Journal of Radiation Research

Trends in radiotherapy use and implementation challenges among patients with cervical cancer: a multicenter study in Osaka, Japan

ABSTRACT Since 2018, the staging system and guidelines for cervical cancer have been revised in Japan. Here, we analyzed trends in radiotherapy use among patients with cervical cancer in Osaka Prefecture, Japan. We obtained records from hospital-based cancer registries (2016–23) linked to Diagnosis Procedure Combination data (2019–23), from 67 nationally or prefecturally designated cancer care hospitals. Eligible patients had epithelial or neuroendocrine cervical cancer, excluding those with clinical stage 0 or unknown clinical stage with pathological stage 0. Between 2016 and 2023, the number of patients per year remained stable (717–787); the number of stage IB–IIA (FIGO 2018) cases decreased, whereas that of stages IIB or IIIC (T1–2) cases increased. The number of patients receiving radiotherapy as initial treatment increased from 229 in 2016 to 294 in 2023; this was accompanied by a decline in surgical treatment. The proportion of patients undergoing radiotherapy increased from 11.9% to 17.2% for stage IB–IIA, from 55.6% to 71.7% for stage IIB and from 38.0% to 69.5% for stage IIIC (T1–2). Among 11 institutions providing brachytherapy, the number of radiotherapy cases increased at three, whereas it remained stable or declined at the other eight. These findings indicate a growing trend in radiotherapy use for cervical cancer in Osaka Prefecture; however, the increase varied by institution. To sustain cervical cancer radiotherapy services, further studies may be needed to assess the adequacy of brachytherapy staffing, explore the financial feasibility of brachytherapy equipment, and examine the potential implications of brachytherapy centralization.

Patterns of care for brachytherapy in Japan

Abstract 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.

Linac-based fractionated stereotactic radiotherapy with a micro-multileaf collimator for large brain metastasis unsuitable for surgical resection

Abstract The aim of this study was to assess clinical outcomes using linac-based, fractionated, stereotactic radiotherapy (fSRT) with a micro-multileaf collimator for large brain metastasis (LBM) unsuitable for surgical resection. Between January 2009 and October 2018 we treated 21 patients with LBM using linac-based fSRT. LBM was defined as a tumor with ≥30 mm maximal diameter in gadolinium-enhanced magnetic resonance images. LBMs originated from the lung (n = 17, 81%), ovary (n = 2, 9.5%), rectum (n = 1, 4.8%) and esophagus (n = 1, 4.8%). The median pretreatment Karnofsky performance status was 50 (range: 50–80). Recursive partition analysis (RPA) was as follows: Classes 2 and 3 were 7 and 14 patients, respectively. The median follow-up was 5 months (range: 1–86 months). The range of tumor volume was 8.7–26.5 cm3 (median: 17.1 cm3). All patients were basically treated with 35Gy in 5 fractions, except in three cases. The progression-free survival was 3.0 months. The median survival time was 7.0 months. There was no permanent radiation injury in any of the patients. Radiation-caused central nervous system necrosis, according to the Common Terminology Criteria for Adverse Events version 4.0, occurred in one patient (grade 3). One patients received bevacizumab for radiation necrosis. Two patients underwent additional surgical resection due to local progression and cyst formation. For patients with LBM unsuitable for surgical resection, linac-based fSRT is a promising therapeutic alternative.

A new hyaluronate gel spacer and injection technique for cervical cancer brachytherapy: a technical report

Abstract Spacers separating the tumor from adjacent organs help improve irradiation dose parameters. We introduce a new hyaluronate gel spacer with MEIJI (ADANT®) as an alternative to the previously used Suvenyl® and its injection technique for cervical cancer brachytherapy. Five patients with cervical cancer underwent hyaluronate gel injection (HGI) with the MEIJI hyaluronate gel in their rectovaginal and vesicovaginal septa. The minimum doses covering 90% of the high-risk clinical target volume (CTVHRD90%), the most exposed 2 cc (D2cc) of organs at risk per session, as well as the total doses for combined external beam radiotherapy (with a central shield) and brachytherapy, were assessed. The median CTVHRD90% was 9.3 (range, 6.4–9.7) Gy per session and 92.2 Gy in the equivalent dose in 2 Gy fractions (EQD2) (80.3–93.3 Gy-EQD2) overall. The median rectum D2cc was 2.9 (1.8–5.0) Gy per session and 45.4 (43.4–57.1) Gy-EQD2 overall. The median D2cc of the bladder (bladder D2cc) was 4.8 (2.4–6.5) Gy per session and 64.6 (62.3–69.6) Gy-EQD2 overall. The MEIJI spacer disappeared within 3 or 7 days with no adverse events associated with HGI or deterioration of the patients’ quality of life. MEIJI HGI facilitates a sufficient CTVHRD90% while keeping the rectal and bladder D2cc within dose constraints, even when the rectum and bladder are in close proximity to the CTVHR. In conclusion, the MEIJI spacer may help appropriately meet dose constraints, thereby potentially contributing to improving local control and/or reducing adverse events for patients receiving radiotherapy for cervical cancer.

Technical report on the first clinical use of a bioabsorbable PGA spacer in HDR brachytherapy for recurrent cervical cancer

Abstract In recurrent gynecologic malignancies following prior pelvic irradiation, definitive radiation therapy is often precluded by cumulative dose constraints to adjacent organs at risk (OARs), and patients may be left with only highly invasive surgical options such as total pelvic exenteration. While some institutions have explored displacement techniques such as artificial ascites or hyaluronic acid gel injection, these approaches are not widely adopted and frequently fail to ensure consistent and stable separation of OARs. We report the first clinical use of Neskeep®, a bioabsorbable polyglycolic acid (PGA) spacer, in high-dose-rate (HDR) brachytherapy for recurrent cervical cancer after prior pelvic radiation. A woman in her 40s with prior hysterectomy and HDR brachytherapy for cervical intraepithelial neoplasia grade III developed vaginal stump recurrence 4 years later. Laparoscopic placement of the PGA spacer was performed to achieve durable displacement of the small bowel, followed by eight fractions of HDR brachytherapy. Hyaluronic acid gel was also injected during each fraction to displace the bladder and rectum. The spacer maintained position and volume throughout treatment without complications. Dose–volume analysis showed a marked reduction in small bowel D₂cc (mean equivalent dose in 2 Gy fractions (EQD₂): 121.6 cGy) compared to the initial treatment (606.0 cGy), while the spacer itself received a mean D₂cc of 690.3 cGy. MRI confirmed complete response at 2 months, with no adverse events observed at that time point. The PGA spacer enabled safe, curative reirradiation in a case that would otherwise be unsuitable for further radiation therapy.

Comparison of rectal and bladder dose between retractor insertion and gauze packing in intracavitary brachytherapy for cervical cancer

ABSTRACT This study aimed to compare and verify the rectal and bladder doses of intracavitary brachytherapy (ICBT) using both rectal retractor (RR) and gauze packing (GP) in the same patients. A total of 37 patients who underwent ICBT using RR and GP for cervical cancer were included in this study. Rectal and bladder dose and volume data were compared with the RR and GP treatments in the same patients and the confounding factors were examined. When comparing RR and GP, the median and interquartile ranges for rectal D2cc were 2.8 (2.5–3.7) Gy with RR and 3.2 (2.7–3.8) Gy with GP. The median bladder D2cc was 4.9 (4.5–6.3) Gy with RR and 4.8 (3.9–5.4) Gy with GP. The Wilcoxon signed-rank test revealed that rectal doses were significantly lower with RR (P = 0.02), whereas bladder doses were significantly higher with RR (P < 0.001). Analysis of the correlation between the number of gauze pieces and the difference in rectal D2cc between GP and RR using Pearson’s distribution revealed no significant correlation (R = −0.20, P = 0.22), as well as bladder D2cc between GP and RR also revealed no significant correlation (R = −0.20, P = 0.22). The number of gauze pieces did not necessarily correlate with a reduction in the rectal and bladder dose. In conclusion, rectal D2cc was lower with RR in image-guided brachytherapy for cervical cancer, whereas bladder D2cc was higher with RR than with GP.

Independent verification system for intracavitary brachytherapy based on a reference plan and statistical model

Abstract High dose rate (HDR) intracavitary brachytherapy (ICBT) with a remote afterloading system plays a vital role in the treatment of cervical cancer. We aimed to develop a new verification system for ICBT for cervical cancer and evaluate the feasibility for clinical plans (PlanClin) generated for different remote afterloaders, applicators and treatment techniques. In total, 517 PlansClin of patients were treated with Elekta 192Ir microSelectron HDR v2r. Reference plans (PlanRef) were generated for the ICBT applicators. An equation to predict total dwell time (Tdwell) of PlanClin was generated by evaluating the relationship between the volume receiving 100% of the prescribed dose (V100%) and the Tdwell. We also developed software to detect human errors in PlanClin by comparing parameters, including applicator and reference point geometries, dwell position and weight patterns and reference point dose, with those of PlanRef. Feasibility was evaluated for 83 PlanClin cases treated with the Elekta Flexitron remote afterloader and six ICBT plans with extra catheters (hybrid BT). The linear fitting function showed good agreement with the correlation between V100% and Tdwell. The developed equation accurately estimated the Tdwell of the PlanClin treated with the Flexitron with an accuracy of 0.26 ± 0.49%. Our system successfully detected intentional human errors including incorrect channel mapping, applicator tip offset, incorrect plan templates, an applicator digitization model and incorrect reference points. A verification system based on PlanRef and a statistical approach is feasible for the new remote afterloaders, applicators and hybrid BT techniques. This system contributes to the implementation of safe treatments.

Impact of RhoA overexpression on clinical outcomes in cervical squamous cell carcinoma treated with concurrent chemoradiotherapy

Abstract The Rho-associated coiled-coil-containing protein kinase (ROCK) pathway is known to influence metastasis in several cancers; however, the impact of the pathway on clinical outcomes in patients undergoing radiotherapy remains unknown. In the present study, the expression of RhoA, RhoC, ROCK-1, ROCK-2 and p53 was immunohistochemically evaluated using biopsy specimens obtained from 49 patients with stage II–III cervical squamous cell carcinoma treated with concurrent chemoradiotherapy (CCRT). The relationship between the expression of these proteins and patient outcomes was investigated. RhoA overexpression was associated with significantly impaired disease-free survival and distant metastasis-free survival (P = 0.045 and P = 0.041, respectively) in stage III cancer patients. No differences in survival were observed based on the expression of the other proteins among stage III cancer patients. In stage II cancer patients, no differences in survival were noted based on the expression of any of the proteins. The expression of RhoA was able to successfully differentiate cervical cancer patients with distant metastasis after CCRT. This information may help stratify patients according to the risk of metastasis, thereby leading to the potential to provide individualized treatment.

Verification of dose distribution in high dose-rate brachytherapy for cervical cancer using a normoxic N-vinylpyrrolidone polymer gel dosimeter

Abstract The polymer gel dosimeter has been proposed for use as a 3D dosimeter for complex dose distribution measurement of high dose-rate (HDR) brachytherapy. However, various shapes of catheter/applicator for sealed radioactive source transport used in clinical cases must be placed in the gel sample. The absorbed dose readout for the magnetic resonance (MR)-based polymer gel dosimeters requires calibration data for the dose-transverse relaxation rate (R2) response. In this study, we evaluated in detail the dose uncertainty and dose resolution of three calibration methods, the multi-sample and distance methods using the Ir-192 source and the linear accelerator (linac) method using 6MV X-rays. The use of Ir-192 sources increases dose uncertainty with steep dose gradients. We clarified that the uniformly irradiated gel sample improved the signal-to-noise ratio (SNR) due to the large slice thickness of MR images and could acquire an accurate calibration curve using the linac method. The curved tandem and ovoid applicator used for intracavitary irradiation of HDR brachytherapy for cervical cancer were reproduced with a glass tube to verify the dose distribution. The results of comparison with the treatment planning system (TPS) calculation by gamma analysis on the 3%/2 mm criterion were in good agreement with a gamma pass rate of 90%. In addition, the prescription dose could be evaluated accurately. We conclude that it is easy to place catheter/applicator in the polymer gel dosimeters, making them a useful tool for verifying the 3D dose distribution of HDR brachytherapy with accurate calibration methods.

Development of a deep learning-based model to evaluate changes during radiotherapy using cervical cancer digital pathology

Abstract This study aims to create a deep learning-based classification model for cervical cancer biopsy before and during radiotherapy, visualize the results on whole slide images (WSIs), and explore the clinical significance of obtained features. This study included 95 patients with cervical cancer who received radiotherapy between April 2013 and December 2020. Hematoxylin–eosin stained biopsies were digitized to WSIs and divided into small tiles. Our model adopted the feature extractor of DenseNet121 and the classifier of the support vector machine. About 12 400 tiles were used for training the model and 6000 tiles for testing. The model performance was assessed on a per-tile and per-WSI basis. The resultant probability was defined as radiotherapy status probability (RSP) and its color map was visualized on WSIs. Survival analysis was performed to examine the clinical significance of the RSP. In the test set, the trained model had an area under the receiver operating characteristic curve of 0.76 per-tile and 0.95 per-WSI. In visualization, the model focused on viable tumor components and stroma in tumor biopsies. While survival analysis failed to show the prognostic impact of RSP during treatment, cases with low RSP at diagnosis had prolonged overall survival compared to those with high RSP (P = 0.045). In conclusion, we successfully developed a model to classify biopsies before and during radiotherapy and visualized the result on slide images. Low RSP cases before treatment had a better prognosis, suggesting that tumor morphologic features obtained using the model may be useful for predicting prognosis.

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

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

Association between pelvic bone marrow dosimetry and acute hematologic toxicity during concurrent chemoradiotherapy for gynecologic malignancies

ABSTRACT Pelvic radiotherapy for gynecologic malignancies damages the primary active bone marrow reservoir, inducing hematologic toxicity exacerbated by chemotherapy. Optimizing pelvic bone marrow dose–volume constraints is critical to mitigate myelosuppression and maintain treatment efficacy. The present retrospective cohort study analyzed patients with gynecological cancer (n = 61) undergoing concurrent chemoradiotherapy between August 2021 and August 2024. Associations between pelvic bone marrow (PBM) dose–volume parameters and acute hematologic toxicity (AHT) were systematically evaluated. All patients received intensity-modulated radiotherapy encompassing pelvic lymph node regions, with weekly complete blood count monitoring during and for 2 weeks after treatment. The overall incidence of AHT was 70.5% (43/61), with grade ≥ 2 and ≥ 3 AHT occurring in 63.9% (39/61) and 30.0% (14/61) of patients, respectively. Multivariate analysis identified PBM-V15 as an independent predictor of grade ≥ 2 AHT [odds ratio (OR), 2.653; 95% CI, 1.054–6.682; P = 0.038], with an optimal cutoff threshold of 80.44% [area under the curve (AUC), 0.854]. Notably, a lower PBM (LPBM)-V5 specifically predicted grade ≥ 3 AHT (OR, 1.425; 95% CI, 1.022–1.987; P = 0.037), with a threshold of 91.25% (AUC, 0.695). Implementing bone marrow-sparing strategies by restricting PBM-V15 to <80.44% significantly reduced the grade ≥ 2 AHT risk, while a stringent LPBM-V5 constraint (< 91.25%) was pivotal for preventing severe (grade ≥ 3) AHT. These dose–volume parameters should be incorporated into optimization protocols for pelvic radiotherapy in gynecological malignancies.

Dosimetric impact of rotational setup errors in volumetric modulated arc therapy for postoperative cervical cancer

Abstract We aimed to evaluate the impact of rotational setup errors on the doses received during postoperative volumetric-modulated arc therapy (VMAT) for cervical cancer. Overall, 121 cone-beam computed tomography (CBCT) sets from 20 patients were rigidly registered to reference computed tomography (CT) sets based on bony landmarks. The rotational setup errors (pitch, yaw and roll) were calculated. Then, 121 CT sets involving rotational setup errors were created, and the dose distribution in these CT sets were recalculated. The recalculated dosimetric parameters for the clinical target volume (CTV) and organs at risk (OAR) were compared to the reference values, and the correlation coefficients between the dosimetric parameter differences and rotational setup errors were calculated. Only the pitch setup error was moderately correlated with CTV coverage (r ≥ 0.40) and strongly correlated with V45 for the bladder (r ≥ 0.91) and V40 for the rectum, small bowel and bone marrow (r ≥ 0.91). The maximum dosimetric difference in a single fraction and overall fractions was −1.59% and −0.69% in D98 for the CTV, 11.72% and 5.17% in V45 for the bladder and −8.03% and −4.68% in V40 for the rectum, respectively. In conclusion, rotational setup errors only slightly impact dose coverage during postoperative cervical cancer VMAT. However, the pitch setup error occasionally affected the doses received by the bladder or the rectum in the overall fraction when the error was systematic. Thus, rotational setup errors should be corrected by adjusting six-degree-of-freedom (DOF) couches to reduce dosimetric differences in the OARs.

Who can benefit from a lymph node boost in definitive chemoradiotherapy for node-positive cervical cancer: an evaluation of nodal failure in patients without nodal boost

Abstract This study was performed to identify risk factors for pelvic nodal failure (PNF) after definitive concurrent chemo-radiotherapy (CCRT) in patients with metastatic pelvic lymph nodes (mPLNs) from squamous cell carcinoma (SCC) of the cervix. We retrospectively reviewed data on 80 patients who received definitive CCRT between 2005 and 2014 at our hospital. All patients underwent brachytherapy and whole-pelvic radiotherapy (WPRT) without nodal boost. mPLNs was diagnosed by magnetic resonance imaging and positron emission tomography. The rate of PNF and factors affecting PNF were analysed. A total of 156 mPLNs were found. The median number of mPLNs was 2 per patient (range 1–6); the median short diameter was 1.7 cm (range 1.0–4.2 cm). After a median follow-up of 64 months, 10 (6.4%) mPLNs failed in 13 (16.3%) patients. The 5-year PNF-free survival (PNFFS), disease-free survival and overall survival rates were 83.4, 62.7 and 74.7%, respectively. The mPLN size was not associated with the risk of PNF. However, pre-radiotherapy SCC antigen (SCC-Ag) >6.8 ng/mL and number of mPLNs >2 were significant risk factors for PNF. Using the two risk factors, we categorized the patients into three risk groups. The 5-year PNFFS rates in patients with 0, 1 and 2 risk factors were 100.0, 78.3 and 44.4%, respectively (P < 0.01). SCC-Ag level and number of mPLNs were significant factors for PNF. Patients with both risk factors developed frequent PNF after WPRT without nodal boost. The two risk factors can be a guide in deciding whether to administer nodal boost radiotherapy.

Clinical experience of pelvic radiotherapy or chemoradiotherapy for postoperative uterine cervical cancer using intensity-modulated radiation therapy

Abstract The purpose of this study was to reveal treatment outcomes and toxicity after pelvic intensity-modulated radiotherapy (IMRT) for postoperative uterine cervical cancer of Japanese patients. Consecutive patients who were treated with pelvic IMRT for postoperative cervical cancer in our institute were retrospectively analyzed. Relapse-free survival (RFS) and overall survival (OS) were calculated using the Kaplan–Meier estimator, and log-rank tests were used to compare differences. From the database, 62 patients were identified. The pathology was squamous cell carcinoma in 44 patients and other pathology in 18 patients. Of the 62 patients, 35 had high-risk prognostic factors and 27 patients had intermediate-risk prognostic factors. The prescribed radiation doses were 50 Gy in 25 fractions for 58 patients and 50.4 Gy in 28 fractions for 4 patients. One patient received a vaginal cuff boost. Chemotherapy was administered in 36 patients. During the median follow-up period of 50.9 months, there was no locoregional failure. Six patients in the high-risk group relapsed, but none of the patients in the intermediate-risk group relapsed (P = 0.02). The 3-year OS and RFS rates were 98.2% and 90.9%, respectively. Significant factors related to RFS were squamous cell carcinoma pathology (P = 0.02), pathological T stage (P = 0.04), surgical margin status (P < 0.01) and multiple lymph nodes metastases (P < 0.01). Grade 3 or more toxicity occurred in 6 patients. Four patients had obstruction of the intestine, and 2 patients had stenosis of the urinary tract. In clinical practice, the use of pelvic IMRT for postoperative cervical cancer of Japanese patients showed a low rate of toxicity without decreasing the efficacy.

Retrospective DVH analysis of point A based intracavitary brachytherapy for uterine cervical cancer

ABSTRACT Combining external beam radiotherapy (EBRT) with intracavitary brachytherapy (ICBT) is important for definitive treatment of cervical cancer. In cervical cancer patients receiving radiotherapy, we evaluated treatment outcomes in relation to dose–volume histogram parameters, including the computed tomography (CT)-based high-risk clinical target volume (HR-CTV) for ICBT. Between 2010 and 2015, 89 consecutive cervical cancer patients were mostly treated with 40 Gy of EBRT in 20 fractions and 18 Gy of ICBT prescribed to point A in 3 fractions. CT scans were obtained during ICBT. The HR-CTV D90 was calculated and the total doses of ICBT and EBRT were converted to the equivalent dose in 2 Gy fractions (EQD2). When the patients were divided into four groups according to EQD2 of the HR-CTV D90, the 3-year local recurrence-free survival rates were 95.2, 78.4, 52.7 and 42.9% for patients receiving >80 , 70–80 , 60–70 and <60 Gy, respectively. There was a significant negative correlation between EQD2 of the HR-CTV D90 and the HR-CTV volume at first ICBT (r = −0.713). Local recurrence was more frequent when the HR-CTV volume was ≥22 cc and EQD2 of the HR-CTV D90 was <70 Gy. Multivariate analysis showed that EQD2 of the HR-CTV D90 and concurrent chemotherapy (≥4 cycles) were significant determinants of overall survival. HR-CTV D90 was an important prognostic indicator for local recurrence. HR-CTV D90 >70 Gy is required for the better local control, especially in patients with a larger HR-CTV (≥22 cc at initial ICBT).

Optimizing dwell time weight for interstitial needles in intracavitary/interstitial hybrid brachytherapy: balancing tumor coverage with organ sparing using the inverse planning technique

ABSTRACT The recommended dwell time weight of the needle in intracavitary/interstitial hybrid brachytherapy (HBT) has been 10–20%. This study aimed to investigate the correlation between the weight constraint of the needle and normal organ doses in uterine cervical cancer HBT. This study included 30 cervical cancer patients who received HBT with tandem/ovoid applicators. In our clinical practice, treatment plans were generated without the constraint of the dwell time weight of the needle. The cases where this weight exceeded 20% were replanned. An inverse planning technique with locking downscaled needle dwell time was used to reproduce isodose lines of clinical plans. Replanning repeated with downscaling of the dwell time until the weight of the needle fell <20% (Needle-Lock plan). The Needle-Lock plans were rescaled to coincide with the high-risk clinical target volumes D90 of clinical plans. D2cc in normal organs and the overdose area >200% of the prescribed dose were evaluated. In 17 of 30 (56.7%) clinical plans, the weight of the needle exceeded 20%. The rectum, bladder and sigmoid colon D2cc significantly increased with the Needle-Lock plan. The overdosage area also increased significantly (P < 0.01). The correlations between the needle number and the increase of D2cc in the rectum and sigmoid colon (P < 0.01) were statistically significant. Limiting needle dwell time weight by 10–20% increased bladder and rectum doses, especially with multiple needles. These findings suggest that needle dwell time weight recommendations could need to be reconsidered based on individual and institutional situation.

Clinical efficacy and safety of neoadjuvant chemotherapy with paclitaxel and cisplatin in combination with concurrent chemoradiotherapy for locally advanced cervical cancer: a systematic review and meta-analysis

Abstract The meta-analysis was to evaluate the therapeutic benefits of neoadjuvant chemotherapy (NACT), primarily consisting of platinum-based regimens in conjunction with paclitaxel, when integrated with concurrent chemoradiotherapy (CCRT) for individuals afflicted with locally advanced cervical cancer (LACC). The outcomes were determined by overall survival (OS), progression-free survival (PFS), complete response rate (CRR), objective response rate, recurrence rate and adverse events. The assessment of these outcomes was based on the relative risk (RR) accompanied by its 95% confidence interval (CI). Eight articles were included for analysis. LACC patients who underwent treatment with paclitaxel combined with cisplatin (TP)-based NACT in conjunction with CCRT demonstrated improved OS at 2 (RR: 1.11, 95% CI: 1.07, 1.16, P < 0.001), 3 (RR: 1.30, 95% CI: 1.23, 1.37, P < 0.001) and 5 years (RR: 1.20, 95% CI: 1.10, 1.32, P < 0.001), as well as PFS at 1 (RR: 1.03, 95% CI: 1.00, 1.06, P = 0.035), 2 (RR: 1.21, 95% CI: 1.04, 1.40, P = 0.012), 3 (RR: 1.26, 95% CI: 1.17, 1.34, P < 0.001) and 5 (RR: 1.39, 95% CI: 1.25, 1.55, P < 0.001) years, when compared with patients who received CCRT alone. Moreover, the TP-based NACT in conjunction with CCRT achieved a higher CRR and exhibited a lower rate of disease recurrence (RR:1.28, 95% CI:1.08, 1.50, P = 0.003). No significant differences in the risk of adverse effects including anemia, leukopenia, thrombocytopenia, radiocystitis and radiation enteritis between the group treated with TP-based NACT combined with CCRT and the group treated with CCRT alone were observed. The combination of TP-based NACT and CCRT demonstrates superior clinical efficacy than CCRT alone. This study may contribute to reducing the burden of LACC by using TP-based NACT plus CCRT.

Effective timing of hyaluronate gel injection in image-guided adaptive brachytherapy for uterine cervical cancer: a proposal of the ‘adjusted dose score’

Abstract Hyaluronate gel injection (HGI) in the rectovaginal septum and vesicovaginal septum is effective in the setting of high-dose-rate image-guided adaptive brachytherapy (IGABT) for cervical cancer. We aimed to retrospectively investigate optimal conditions for HGI to achieve optimal dose distribution with a minimum number of HGI. We classified 50 IGABT plans of 13 patients with cervical cancer who received IGABT both with and without HGI in the rectovaginal septum and vesicovaginal septum into the following two groups: plan with (number of plans = 32) and plan without (number of plans = 18) HGI. The irradiation dose parameters of high-risk clinical target volume (CTVHR) and organs at risk per fraction were compared between these groups. We also developed the adjusted dose score (ADS), reflecting the overall irradiation dose status for four organs at risk and CTVHR in one IGABT plan and investigated its utility in determining the application of HGI. HGI reduced the maximum dose to the most exposed 2.0 cm3 (D2.0 cm3) of the bladder while increasing the minimum dose covering 90% of CTVHR and the percentage of CTVHR receiving 100% of the prescription dose in one IGABT plan without causing any associated complications. An ADS of ≥2.60 was the optimum cut-off value to decide whether to perform HGI. In conclusion, HGI is a useful procedure for improving target dose distribution while reducing D2.0 cm3 in the bladder in a single IGABT plan. The ADS can serve as a useful indicator for the implementation of HGI.

A potential usefulness of ultra-high-resolution computed tomography in quality assurance of remote after-loading system for cervical cancer

Abstract Intracavitary brachytherapy with a remote after-loading system (RALS) is performed as a part of radical radiation therapy in cervical cancer. The radiation source is delivered directly through an applicator placed inside the uterus or vagina. Thorough quality control is important to prevent accidents that can lead to serious irradiation error, and an applicator check is one such quality control measure. We experienced a clinical situation in which a small volume of water was observed in the lumen of a post-sterilized applicator on treatment-planning CT. Although the submersion test was negative and no air bubbles emerged from the applicator, ultra-high-resolution computed tomography (U-HRCT) showed a linear crack reaching the inside of the applicator. This abnormality was not identified on treatment-planning CT, which has lower spatial resolution than U-HRCT. In addition, no linear cracks were seen on U-HRCT images of eight other applicators considered to be free from damage. U-HRCT may have superior potential to detect applicator damage and could be useful for quality assurance of the RALS procedure.

Preliminary result of combined treatment with scanning carbon-ion radiotherapy and image-guided brachytherapy for locally advanced cervical adenocarcinoma

Abstract Although there is growing evidence of the efficacy of carbon-ion radiotherapy (CIRT) for locally advanced cervical adenocarcinoma, reports on combined treatment with CIRT and image-guided brachytherapy (IGBT) are scarce. We retrospectively analyzed patients with International Federation of Gynecology and Obstetrics (2008) stage II–IVA locally advanced cervical adenocarcinoma who received combined scanning CIRT (sCIRT) and IGBT between April 2019 and March 2022. sCIRT consisted of whole-pelvic irradiation with 36 Gy (relative biological effectiveness [RBE]) in 12 fractions and subsequent local boost irradiation with 19.2 Gy (RBE) in 4 fractions. Three sessions of IGBT were administered after completion of sCIRT. Concurrent chemotherapy using weekly cisplatin (40 mg/m2/week) was also administered. Efficacy, toxicity and dose–volume parameters were analyzed. Fifteen patients were included in the analysis. The median follow-up period was 25 months. The 2-year overall survival, progression-free survival and local control rates were 92.3% (95% confidence interval [CI] = 77.8–100%), 52.5% (95% CI = 26.9–78.1%) and 84.8% (95% CI = 65.2–100%), respectively. Neither severe acute toxicity necessitating treatment cessation nor grade 3 or higher late toxicity were observed. The sigmoid D2cm3 of the patient who developed grade 2 late sigmoid hemorrhage was 65.6 Gy, which exceeded the standard deviation and target dose. The combination of sCIRT and IGBT for locally advanced cervical adenocarcinoma showed acceptable efficacy and safety. Further large-scale and long-term studies are warranted to confirm the efficacy and safety of this treatment.

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

Abstract 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.

Effects of irradiation on cumulative mortality in mice: shifting toward a younger age of death

AbstractRecently, the question of whether cancer risk is only accelerated but not increased by radiation exposure has been raised. To explore this matter, we analyzed whether the cumulative mortality of irradiated mice could be explained by x-axis (age) shifted cumulative mortality of nonirradiated mice. We reanalyzed publicly available data on observed cumulative mortality or prevalence in irradiated female B6C3F1 mice that lived their entire lifespan. The results showed that the irradiated curve was well matched to uniformly shifted nonirradiated curve for the cumulative mortality of all causes of death but not for the cumulative mortality of all solid tumors and prevalence of ovarian tumors as is. After adjusting lifetime mortalities, it was also well matched for all solid and ovarian tumors. The shifted days by irradiation were 71–116 days for all causes of death, 56–135 days for all solid tumors, and 41–140 days for ovarian tumors in the 1.9 Gy-irradiated group. The response was switched between irradiation at 35 and 105 days consistently for all the above indexes, supporting the hypothesis that radiation sensitivity differs between juvenile and adults. The shifted days of all causes of death showed a tendency of linear response to dose. This concept of shifting the age of death can be applied not only for all cause of death but also for mortality of all solid tumors after adjusting the magnitude. These findings contribute to the discussion on the application of the ‘shifting age of death’ concept to radiation protection.

Intensity-modulated radiation therapy with the central shielding technique for patients with uterine cervical cancer

Abstract We aimed to examine outcomes and toxicities of intensity-modulated radiation therapy (IMRT) with the central shielding (CS) technique for patients with uterine cervical cancer. This retrospective study included 54 patients with International Federation of Gynecology and Obstetrics IB-IVA cancer. Whole pelvic radiotherapy or extended-field radiotherapy were performed at the dose of 50.4 Gy in 28 fractions with helical tomotherapy (HT). Six patients had para-aortic lymph node metastases. The CS technique with HT was utilized after a total dose of 28.8–41.4 Gy to reduce doses to the rectum and bladder. The prescribed dose of intracavitary brachytherapy was mainly 18–24 Gy in three or four fractions at point A. Concurrent chemotherapy was used for 47 patients (87%). Median follow-up time was 56 months. Seventeen patients (31%) developed recurrence. The recurrence of the cervix was observed in two patients (4%). The 5-year rates of the locoregional control, progression-free survival (PFS) and overall survival were 79, 66 and 82%, respectively. Among several factors evaluated, histological type of adenocarcinoma was only a significantly worse prognostic factor for PFS by multivariate analysis (hazard ratio, 4.9 [95% confidence interval, 1.3–18], P = 0.018). Grade 2 or higher late toxicities were observed in nine patients (17%). Two patients (4%) each had grade 3 proctitis and grade 3 ileus, respectively. No grade 4 toxicity or treatment-related death was observed. The results suggest that IMRT with the CS technique allows a high local control without increasing the risk of complications for cervical cancer patients.

Automatic contour segmentation of cervical cancer using artificial intelligence

Abstract In cervical cancer treatment, radiation therapy is selected based on the degree of tumor progression, and radiation oncologists are required to delineate tumor contours. To reduce the burden on radiation oncologists, an automatic segmentation of the tumor contours would prove useful. To the best of our knowledge, automatic tumor contour segmentation has rarely been applied to cervical cancer treatment. In this study, diffusion-weighted images (DWI) of 98 patients with cervical cancer were acquired. We trained an automatic tumor contour segmentation model using 2D U-Net and 3D U-Net to investigate the possibility of applying such a model to clinical practice. A total of 98 cases were employed for the training, and they were then predicted by swapping the training and test images. To predict tumor contours, six prediction images were obtained after six training sessions for one case. The six images were then summed and binarized to output a final image through automatic contour segmentation. For the evaluation, the Dice similarity coefficient (DSC) and Hausdorff distance (HD) was applied to analyze the difference between tumor contour delineation by radiation oncologists and the output image. The DSC ranged from 0.13 to 0.93 (median 0.83, mean 0.77). The cases with DSC <0.65 included tumors with a maximum diameter < 40 mm and heterogeneous intracavitary concentration due to necrosis. The HD ranged from 2.7 to 9.6 mm (median 4.7 mm). Thus, the study confirmed that the tumor contours of cervical cancer can be automatically segmented with high accuracy.

Prediction of out-of-field recurrence after chemoradiotherapy for cervical cancer using a combination model of clinical parameters and magnetic resonance imaging radiomics: a multi-institutional study of the Japanese Radiation Oncology Study Group

Abstract We retrospectively assessed whether magnetic resonance imaging (MRI) radiomics combined with clinical parameters can improve the predictability of out-of-field recurrence (OFR) of cervical cancer after chemoradiotherapy. The data set was collected from 204 patients with stage IIB (FIGO: International Federation of Gynecology and Obstetrics 2008) cervical cancer who underwent chemoradiotherapy at 14 Japanese institutes. Of these, 180 patients were finally included for analysis. OFR-free survival was calculated using the Kaplan–Meier method, and the statistical significance of clinicopathological parameters for the OFR-free survival was evaluated using the log-rank test and Cox proportional-hazards model. Prediction of OFR from the analysis of diffusion-weighted images (DWI) and T2-weighted images of pretreatment MRI was done using the least absolute shrinkage and selection operator (LASSO) model for engineering image feature extraction. The accuracy of prediction was evaluated by 5-fold cross-validation of the receiver operating characteristic (ROC) analysis. Para-aortic lymph node metastasis (p = 0.003) was a significant prognostic factor in univariate and multivariate analyses. ROC analysis showed an area under the curve (AUC) of 0.709 in predicting OFR using the pretreatment status of para-aortic lymph node metastasis, 0.667 using the LASSO model for DWIs and 0.602 using T2 weighted images. The AUC improved to 0.734 upon combining the pretreatment status of para-aortic lymph node metastasis with that from the LASSO model for DWIs. Combining MRI radiomics with clinical parameters improved the accuracy of predicting OFR after chemoradiotherapy for locally advanced cervical cancer.

Dosimetric feasibility of computed tomography-based image-guided brachytherapy in locally advanced cervical cancer: a Japanese prospective multi-institutional study

ABSTRACT The aim of this study was to assess the feasibility of planning dose–volume histogram (DVH) parameters in computed tomography-based 3D image-guided brachytherapy for locally advanced cervical cancer. In a prospective multi-institutional study, 60 patients with stage IIA2–IVA cervical cancer from eight institutions were treated with external beam radiotherapy using central shielding and intracavitary or hybrid (combined intracavitary/interstitial) brachytherapy (HBT). The dose constraints were set as a cumulative linear quadratic equivalent dose (EQD2) of at least 60 Gy for high-risk clinical target volume (HR-CTV) D90, D2cc ≤ 75 Gy for rectum, D2cc ≤ 90 Gy for bladder and D2cc ≤ 75 Gy for sigmoid. The median HR-CTV D90 was 70.0 Gy (range, 62.8–83.7 Gy) in EQD2. The median D2cc of rectum, bladder and sigmoid was 57.1 Gy (range, 39.8–72.1 Gy), 68.9 Gy (range, 46.5–84.9 Gy) and 57.2 Gy (range, 39.2–71.2 Gy) in EQD2, respectively. In 76 of 233 sessions (33%), 23 patients underwent HBT, and the median number of interstitial needles was 2 (range, 1–5). HBT for a bulky HR-CTV (≥40 cm3) significantly improved the HR-CTV D90 compared with intracavitary brachytherapy alone (P = 0.010). All patients fulfilled the dose constrains for target and at risk organs by undergoing HBT in one-third of sessions. We conclude that the planning DVH parameters used in our protocol are clinically feasible.

A multi-institutional survey of the quality of life after treatment for uterine cervical cancer: a comparison between radical radiotherapy and surgery in Japan

Abstract This study aimed to research the post-treatment quality of life (QOL) between radiotherapy (RT)- and operation (OP)-treated early cervical cancer survivors, using separate questionnaires for physicians and patients. We administered an observational questionnaire to patients aged 20–70 years old with Stages IB1–IIB cervical cancer who had undergone RT or OP and without recurrence as outpatients for ≥6 months after treatment. We divided 100 registered patients equally into two treatment groups (n = 50 each). The average age was 53 and 44 years in the RT and OP groups, respectively. The RT group included 34 and 66% Stage I and II patients, respectively, whereas the OP group included 66 and 34% Stage I and II patients, respectively. The OP group included 58% of patients with postoperative RT. Combination chemotherapy was performed in 84 and 48% of patients in the RT and OP groups, respectively. On the physicians’ questionnaire, we observed significant differences in bone marrow suppression (RT) and leg edema (OP). On the patients’ questionnaire, significantly more patients had dysuria and leg edema in the OP group than in the RT group, and severe (Score 4–5) leg edema was significantly higher in the post-operative RT group than in the OP only group. The frequency of sexual intercourse decreased after treatment in both groups. On the patients’ questionnaire, there were no significant differences between the two groups regarding sexual activity. These findings are useful to patients and physicians for shared decision-making in treatment choices. The guidance of everyday life and health information including sexual life after treatment is important.

A dummy-run evaluation of postoperative hypofractionated intensity-modulated radiation therapy (POHIM-RT) trials for cervical cancer

Abstract The postoperative hypofractionated intensity-modulated radiation therapy (POHIM-RT) trial is a phase II study to evaluate toxicity following hypofractionated intensity modulated radiation therapy (IMRT) for cervical cancer. This study describes the results of a benchmark procedure for RT quality assurance of the POHIM-RT trial. Six participating institutions were provided computed tomography for RT planning and an IMRT plan for a sample and were instructed to delineate volumes, create a treatment plan and quality assurance (QA) plan, and submit the results of all procedures. The inter-institutional agreements on RT volume and plan results were evaluated using the kappa value and dice similarity coefficients. The simultaneous truth and performance level estimation (STAPLE) method was employed to generate a consensus target volume. The treatment volumes, organs-at-risk volumes, and results of the RT plan and QA reported by the institutions were acceptable and adhered well to the protocol. In terms of clinical target volume (CTV) delineation, there were differences between the institutions, particularly in vaginal cuff and paracolpium subsites. Consensus CTV was generated from the collected CTVs with the STAPLE method. The participating institutions showed considerable agreement regarding volume, dose and QA results. To improve CTV agreement in CTV, we provided feedback with images of the consensus target volume and detailed written guidelines for specific subsites that were the most heterogeneous.

Comparison of predictive performance for toxicity by accumulative dose of DVH parameter addition and DIR addition for cervical cancer patients

Abstract We compared predictive performance between dose volume histogram (DVH) parameter addition and deformable image registration (DIR) addition for gastrointestinal (GI) toxicity in cervical cancer patients. A total of 59 patients receiving brachytherapy and external beam radiotherapy were analyzed retrospectively. The accumulative dose was calculated by three methods: conventional DVH parameter addition, full DIR addition and partial DIR addition. ${D}_{2{cm}^3}$, ${D}_{1{cm}^3}$ and ${D}_{0.1{cm}^3}$ (minimum doses to the most exposed 2 cm3, 1cm3 and 0.1 cm3 of tissue, respectively) of the rectum and sigmoid were calculated by each method. V50, V60 and V70 Gy (volume irradiated over 50, 60 and 70 Gy, respectively) were calculated in full DIR addition. The DVH parameters were compared between toxicity (≥grade1) and non-toxicity groups. The area under the curve (AUC) of the receiver operating characteristic (ROC) curves were compared to evaluate the predictive performance of each method. The differences between toxicity and non-toxicity groups in ${D}_{2{cm}^3}$ were 0.2, 5.7 and 3.1 Gy for the DVH parameter addition, full DIR addition and partial DIR addition, respectively. The AUCs of ${D}_{2{cm}^3}$ were 0.51, 0.67 and 0.57 for DVH parameter addition, full DIR addition and partial DIR addition, respectively. In full DIR addition, the difference in dose between toxicity and non-toxicity was the largest and AUC was the highest. AUCs of V50, V60 and V70 Gy were 0.51, 0.63 and 0.62, respectively, and V60 and V70 were high values close to the value of ${D}_{2{cm}^3}$ of the full DIR addition. Our results suggested that the full DIR addition may have the potential to predict toxicity more accurately than the conventional DVH parameter addition, and that it could be more effective to accumulate to all pelvic irradiation by DIR.

Tumor size before image-guided brachytherapy is an important factor of local control after radiotherapy for cervical squamous cell carcinoma: analysis in cases using central shielding

Abstract We analyzed the local control (LC) of cervical squamous cell carcinoma treated by computed tomography (CT)-based image-guided brachytherapy (IGBT) using central shielding (CS). We also examined the value of tumor diameter before brachytherapy (BT) as a factor of LC. In total, 97 patients were analyzed between April 2016 and March 2020. Whole-pelvic (WP) radiotherapy (RT) with CS was performed, and the total pelvic sidewall dose was 50 or 50.4 Gy; IGBT was delivered in 3–4 fractions. The total dose was calculated as the biologically equivalent dose in 2 Gy fractions, and distribution was modified manually by graphical optimization. The median follow-up period was 31.8 months (6.3–63.2 months). The 1- and 2-year LC rates were 89% and 87%, respectively. The hazard ratio was 10.11 (95% confidence interval: 1.48–68.99) for local recurrence in those with a horizontal tumor diameter ≥ 4 cm compared to those with < 4 cm before BT. In CT-based IGBT for squamous cell carcinoma, favorable LC can be obtained in patients with a tumor diameter < 4 cm before BT. However, if the tumor diameter is ≥ 4 cm, different treatment strategies such as employing interstitial-BT for dose escalation may be necessary.

Survival outcome of cervical cancer patients treated by image-guided brachytherapy: a ‘real world’ single center experience in Thailand from 2008 to 2018

Abstract The objective of our study was to evaluate the survival outcome of cervical cancer patients treated using image-guided brachytherapy (IGBT). From 2008 to 2018, 341 patients with cervical cancer were treated by radical radiotherapy. IGBT (by computed tomography [CT] or transabdominal ultrasound [TAUS]) was used to treat all of these patients. The characteristic data and patient status after treatment were recorded. All data were evaluated for survival outcome analysis. From a total of 341 patients, 295 patients were analyzed and 46 patients were excluded due to data missing in the survival outcomes. At the median follow-up time of 48 months (IQR 30–80 months), The 4-year local control, progression-free survival and overall survival rates were 89.5%, 74.9% and 69.1%, respectively. For overall survival, the size (> 5 cm), pathology (non-SCCA), stage (stage III–IV by FIGO 2009), lymph node (LN) (presented) and overall treatment time (OTT) (> 56 days) showed statistical significance in univariate analysis while non-SCCA pathology, advanced stage, presented LN and longer OTT showed statistical significance in multivariate analysis. In conclusion, our analysis reports a 4-year overall survival rate of 69.1%. Non-SCCA pathology, advanced stage disease, LN presence and longer OTT showed worse prognostic factors in multivariate analysis.

Now is it time to implement spacers in cervical cancer brachytherapy?

Abstract Although the international study on MRI-guided brachytherapy in cervical cancer (EMBRACE-I) demonstrated excellent local control regardless of the T stage, up to 14.6% of grade 3–5 late radiation-related toxicities were observed, which is unacceptable. While the efficacy of hydrogel spacers has been established in prostate radiotherapy, its implementation speed in cervical cancer brachytherapy is relatively slow, despite the fact that several articles have reported its efficacy in cervical cancer brachytherapy. The authors believe that using a spacer in cervical cancer brachytherapy and brachytherapy for other gynecologic malignancies will reduce late radiation-related toxicity and improve patients’ quality of life; therefore, its rapid implementation is required.

A retrospective study of small-pelvis radiotherapy plus image-guided brachytherapy in stage I–II non-bulky cervical squamous cell carcinoma

Abstract We herein report a retrospective analysis of the efficacy of a combination therapy of pelvic irradiation that excluded the common iliac lymph nodes region and image-guided brachytherapy (IGBT) for non-bulky (≤4 cm) cervical cancer. Thirty-three patients with stage I–II cervical squamous cell carcinoma (≤4 cm) and without pelvic/para-aortic lymphadenopathy who were treated with definitive radiotherapy alone between February 2009 and September 2016 were included. The radiotherapy consisted of CT-based small-pelvis irradiation (whole pelvis minus common iliac lymph node area) of 20 Gy/10 fractions followed by pelvic irradiation with a midline block of 30 Gy/15 fractions and IGBT of 24 Gy/4 fractions (6 Gy/fraction for high-risk [HR] clinical target volume [CTV] D90%). In-room computed tomography (CT) imaging with applicator insertion was used for brachytherapy planning, with physical examinations and diagnostic magnetic resonance imaging (MRI) also being referred to for determination of HR CTV. Over a median follow-up of 60.5 months (range, 7–89), two patients developed distant recurrence and one developed local and distant recurrence. Two patients died from cervical cancer, one from hepatocellular carcinoma and one from non-cancerous disease. The 2/5-year local control (LC), progression-free survival (PFS) and overall survival (OS) rates were 100%/96.7%, 93.8%/90.6% and 93.9%/93.9%, respectively. No pelvic/para-aortic lymph node recurrence was observed. There were no late complications of grade 3 or higher in the small bowel, large bowel/rectum, or bladder. Our results suggest that a combination therapy of IGBT plus small-pelvis irradiation excluding common iliac lymph nodes provides reasonable clinical outcomes and can be a treatment option in non-bulky (≤4 cm) cervical squamous cell carcinoma.

How should we appropriately classify low-risk uterine cervical cancer patients suitable for de-intensified treatment?

Abstract We suggested de-escalation would be possible for cervical cancer like human papillomavirus (HPV)-related oropharyngeal cancer. However, the classification was based on tumor shrinkage that can be obtained after half of the treatment was finished. Our other article found adverse factors which can be obtained prior to treatment, and they might classify patients earlier.

Small dose of oral gastrografin for computed tomography-based image-guided brachytherapy in patients with uterine cervical cancer

Abstract Oral administration of a water-soluble iodine contrast agent (gastrografin) was reported to assist in the appropriate contouring of the small intestine on computed tomography (CT)-based radiotherapy (RT) planning. The efficacy and optimal dose of gastrografin in CT-based image-guided brachytherapy (IGBT) for cervical cancer remain unknown. This study aimed to investigate the efficacy of pretreatment oral administration of gastrografin at a small dose of 50 ml in CT-based IGBT for cervical cancer. A total of 422 sessions in 137 patients who underwent CT-based IGBT with 50 ml of oral gastrografin (concentration, 3% or 4%) were analyzed. Preparation of gastrografin was judged as effective when the small intestine was contrast-enhanced at the area where the small intestine was in contact with the uterus/adnexa. About 287 out of 422 sessions (68%) were judged as effective with gastrografin preparation. The 135 ineffective sessions were considered as follows: (i) the contrast enhancement of the small intestine was not confirmed (n = 36), (ii) the small intestine was not in contact with the uterus/adnexa despite the confirmation of the contrast enhancement of the small intestine (n = 34), and (iii) gastrografin was absent in the small intestine at the area in contact with the uterus/adnexa, even when gastrografin was observed in the small intestine at the area not in contact with the uterus/adnexa (n = 65). In conclusion, pretreatment oral administration of a small dose gastrografin achieved moderate efficacy for accurate contouring of the small intestine close to the uterus/adnexa in CT-based IGBT for cervical cancer.

Preliminary survey of 3D image-guided brachytherapy for cervical cancer at representative hospitals in Asian countries

Abstract 3D image-guided brachytherapy (3D-IGBT) has become a standard therapy for cervical cancer. However, the use of 3D-IGBT is limited in East and Southeast Asia. This study aimed to clarify the current usage patterns of 3D-IGBT for cervical cancer in East and Southeast Asia. A questionnaire-based survey was performed in 11 countries within the framework of the Forum for Nuclear Cooperation in Asia. The questionnaire collected the treatment information of patients with cervical cancer who underwent 3D-IGBT. The cumulative external beam radiotherapy and 3D-IGBT doses were summarized and normalized to a biological equivalent dose of 2 Gy per fraction (EQD2) using a linear-quadratic model. Of the 11 institutions representing the participating countries, six (55%) responded to the questionnaire. Overall, data of 36 patients were collected from the six institutions. Twenty-one patients underwent whole-pelvic irradiation and 15 underwent whole-pelvic irradiation with central shielding. Patients received a median of four treatment sessions of 3D-IGBT (range, 2–6). All 3D-IGBT sessions were computed tomography (CT)-based and not magnetic resonance image-based. The median doses to the high-risk clinical target volume D90, bladder D2cc, rectum D2cc and sigmoid colon D2cc were 80.9 Gy EQD2 (range, 58.9–105.9), 77.7 Gy EQD2 (range, 56.9–99.1), 68.0 Gy EQD2 (range, 48.6–90.7) and 62.0 Gy EQD2 (range, 39.6–83.7), respectively. This study elucidated the current patterns of 3D-IGBT for the treatment of cervical cancer in East and Southeast Asia. The results indicate the feasibility of observational studies of CT-based 3D-IGBT for cervical cancer in these countries.

Treatment outcomes of patients with adenocarcinoma of the uterine cervix after definitive radiotherapy and the prognostic impact of tumor-infiltrating CD8+ lymphocytes in pre-treatment biopsy specimens: a multi-institutional retrospective study

Abstract 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.

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.

Dose rate in the highest irradiation area of the rectum correlates with late rectal complications in patients treated with high-dose-rate computed tomography-based image-guided brachytherapy for cervical cancer

Abstract The purpose of this study was to evaluate the effect of dose rate to the rectum on late rectal complications in patients treated with computed tomography (CT)-based image-guided brachytherapy (IGBT) for cervical cancer. The subjects were 142 patients with cervical cancer who underwent Ir-192 high-dose-rate (HDR)-IGBT between March 2012 and January 2018. The dose rate to the rectum was calculated using in-house software. The minimum, mean and maximum effective dose rate (EDR) was calculated for voxels of the rectal volume covered by cumulative doses >D0.1cc, >D2cc, and > D5cc. The average EDR of three to four brachytherapy sessions was calculated (EDR for patients; EDRp). The total dose of the rectum was calculated as the biologically equivalent dose in 2-Gy fractions (EQD2). The associations between EDRp for D0.1cc, D2cc, and D5cc and the respective rectal EQD2 values with late rectal complications were then analyzed. The median follow-up period was 40 months. Patients with rectal complications of ≥Grade 1 received a significantly higher mean EDRp for D0.1cc–5cc and had a greater EQD2 for D0.1cc–5cc. Multivariate analysis was performed using the mean EDRp for D2cc, EQD2 for D2cc, heavy smoking and BMI. Of these four variables, mean EDRp for D2cc (HR = 3.38, p = 0.004) and EQD2 for D2cc (HR = 2.59, p = 0.045) emerged as independent predictors for late rectal complications. In conclusion, mean EDRp and EQD2 were associated with late rectal complications in patients treated with HDR CT-based IGBT for cervical cancer.

An Asian multi-national multi-institutional retrospective study comparing intracavitary versus the hybrid of intracavitary and interstitial brachytherapy for locally advanced uterine cervical carcinoma

Abstract This study is an international multi-institutional retrospective study comparing the clinical outcomes between intracavitary brachytherapy (ICBT) and the hybrid of intracavitary and interstitial brachytherapy (HBT) for locally advanced cervical cancer patients treated with definitive radiation therapy. Locally advanced cervical cancer, the initial size of which is larger than 4 cm and treated by concurrent chemoradiotherapy and image-guided adaptive brachytherapy, were eligible for this retrospective study. Patients who received HBT at least once were included in the HBT group, and patients who received only ICBT were included in the ICBT group. Anonymized data from 469 patients from 13 institutions in Japan, one from Korea and one from Thailand, were analyzed. Two hundred eighty and 189 patients were included in the ICBT group and the HBT group, respectively. Patients in the HBT group had more advanced stage, non-Scc histopathology, a higher rate of uterine body involvement, larger tumor at diagnosis, larger tumor before brachytherapy and a lower tumor reduction ratio. With a median follow-up of 51.3 months (2.1–139.9 months), 4-y local control (LC), progression-free survival (PFS) and overall survival (OS) for the entire patient population were 88.2%, 64.2% and 83%, respectively. The HBT group received a higher HR-CTV D90 than that of the ICBT group (68.8 Gy vs 65.6 Gy, P = 0.001). In multivariate analysis, the non-Scc histological subtype, HR-CTV D95 ≤ 60 Gy, reduction ratio ≤ 29% and total treatment time (TTT) ≥ 9 weeks were identified as the independent adverse prognostic factors for LC. Regarding LC, no difference was found between ICBT and HBT (4-y LC 89.3% vs 86.8%, P = 0.314). After adjustment for confounding factors by propensity score matching, no advantage of applying HBT was demonstrated regarding LC, PFS, or OS. Despite the fact that HBT patients had more adverse clinical factors than ICBT patients, HBT delivered a higher dose to HR-CTV and resulted in comparable LC.

Japanese Society for Radiation Oncology Consensus Guidelines of combined intracavitary and interstitial brachytherapy for gynecological cancers

Abstract It has been postulated that the combination of intracavitary and interstitial brachytherapy (IC/IS) is effective and safe for large and irregularly shaped uterine cervical cancer patients. However, due to its invasiveness compared to conventional intracavitary brachytherapy (ICBT), it has to be said that the implementation speed of IC/IS is slow. Until now, there have been no guidelines for required equipment, human resources, and procedural guide focusing solely on IC/IS. The purpose of this guideline is to provide radiation oncologists and medical physicists who wish to start IC/IS with practical and comprehensive guidance for a safe IC/IS introduction and to help accelerate the spread of the utilization of IC/IS nationwide. This is the English translation of the Japanese IC/IS Guidelines, and it was created in an effort to share the Japanese approach to the management of locally advanced uterine cervical cancer worldwide.