPV-related OPSCC in stages III and IV by the TNM classification 7th edition (TNM-7) were treated curatively at a single institution in Japan. The median age was 62.7 years. Over 50% of the patients underwent surgery with or without adjuvant therapy. The influence of multiple factors on survival was analyzed. RESULTS: The amount of smoking dichotomized at 10 pack-year, which was used in Ang's risk classification, was not predictive of prognosis, and Ang's risk classification was not significantly influential on prognosis in multivariate analysis. In the patients treated with definitive radiation therapy, Ang's risk classification was not predictive of the prognosis in univariate analysis. The impact of smoking was significant only in the patients undergoing the definitive operation. CONCLUSIONS: Ang's risk classification was not robust in predicting the prognosis of general Japanese HPV-related OPSCC patients. The amount of smoking might have different prognostic influences depending on the therapeutic method.

Large volume was associated with increased risk of acute non-hematologic adverse events in the hybrid of intracavitary and interstitial brachytherapy for locally advanced uterine cervical cancer: preliminary results of prospective phase I/II clinical trial.

OBJECTIVE: This is the preliminary results of a multi-center prospective clinical trial evaluating the feasibility of the hybrid of intracavitary and interstitial brachytherapy for locally advanced cervical cancer. METHODS: Patients with FIGO stage IB2, IIA2, IIB, IIIA, IIIB and IVA uterine cervical cancer pretreatment width of which was ≥5 cm measured by MRI were eligible. Protocol therapy consisted of 30-30.6 Gy in 15-17 fractions of whole pelvic radiotherapy concurrent with weekly CDDP, followed by 24 Gy in 4 fractions of hybrid of intracavitary and interstitial and pelvic radiotherapy with central shield up to 50-50.4 Gy in 25-28 fractions. The primary endpoint of phase I part was that the rate of grade ≥ 3 acute non-hematologic adverse events related to hybrid of intracavitary and interstitial would be <10%. RESULTS: Between October 2015 and October 2019, 74 patients underwent primary registration, with 52 patients eventually proceeding to the secondary registration. The median pretreatment tumor width was 5.7 cm, and FIGO Stages were IB2 10, IIA2 2, IIB 20 and IIIB 20, respectively. The median high-risk clinical target volume D90 was 72.0 Gy (54.8-86.6 Gy, EQD2), rectum D2cc was 53.7 Gy (29.3-80.3 Gy) and bladder D2cc was 69.8 Gy (38.9-84.8 Gy). The rate of grade ≥ 3 non-hematologic adverse events related to hybrid of intracavitary and interstitial was 1.9% (1/52), and 17.3% (9/52) of patients experienced non-hematologic adverse events related to hybrid of intracavitary and interstitial of any grade. In multivariate analysis, high-risk clinical target volume ≥ 35 ml was associated with an increased risk of any grade of acute non-hematologic adverse events related to hybrid of intracavitary and interstitial (P = 0.036). CONCLUSION: The feasibility and reproducibility of hybrid of intracavitary and interstitial were demonstrated from a multi-center prospective clinical trial.

Bevacizumab increases late toxicity in re-irradiation with image-guided high-dose-rate brachytherapy for gynecologic malignancies.

INTRODUCTION: Patients with recurrent gynecologic malignancies having had pelvic irradiation, generally have limited salvage options. This study investigated patients with gynecologic malignancies, who had a history of pelvic irradiation and received salvage re-irradiation using image-guided high-dose-rate brachytherapy (IG-HDR-BT). MATERIAL AND METHODS: Patients with gynecologic malignancies, who had a history of previous irradiation and received re-irradiation using IG-HDR-BT for disease recurrences from June 2014 to March 2020 were included in this study. RESULTS: A total of 37 patients were included in this retrospective analysis. Primary tumor was uterine cervical cancer in 31 patients, endometrial cancer in 5 patients, and vaginal cancer in 1 patient. Median follow-up period of patients who were alive at the time of analysis was 15.4 months (range, 4.1-61.4 months). Two-year overall survival, progression-free survival, and local control were 68.9%, 49.3%, and 67.5%, respectively. Severe late toxicities ≥ grade 3, which were related to re-irradiation, were observed in 9 patients (24.3%). Usage of bevacizumab in the entire course of treatment was associated with development of late ≥ grade 3 fistula formation, bowel perforation, or vaginal ulcer (50% vs. 6.9%, p = 0.013). Tumor size ≥ 2.5 cm was associated with development of late ≥ grade 3 of rectum, bladder, or vaginal toxicities (0% vs. 28%, p = 0.047). CONCLUSIONS: If the recurrent disease was found in small size and there was no history of bevacizumab usage, re-irradiation with IG-HDR-BT could be considered, even in patients with a previous history of pelvic irradiation.