Noriyuki Okonogi

Carbon-Ion Radiation Therapy for Adenocarcinoma of the Uterine Cervix: Clinical Outcomes of a Multicenter Prospective Registry-Based Study in Japan (2016-2020)

Cases of adenocarcinoma of the uterine cervix (AUC) have poorer prognoses than those of squamous cell carcinoma. Carbon-ion radiation therapy (CIRT) outcomes for AUC have been reported in retrospective or single-institutional prospective studies but not prospective multicenter studies. We present the results of CIRT for AUC in a prospective multicenter study using a nationwide hospital-based registry in Japan. Patients with locally advanced untreated AUC who received CIRT at 4 Japanese centers between June 2016 and April 2020 were included in this study. In the absence of organ dysfunction, up to 5 weekly 40 mg/m Forty-two patients were enrolled with a median age of 54 years (range, 34-76 years). Patients were diagnosed with stage IIB (n = 26), IIIB (n = 12), or IVA (n = 4) disease. The median follow-up period was 24 months. The 2-year overall survival, local control, and disease-free survival rates were 97.5% (95% CI, 92.7%-100.0%), 80.9% (95% CI, 66.9%-94.8%), and 64.3% (48.1%-80.4%), respectively. Two patients developed grade 3 rectum/sigmoid AE. One patient required urinary diversion surgery during a salvage operation for local tumor recurrence (grade 3 genitourinary AE). No other grade 3 or worse toxicities were reported. CIRT is an effective treatment for locally advanced AUC. Further research is required to validate the safety and efficacy of CIRT for AUC.

Significance of PD-L1 expression in carbon-ion radiotherapy for uterine cervical adeno/adenosquamous carcinoma

Programmed cell death-ligand 1 (PD-L1) is expressed in tumor cells and has been shown to predict clinical outcomes of several types of malignancies. The aim of this study was to investigate the effects of carbon-ion (C-ion) beam irradiation on PD-L1 expression in human uterine cervical adeno/adenosquamous carcinoma (UCAA) cells and clinical samples and to identify the prognostic factors for outcomes after C-ion radiotherapy (CIRT). The effects of C-ion irradiation on PD-L1 expression in human UCAA and cervical squamous cell carcinoma cells were examined by flow cytometry. We examined PD-L1 expression in UCAA biopsy specimens from 33 patients before CIRT started (pre-CIRT) and after 12 Gy (relative biological effectiveness [RBE]) irradiation (post-12Gy-C) in 4 fractions of CIRT to investigate the correlation between PD-L1 status and clinical outcomes. The PD-L1 expression was upregulated by C-ion beam in a dose-dependent manner in HeLa and SiHa cells through phosphorylated Chk1. The overall frequencies of pre-CIRT and post-12Gy-C PD-L1 positivity were 45% (15/33) and 67% (22/33), respectively. The post-12Gy-C PD-L1 expression was significantly elevated compared to the pre-CIRT PD-L1 expression. There was no significant relationship between the pre-CIRT PD-L1 status and clinical outcomes, such as local control (LC), progression-free survival (PFS), and overall survival (OS). However, the post-12Gy-C PD-L1 expression had better correlation with PFS, but not with LC and OS. CIRT can induce PD-L1 expression in UCAA and we propose that PD-L1 expression after starting CIRT may become as a predictive prognostic marker in CIRT for UCAA.

Significance of concurrent use of weekly cisplatin in carbon‐ion radiotherapy for locally advanced adenocarcinoma of the uterine cervix: A propensity score‐matched analysis

AbstractBackgroundAlthough 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.MethodsWe 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.ResultsThe 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.ConclusionsChemo‐C‐ion RT for locally advanced AC of the uterine cervix is associated with a long‐term survival benefit.

Clinical outcomes and prognostic factors of adjuvant radiotherapy for vulvar cancer: a Japanese Gynecologic Oncology Group nationwide survey study

Abstract This study aimed to analyze the clinical outcomes and prognostic factors of postoperative adjuvant radiotherapy (RT) for vulvar cancer based on a retrospective Japanese nationwide survey. Data were collected from 108 institutions for patients diagnosed with vulvar cancer between January 2001 and December 2010. Patients with histologically confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma who underwent curative surgery and adjuvant radiotherapy were included in this study. Survival outcomes were estimated using the Kaplan–Meier method, and prognostic factors were analyzed via univariate and multivariate models. A total of 139 patients were included, with a median follow-up of 44 months (range: 3–169). The 5-year overall survival (OS) rates (95% confidence interval [CI]) for stages I, II, III, and IV were 71.8% (50.8–92.8%), 61.3% (40.1–82.5%), 58.0% (45.8–70.2%), and 47.3% (27.5–67.1%), respectively. The corresponding 5-year cause-specific survival (CSS) rates (95% CI) for stages I, II, III, and IV were 71.8% (50.8–92.8%), 73.4% (53.0–93.8%), 62.2% (50.0–74.4%), and 47.3% (27.5–67.1%). Multivariate analysis identified age ≥70 years as an independent adverse prognostic factor for OS (hazard ratio [HR]: 1.848; 95% CI: 1.039–3.281; P = 0.042), while the presence of ≥2 inguinofemoral lymph node metastases was significantly associated with poorer CSS (HR: 2.179; 95% CI: 1.109–4.280; P = 0.030). Our analysis identified advanced age and a higher nodal burden as significant predictors of poorer survival outcomes in patients with vulvar cancer receiving postoperative adjuvant RT.

Significance of definitive concurrent chemoradiotherapy for vulvar cancer: a Japanese Gynecologic Oncology Group nationwide survey study

Abstract Objective This study aimed to show the results of radical radiation therapy (RT) and concurrent chemoradiotherapy (CCRT) for vulvar cancer (VC) based on data from a Japanese nationwide survey. Materials and methods We collected data from 108 institutions on cases of VC diagnosed between January 2001 and December 2010. Patients with histologically proven squamous cell carcinoma and adenocarcinoma with curative intent were selected, and 172 patients with VC were included in this study. The collected data were analyzed for overall survival (OS) using the Kaplan–Meier method. Univariate and multivariate analyses were performed to examine the prognostic factors for patients with VC. Results The median follow-up period was 16.8 (range; 3.2–154.8) months. Fifty-five patients received CCRT, and 117 patients received RT alone. The 2-year OS rates (95% confidence interval [CI]) for stages I, II, III, and IV were 77.9% (55.8–100.0), 71.9% (53.8–89.9), 55.4% (42.5–68.3), and 41.5% (27.3–55.7) respectively. Univariate analyses showed that the FIGO stage (p = 0.001), tumor diameter (p = 0.005), and lymph node (LN) status (p = 0.001) were associated with OS. The concurrent use of chemotherapy resulted in a significantly longer OS in Stage III (p = 0.013). Multivariate analysis showed that the hazard ratios (95% CI) for tumor diameter, positivity for LN metastasis, and RT alone (no concurrent chemotherapy) were 1.502 (1.116–2.021), 1.801 (1.287–2.521), and 1.936 (1.187–3.159), respectively. Conclusions Our analysis revealed that CCRT should be recommended, especially for Stage III VC patients. Further studies are warranted to determine who benefits from CCRT, considering primary tumor size and LN status. The study was registered at the University Hospital Medical Information Network (protocol number: UMIN000017080) on April 8th, 2015.

Secondary cancers after carbon‐ion radiotherapy and photon beam radiotherapy for uterine cervical cancer: A comparative study

AbstractBackgroundThere 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.MethodsThis 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.ResultsThe 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).ConclusionsThe 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.

Phase Ib study of durvalumab (MEDI4736) in combination with carbon-ion radiotherapy and weekly cisplatin for patients with locally advanced cervical cancer (DECISION study): study protocol for a prospective open-label single-arm study

Introduction Concurrent chemoradiotherapy is considered the standard treatment strategy for locally advanced cervical cancer. Most recent reports indicate that patients with bulky tumours or adenocarcinoma subtypes have poorer local control. Carbon-ion radiotherapy (CIRT) with the concurrent use of chemotherapy has shown promising results in such cases of difficult-to-treat uterine cervical cancer. Programmed death-ligand 1 (PD-L1) upregulation was observed in tumour tissue samples from patients who had undergone CIRT. Thus, a combination of CIRT and anti-PD-L1 antibody may suppress metastasis by activating antitumour immune response, in addition to exhibiting strong local effects. Objective We will assess the safety and tolerability (primary endpoint) of the concomitant use of durvalumab, an anti-PD-L1 antibody, with CIRT and weekly cisplatin for locally advanced cervical cancer. Methods and analysis This study is a non-randomised, open-label, prospective phase 1b study. Up to 10 patients with histologically proven uterine cervical cancer at stage IIB, IIIA, IIIB, IIIC1 or IVA as per International Federation of Gynecology and Obstetrics (2018) staging will be enrolled. All patients will receive CIRT of 74.4 Gy relative biological effectiveness in 20 fractions over 5 weeks (four fractions per week). Weekly cisplatin at a dose of 40 mg/m 2 will be administrated up to five times. Durvalumab at a dose of 1500 mg/body will be administrated at weeks 2 and 6. Safety and tolerability will be evaluated based on the frequency of dose-limiting toxicities until 92 days after CIRT starts. Patients will be followed-up strictly as per the scheduled protocol for 1 year after CIRT initiation. Ethics and dissemination The Human Research Ethics Committees of QST Hospital (#C21-002) and Chiba University (#2021006) have approved this study protocol. The findings will be published in peer-reviewed journals and presented at scientific conferences. Trial registration number Japan Registry of Clinical Trials (jRCT2031210083), registered on 12 May 2021.

Clinical advantage and outcomes of computed tomography‐based transvaginal hybrid brachytherapy performed only by sedation without general or saddle block anesthesia

AbstractBackgroundThree‐dimensional image‐guided brachytherapy is the standard of care in cervical cancer radiotherapy. In addition, the usefulness of the so‐called “hybrid brachytherapy (HBT)” has been reported, which involves the addition of needle applicators to conventional intracavitary brachytherapy for interstitial irradiation.AimTo evaluate the clinical outcomes of CT‐based HBT consisting of transvaginal insertion of needle applicators (CT‐based transvaginal HBT) and only intravenous sedation without general or saddle block anesthesia.Methods and resultsThis is a retrospective chart review of patients who received definitive radiotherapy, including CT‐based transvaginal HBT, between February 2012 and July 2019. The inclusion criteria were as follows: (i) histologically diagnosed disease, (ii) untreated cervical cancer, (iii) International Federation of Gynecology and Obstetrics (FIGO) stage IB1–IVA disease in the 2008 FIGO staging system, and (iv) patients who underwent CT‐based transvaginal HBT at least once in a series of intracavitary brachytherapy. Overall, 54 patients fulfilled the eligibility criteria in the present study. The median follow‐up period was 32 (IQR, 19–44) months. No patient complained of symptoms such as persistent bleeding or abdominal pain after the treatment. The 3‐year local control (LC), disease‐free survival, and overall survival rates for all 54 patients were 86.6%, 60.3%, and 90.7% (95% CI [81.3%–100.0%]), respectively. The 3‐year LC rate was 87.7% in patients with FIGO III–IVA and 90.4% in tumor size >6.0 cm. The incidence rate of late adverse events, grade ≥3, in the rectum and bladder was 0% and 1.8%, respectively. In the dose‐volume histogram analyses, transvaginal HBT increased the dose of HR‐CTVD90 by ~7.5% without significantly increasing the dose of organs at risk.ConclusionConsidering the favorable clinical outcomes, CT‐based transvaginal HBT may be a good option for treating cervical cancer.

A Phase Ib Study of Durvalumab (MEDI4736) in Combination with Carbon-Ion Radiotherapy and Weekly Cisplatin for Patients with Locally Advanced Cervical Cancer (DECISION Study): The Early Safety and Efficacy Results

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.