Combined External Beam Radiotherapy Research Articles

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

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

Treatment intensification strategies for men undergoing definitive radiotherapy for high-risk prostate cancer.

Treatment intensification of external beam radiotherapy (EBRT) plays a crucial role in the treatment of high-risk prostate cancer. We performed a critical narrative review of the relevant literature and present new developments in evidence-based treatment intensification strategies. For men with high-risk prostate cancer, there is strong evidence to support prolonging androgen deprivation therapy (ADT) to 18-36months and escalating the dose to the prostate using a brachytherapy boost. A potentially less toxic alternative to a brachytherapy boost is delivering a focal boost to dominant intraprostatic lesions using EBRT. In patients who meet STAMPEDE high-risk criteria, there is evidence to support adding a second-generation anti-androgen agent, such as abiraterone acetate, to long-term ADT. Elective pelvic lymph node irradiation may be beneficial in select patients, though more prospective data is needed to elucidate the group of patients who may benefit the most. Tumor genomic classifier (GC) testing and advanced molecular imaging will likely play a role in improving patient selection for treatment intensification as well as contribute to the evolution of treatment intensification strategies for future patients. Treatment intensification using a combination of EBRT, advanced hormonal therapies, and brachytherapy may improve patient outcomes and survival in men with high-risk prostate cancer. Shared decision-making between patients and multidisciplinary teams of radiation oncologists, urologists, and medical oncologists is essential for personalizing care in this setting and deciding which strategies make sense for individual patients.

External beam radiation therapy for recurrent or residual thyroid cancer: What is the best treatment time and the best candidate for long-term local disease control?

Cervical disease control might be challenging in advanced thyroid cancer (DTC). Indications for cervical external beam radiation therapy (EBRT) are controversial. To identify clinical and molecular factors associated with control of cervical disease with EBRT. Retrospective evaluation and molecular analysis of the primary tumor DTC patients who underwent cervical EBRT between 1995 and 2022 was performed. Eighty adults, median age of 61 years, were included. T4 disease was present in 43.7%, lymph node involvement in 42.5%, and distant metastasis in 47.5%. Those with cervical progression were older (62.5 vs. 57.3, p = 0.04) with more nodes affected (12.1 vs. 2.8, p = 0.04) and had EBRT performed later following surgery (76.6 vs. 64 months, p = 0.05). EBRT associated with multikinase inhibitors showed longer overall survival than EBRT alone (64.3 vs. 37.9, p = 0.018) and better local disease control. Performing EBRT before radioiodine (RAI) was associated with longer cervical progression-free survival (CPFS) than was RAI before (67.5 vs. 34.5, p < 0.01). EBRT ≥2 years after surgery was associated with worse CPFS (4.9 vs. 34, p = 0.04). The most common molecular alterations were ERBB2, BRAF, FAT1, RET and ROS1 and TERT mutation was predictive of worse disease control after EBRT (p = 0.04). Younger patients, with fewer affected nodes and treated earlier after surgery had better cervical disease control. Combination of EBRT with MKI improved OS. TERT mutation might indicate worse responders to EBRT; however, further studies are necessary to clarify the role of molecular testing in selecting candidates for cervical EBRT.

A Randomized Trial Comparing Quality of Life After Low-Dose Rate or High-Dose Rate Prostate Brachytherapy Boost With Pelvic External Beam Radiation Therapy

Purpose/ObjectivesTo compare health-related Quality of Life (QoL) in urinary, bowel and sexual domains after combined external beam radiotherapy (EBRT) and either low dose rate (LDR) or high dose rate (HDR) prostate brachytherapy (BT). Materials/MethodsEligible men with intermediate or high-risk prostate cancer, treated with combined pelvic EBRT and BT were randomly assigned to either HDR (15 Gy) or LDR (110 Gy) boost. International Prostate Symptom Score (IPSS), Index of Erectile Function (IIEF), Expanded Prostate Cancer Composite (EPIC-26) were collected at baseline, 1,3,6 and 12 months, q6 months to 3 years and then annually along with PSA/testosterone. Fisher's exact test compared categorical variables and the Mann Whitney U test EPIC domain scores. ResultsFrom 01/2014 to 12/2019, a random number generator assigned 195 men: 108 to HDR and 87 to LDR. Median age was 71 years. Risk group was high in 57% and unfavorable intermediate in 43%. Androgen deprivation (used in 74%) began with 3 months neoadjuvant and continued for median 12 months. Baseline EPIC scores were similar for the LDR/HDR cohorts: 89/88 for GU and 92/93 for GI. EPIC urinary scores decreased at one month for HDR but recovered promptly to a steady state by 6 months. LDR scores reached a nadir at 3 months with slow recovery to 18 months, after which urinary QoL was similar for HDR and LDR. Bowel QOL scores fell in both cohorts reaching respective nadirs at 12 months. HDR patients recovered close to baseline and maintained higher scores than LDR patients to 5 years. The decline for LDR patients remained > the MCID out to 5 years. ConclusionsPatient experience for combined EBRT and prostate BT is improved with HDR BT. Urinary QoL improves over time to be equivalent between the 2 modalities after 18 months, but LDR patients report lasting bowel symptoms.

Comparative Study between Two Fractions of 9Gy &amp; Three Fractions of 7Gy High Dose Rate Brachytherapy Following Concurrent Chemo Radiotherapy in Patients with Locally Advanced Carcinoma of Uterine Cervix

Introduction: Traditionally, a judicious combination of external beam radiotherapy (EBRT) and intracavitary brachytherapy (ICBT) is the widely accepted primary modality of treatment for locally advanced carcinoma of the cervix. Although the recommendation ofAmerican Brachytherapy Society is &lt;7.5 Gyfor individual fraction and four to eight should be the range of fractions; however, literature showed high dose rate (HDR) brachytherapy of two fractions of 9Gyresults in acceptable toxicity without compromising the local control. Methods: This was a Prospective Quasi-Experimental study, conducted in Department of Radiation Oncology, National Institute of Cancer Research and Hospital, Mohakhali, Dhaka from July 2018 to June 2019. Patients with Clinically diagnosed and histopathologically proven squamous cell carcinoma of uterine cervix in locally advanced stage (FIGO stage IIB to IVA) were selected. Total 60 patients were enrolled according to selection criteria and allocated in to group. Both arm was received 50Gy EBRT in 25 fractions with concurrent inj.Cisplatin 40 mg/m2 weekly. Then Arm A was given HDR Brachytherapy 9Gy in each fraction for 2 fractions and Arm B was given HDR Brachytherapy 7Gy in each fraction for 3 fractions. Then treatment responses, locoregional control of disease and acute toxicities were compared between groups. Result:Follow up at 6 months after completion of treatment, complete remission was 90% and 86% respectively for arm A and arm B. The overall complete response was 88%. The common toxicities associated with treatment were bladder and rectal toxicities, skin reaction, small bowel toxicity and haematologic complications which were managed well. During follow up after 6 months, 3 patients in arm A and 2 patients in arm B developed grade II bladder toxicities and only 2 patients in arm A developed rectal grade II toxicities, but there was no rectal toxicity in arm B. Conclusions: Present study showed that a total dose of 18 Gy ICRT in two fractions of 9 Gy over 2 weeks is equally effective in short term local control with acceptable toxicities in comparison with a total dose of 21 Gy in three fractions of 7 Gy ICRT. J Bangladesh Coll Phys Surg 2024; 42: 49-56

Exploring the role of combined external beam radiotherapy and targeted radioligand therapy with [177Lu]Lu-PSMA-617 for prostate cancer - from bench to bedside.

Management of prostate cancer (PC) might be improved by combining external beam radiotherapy (EBRT) and prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with lutetium-177 (177Lu)-labeled PSMA inhibitors. We hypothesized a higher efficacy of the combination due to augmentation of the radiation dose to the tumor and interactions of EBRT with PSMA expression potentially increasing radiopharmaceutical uptake. Therefore, this study analyzed the influence of radiation on PSMA expression levels in vitro. The results were translated to evaluate the efficacy of the combination of photon EBRT and [177Lu]Lu-PSMA-617 in a murine PC xenograft model. Finally, a clinical case report on a combined elective field EBRT with RLT dose escalation illustrates a proof-of-concept. Methods: PSMA gene and protein expression were assessed in human PSMA-overexpressing LNCaP cells after irradiation using reverse transcription quantitative polymerase chain reaction (RT-qPCR), flow cytometry and On-Cell Western assays. In the in vivo therapy study, LNCaP tumor-bearing BALB/c nu/nu mice were irradiated once with 2 Gy X-ray EBRT and injected with 40 MBq [177Lu]Lu-PSMA-617 after 4 h or received single or no treatment (n = 10 each). Tumor-absorbed doses by [177Lu]Lu-PSMA-617 were calculated according to the Medical Internal Radiation Dosimetry (MIRD) formalism after deriving time-activity curves using a gamma probe. An exemplified patient case is demonstrated where fractionated EBRT (54 Gy to prostate; 45 Gy to pelvic lymphatics) and three cycles of [177Lu]Lu-PSMA-617 (3.4-6.0 GBq per cycle) were sequentially combined under concurrent androgen deprivation for treating locally advanced PC. Results: At 4 h following irradiation with 2-8 Gy, LNCaP cells displayed a PSMA protein upregulation by around 18% relative to non-irradiated cells, and a stronger upregulation on mRNA level (up to 2.6-fold). This effect was reversed by 24 h when PSMA protein levels were downregulated by up to 22%. Mice treated with the combination therapy showed significantly improved outcomes regarding tumor control and median survival (p < 0.0001) as compared to single or no treatment. Relative to monotherapy with PSMA-RLT or EBRT, the tumor doubling time was prolonged 1.7- or 2.7-fold and the median survival was extended by 24% or 60% with the combination, respectively. Additionally, tumors treated with EBRT exhibited a 14% higher uptake of the radiopharmaceutical as evident from the calculated tumor-absorbed dose, albeit with high variability in the data. Concerning the patient case, the tri-modality treatment was well tolerated and the patient responded with a long-lasting complete biochemical remission for five years following end of PSMA-RLT. The patient then developed a biochemical relapse with oligo-recurrent disease on follow-up imaging. Conclusion: The present preclinical and clinical data demonstrate that the combination of EBRT with dose escalation by PSMA-RLT improves tumor control and potentially prolongs survival. This may pave the way for further clinical investigations of this approach to explore the curative potential of the combination therapy.

Concurrent nivolumab and external beam radiation therapy for hepatocellular carcinoma with macrovascular invasion: A phase II study

Nivolumab was the first immune checkpoint inhibitor approved for hepatocellular carcinoma (HCC). External beam radiation therapy (EBRT) is locally effective and may enhance the effectiveness of immunotherapy. This study investigated the efficacy and safety of concurrent nivolumab and EBRT in HCC with macrovascular invasion. In this phase II multicenter trial, patients with HCC and macrovascular invasion were concurrently treated with intravenous nivolumab (3mg/kg every 2 weeks) and EBRT, followed by maintenance nivolumab until progression or unacceptable toxicity. Primary endpoints were progression-free survival (PFS) and safety, and secondary endpoints were overall survival, time-to-progression, objective response rate, and disease control rate. Between January 2020 and June 2021, 50 patients (male 84%, median age 62.5) were enrolled; 47 (94.0%) and 13 (26.0%) with portal (Vp1/2, n= 21; Vp3, n= 23; Vp4, n= 3) and hepatic vein invasion, respectively. Patients received EBRT (median dose: 50 [IQR 43-50] Gy) after the first nivolumab dose. The median number of nivolumab doses was 8.5. Median PFS was 5.6 (90% CI 3.6-9.9) months. Median overall survival and time-to-progression were 15.2 (90% CI 10.8-19.6) and 5.6 (90% CI 3.6-9.9) months, respectively. The objective response rate and disease control rate were 36.0% and 74.0%, respectively. The median duration of response was 9.9 months. Of 35 patients with follow-up data, 23 received subsequent systemic treatment, including atezolizumab-bevacizumab, sorafenib, lenvatinib, and regorafenib. Treatment-related any grade adverse events (AEs) and grade 3/4 AEs occurred in 40 (80.0%) and 6 (12.0%) patients, respectively. Common treatment-related AEs included pruritus (38.0%) and rash (16.0%), with no treatment-related deaths. Concurrent nivolumab therapy and EBRT showed encouraging PFS with acceptable safety in patients with advanced HCC and macrovascular invasion. Immune checkpoint inhibitors, the standard care for advanced hepatocellular carcinoma (HCC), show relatively poor therapeutic effects in patients with advanced HCC and macrovascular invasion. In this investigator-initiated phase II study, we, for the first time, show that concurrent external beam radiation therapy with nivolumab, an immune checkpoint inhibitor, led to encouraging progression-free survival in patients with HCC and macrovascular invasion. The concurrent treatment was tolerable without significant safety concerns. Further randomized studies investigating the combination of immunotherapy and external beam radiation therapy are required. NCT04611165.

A potential biomarker of radiosensitivity in metastatic hormone sensitive prostate cancer patients treated with combination external beam radiotherapy and radium-223

PurposeThe ADRRAD trial reported the safety and feasibility of the combination of external beam radiotherapy and radium-223 in the treatment of de novo bone metastatic prostate. This study aimed to determine if any biomarkers predictive of response to these treatments could be identified. Experimental design30 patients with newly diagnosed bone metastatic hormone sensitive prostate cancer were recruited to the ADRRAD trial. Blood samples were taken pre-treatment, before cycles 2 to 6 of radium-223, and 8 weeks and 6 months after treatment. Mononuclear cells were isolated and DNA damage was assessed at all timepoints. ResultsDNA damage was increased in all patients during treatment, with bigger increases in foci observed in patients who relapsed late compared to those who relapsed early. Increases in DNA damage during the radium-223 only cycles of treatment were specifically related to response in these patients. Analysis of hematology counts also showed bigger decreases in red blood cell and hemoglobin counts in patients who experienced later biochemical relapse. ConclusionsWhile some patients responded to this combination treatment, others relapsed within one year of treatment initiation. This study identifies a biomarker based approach that may be useful in predicting which patients will respond to treatment, by monitoring both increases in DNA damage above baseline levels in circulating lymphocytes and decreases in red blood cell and hemoglobin counts during treatment.

Prospective study of HDR brachytherapy (BT), external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT): 10-years experience of an MRI-guided approach

ObjectivesTo evaluate the predictive factors for biochemical failure and distant metastases in a prospective cohort of patients with localized prostate cancer treated with the combination of HDR BT and EBRT. Methods and materialsPatients with intermediate (IR) or high-risk (HR) prostate adenocarcinoma received a single fraction of HDR of 15 Gy combined with RT of 37.5 Gy in 15 fractions. ADT duration was used depending on risk-group. Descriptive analyses were performed. Univariate and multivariate Hazard Ratios were obtained. Finally, the Kaplan-Meier model was used to describe the survival of the events of interest. Results309 patients were treated prospectively (199 were IR and 110 HR). Median age was 72 years; 58.3 % were MRI stage ≤ T2c, 34.1 % T3a and 7.6 % T3b; ISUP-grade 1–3 in 78.9 % and ISUP 4–5 in 21.1 %. 71.8 % of patients had ≤ 50 % positive-cores in biopsy and 28.2 % had > 50 %. Median pre-treatment PSA was 9.9 ng/mL. After a median follow-up of 88 months, 41 patients presented biochemical failure and 18 developed distant metastases. Multivariate cox-regression analyses found that MR-T3b Stage (HR 3.88, p = 0.001) and ADT use (HR 3.99, p = 0.03) were the only predictive factors for biochemical failure and the number of positive cores (>50 %) the only independent predictive factor of distant metastases (HR 4.36, p = 0.002). ConclusionsPatients with mpMRI evidence of invasion of the SV and involvement of more than 50% of the cores in the prostate biopsy are patients with a higher risk of presenting a biochemical recurrence or developing metastasis due to their prostate cancer, respectively.

Vaginal Dose Reduction by Changing the Ovoid Loading Pattern in Image Guided Intracavitary Brachytherapy of Cervix.

Locally advanced cervical cancer is frequently treated using a combination of external beam radiotherapy and brachytherapy. Radiotherapy often leads to vaginal morbidity, which poses a significant problem. This study aims to analyze the impact of reducing ovoid loading on dosimetry. We analyzed forty-five CT-based intracavitary brachytherapy plans from fifteen patients. Three plan sets were created for the 45 applications: a standard loading plan (A), a plan with reduced ovoid loading (B), and a tandem-only loading plan (C). We generated Dose-Volume Histograms and recorded dose volume parameters for the three plan sets. The D90 for the Clinical Target Volume (CTV) did not show significant differences among the three plan sets (p = 0.20). The average D90 values for plans A, B, and C were 8.15Gy, 8.16Gy, and 7.4Gy, respectively. No statistically significant differences were observed in D2cc bladder (p = 0.09) (average values: 6.8Gy, 6.5Gy, and 5.9Gy for plans A, B, and C, respectively) and D2cc sigmoid (p = 0.43) (average values: 2.8Gy, 2.6Gy, and 2.4Gy, respectively) among the three plan sets. However, there was a statistically significant difference in D2cc rectum (p < 0.001) (average values: 4Gy, 3.3Gy, and 1.8Gy, respectively), as well as in vaginal dose points (p < 0.001). Reducing ovoid loading significantly decreased the doses to vaginal dose points and the rectum without compromising the dose to the Clinical Target Volume (CTV). Therefore, in carefully selected cases, the adoption of tandem-only loading or reduced ovoid loading could be considered to minimize vaginal morbidity following high dose rate intracavitary brachytherapy.

Retrospective analysis of tooth extraction and osteoradionecrosis after low-dose rate brachytherapy for patients with tongue cancer.

This study aimed to investigate the incidence of osteonecrosis of the jawbones (ORN) after tooth extraction in patients undergoing low-dose rate brachytherapy (LDR-BT) and assess its safety. This study retrospectively analyzed 145 patients with tongue cancer treated at Hiroshima University Hospital from 2007 to 2021 with LDR-BT using 192Ir or 198Au alone, LDR-BT and external beam radiotherapy (EBRT) with or without chemotherapy, and LDR-BT with chemotherapy. Patients' mandible and maxilla were protected with spacers. Forty-seven patients underwent tooth extraction, and the incidence, site, and relationship of ORN with tooth extraction were recorded. A subgroup of 26 patients received additional EBRT to the neck after dissection for late cervical lymph node metastases. Of 145 patients, six (4.1%) developed ORN on the same side of the mandible as LDR-BT, and EBRT was performed before and/or after LDR-BT on the sites where ORNs developed. Five of 47 (10.6%) patients who underwent tooth extraction after LDR-BT developed ORN. ORN incidence was 1.8% (2/109) in the LDR-BT and/or chemotherapy group and 11.1% (4/36) in the combination LDR-BT and EBRT and/or chemotherapy group for primary tongue cancer. Different irradiation methods (LDR-BT and/or chemotherapy and combination LDR-BT and EBRT and/or chemotherapy) and the presence or absence of tooth extraction showed significant differences (p = 0.0335 and p = 0.0139, respectively) with or without ORN. Mandibular tooth extraction should be avoided on the side of LDR-BT in combined EBRT cases. However, tooth extraction is feasible using a spacer in LDR-BT and/or chemotherapy.

Long-Term Urinary Toxicity Follow-Up of Combined External Beam Radiation and Cs-131 LDR Brachytherapy Boost for Prostate Cancer

To evaluate and update our institutional data on chronic patient-reported urinary symptoms in patients with prostate cancer treated with combined external beam radiation therapy (EBRT) and Cesium-131 (Cs-131) LDR brachytherapy boost. Patients treated from September 2006-July 2022 and with at least 6 months of follow-up were analyzed. Patients filled out the Expanded Prostate Cancer Index Composite (EPIC) questionnaire pre-treatment and at each scheduled follow-up. Mean EPIC urinary scores were calculated for urinary summary, urinary function, urinary bother, urinary incontinence, and urinary irritative/obstructive domains. Changes of 7-points or more in mean domain scores were deemed clinically significant. The prevalence of urinary bleeding was calculated and bleeding occurring more than "about once a week" ("more than once a week", "about once a day", and "more than once a day") was deemed clinically significant. Outcomes were analyzed at each follow-up timepoint using paired t-test. A total of 341 patients with prostate cancer were included in the analysis of which 183 were intermediate-risk and 158 high-risk. 174 patients were treated with tri-modality therapy, and SpaceOAR was used in 108 patients. Long-term statistically significant decreases in mean EPIC QOL scores were seen in urinary summary, urinary function, urinary bother, urinary incontinence, and urinary irritative/obstructive domains at 6 months, with clinically and statistically significant decreases in urinary function and urinary incontinence at 6 months (86±17.4, 83.4±22.2 respectively) and up to 18 months post-treatment (84.8±17.4, 83.6±20.7 respectively) compared with pre-treatment scores (93.1±10.7, 90.8±14.8 respectively), with both domains returning to clinical baseline at 24 months. Urinary irritative/obstructive mean scores clinically and significantly decreased at 9 months (77±17.4) compared to pre-treatment (84.7±13.5), returning to clinical baseline at 12 months. The prevalence of clinically significant urinary bleeding at 6, 12, 24, 36, 48, and 60 months was 1.3%, 2.6%, 3.7%, 0.7%, 0.9%, and 2.3% respectively. At the median follow-up of 42 months (IQR 54, 18-72), mean EPIC scores were clinically improved (≥7-point increase) from pre-treatment baseline in 15-30% of patients across the analyzed urinary domains. Long-term patient-reported clinically significant decreases in urinary function and urinary incontinence mean EPIC scores occurred up to 18 months following combined external beam radiation and Cs-131 prostate brachytherapy and returned to baseline at 24 months, while clinically significant decrease in urinary irritability/obstructive mean scores occurred at 9 months and returned to baseline at 12 months. At 42 months follow-up, mean urinary domain scores improved from pre-treatment baseline in 15-30% of patients.

Health-Related Quality of Life after Combined External Beam and Either High Dose Rate (HDR) or Low Dose Rate (LDR) Brachytherapy: Does the Rectal Dose from the LDR Brachytherapy Make a Difference?

The recently reported randomized Phase III trial comparing health related quality of life (HRQOL) after combined external beam radiation therapy (EBRT) and either HDR or LDR brachytherapy (BT) found a significant decline in the EPIC Bowel domain HRQOL score at 24- 48 months after treatment in the LDR arm of the trial. As all patients in the trial received the same EBRT dose, and HDR rectal dose was strictly controlled to be <9.5 Gy to 1cc of rectal wall (RD1cc), we investigated whether the variable rectal dose from the LDR component of treatment was related to the decline in Bowel HRQOL for these patients. A total of 195 men with upper tier intermediate or high-risk prostate cancer were assigned by a random number generator to receive either an HDR (15 Gy, n = 108) or LDR (110Gy, n = 87) brachytherapy boost combined with 46Gy/23 fractions EBRT. All LDR patients had 1 month post implant quality assurance using CT-MRI fusion. The Expanded Prostate Cancer Composite (EPIC) questionnaire was used to evaluate HRQOL at baseline, q3 mo for 1 year, q6mo for 3 yr and then annually. A multivariate linear regression model was used to investigate the dose-response relationship between EPIC bowel domain score at 24- 48 months and RD1cc. With a median follow up of 48 months, the previous analysis confirmed the expected time course of acute bowel/urinary symptoms, with LDR showing more prolonged decline in HRQOL bowel domain at 3 and 6 months, but equivalence to HDR by 12 months. HRQOL urinary domain remained equivalent from 12-60 mo. The decline in the HRQOL bowel domain observed for LDR patients from 24-48 mo was analyzed for the 79 patients with sufficient data. The mean baseline HRQOL bowel domain score was 92 and fell on average to 85 at 24-48 mo. Mean RD1cc for the LDR patients was 82Gy (SD 22 Gy), with a maximum value of 129 Gy. In this range of rectal doses, a 20Gy increase in RD1cc, was associated on average with a 1.5-point decrease in EPIC HRQOL bowel domain score (p = 0.21). The rectal dose received by the LDR patients showed a non-significant dose-response with the EPIC Bowel domain HRQOL score. This confirms the accepted rectal dose constraints for LDR brachytherapy but does not explain the observed decline in bowel scores from 24-48 months.

Assessing the Sexual Health of Female Survivors of Pelvic Malignancies after Radiotherapy

To assess patient-reported sexual health outcomes of female survivors of pelvic malignancies after radiotherapy (RT). Female patients treated with curative intent RT for pelvic malignancies between 2013 and 2019 were surveyed electronically post-RT using the PROMIS Sexual Function and Satisfaction Full Profile and Female Sexual Distress Scale-Revised questionnaires. Cervical and vaginal cancers were grouped together due to the similar treatment characteristics. Surveys were sent to 544 patients, and 53 (10%) completed the questionnaires. Respondents included survivors of anal canal (N = 11), cervical or vaginal (N = 10), uterine (N = 30), and vulvar cancers (N = 2). The median age of patients at the time of treatment was 60 years (range 31,77). The median time between RT and survey completion was 6 years (range 3,9). A total of 22 (42%), 17 (32%), and 14 patients (26%) were treated with brachytherapy (BT), external beam RT (EBRT), or a combination of EBRT and BT, respectively. Of respondents, 96% were free of disease recurrence. Sexually active was defined as partaking in sexual activity within 30 days of survey response. Patients were stratified by age greater than or less than 52 at time of RT, representing the average age of menopause. A total of 30 patients (57%) had at least somewhat interest in sex. There was no difference in the proportion of patients who had at least somewhat interest in sex over 52 years compared to those 52 and (54% vs 67%, p = 0.424). A total of 39 patients (74%) were sexually active, and of those 30 (77%) were over the age of 52 at the time of RT. Of sexually active patients, 28 (72%) reported some, quite a bit, or a lot of satisfaction with their sex lives, whereas the remaining 11 (28%) reported having none or a little bit of satisfaction with their sex lives; the proportion of those with at least some satisfaction with their sex lives did not differ between those who were over or under 52 years at the time of RT (73% vs 67%, p = 0.697). Satisfaction with sex life differed by site of malignancy with 71% cervical or vaginal, 44% anal canal, 86% uterine, and 0% vulvar patients reporting at least some satisfaction (p = 0.043). Patients treated for anal canal cancer tended to have quite a bit or a lot of vaginal discomfort during sex (78%), compared to those treated for cervical/vaginal (29%), or endometrial (18%) cancers (p = 0.006). There was no difference in patients feeling frequently or always stressed about sex between those who were sexually active compared to those who were not (13% vs 14%, p = 0.890). Patients 52 or under at the time of RT were more likely to feel frequently or always stressed about sex compared to those receiving RT over the age of 52 (42% vs 5%, p<0.001). In our cohort, the majority of female survivors of pelvic malignancies were sexually active post-RT, and this important topic warrants further investigation.

The oncologic and safety outcomes of low-dose-rate brachytherapy for the treatment of prostate cancer.

Around 40years have passed since a modern low-dose-rate (LDR) brachytherapy for prostate cancer was introduced. LDR brachytherapy has become one of the definitive treatment options besides radical prostatectomy (RP) and external beam radiation therapy (EBRT). LDR brachytherapy has several advantages over EBRT such as a higher prescribed dose to the prostate gland while avoiding unnecessary irradiation of organs at risk, a precipitous dose gradient, a brief treatment time, and a short hospital stay. Previous reports revealed that the long-term oncologic outcomes of LDR brachytherapy are superior to those of EBRT. The oncologic outcomes of low- to intermediate-risk patients are equivalent to those of RP using the recurrence definition of surgery of prostate specific antigen (PSA) >0.2ng/mL, while the oncologic outcomes of LDR brachytherapy as tri-modality (combined EBRT and androgen deprivation therapy) for high-risk patients is superior to that of RP using the recurrence definition of surgery. In respect of toxicity, urinary disorders such as urgency and frequency are often observed after the acute phase of treatment, but these events usually resolve, while the quality of life of urinary continence is well preserved for a long time. Erectile function decreases yearly, but is relatively preserved compared to RP. In conclusion, the most noteworthy strength of LDR brachytherapy for low- to intermediate-risk patients is the "brief treatment time" that provides long recurrence-free survival, while that for high-risk patients who received LDR brachytherapy (tri-modality) is "excellent disease control."

A comparative study of the effectiveness of multiagent platinum based concurrent plus adjuvant versus conventional single agent platinum based concurrent chemotherapy in carcinoma cervix.

85 Background: Cervical cancer is the 4th most common cancer in females worldwide. Combination of external beam radiotherapy (EBRT) and intracavitary brachytherapy (BT) with concurrent chemotherapy is the current standard of care for locally advanced cervical cancer. Even though the trials used separate combinations, the common end point suggested that platinum is single most effective chemotherapy agent. Since the latest data on platinum based polychemotherapy globally indicates its overall benefit, further trials are required to determine what regimens would be ideal for treatment of cervical cancer with maximum benefits and least toxicities. Objectives: 1. To compare the response to doublet polychemotherapy with conventional chemotherapy in carcinoma cervix treated with chemoradiation. 2. To compare toxicity profile of doublet polychemotherapy with conventional chemotherapy. Methods: 66 patients of carcinoma cervix were enrolled in this study and were randomized to two arms. Arm A (n=34) was the experimental arm and the patients received concurrent weekly cycles of cisplatin(40mg/m2) plus gemcitabine (125mg/m2) along with EBRT followed by HDR brachytherapy, after 2-3 weeks of which they received 2 adjuvant cycles (21 days each) of gemcitabine (1000mg/m2 on Day1 and Day 8) and cisplatin (50mg/m2 on Day 1). Arm B(n=32) was the control arm and the patients received standard treatment which is concurrent weekly cycles single agent cisplatin(40mg/m2) with EBRT followed by HDR brachytherapy. EBRT doses ranged from 45Gy to 50.4 Gy at 1.8 to 2 Gy per fraction .BT application was either ICBT or ISBT depending on tumour response to EBRT, assessed by MRI. Patients were followed up for response assessment and late toxicities within 6 months of completion of treatment by clinical examination and MRI which was reported using RECIST 1.1 criteria. Results: On 6 month follow up MRI, number of patients achieving CR was 10% higher in the experimental arm (Arm A, n=33;97.06%) than the control arm (Arm B, n=28;87.5%).PR was seen in 2 patients, both from Arm B. Of the 3 patients presenting with PD at follow up 1 belonged to Arm A and 2 to Arm B (2.94% vs 6.25%). On pre-brachytherapy MRIs, the size reduction was better in Arm A and this reduction allowed a majority of patients in said arm to undergo ICBT instead of ISBT. The number of patients achieving &gt;50% reduction post EBRT was 40% higher in Arm A. Acute GI and Hematological toxicities were seen in both arms but were higher in Arm A. as was Grade 3 neutropenia. Late toxicities were similar in both arms. Conclusions: The study concluded that the use of multiagent platinum-based chemotherapy in concurrent plus adjuvant setting can be advantageous. Improved tumour reduction can be achieved &amp; disease can be made more amenable for ICBT. The accompanying toxicities were transient and clinically manageable.

IMRT followed by pembrolizumab in the adjuvant setting in anaplastic cancer of the thyroid (IMPAACT): Phase II trial adjuvant pembrolizumab after IMRT in ATC.

TPS6117 Background: Anaplastic thyroid carcinoma (ATC) has historically been an almost uniformly rapidly fatal disease. In patients with loco-regional disease with no distant metastasis (stage IVB), and without a targetable mutation, a combination of external beam radiation delivered via intensity modulated techniques (IMRT) +/- concurrent cytotoxic chemotherapy is the current standard of care. However, the relapse rate is very high within the first year of diagnosis. Our data show that 90% of ATCs express PD-L1, with 43% having expression levels greater than 50%. A clinical trial with an anti-PD1 drug in ATC patients with active disease showed that patients with ATC had a response rate of 19%. Additionally, as tumor PD-L1 expression has been linked to radioresistance and there is a need to target micrometastatic disease, using adjuvant checkpoint inhibitor is a rational strategy in these patients. Methods: This is an open label, single center, phase 2 trial of adjuvant pembrolizumab after external beam radiation to the primary tumor in patients with stage IVB ATC. The primary cohorts will include those with gross, locoregional disease who have completed treatment with IMRT +/- concurrent radiosensitizing chemotherapy. Patients will be treated with adjuvant pembrolizumab (400mg IV Q6 weeks for up to 9 cycles), 2-6 weeks after completion of radiation. Patients will be enrolled based on dose of radiation in cohort 1 (high dose group, &gt; 51 Gy), cohort 2 (palliative dose group, &lt; 50 Gy). Cohort 3, consisting of those who underwent surgery followed by IMRT plus concurrent chemotherapy will be an exploratory cohort. Restaging scans will be performed every 12 weeks after enrollment. MRI brain will be repeated every 6 months in the absence of evidence of progression. The primary endpoint is median PFS (from the start of adjuvant pembrolizumab) in cohorts 1 and 2. Secondary endpoint is median overall survival in cohorts 1 and 2. Cohort 3 (5 patients) will have an exploratory endpoint, to estimate the median disease-free survival (DFS). Statistics: Survival analyses will be performed using the Kaplan-Meier method. Based on historical data, the median PFS for unresected patients is 6.8 months. For an expected improvement of median PFS by 3.7 months, with a combined total of 30 evaluable patients in cohorts 1 and 2, we anticipate having 80.0% power using 1-sided 10% alpha for a one-sample log rank test. The trial began enrollment in July 2022. This trial is sponsored by philanthropic funds and Merck. ClinicalTrials.gov ID NCT05059470. Clinical trial information: NCT05059470 .

EXCEPTIONAL LONG-TERM SURVIVAL OF AN ELDERLY PATIENT WITH METASTATIC SMALL CELL NEUROENDOCRINE CARCINOMA OF THE CERVIX – A CASE REPORT

Small cell neuroendocrine cervical carcinoma (SCCC) is known for its aggressive nature and poor prognosis. There are no standard treatments so small cell lung cancer treatments are often referenced due to their similar morphology. Typical treatment options include a combination of external beam radiotherapy and brachytherapy for localised disease and palliative chemotherapy for advanced disease. The 5-year survival rate for patients presenting with advanced disease is dismal, around 0–14%. Here, we report a case of a 75-year-old woman who was diagnosed with small cell neuroendocrine cervical carcinoma (SCCC) in 2015. She presented with locally advanced SCCC with vaginal involvement, as well as solitary lung and peripancreatic metastases. She was treated with a combination of chemotherapy, chemoradiation and stereotactic radiotherapy, followed by maintenance etoposide, and achieved a very long-term survival. The patient continues to survive today.

Tolerability of concurrent external beam radiotherapy and [177Lu]Lu-PSMA-617 for node-positive prostate cancer in treatment naïve patients, phase I study (PROQURE-I trial)

BackgroundProstate cancer patients with locoregional lymph node disease at diagnosis (N1M0) still have a limited prognosis despite the improvements provided by aggressive curative intent multimodal locoregional external beam radiation therapy (EBRT) with systemic androgen deprivation therapy (ADT). Although some patients can be cured and the majority of patients have a long survival, the 5-year biochemical failure rate is currently 29–47%. [177Lu]Lu-PSMA-617 has shown impressive clinical and biochemical responses with low toxicity in salvage setting in metastatic castration-resistant prostate cancer. This study aims to explore the combination of standard EBRT and ADT complemented with a single administration of [177Lu]Lu-PSMA-617 in curative intent treatment for N1M0 prostate cancer. Hypothetically, this combined approach will enhance EBRT to better control macroscopic tumour localizations, and treat undetected microscopic disease locations inside and outside EBRT fields.MethodsThe PROQURE-I study is a multicenter prospective phase I study investigating standard of care treatment (7 weeks EBRT and 3 years ADT) complemented with one concurrent cycle (three, six, or nine GBq) of systemic [177Lu]Lu-PSMA-617 administered in week two of EBRT. A maximum of 18 patients with PSMA-positive N1M0 prostate cancer will be included. The tolerability of adding [177Lu]Lu-PSMA-617 will be evaluated using a Bayesian Optimal Interval (BOIN) dose-escalation design. The primary objective is to determine the maximum tolerated dose (MTD) of a single cycle [177Lu]Lu-PSMA-617 when given concurrent with EBRT + ADT, defined as the occurrence of Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 grade three or higher acute toxicity. Secondary objectives include: late toxicity at 6 months, dosimetric assessment, preliminary biochemical efficacy at 6 months, quality of life questionnaires, and pharmacokinetic modelling of [177Lu]Lu-PSMA-617.DiscussionThis is the first prospective study to combine EBRT and ADT with [177Lu]Lu-PSMA-617 in treatment naïve men with N1M0 prostate cancer, and thereby explores the novel application of [177Lu]Lu-PSMA-617 in curative intent treatment. It is considered likely that this study will confirm tolerability as the combined toxicity of these treatments is expected to be limited. Increased efficacy is considered likely since both individual treatments have proven high anti-tumour effect as mono-treatments.Trial registrationClinicalTrials, NCT05162573. Registered 7 October 2021.

Outcomes following brachytherapy boost for intermediate- and high-risk prostate cancer: A retrospective bicenter study by the SFRO brachytherapy group

IntroductionRadiotherapy dose escalation improves biochemical control in intermediate- or high-risk prostate cancer. Brachytherapy boost was shown to further improve biochemical control compared to radiotherapy alone in three randomized trials. The SFRO brachytherapy group sought to evaluate the efficacy and toxicity of BT-boost for intermediate and high-risk prostate cancer in real life, and to determine prognostic factors for efficacy and toxicity. Material and methodA retrospective study was conducted, including all patients with intermediate- or high-risk prostate cancer treated with a combination of external beam radiotherapy (EBRT) and high dose-rate brachytherapy boost (HDR-BB), from 2006 until December 2019 at two centers. Patient characteristics, initial disease, treatment and follow-up were collected. Results709 patients from two centers were analyzed given a short follow-up in the other centers. Out of those, 277 were intermediate risk (170 favorable and 107 unfavorable) and 432 were high risk. The median EBRT and HDR-BB doses were 46 Gy (35–50) and 14 Gy (10–20). After a median follow-up of 62 months, biochemical control at 5 years was 87.5 % for the overall population, 91 % and 85 % for intermediate- and high-risk cancers, respectively. At 5 years, biochemical and clinical relapse-free survival, metastasis-free survival and local control rates were 83 %, 90 % and 97 % respectively. 5-years overall survival was 94 %. Late grade 2 or higher GU or GI toxicity was found in 36 patients (5 %) and 9 patients (1.3 %). ConclusionThis bicenter analysis shows the efficacy and tolerability of HDR-BB as a complement to external radiotherapy. Further improvements such as combination with new hormonal agents or new brachytherapy-radiotherapy fractionation regimens are warranted to improve further the outcomes and therapeutic ratio.