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.

Safety evaluation of immune-cell therapy for malignant tumor in the Cancer Immune-cell Therapy Evaluation Group (CITEG).

BACKGROUND AIMS: With the aim of strengthening the scientific evidence of immune-cell therapy for cancer and further examining its safety, in October 2015, our hospital jointly established the Cancer Immune-Cell Therapy Evaluation Group (CITEG) with 39 medical facilities nationwide. METHODS: Medical information, such as patients' background characteristics, clinical efficacy and therapeutic cell types obtained from each facility, has been accumulated, analyzed and evaluated by CITEG. In this prospective study, we analyzed the adverse events associated with immune-cell therapy until the end of September 2022, and we presented our interim safety evaluation. RESULTS: A total of 3839 patients with malignant tumor were treated with immune-cell therapy, with a median age of 64 years (range, 13-97 years) and a male-to-female ratio of 1:1.08 (1846:1993). Most patients' performance status was 0 or 1 (86.8%) at the first visit, and 3234 cases (84.2%) were advanced or recurrent cases, which accounted for the majority. The total number of administrations reported in CITEG was 31890, of which 960 (3.0%) showed adverse events. The numbers of adverse events caused by treatment were 363 (1.8%) of 19661 administrations of αßT cell therapy, 9 of 845 administrations of γδT-cell therapy (1.1%) and 10 of 626 administrations of natural killer cell therapy (1.6%). The number of adverse events caused by dendritic cell (DC) vaccine therapy was 578 of 10748 administrations (5.4%), which was significantly larger than those for other treatments. Multivariate analysis revealed that αßT cell therapy had a significantly greater risk of adverse events at performance status 1 or higher, and patients younger than 64 years, women or adjuvant immune-cell therapy had a greater risk of adverse events in DC vaccine therapy. Injection-site reactions were the most frequently reported adverse events, with 449 events, the majority of which were associated with DC vaccine therapy. Among all other adverse events, fever (228 events), fatigue (141 events) and itching (131 events) were frequently reported. In contrast, three patients had adverse events (fever, abdominal pain and interstitial pneumonia) that required hospitalization, although they were weakly related to this therapy; rather, it was considered to be the effect of treatment for the primary disease. CONCLUSIONS: Immune-cell therapy for cancer was considered to be a safe treatment without serious adverse events.

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.

A 54 Gy in three fractions of stereotactic body radiotherapy using CyberKnife for T1b-2aN0M0 pathologically confirmed non-small cell lung cancer.

OBJECTIVE: Optimal dose-fractionation regimen of stereotactic body radiotherapy for peripheral early-stage non-small cell lung cancer remains unclear. We retrospectively investigated outcomes of stereotactic body radiotherapy using CyberKnife at 54 Gy in three fractions in 26 patients (median age: 76 years) with pathologically confirmed T1b-T2aN0M0 non-small cell lung cancer. METHODS: A 54 Gy in three fractions was prescribed to cover the 99% of gross tumor volume. We estimated cumulative local control, progression-free survival and overall survival rates (Kaplan-Meier method), and toxicity (Common Toxicity Criteria for Adverse Events, version 5.0). RESULTS: All the tumors were located at peripheral area of lung. Mean distance from chest wall to tumor was 6.5 mm (range: 0-32 mm). The patients' pathological diagnoses were: adenocarcinoma: n = 18, squamous cell carcinoma: n = 7 and non-small cell carcinoma: n = 1. Their stages were T1b: n = 9, T1c: n = 14 and T2a: n = 3. Median follow-up was 24 months (range: 6-54). Cumulative 2-year effect rates were local control: 100%, progression-free survival 70% and overall survival: 92%. Twenty patients developed grade one radiation pneumonitis, but grade 2 or greater radiation pneumonitis was not observed. CONCLUSIONS: We found CyberKnife-stereotactic body radiotherapy for pathologically confirmed T1b-T2aN0M0 non-small cell lung cancer to be effective and safe. However, these results should be validated with a larger patient cohort and prospective follow-up monitoring.

Mutation profiling of uterine cervical cancer patients treated with definitive radiotherapy.

OBJECTIVE: To elucidate tumor mutation profiles associated with outcomes of uterine cervical cancer (UCC) patients treated with definitive radiotherapy. METHODS: Ninety-eight patients with newly diagnosed and pathologically confirmed UCC (82 squamous cell carcinomas, 12 adenocarcinomas, and four adenosquamous carcinomas) who were treated with definitive radiotherapy were analyzed. DNA was extracted from pre-treatment tumor biopsy specimens. The exons of 409 cancer-related genes were sequenced using a next-generation sequencer. Genetic mutations were identified and analyzed for correlations with clinical outcome. RESULTS: Recurrent mutations were observed in PIK3CA (35.7%), ARID1A (25.5%), NOTCH1 (19.4%), FGFR3 (16.3%), FBXW7 (19.4%), TP53 (13.3%), EP300 (12.2%), and FGFR4 (10.2%). The prevalence of mutations in FGFR family genes (i.e., FGFR1-4) was almost as high (24.5%) as that in PIK3CA and ARID1A, both of which are well-studied drivers of UCC. Fifty-five percent (21 of 38) of the identified FGFR mutations were located in the FGFR protein tyrosine kinase domain. Five-year progression-free survival (PFS) rates for FGFR mutation-positive patients (n = 24) were significantly worse than those for FGFR mutation-negative patients (n = 74) (43.9% vs. 68.5%, respectively; P = 0.010). Multivariate analysis identified FGFR mutations as significant predictors of worse 5 year PFS (P = 0.005), independent of clinicopathological variables. CONCLUSIONS: FGFR mutations are associated with worse PFS in UCC patients treated with definitive radiotherapy. These results warrant further validation in prospective studies.

Development of an HDR-BT QA tool for source position verification.

PURPOSE: This study aimed to develop a high-dose-rate brachytherapy (HDR-BT) quality assurance (QA) tool for verification of source positions, and to report on its effectiveness. METHODS: We fabricated a cuboid phantom measuring 30 × 30×3 cm3 with spaces to embed Fletcher-Williamson tandem and ovoid applicators. Lead-based, cylindrically shaped radiopaque markers, which scatter radiation and blacken the Gafchromic® RTQA2 films placed on the applicators, were inserted into the phantom to determine the applicator tip and reference source positions. A three-dimensional image-guided brachytherapy (3D-IGBT) plan was generated, and the source positions on the film and radiation treatment planning system (RTPS) were verified with the tool. Source position errors were evaluated as the distance in the applicator axis direction between the source position and the center position of two radiopaque marker pairs. RESULTS: Source position errors on the film and RTPS were in good agreement with one another and were all within 0.5 mm for all applicators. Offset values of each applicator were in good agreement with the value determined in treatment planning (6 mm). The expanded measurement uncertainty of our QA tool was estimated to be 0.87 mm, with a coverage factor k of 2. CONCLUSIONS: Our new HDR-BT QA tool developed for comprehensive source position verification will be useful for cross checking actual source positions and planned source positions on the RTPS.

FGFR Signaling as a Candidate Therapeutic Target for Cancers Resistant to Carbon Ion Radiotherapy.

Radiotherapy is an essential component of cancer therapy. Carbon ion radiotherapy (CIRT) promises to improve outcomes compared with standard of care in many cancers. Nevertheless, clinicians often observe in-field recurrence after CIRT. This indicates the presence of a subset of cancers that harbor intrinsic resistance to CIRT. Thus, the development of methods to identify and sensitize CIRT-resistant cancers is needed. To address this issue, we analyzed a unique donor-matched pair of clinical specimens: a treatment-naïve tumor, and the tumor that recurred locally after CIRT in the same patient. Exon sequencing of 409 cancer-related genes identified enrichment of somatic mutations in FGFR3 and FGFR4 in the recurrent tumor compared with the treatment-naïve tumor, indicating a pivotal role for FGFR signaling in cancer cell survival through CIRT. Inhibition of FGFR using the clinically available pan-FGFR inhibitor LY2874455 sensitized multiple cancer cell lines to carbon ions at 3 Gy (RBE: relative biological effectiveness), the daily dose prescribed to the patient. The sensitizer enhancement ratio was 1.66 ± 0.17, 1.27 ± 0.09, and 1.20 ± 0.18 in A549, H1299, and H1703 cells, respectively. Our data indicate the potential usefulness of the analytical pipeline employed in this pilot study to identify targetable mutations associated with resistance to CIRT, and of LY21874455 as a sensitizer for CIRT-resistant cancers. The results warrant validation in larger cohorts.

Tumor-specific CD8-positive T cell-mediated antitumor immunity is implicated in the antitumor effect of local hyperthermia.

PURPOSE: This study aimed to elucidate the contribution of T cell-mediated antitumor immunity in the antitumor effect of local hyperthermia (LH). MATERIALS AND METHODS: C57BL/6J mice were injected with the mouse lymphoma cell line, E.G7-OVA, in the right femur on day 0. LH was induced by immersing the right femur in a water bath at 42 °C for 60 min on day 7, followed by administration of anti-CD8 monoclonal antibodies (mAb) or anti-CTLA-4 mAb (days 8, 11, and 14). The effect of LH on tumor growth (TG) was assessed by measuring the duration until tumor volume reached 1000 mm3 and survival time. Tumor-specific T cell responses were measured using enzyme-linked immunospot (ELISpot) assay. RESULTS: TG with and without LH treatment was 9.0 ± 9.6 and 7.0 ± 1.6 days, respectively. TG was significantly slower with LH treatment (p = .01). The therapeutic effect of LH was mitigated by addition of anti-CD8 mAb (p < .05 for both TG and survival) compared with the untreated (control) group. Furthermore, addition of anti-CTLA-4 mAb did not significantly affect the therapeutic effect of LH. The ELISpot assay showed that the number of spots in the LH group (276.3 ± 14.5) was significantly greater than in the control group (59.0 ± 4.5, p < .001). CONCLUSION: CD8-positive T cell-mediated antitumor immunity significantly contributes to the antitumor effect of LH.

Phase II study of concurrent chemoradiotherapy with weekly cisplatin and paclitaxel in patients with locally advanced uterine cervical cancer: The JACCRO GY-01 trial.

OBJECTIVE: A multicenter phase II trial was conducted to assess the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) with weekly cisplatin (CDDP) and paclitaxel (PTX) in patients with locally advanced uterine cervical cancer. METHODS: Patients with FIGO stage III-IVA uterine cervical cancer without para-aortic lymphadenopathy were enrolled. Patients received definitive radiotherapy (RT) consisting of external beam whole-pelvic RT and high-dose-rate intracavitary brachytherapy. The cumulative linear quadratic equivalent dose was 62-65Gy prescribed at point A. weekly CDDP at 30mg/m(2) and PTX at 50mg/m(2) were administered concurrently with RT for ≥5 courses. RESULTS: Sixty-eight of the 70 registered patients were eligible. The complete response rate was 76.5% (95% confidence interval [CI], 66.4-86.6%). With a median follow-up of 27months (range, 7.9-33.5), the 2-year cumulative progression-free survival and the 2-year cumulative overall survival rates were 83.8% (95% CI, 75.1-92.6%) and 92.7% (95% CI, 86.4-98.9%), respectively. The pelvic cumulative disease progression-free and the 2-year cumulative distant metastasis rates were 89.6% (95% CI, 82.3-96.9%) and 13.2% (95% CI, 5.2-21.3%), respectively. The 2-year cumulative late complication rates were 25% for all grades, 13.2% for grade 1, 5.9% for grade 2, 2.9% for grade 3, and 2.9% for grade 4. CONCLUSIONS: For locally advanced cervical cancer, CCRT with weekly CDDP 30mg/m(2) and PTX at 50mg/m(2) demonstrated favorable antitumor activity, and was feasible and safe with respect to the protocol-specified serious adverse reactions and events. Evaluation of this regimen in phase III trials is warranted.

The prognostic effect of tumor volume, reduction ratio, and cumulative doses on external beam radiotherapy with central-shielding method and image-guided adaptive brachytherapy for cervical cancer.

Objective: To evaluate the prognostic effect of tumor volume at diagnosis, tumor reduction ratio during external beam radiotherapy (EBRT) with central-shielding method, and cumulative minimal dose to 90% of the high-risk clinical target volume (CTVHR D90) on combined EBRT and image-guided adaptive brachytherapy (IGABT) for cervical cancer. Methods: Consecutive patients who underwent definitive radiotherapy or concurrent chemoradiotherapy for cervical cancer at Gunma University Hospital between January 2010 and December 2019 were retrospectively reviewed. Tumor volume at diagnosis and reduction ratio were calculated using magnetic resonance imaging at diagnosis and before the first IGABT session. The cumulative dose of EBRT and IGABT was calculated as an equivalent dose in 2 Gy fractions (EQD2). Optimal cutoff values were determined according to a receiver operating characteristic curve. Treatment outcomes were evaluated using the Kaplan-Meier method and compared using the log-rank test and Cox proportional hazards regression. Results: A total of 254 patients were included in the analysis. The median follow-up for all patients was 57 (2-134) months. The 5-year overall survival (OS) was 81.9%, progression-free survival (PFS) was 71.3%, and local control (LC) was 94.5%. The patients were divided into four groups according to tumor volume at diagnosis and reduction ratio. The group with tumor volume at diagnosis ≥ 34.1 cm3 and reduction ratio < 68.8% showed significantly worse OS, PFS, and LC than the other three groups (All p < 0.05). In this group, the patients with a cumulative CTVHR D90 < 69.6 GyEQD2 showed significantly worse PFS and LC (p = 0.042 and p = 0.027, respectively). In the multivariate analysis of OS, adenocarcinoma/adenosquamous carcinoma, International Federation of Gynecology and Obstetrics 2009 stage III/IV, and a reduction ratio of < 68.8% were independent significant poor prognostic factors (p = 0.045, p = 0.009 and p = 0.001, respectively). In the univariate analysis of LC, a reduction ratio of < 68.8% was the only poor prognostic factor (p = 0.041). Conclusion: The patients with large and poorly responding tumors had significantly worse prognoses in terms of OS, PFS, and LC, suggesting that dose escalation should be considered for such tumors.

Carbon ion radiotherapy for mesonephric adenocarcinoma of the uterine cervix: a case report.

BACKGROUND: Mesonephric adenocarcinoma is an extremely rare subtype of uterine cervical cancer that is associated with a poor prognosis and for which a standardized treatment protocol has not been established. Carbon ion radiotherapy (CIRT) is an emerging radiotherapy modality that has been shown to have a favorable anti-tumor effect, even for tumors resistant to conventional photon radiotherapy or chemotherapy. However, there is no report on CIRT outcomes for mesonephric adenocarcinoma of the uterine cervix. CASE PRESENTATION: We treated a 47-year-old Japanese woman with mesonephric adenocarcinoma of the uterine cervix (T2bN0M0 and stage IIB according to the 7th edition of the Union for International Cancer Control and International Federation of Gynecology and Obstetrics, respectively) with CIRT combined with brachytherapy and concurrent chemotherapy. CIRT consisted of whole pelvic irradiation and boost irradiation to the gross tumor; 36.0 Gy (relative biological effectiveness [RBE]) in 12 fractions and 19.2 Gy (RBE) in 4 fractions, respectively, performed once a day, four times per week. Computed tomography-based image-guided adaptive brachytherapy was performed after completion of CIRT, for which the D90 (i.e., the dose prescribed to 90% of the target volume) for the high-risk clinical target volume was 20.4 Gy in a total of 3 sessions in 2 weeks. A weekly cisplatin (40 mg/m2) dose was administered concomitantly with the radiotherapy for a total of five courses. From 4 months post-CIRT, the patient developed metastasis of the lung, with a total of 10 lung metastases over 70 months; these lesions were treated on each occasion by photon stereotactic body radiotherapy and/or systemic therapy. At 8 years from initial treatment (i.e., 2 years after the last treatment), the patient is alive without any evidence of recurrence and maintains a high quality of life. CONCLUSIONS: This is the first report of CIRT for treatment of mesonephric adenocarcinoma of the uterine cervix. The present case indicates the potential efficacy of CIRT in combination with brachytherapy for treatment of this disease.

Hands-on-training tailored in response to pre-questionnaire-based survey on image-guided brachytherapy effectively reduces anxiety about its implementation.

This study assessed the significance of hands-on-training (HoT) and questionnaire-based surveys on 3D image-guided brachytherapy (3D-IGBT) and a combination of intracavitary and interstitial brachytherapy, the so-called 'hybrid' BT (HBT), in uterine cervical cancer. In October 2023, 29 radiation oncologists, nurses, radiologic technologists and medical physicists from 10 Japanese facilities participated in an HoT on 3D-IGBT and HBT. Questionnaires were distributed to each participant before and after the HoT, and feedback was obtained through online channels. The questionnaire response rate was 83% (24/29), with at least one participant responding from each facility. 'Insertion of applicators and needles', 'human resource shortage' and 'pain relief and sedation' were the primary concerns of radiation oncologists. 'Applicator reconstruction', ' optimization of dwell positions', ' treatment planning' and ' human resource shortages ' were the primary concerns of radiological technologists and medical physicists. The HoT content was adjusted according to the results of preliminary surveys. The concerns expressed by the participants were addressed during the lectures and practical training. Significant reductions in anxiety were observed toward all items of the 10-point self-assessment after the HoT, regardless of the profession. The average score on satisfaction with the HoT (on a 10-point scale) was 9.52 (minimum of 8 and maximum of 10). In conclusion, HoT tailored in response to a pre-questionnaire-based survey effectively reduced participants' anxiety regarding the implementation of 3D-IGBT and HBT.

Patterns of care for brachytherapy in Japan.

This study aimed to assess the current state of brachytherapy (BT) resources, practices and resident education in Japan. A nationwide survey was undertaken encompassing 177 establishments facilitating BT in 2022. Questionnaires were disseminated to each BT center, and feedback through online channels or postal correspondence was obtained. The questionnaire response rate was 90% (159/177), and every prefecture had a response in at least one center. The number of centers in each prefecture ranged from 0.6 to 3.6 (median: 1.3) per million population. The annual number of patients in each center ranged from 0 to 272 (median: 31). While most prefectures provided intracavitary (IC) BT for gynecological cancers and interstitial (IS) BT for prostate cancer, only one-third of the prefectures provided IS BT for cancer sites other than the prostate. The institutional image-guided BT implementation rate was 71%. IC and IS BT was performed for 15.4% of IC BT cases of gynecological cancer. Only 47% of the BT training centers answered that they could provide adequate training in BT for residents. The most common reason for this finding was the insufficient number of patients in each center. The results show that, although BT has achieved uniformity in terms of facility penetration, new technologies are not yet widespread enough. Furthermore, IS BT, which requires advanced skills, is limited to a few BT centers, and considerable number of BT training centers do not have sufficient caseloads to provide the necessary experience for their residents.

Results of Definitive (Chemo)radiotherapy Using Computed Tomography-based Brachytherapy for Cervical Cancer.

BACKGROUND/AIM: Concurrent cisplatin-based chemoradiotherapy (CCRT) is the standard treatment for locally advanced cervical cancer. Especially, CCRT with magnetic resonance imaging (MRI) or computed tomography-based image-guided brachytherapy (CT-based 3D-IGBT) for cervical cancer has resulted in good LC rates. However, progression-free survival (PFS) and overall survival (OS) rates for locally advanced cervical cancer are still low and could be improved. The aim of the study was to evaluate treatment efficacy and late toxicity of external beam radiotherapy (EBRT) and CT-based IGBT with or without concurrent chemotherapy in patients with squamous cell carcinoma of the uterine cervix and investigate patterns of failure. PATIENTS AND METHODS: We retrospectively analyzed clinical data of cervical squamous cell carcinoma patients treated with definitive radiotherapy with or without concurrent chemotherapy at Saitama Medical University International Medical Center. Local control (LC), PFS, patterns of failure, and late toxicity were the evaluated outcomes. RESULTS: Overall, 290 patients were enrolled in the study. Median follow-up was 51.5 months. During follow-up, 74 patients developed recurrence: 10 patients with intra-pelvic failure only, 45 with extra-pelvic failure only, and 19 with both. The 3-year LC was 100% for T1b-T2a, 96.8% for T2b, 89.5% for T3b, and 88.5% for T4 disease. The 3-year PFS was 100% for stage IB-IIA, 89.0% for stage IIB, 70.7% for stage IIIB, 72.6% for stage IIIC1r, and 40.1% for stage IVA. The incidence of grade 3-4 gastrointestinal and genitourinary toxicities was 3.0% and 1.7%, respectively. CONCLUSION: Combination of EBRT and CT-based IGBT with or without concurrent chemotherapy produced favorable LC with acceptable rates of late toxicities. However, extra-pelvic failures frequently occurred and PFS was less satisfactory in patients with stage III-IVA disease, which indicated the need for additional treatment in these patients.

Learning curve of lung dose optimization in intensity-modulated radiotherapy for locally advanced non-small cell lung cancer.

BACKGROUND: Intensity-modulated radiotherapy (IMRT) has been increasingly used for patients with locally advanced non-small cell lung cancer (LA-NSCLC). However, there are some barriers to implementing IMRT for LA-NSCLC, including the complexity of treatment plan optimization. This study aimed to evaluate the learning curve of lung dose optimization in IMRT for LA-NSCLC and identify the factors that affect the degree of achievement of lung dose optimization. METHODS: We retrospectively evaluated 40 consecutive patients with LA-NSCLC who received concurrent chemoradiotherapy at our institution. These 40 patients were divided into two groups: 20 initially treated patients (earlier group) and 20 subsequently treated patients (later group). Patient and tumor characteristics were compared between the two groups. The dose-volume parameter ratio between the actually delivered IMRT plan and the simulated three-dimensional conformal radiotherapy plan was also compared between the two groups to determine the learning curve of lung dose optimization. RESULTS: The dose-volume parameter ratio for lung volume to receive more than 5 Gy (lung V5) and mean lung dose (MLD) significantly decreased in later groups. The spread of the beam path and insufficient optimization of dose coverage of planning target volume (PTV) might cause poor control of lung V5, MLD. CONCLUSIONS: A learning curve for lung dose optimization was observed with the accumulation of experience. Appropriate techniques, such as restricting the beam path and ensuring dose coverage of PTV during the optimization process, are essential to control lung dose in IMRT for LA-NSCLC.

Optimal Number of Needle Applicators Inserted in Combined Intracavitary and Interstitial Brachytherapy for Cervical Cancer.

BACKGROUND/AIM: Combined intracavitary and interstitial brachytherapy (IC/IS-BT) is an effective treatment for extensive and bulky cervical cancer. However, the optimum number of interstitial needle applicators ("needles") inserted in IC/IS-BT can be difficult to determine. To examine the number of needles required for adequate dose coverage of cervical tumors, we retrospectively analyzed IC/IS-BT plans. PATIENTS AND METHODS: IC/IS-BT plans for cervical cancer patients treated from January 2014 to January 2021 were analyzed. All tumors were controlled locally at the time of analysis (August 2022). The relationship between the number of needles and several volumetric parameters of high-risk clinical target volume (CTVHR) were analyzed, including maximum diameter, maximum cross-sectional area, and the volume of CTVHR Spearman's rank correlation coefficients (r) were used to evaluate correlations. RESULTS: Eighty-two plans in 32 patients were analyzed. The median maximum cross-sectional area and volume of CTVHR were 18.9 (12.3-42.5) cm2 and 53.8 (30.1-152.2) cm3, respectively. The mean D90% and D98% of CTVHR at each BT session were 7.0±0.8 Gy and 5.9±0.8 Gy, respectively. There was a positive correlation between the number of needles and the maximum cross-sectional area of CTVHR (r=0.53). The average numbers of needles were 1.3, 1.9, 2.2, 3.1, and 4.0 when the maximum cross-sectional area of CTVHR were ≤15 cm2, 15-20 cm2, 20-25 cm2, 25-30 cm2, and >30 cm2, respectively. CONCLUSION: The optimal number of needles can be determined from the maximum cross-sectional area of CTVHR.

CD8-positive Tumor-infiltrating Lymphocytes and Prognosis in Radiotherapy for Uterine Cervical Squamous Cell Carcinoma.

BACKGROUND/AIM: Prognostic factors, including CD8-positive tumor-infiltrating lymphocytes (CD8+TILs), in definitive radiotherapy (RT) for squamous cell carcinoma (SqCC) of the uterine cervix need to be studied. This study aimed to explore these factors in a retrospective cohort. PATIENTS AND METHODS: Patients with SqCC who underwent definitive RT comprising external beam RT and intracavitary brachytherapy at our facility between April 2006 and November 2013 were evaluated. CD8 immunohistochemistry was performed in pre-treatment biopsy samples to analyze the prognostic significance of CD8+TILs in the tumor nest. Positive staining was defined as at least one CD8+ lymphocyte infiltrating the tumor area in the specimen. RESULTS: In total, 150 consecutive patients were included. Among them, 66 (43.7%) patients had International Federation of Gynecology and Obstetrics (FIGO, 2008 edition) stage IIIA or higher progressive disease. The median follow-up period was 61 months. In the entire cohort, the 5-year cumulative rates of overall survival (OS), progression-free survival (PFS), and pelvic recurrence-free rate (PRFR) were 75.6%, 69.6%, and 84.8%, respectively. Of the 150 patients, 120 (80.0%) patients were CD8+TIL positive. The independent favorable prognostic factors were FIGO stage I or II disease, administration of concurrent chemotherapy, and CD8+TILs for OS (p=0.028, 0.005, and 0.038, respectively); FIGO stage I or II disease and CD8+TILs for PFS (p=0.015 and <0.001, respectively); and CD8+TILs for PRFR (p=0.017). CONCLUSION: The presence of CD8+TILs in the tumor nest may be a favorable prognostic factor of survival after definitive RT in patients with SqCC of the uterine cervix.

A Case of Bile Duct Mixed Neuroendocrine-nonendocrine Neoplasm with a Complete Response to Chemoradiotherapy.

The incidence of neuroendocrine carcinomas arising from the bile duct is low, and that of mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) is even lower; therefore, there is no standard treatment for MiNENs. Choosing the appropriate treatment in clinical practice is difficult. We herein report a case of unresectable extrahepatic bile duct MiNEN in a 66-year-old man who received curative chemoradiotherapy and achieved a complete response, remaining recurrence-free for 2.5 years. We consider the findings of this case to be valuable in selecting a treatment strategy for unresectable bile duct MiNENs.

Calreticulin Upregulation in Cervical Cancer Tissues From Patients After 10 Gy Radiation Therapy.

Purpose: Understanding the immune response during radiation therapy (RT) in a clinical setting is imperative for maximizing the efficacy of combined RT and immunotherapy. Calreticulin, a major damage-associated molecular pattern that is exposed on the cell surface after RT, is presumed to be associated with the tumor-specific immune response. Here, we examined changes in calreticulin expression in clinical specimens obtained before and during RT and analyzed its relationship with the density of CD8+ T cells in the same patient set. Methods and Materials: This retrospective analysis evaluated 67 patients with cervical squamous cell carcinoma who were treated with definitive RT. Tumor biopsy specimens were collected before RT and after 10 Gy irradiation. Calreticulin expression in tumor cells was evaluated via immunohistochemical staining. Subsequently, the patients were divided into 2 groups according to the level of calreticulin expression, and the clinical outcomes were compared. Finally, the correlation between calreticulin levels and density of stromal CD8+ T cells was evaluated. Results: The calreticulin expression significantly increased after 10 Gy (82% of patients showed an increase; P < .01). Patients with increased calreticulin levels tended to show better progression-free survival, but this was not statistically significant (P = .09). In patients with high expression of calreticulin, a positive trend was observed between calreticulin and CD8+ T cell density, but the association was not statistically significant (P = .06). Conclusions: Calreticulin expression increased after 10 Gy irradiation in tissue biopsies of patients with cervical cancer. Higher calreticulin expression levels are potentially associated with better progression-free survival and greater T cell positivity, but there was no statistically significant relationship between calreticulin upregulation and clinical outcomes or CD8+ T cell density. Further analysis will be required to clarify mechanisms underlying the immune response to RT and to optimize the RT and immunotherapy combination approach.

Comparison of the Efficacy and Toxicity of Concurrent Chemoradiotherapy and Durvalumab and Concurrent Chemoradiotherapy Alone for Locally Advanced Non-small Cell Lung Cancer With N3 Lymph Node Metastasis.

BACKGROUND/AIM: Efficacy and toxicity of concurrent chemoradiotherapy (CCRT) and durvalumab for locally advanced non-small cell lung cancer (LA-NSCLC) with N3 lymph node metastasis remain unclear. We aimed to evaluate the clinical outcomes of patients who received CCRT and durvalumab (durvalumab cohort) and compare their outcomes with those of patients who received CCRT alone (CCRT-alone cohort). PATIENTS AND METHODS: The data of patients who had received treatment between November 2008 and February 2022 and were followed up for at least 3 months were retrospectively analyzed. Local control, progression-free survival, and overall survival were evaluated using Kaplan-Meier analysis and compared using the log-rank test. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events version 5.0. RESULTS: The data of 29 patients were analyzed (median follow-up period: 22 months). Among them, 17 received CCRT alone and 12 received CCRT and durvalumab. There were 14 patients with stage IIIB and 15 with stage IIIC LA-NSCLC. The durvalumab cohort (89%) had a significantly higher 1-year local control rate than the CCRT-alone cohort (47%; p=0.035). No significant difference was observed in either progression-free or overall survival between the two cohorts. Grade ≥2 pneumonitis was observed in 6 (50%) and 7 (41%) patients in the durvalumab and CCRT-alone cohorts, respectively. CONCLUSION: CCRT with durvalumab may be effective against LA-NSCLC with N3 lymph node metastasis. The incidence of grade 2 pneumonitis was slightly higher in the durvalumab cohort than in the CCRT-alone cohort, suggesting the need for careful patient monitoring after treatment.