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The purpose of this study was to evaluate the efficacy and toxicities of carbon-ion radiotherapy (C-ion RT) for locally advanced cervical cancer with bladder invasion by a subset analysis of pooled data from eight prospective clinical trials at the National Institute of Radiological Sciences. Between June 1995 and January 2014, 29 patients with locally advanced cervical cancer with bladder invasion were identified. The median age was 56 years old (range 31-79 years old). The median tumor size at diagnosis on magnetic resonance imaging was 6.7 cm (range 3.5-11.0 cm). Histologically, 20 patients had squamous cell carcinoma and 9 had adenocarcinoma. C-ion RT was performed as a dose-escalation study in the initial trials. All patients received prophylactic whole-pelvic or extended-field irradiation and local boost. The total dose to the cervical tumor was 52.8-74.4 Gy (relative biological effectiveness) in 20 or 24 fractions. Weekly cisplatin (40 mg/m 2 /week, five cycles) was concurrently given to four patients. The median follow-up of all patients was 28.6 months (range 8.8-238.6 months). Grade 2 or higher late complications in the bladder were observed in eight patients, with seven developing vesicovaginal fistula. Six patients had Grade 2 or higher complications in the rectosigmoid colon. The 3-year overall survival rate was 47%, the 3-year local control rate was 66%, and the 3-year disease-free survival rate was 28%. In this study, C-ion RT showed favorable local control with reasonable toxicities, but the results were still unsatisfactory. We have the expectation of improvement of therapeutic effects by using C-ion RT with concurrent chemotherapy., (© The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

The aim of this retrospective study was to identify clinical predictors of early biochemical recurrence (BCR) in patients with high-risk prostate cancer (PCa) treated with carbon-ion radiotherapy (CIRT) and androgen deprivation therapy (ADT). A total of 670 high-risk PCa patients treated with CIRT and ADT were included in the study. Early BCR was defined as recurrence occurring during adjuvant ADT after CIRT or within 2 years after completion of ADT. Univariate and multivariate analyses were performed to identify clinical predictors of early BCR. Patients were also classified according to the Systemic Therapy in Advancing or Metastatic Prostate cancer (STAMPEDE) PCa classification. Early BCR was observed in 5.4% of the patients. Multivariate analysis identified clinical T3b stage and ≥75% positive biopsy cores as clinical predictors of early BCR after CIRT and ADT. The STAMPEDE PCa classification was also significantly associated with early BCR based on univariate analysis. These predictors can help clinicians identify patients who are at risk of early BCR. In the future, combination therapy of ADT with abiraterone may be an option for high-risk PCa patients who are at risk of early BCR, based on the results of the STAMPEDE study. [ABSTRACT FROM AUTHOR]

We conducted a phase Ib study to examine the safety of a combination of carbon-ion RT (CIRT) with durvalumab (MEDI4736; AstraZeneca) in patients with locally advanced cervical cancer. This was an open-label, single-arm study with a modified 3 + 3 design. Patients with newly diagnosed histologically proven locally advanced cervical cancer were enrolled. All patients received 74.4 Gy of CIRT in 20 fractions and concurrent weekly cisplatin (chemo-CIRT) at a dose of 40 mg/m2. Durvalumab was administered (1500 mg/body) at weeks two and six. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs), including dose-limiting toxicity (DLT). All three enrolled patients completed the treatment without interruption. One patient developed hypothyroidism after treatment and was determined to be an SAE. No other SAEs were observed. The patient recovered after levothyroxine sodium hydrate treatment. None of the AEs, including hypothyroidism, were associated with DLT in the present study. All three patients achieved complete responses within the CIRT region concerning treatment efficacy. This phase 1b trial demonstrates the safety of combining chemo-CIRT and durvalumab for locally advanced cervical cancer in the early phase. Further research is required as only three patients were included in this study. [ABSTRACT FROM AUTHOR]

Background: To evaluate the clinical relative biological effectiveness (RBE) of carbon‐ion radiotherapy (C‐ion RT) for prostate cancer. Methods: The records of 262 patients with low‐risk prostate cancer (median age, 65 [47–80] years) treated with C‐ion RT at QST Hospital, National Institutes for Quantum Science and Technology in Japan during 2000–2018 were reviewed retrospectively. Four different protocol outcomes and prostate‐specific antigen (PSA) responses were evaluated. The median follow‐up was 8.4 years. The Kaplan–Meier method was used to estimate the biochemical or clinical failure‐free rate (BCFFR). Clinical RBE was calculated using the tumor control probability model. Results: The 5‐, 7‐, and 10‐year BCFFRs were 91.7%, 83.8%, and 73.2%, respectively. The 10‐year BCFFRs of patients who received C‐ion RT at 66 Gy (RBE) in 20 fractions, 63 Gy (RBE) in 20 fractions, and 57.6 Gy (RBE) in 16 fractions were 81.4%, 70.9%, and 68.9%, respectively. The PSA level and density during follow‐up were better in the patients treated with the lower fraction size. A higher PSA nadir and shorter time to PSA nadir were risk factors for biochemical or clinical failure by multivariate Cox regression. The tumor control probability analysis showed that the estimated clinical RBE values to achieve an 80% BCFFR at 10 years for 20, 16, and 12 fractions were 2.19 (2.18–2.24), 2.16 (2.14–2.23), and 2.12 (2.09–2.21), respectively. Conclusions: Using clinical data from low‐risk prostate cancer patients, we showed the clinical RBE of C‐ion RT decreased with increasing dose per fraction. [ABSTRACT FROM AUTHOR]

• We assessed the prognostic factors for sacrum insufficiency fractures (SIFs) in carbon-ion RT. • Median RBE-weighted dose to the sacrum was a risk factor for SIF. • Neither LET nor physical dose parameters were significant risk factors for SIF. The correlation between dose-averaged linear energy transfer (LETd) and its therapeutic or adverse effects, especially in carbon-ion radiotherapy (CIRT), remains controversial. This study aimed to investigate the effects of LETd and dose on pelvic insufficiency fractures after CIRT. Among patients who underwent CIRT for uterine carcinoma, 101 who were followed up for > 6 months without any other therapy were retrospectively analyzed. The sacrum insufficiency fractures (SIFs) were graded according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity criteria. The correlations between the relative biological effectiveness (RBE)-weighted dose, LETd, physical dose, clinical factors, and SIFs were evaluated. In addition, we analyzed the association of SIF with LETd, physical dose, and clinical factors in cases where the sacrum D50% RBE-weighted dose was above the median dose. At the last follow-up, 19 patients developed SIFs. Receiver operating characteristic curve analysis revealed that the sacrum D50% RBE-weighted dose was a valuable predictor of SIF. Univariate analyses suggested that LETd V10 keV/µm, physical dose V5 Gy, and smoking status were associated with SIF. Cox regression analysis in patients over 50 years of age validated that current smoking habit was the sole risk factor for SIF. Therefore, LETd or physical dose parameters were not associated with SIF prediction. The sacrum D50% RBE-weighted dose was identified as a risk factor for SIF. Additionally, neither LETd nor physical dose parameters were associated with SIF prediction. [ABSTRACT FROM AUTHOR]

Background: There are limited studies on the risk of secondary cancers after carbon‐ion radiotherapy (CIRT). We assessed the incidence of secondary cancers in patients treated with CIRT for cervical cancer. We also evaluated the incidence of secondary cancers in patients who received standard photon radiotherapy (RT) throughout the same period. Methods: This retrospective study included patients with cervical cancer who underwent curative RT at our hospital. All cancers discovered for the first time after RT were classified as secondary cancers. To compare the risk of secondary cancers among cervical cancer survivors to the general population, standardized incidence ratios (SIRs) were calculated. Results: The analysis included a total of 197 and 417 patients in the CIRT and photon RT groups, respectively. The total person‐years during the observation period were 1052.4 in the CIRT group and 2481.5 in the photon RT group. The SIR for all secondary cancers was 1.1 (95% confidence interval [CI], 0.6–2.1) in the CIRT group and 1.4 (95% CI, 1.0–2.1) in the photon RT group. The 10‐year cumulative incidence of all secondary cancers was 9.5% (95% CI, 4.0–21.5) in the CIRT group and 9.4% (95% CI, 6.2–14.1) in the photon RT group. The CIRT and photon RT groups were not significantly different in incidence (p = 0.268). Conclusions: The incidence of secondary cancers after CIRT for cervical cancer was similar to that after photon RT. Validation of our findings after long‐term observation is warranted. [ABSTRACT FROM AUTHOR]

Byline: Motohiro. Kawashima, Hidemasa. Kawamura, Masahiro. Onishi, Yosuke. Takakusagi, Noriyuki. Okonogi, Atsushi. Okazaki, Tetsuo. Sekihara, Yoshitaka. Ando, Takashi. Nakano Discretization errors due to the digitization of computed tomography images and [...]

• We assessed prognostic factors for late rectal toxicities in carbon-ion RT. • Clinical dose, linear energy transfer (LET), and physical dose were assessed. • Severe rectal toxicities were related to clinical doses. • No correlations existed between severe rectal toxicities and LET or physical dose. Several studies have focused on increasing the linear energy transfer (LET) within tumours to achieve higher biological effects in carbon-ion radiotherapy (C-ion RT). However, it remains unclear whether LET affects late complications. We assessed whether physical dose and LET distribution can be specific factors for late rectal complications in C-ion RT. Overall, 134 patients with uterine carcinomas were registered and retrospectively analysed. Of 134 patients, 132 who were followed up for >6 months were enrolled. The correlations between the relative biological effectiveness (RBE)-weighted dose based on the Kanai model (the ostensible "clinical dose"), dose-averaged LET (LETd), or physical dose and rectal complications were evaluated. Rectal complications were graded according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. Nine patients developed grade 3 or 4 late rectal complications. Linear regression analysis found that D 2cc in clinical dose was the sole risk factor for ≥grade 3 late rectal complications (p = 0.012). The receiver operating characteristic analysis found that D 2cc of 60.2 Gy (RBE) was a suitable cut-off value for predicting ≥grade 3 late rectal complications. Among 35 patients whose rectal D 2cc was ≥60.2 Gy (RBE), no correlations were found between severe rectal toxicities and LETd alone or physical dose per se. We demonstrated that severe rectal toxicities were related to the rectal D 2cc of the clinical dose in C-ion RT. However, no correlations were found between severe rectal toxicities and LETd alone or physical dose per se. [ABSTRACT FROM AUTHOR]

Significant technological advances in radiotherapy have been made in the past few decades. High-precision radiotherapy has recently become popular and is contributing to improvements in the local control of the irradiated target lesions and the reduction of adverse effects. Accordingly, for long-term survival, the importance of systemic cancer control, including at non-irradiated sites, is growing. Toward this challenge, the treatment methods in which anti-PD-1/PD-L1 antibodies that exert systemic effects by restoring anti-tumour immunity are combined with radiotherapy has attracted attention in recent years. Previous studies have reported the activation of anti-tumour immunity by radiotherapy, which simultaneously elevates PD-L1 expression, suggesting a potential for combination therapy. Radiotherapy induces so-called 'immunogenic cell death', which involves cell surface translocation of calreticulin and extracellular release of high-mobility group protein box 1 (HMGB-1) and adenosine-5′-triphosphate (ATP). Furthermore, radiotherapy causes immune activation via MHC class I upregulation and cGAS–STING pathway. In contrast, induction of immunosuppressive lymphocytes and the release of immunosuppressive cytokines and chemokines by radiotherapy contribute to immunosuppressive reactions. In this article, we review immune responses induced by radiotherapy as well as previous reports to support the rationale of combination of radiotherapy and anti-PD-1/PD-L1 antibodies. A number of preclinical and clinical studies have shown the efficacy of radiotherapy combined with immune checkpoint inhibition, hence combination therapy is considered to be an important future strategy for cancer treatment. [ABSTRACT FROM AUTHOR]

The current study aimed to evaluate the outcomes of patients with adenocarcinoma (AC) of the uterine cervix after definitive radiotherapy (RT) and to evaluate prognostic factors, including immunity-related molecules. A total of 71 patients with AC of the uterine cervix from multiple Japanese institutions were retrospectively analysed. Histological subtypes were diagnosed according to the 2014 World Health Organization classification. All patients underwent definitive RT comprising external beam RT and intracavitary brachytherapy with or without concurrent chemotherapy. Immunohistochemical studies were performed to detect the expression of programmed cell death-ligand 1(PD-L1) and CD8. The 5-year locoregional control (LC), overall survival (OS) and progression-free survival (PFS) rates for all patients were 61.8, 49.7 and 36.1%, respectively. The LC, OS and PFS rates were not significantly different among the histological subtypes. Membranous PD-L1 expression was not significantly associated with prognosis. Patients with CD8-positive tumor-infiltrating lymphocytes (CD8+TILs) in the tumor nests had significantly better OS than patients without CD8+TILs in the tumor nests (5-year OS: 53.8 vs 23.8%, P  = 0.038). As expected, the International Federation of Gynecology and Obstetrics (FIGO) stage (2008) III–IVA and maximum tumor diameter > 40 mm were significantly associated with worse prognosis. In summary, the presence of CD8+TILs in the tumor nests has the potential to be an independent favorable prognostic factor for patients with AC of the uterine cervix after definitive RT. [ABSTRACT FROM AUTHOR]

Background: Although carbon‐ion radiotherapy (C‐ion RT) with concurrent chemotherapy (chemo‐C‐ion RT) is a promising treatment for adenocarcinoma (AC) of the uterine cervix, its long‐term efficacy remains unclear. We evaluated the long‐term significance of concurrent weekly cisplatin and C‐ion RT for locally advanced AC of the uterine cervix. Methods: We performed a pooled analysis of patients with stage IIB–IVA AC of the uterine cervix who underwent C‐ion RT alone or chemo‐C‐ion RT between September 2007 and December 2018 at our institution. Patients received 74.4 Gy (relative biological effectiveness) with or without cisplatin (40 mg/m2 per week for up to 5 weeks), underwent no prior pelvic RT or systemic therapy, and had a performance status of 0‐2. Propensity score matching was based on the year of diagnosis, regional lymph node metastasis, and stage. Results: The matched cohort contained 26 patients who underwent C‐ion RT and 26 who underwent chemo‐C‐ion RT. The median age and follow‐up period were 57 (range, 28‐79) years and 34 (range, 2‐126) months, respectively. The 5‐year overall survival rate was significantly better in the chemo‐C‐ion RT group (72%) than in the C‐ion RT group (46%; P =.041). The 5‐year distant metastatic‐free rate was also significantly better in the chemo‐C‐ion RT group (66%) than in the C‐ion RT group (41%; P =.048). The incidence of grade ≥ 3 late toxicities was comparable between the two groups. Conclusions: Chemo‐C‐ion RT for locally advanced AC of the uterine cervix is associated with a long‐term survival benefit. [ABSTRACT FROM AUTHOR]

Three-dimensional image-guided brachytherapy (3D-IGBT) has become the standard therapy for patients with cervical cancer. However, in this population, the impact of 3D-IGBT in elderly individuals remains unknown. This study assessed the efficacy of 3D-IGBT for elderly patients with cervical cancer. We performed a retrospective chart review of 105 consecutive patients with cervical squamous cell carcinoma aged ≥70 years who received radiotherapy alone between January 2001 and September 2014. All patients were treated with external beam radiotherapy and high-dose-rate intracavitary brachytherapy. We assessed the treatment outcomes in all patients. We then compared outcomes between two groups: patients treated by changing the Point A dose at brachytherapy (Group A, n = 71) and those treated with 3D-IGBT at least twice (Group B, n = 34). The median followup period was 59 (range, 6–203) months; the median age was 77 years. The 5-year local control and cause-specific survival rates were 89% and 78%, respectively. The 5-year cumulative rates of late toxicities of the rectum and bladder of Grade ≥3 were 2.0% and 4.2%, respectively. No statistically significant differences were observed in the local control and cause-specific survival rates, or in the incidence of rectal toxicities between groups. The 3-year cumulative rates of urinary toxicity of Grade ≥1 were 20.4% and 6.9% in Group A and Group B, respectively (p = 0.035). In elderly patients with cervical cancer, 3D-IGBT could be performed safely and effectively and contributed to decreasing urinary toxicity incidence rates. [ABSTRACT FROM AUTHOR]

Purpose: This study evaluated the safety and efficacy of carbon-ion radiation therapy (C-ion RT) with concurrent chemotherapy for locally advanced uterine cervical squamous cell carcinoma in a phase 1/2 clinical trial.Methods and Materials: Twenty-two patients were treated with C-ion RT with concurrent weekly cisplatin at a dose of 40 mg/m2. The phase 1 component evaluated the safety of 72.0 Gy (relative biological effectiveness) of C-ion RT with concurrent chemotherapy. In the phase 2 component, the safety and efficacy of C-ion RT with concurrent chemotherapy were assessed using the dose determined in phase 1.Results: The median follow-up period was 32 months, and the median tumor size was 71 mm (range, 51-150 mm). No patient had dose-limiting toxicities in the phase 1 component; the recommended dose was determined to be 72.0 Gy (relative biological effectiveness) with 40 mg/m2 of cisplatin. In the phase 2 component, 2 patients developed grade 3 gastrointestinal tract toxicities. In patients treated with the recommended dose, the 2-year local control (LC), LC including salvage therapy, and overall survival rates were 67%, 81%, and 82%, respectively. The 2-year LC and overall survival rates for patients with tumor sizes ≤7.1 cm were 92% and 100%, respectively; for those with tumor sizes >7.1 cm they were 33% and 60%, respectively.Conclusions: C-ion RT with concurrent weekly cisplatin was tolerated by patients with locally advanced uterine cervical squamous cell carcinoma. Outcomes were good in patients with tumor sizes ≤7.1 cm but not in those with larger tumors. The results of the present study should be validated with larger multi-institutional prospective studies. Further study is needed, and perhaps incorporating carbon ion external beam radiation with brachytherapy will further reduce the risk of central recurrence. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate the efficacy of combination therapy with intravenously injected microglia (MI) and radiation therapy (RT) for malignant glioma in rats.Methods and Materials: Transgenic rats expressing v-erbB and spontaneously developing malignant glioma were used. The rats were divided into 4 groups: control (n = 19), RT alone (n = 10), MI alone (n = 9), and combination MI and RT (MI + RT) (n = 10). Cranial x-ray irradiation (8 Gy per fraction; once per week) was performed at 50 and 51 weeks of age. Cultured rat microglial cells (5 × 106 cells/rat) were intravenously injected via the tail vein within 30 minutes after RT.Results: No evidence of side effects, including thrombosis or graft-versus-host disease, was noted. Rats treated with RT alone, MI alone, MI + RT, and control survived 60.9, 56.3, 66.0, and 56.1 weeks, respectively. The survival period of MI + RT was significantly longer than that of control (P = .014), MI alone (P = .027), and RT alone (P = .049). Immunohistochemical analysis showed a significantly higher number of tumor-infiltrated MI in the RT alone (P = .041) and MI + RT groups (P = .014) compared with the control. Significantly more CD8-positive lymphocytes were observed in the MI + RT group (P = .049) compared with the control. A positive correlation was found between the number of MI and CD8-positive lymphocytes (R2 = 0.556). A positive correlation was also found between CD8-positive lymphocytes and survival periods (R2 = 0.460).Conclusions: MI + RT increased infiltrated MI and CD8-positive T cells and prolonged survival in transgenic rats that spontaneously developed malignant glioma. Combined immunocellular therapy and RT may provide a novel treatment strategy for malignant glioma. [ABSTRACT FROM AUTHOR]

Abstract: We conducted a phase 1/2 study to evaluate the efficacy and safety of carbon ion radiotherapy (C‐ion RT) with concurrent chemotherapy for locally advanced uterine cervical adenocarcinoma. Thirty‐three patients were enrolled between April 2010 and March 2014. Treatment consisted of C‐ion RT with concurrent weekly cisplatin at a dose of 40 mg/m2. In the phase 1 component, the total dose was escalated from 68.0 Gy (relative biological effectiveness [RBE]) to 74.4 Gy (RBE) to determine the maximum tolerated dose of C‐ion RT. In the phase 2 component, the efficacy and safety of C‐ion RT with concurrent chemotherapy were evaluated using the dose determined in the phase 1 component. The median follow‐up duration was 30 months. Two patients did not receive chemotherapy because of anemia or leukocytopenia immediately prior to commencing treatment; 31 patients were analyzed. None of the patients developed dose‐limiting toxicities. The recommended dose (RD) was determined to be 74.4 Gy (RBE). In the phase 2 component, two patients developed Grade 3–4 toxicities in the gastrointestinal tract, due to repeated laser coagulation or peritonitis caused by appendicitis. In the patients treated with the RD, the 2‐year local control, progression‐free survival, and overall survival rates were 71%, 56%, and 88%, respectively. C‐ion RT with concurrent weekly cisplatin was well tolerated in patients with locally advanced uterine cervical adenocarcinoma. Our findings support further investigations into the efficacy of this strategy. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) infection is well known as a major etiological risk factor associated with carcinogenesis in uterine cervical cancer. However, few reports have investigated the association between HPV genotype and outcome in patients with uterine cervical cancer following radiotherapy (RT). The aim of the present study was to investigate the association between the HPV genotype and clinical outcome following RT in Japanese patients with uterine cervical cancer. Between November 2001 and August 2006, 157 Japanese women with uterine cervical cancer were treated with RT or concurrent chemoradiotherapy with curative intent. Pretreatment, formalin-fixed, paraffin-embedded biopsies were obtained from 83 patients. HPV genotypes were determined using the polymerase chain reaction method. Patients were categorized, according to HPV L1 protein sequence homology, into the HPV α-9 (HPV 16, 31, 33, 52, and 58), HPV α-7 (HPV 18, 39, 45, 59, and 68) or 'other' (HPV 51 and 56) groups. Associations between HPV genotype and clinical outcome following RT were evaluated. A total of 54 (65.1%) tumors were HPV α-9-positive, 13 (15.7%) were HPV α-7-positive, 2 (2.4%) were categorized under 'other' and 14 (16.9%) were HPV-negative. There were no significant differences in age, FIGO stage, regional lymph node metastases rate at diagnosis, or concurrent chemotherapy administration between the HPV α-9 and α-7 groups. The median follow-up period was 52 months (range, 2-156 months). The 5-year disease-free survival rates were 54.5 and 30.8% in the HPV α-9 and α-7 groups, respectively (P=0.034), and the 5-year distant metastasis rates were 38.0 and 69.2%, respectively (P=0.015). There were no significant differences in the 5-year local control or overall survival (OS) rates between the two groups. HPV genotype affected the 5-year distant metastatic rate, however not the 5-year local control or OS rate in patients with uterine cervical cancer following RT. [ABSTRACT FROM AUTHOR]

The safety of weekly regional hyperthermia performed with 8 MHz radiofrequency (RF) capacitive heating equipment has been established in rectal cancer. We aimed to standardize hyperthermia treatment for scientific evaluation and for assessing local tumor response to RF hyperthermia in rectal cancer. Fortynine patients diagnosed with rectal adenocarcinoma were included in the study. All patients received chemoradiation with intensity-modulated radiation therapy 5 days/week (dose, 50 Gy/25 times) concomitant with 5 days/week for five times of capecitabine (1700 mg/m2 per day) and once a week for five times of 50 min irradiations by an 8 MHz RF capacitive heating device. Thirty-three patients underwent surgery 8 weeks after treatment. Three patients did not undergo surgery because of progressive disease (PD) and 13 refused. Eight (16.3%) patients had a pathological complete response (ypCR) after surgery. Among patients without surgery, 3 (6.1%) had clinical complete response (CR) and 3 (6.1%) had local CR but distant PD (CRPD). Ninety percent of ypCR + CR patients were shown in 6.21 W min-1 m-2/treatment or higher group of average total accumulated irradiation output with 429°C min-1 m-2 or higher group of total accumulated thermal output. However, a patient with CRPD was in the higher total accumulated thermal output group. We propose a new quantitative parameter for the hyperthermia and demonstrated that patients can benefit from mild irradiation with mild temperature. Using these parameters, the exact output, optimal thermal treatment, and contraindications or indications of this modality could be determined in a multi-institutional, future study. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the large use of inhibitors of Poly-ADP ribose polymerase (PARP-I), the feasibility and safety of their combination with radiotherapy (RT) are unclear. The combination may be particularly interesting in the oligometastatic setting in which patients may benefit from local RT during the treatment with PARP-I. The aim of the current review was to evaluate the outcome and the toxicity in patients with newly diagnosed or recurrent tumors treated with a combination of PARP-I and RT. A total of 12 clinical studies met the inclusion criteria and, despite the heterogeneity of the evaluated patient populations and tumor types, this review suggests that a combination approach is feasible even though the efficacy profile remains unclear. Background: Despite the large use of inhibitors of Poly-ADP ribose polymerase (PARP-I), the feasibility and safety of their combination with radiotherapy (RT) is unclear. Aim: We conducted a literature analysis with the aim to evaluate the efficacy and safety profile of a combination with RT and PARP-I. Method: The key issues for the current review were expressed in two questions according to the Population, Intervention, Control, Outcome (PICO) criteria: 1. What is the outcome and 2. What is the toxicity in patients treated with a combination of PARP-I and RT for a newly diagnosed or recurrent tumors? Results: A total of 12 clinical studies met the inclusion criteria including seven single-arm dose-escalation phase I studies, two phase II (two- and three-arms controlled trials) trials, one parallel-arm phase I study, and two phase I/II studies published between 2015 and 2021. RT was performed with photon beams and several schedules according to the clinical situation. The acute toxicity ≥ grade 3 ranged between 25% and >96%, which was divided into hematological or non-hematological adverse events. Conclusions: despite the heterogeneity of the evaluated patient populations and tumor types, and the limited number of the studies, this review suggests that a combination approach is feasible even though the efficacy profile remains unclear. [ABSTRACT FROM AUTHOR]

Simple Summary: Recently, it has been shown that radiation therapy (RT) together with androgen-depletion therapy (ADT) might be more beneficial compared with ADT alone for clinically node-positive (cN1) prostate cancer. However, there are a limited number of studies that have addressed specific RT techniques and analyzed their clinical results. The present study was a retrospective analysis of cN1 prostate cancer patients treated with intensity-modulated radiation therapy with simultaneous integrated boost (SIB-IMRT), in addition to ADT, in our hospital. The present study suggests that ADT plus SIB-IMRT for cN1 prostate cancer treatment was safe and effective, was well tolerated, and had acceptable rates of late toxicity. Further prospective multicenter studies would be required to confirm the robustness of the present results. This study aimed to evaluate clinical outcomes and the toxicity of intensity-modulated radiation therapy with simultaneous integrated boost (SIB-IMRT) combined with androgen-deprivation therapy for clinically node-positive (cN1) prostate cancer. We retrospectively analyzed 97 patients with cN1 prostate cancer who received SIB-IMRT between June 2008 and October 2017 at our hospital. The prescribed dosages delivered to the prostate and seminal vesicle, elective node area, and residual lymph nodes were 69, 54, and 60 Gy in 30 fractions, respectively. Kaplan–Meier analysis was used to determine 5-year biochemical relapse-free survival (bRFS), relapse-free survival (RFS), overall survival (OS), and prostate cancer-specific survival (PCSS). Toxicity was evaluated using the Common Terminology Criteria for Adverse Events ver. 4.0. Over a median follow-up duration of 60 months, the 5-year bRFS, RFS, OS, and PCSS were 85.1%, 88.1%, 92.7% and 95.0%, respectively. Acute Grade 2 genito-urinary (GU) and gastro-intestinal (GI) toxicities were observed in 10.2% and 2.1%, respectively, with no grade ≥3 toxicities being detected. The cumulative incidence rates of 5-year Grade ≥2 late GU and GI toxicities were 4.7% and 7.4%, respectively, with no Grade 4 toxicities being detected. SIB-IMRT for cN1 prostate cancer demonstrated favorable 5-year outcomes with low incidences of toxicity. [ABSTRACT FROM AUTHOR]

Simple Summary: We conducted a multi-institutional survey of carbon-ion radiotherapy (CIRT) for locally advanced adenocarcinoma (LAAC) of the uterine cervix. We retrospectively analyzed the clinical outcomes of patients with stage IIB–IVA LAAC of the uterine cervix who underwent chemo-CIRT or CIRT alone between April 2010 and April 2016. Fifty-five patients were enrolled in this study. The median follow-up period was 67.5 months. The 5-year overall survival (OS) and local control (LC) rates were 68.6% and 65.2%, respectively. Multivariate analysis showed that the initial tumor response within 6 months was significantly associated with LC and OS. The present study represents promising outcomes of CIRT or chemo-CIRT for LAAC of the uterine cervix, especially in the cases showing initial rapid regression of the tumor. The clinical significance of carbon-ion radiotherapy (CIRT) for adenocarcinoma (AC) of the uterine cervix has been assessed in several single-institutional studies. To validate the significance, we conducted a multi-institutional survey of CIRT for locally advanced AC (LAAC) of the uterine cervix. We retrospectively analyzed the clinical outcomes of patients with stage IIB–IVA LAAC of the uterine cervix who underwent chemo-CIRT or CIRT alone between April 2010 and April 2016. Patients received 74.4 Gy (relative biological effectiveness [RBE]) in 20 fractions of CIRT or 55.2 Gy (RBE) in 16 fractions of CIRT plus three sessions of brachytherapy. Patients aged ≤ 70 years with adequate bone marrow and organ function were administered cisplatin weekly (40 mg/m2 per week for up to 5 weeks). Fifty-five patients were enrolled in this study. The median follow-up period was 67.5 months. The 5-year overall survival (OS) and local control (LC) rates were 68.6% and 65.2%, respectively. Multivariate analysis showed that the initial tumor response within 6 months was significantly associated with LC and OS. The present study represents promising outcomes of CIRT or chemo-CIRT for LAAC of the uterine cervix, especially in the cases showing initial rapid regression of the tumor. [ABSTRACT FROM AUTHOR]

Radiotherapy induces an immune response in the cancer microenvironment that may influence clinical outcome. The present study aimed to analyse the alteration of CD8+ T-cell infiltration and programmed death-ligand 1 (PD-L1) expression following radiotherapy in clinical samples from patients with uterine cervical squamous cell carcinoma. Additionally, the current study sought to analyse the association between these immune responses and clinical outcomes. A total of 75 patients who received either definitive chemoradiotherapy or radiotherapy were retrospectively analyzed. CD8+ T-cell infiltration and PD-L1 expression were determined by immunohistochemistry using biopsy specimens before radiotherapy (pre-RT) and after 10 Gy radiotherapy (post-10 Gy). The PD-L1+ rate was significantly increased from 5% (4/75) pre-RT to 52% (39/75) post-10 Gy (P<0.01). Despite this increase in the PD-L1+ rate post-10 Gy, there was no significant association between both pre-RT and post-10 Gy and overall survival (OS), locoregional control (LC) and progression-free survival (PFS). On the other hand, the CD8+ T-cell infiltration density was significantly decreased for all patients (median, 23.1% pre-RT vs. 16.9% post-10 Gy; P=0.038); however, this tended to increase in patients treated with radiotherapy alone (median, 17.7% pre-RT vs. 24.0% post-10 Gy; P=0.400). Notably, patients with high CD8+ T-cell infiltration either pre-RT or post-10 Gy exhibited positive associations with OS, LC and PFS. Thus, the present analysis suggested that CD8+ T-cell infiltration may be a prognostic biomarker for patients with cervical cancer receiving radiotherapy. Furthermore, immune checkpoint inhibitors may be effective in patients who have received radiotherapy, since radiotherapy upregulated PD-L1 expression in cervical cancer specimens. [ABSTRACT FROM AUTHOR]

Surgical resection is considered a standard therapy for malignant melanoma (MM). However, it has not yet been established as an optimal treatment strategy for gynecological MMs, particularly owing to their very low incidence rates. We retrospectively analyzed clinical outcomes of carbon-ion radiotherapy (C-ion RT) for gynecological MMs. The eligibility criterion was the presence of histologically confirmed gynecological MM. Patients with pelvic or inguinal lymph node metastases were included, while those with distant metastases were excluded. The pelvic and inguinal lymph node regions were irradiated with up to 36 gray relative biological effectiveness (Gy (RBE)) followed by a gross tumor volume boost of up to 57.6 Gy (RBE) or 64 Gy (RBE) in 16 fractions over 4 weeks. Thirty-seven patients (median age: 71 years) were examined. In total, 22 patients had vaginal tumors, 12 had vulval tumors, and 3 had cervical uterine tumors. The median follow-up periods were 23 months (range: 5–103 months) for all patients and 53 months (range: 16–103 months) for survivors. Thirty of 37 patients (81%) achieved complete tumor disappearance. The 2-year local control, overall survival, and progression-free survival rates were 71%, 53%, and 29%, respectively. C-ion RT may be a definitive treatment option for patients with gynecological MM. [ABSTRACT FROM AUTHOR]

Background: Carbon-ion radiotherapy (C-ion RT) provides better dose distribution in cancer treatment compared to photons. Additionally, carbon-ion beams provide a higher biological effectiveness, and thus a higher tumor control probability. However, information regarding the dose constraints for organs at risk in C-ion RT is limited. This study aimed to determine the predictive factors for late morbidities in the rectum and bladder after carbon-ion C-ion RT for uterus carcinomas.Methods: Between June 1995 and January 2010, 134 patients with uterus carcinomas were treated with C-ion RT with curative intent; prescription doses of 52.8-74.4 Gy (relative biological effectiveness) were delivered in 20-24 fractions. Of these patients, 132 who were followed up for > 6 months were analyzed. We separated the data in two subgroups, a 24 fractions group and a 20 fractions group. Late morbidities, proctitis, and cystitis were assessed according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria. The correlations of clinical and dosimetric parameters, V10-V60, D5cc, D2cc, and Dmax, with the incidence of ≥grade 1 morbidities were retrospectively analyzed.Results: In the 24 fractions group, the 3-year actuarial occurrence rates of ≥grade 1 rectal and bladder morbidities were 64 and 9%, respectively. In addition, in the 20 fractions group, the 3-year actuarial occurrence rates of ≥grade 1 rectal and bladder morbidities were 32 and 19%, respectively. Regarding the dose-volume histogram data on the rectum, the D5cc and D2cc were significantly higher in patients with ≥grade 1 proctitis than in those without morbidity. In addition, the D5cc for the bladder was significantly higher in patients with ≥grade 1 cystitis than in those without morbidity. Results of univariate analyses showed that D2cc of the rectum was correlated with the development of ≥grade 1 late proctitis. Moreover, D5cc of the bladder was correlated with the development of ≥grade 1 late cystitis.Conclusions: The present study identified the dose-volume relationships in C-ion RT regarding the occurrence of late morbidities in the rectum and bladder. Assessment of the factors discussed herein would be beneficial in preventing late morbidities after C-ion RT for pelvic malignancies.Trial Registration: Retrospectively registered ( NIRS: 16-040 ). [ABSTRACT FROM AUTHOR]