Genetic markers of late radiation toxicity in the era of image-guided radiotherapy: lower toxicity rates reduce the predictive value of γ-H2AX foci decay ratio in patients undergoing pelvic radiotherapy.

BACKGROUND: A predictive assay for late radiation toxicity would allow more personalized treatment planning, reducing the burden of toxicity for the more sensitive minority, and improving the therapeutic index for the majority. In a previous study in prostate cancer patients, the γ-H2AX foci decay ratio (γ-FDR) was the strongest predictor of late radiation toxicity. The current study aimed to validate this finding in a more varied group of patients with pelvic cancer. Additionally, the potential correlation between the γ-FDR and patient-reported outcomes was investigated. METHODS: Prostate and gynecological cancer patients with ≥ 24 months of follow-up were included in the current analysis. Toxicity was evaluated by physician (CTCAE version 4) and patient (EORTC questionnaires). γ-FDRs were determined in ex vivo irradiated lymphocytes. Correlation between γ-FDR and toxicity was assessed using both linear and logistic regression analyses. The highest toxicity grade recorded during follow-up was used. The association between global quality of life and γ-FDR was tested by comparing the change in quality of life over time in patients with γ-FDR < or ≥ 3.41, a previously established threshold. RESULTS: Eighty-eight patients were included. Physician-assessed and patient-reported cumulative grade ≥ 2 toxicity was 25% and 29%, respectively; which is much lower than in the previous cohort (i.e., 51% CTCAE grade ≥ 2). Patients with toxicity exhibited less favorable dose-volume parameters. In men, these parameters showed significant improvement compared to the previous cohort. The proportion of patients with a low γ-FDR increased with severity of toxicity, but this trend was not statistically significant. In addition, a γ-FDR < 3.41 was not correlated with the development of moderate to severe toxicity. Post-treatment decline in global quality of life was minimal, and similar for patients with γ-FDR < or ≥ 3.41. CONCLUSIONS: In the present study, the γ-H2AX foci decay ratio could not be validated as a predictor of late radiation toxicity in patients with pelvic cancer. Improved radiotherapy techniques with smaller irradiated bladder and bowel volumes have probably resulted in less toxicities. Future studies on genetic markers of toxicity should be powered on these lower incidences. We further recommend taking persistency, next to severity, into consideration.

A dosimetric comparison of 3D-CRT, IMRT and IMAT treatment techniques - assessment from radiation protection point of view.

Background: The purpose was to assess the impact of irradiation technique type and beam energy on the mixed radiation field around the medical linear accelerator (linac) in terms of radiation quality and related radiation protection quantities. Materials and methods: Seven radiotherapeutic plans with Alderson-Rando anthropomorphic phantom [different techniques: conventional three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT) and intensity modulated arc therapy (IMAT), different beams: 6 MV or 18 MV, and their arrangements) were prepared for the case of prostate malignancy. Recombination chambers REM-2 and GW2 were positioned on the treatment couch 100 cm from the beam axis at the height of the isocentre. Recombination chambers REM-2 and GW2 were used for recombination index of radiation quality Q4 determination, measurement of total tissue dose Dt and calculation of gamma and neutron components to Dt. Estimation of Dt and Q4 allowed for the ambient dose equivalent H*(10) calculations for each plan. Results: For plans prepared with 6 MV beams, Q4 values within the limits of uncertainty were equal to one, which confirms the correctness of the measurement method. For plans implemented with 18 MV beams, the value of Q4 was in the range of 3.7-5.7. Comparison between treatment techniques indicates that the lowest exposure resulting from out-of-field doses comes from 6 MV IMAT (0.7 mSv), whereas the highest one is from 18 MV IMRT (55.1 mSv). Conclusion: With the recombination chambers technique it was confirmed that the choice of beam energy directly affects the generation of photoneutrons. The treatment plan technique can have a significant impact on the out-of-field dose.

Investigating and Analyzing Prognostic Factors and Their Impact on Recurrent Cervical Cancers.

The incidence of cervical cancer in India is significantly high, and the average recurrence age is much less. The standard line of treatment consists of concurrent chemoradiotherapy. If a recurrence occurs, the treatment options or set of interventions are limited and suboptimal. Through this review, we have analyzed and classified the possible prognostic factors for cervical cancer into three broad categories, viz., (a) disease-related factors, (b) patient-related factors, and (c) treatment-related factors. Disease-related factors include tumor histology, tumor size, stage, parametrial involvement (PMI), Prognostic Nutritional Index (PNI), lymphovascular space invasion (LVSI), and nodal status. Patient-related factors include overall treatment time (OTT), nutritional status, hemoglobin level, comorbidities, and age. Treatment-related factors include addition of chemotherapy, techniques of external beam radiotherapy (EBRT), techniques of brachytherapy, and quality assurance for radiation therapy delivery. Out of these, extremely significant prognostic factors were tumor size and stage, nodal status, PMI, nutritional status, and addition of chemotherapy. Impactful factors include younger age, histology, LVSI, associated comorbidities, hemoglobin level, OTT, and patient-specific quality assurance. The factor that is not related or significant is the technique used for EBRT and brachytherapy delivery.

Intraoperative radiotherapy: An alternative to whole-breast external beam radiotherapy in the management of highly selective breast cancer: A SEER database analysis.

OBJECTIVE: This study aimed to verify if intraoperative radiotherapy (IORT) can achieve the same survival outcome as whole-breast external beam radiotherapy (EBRT) in early breast cancer after breast-conserving surgery (BCS), and to explore the suitable candidates that can safely receive IORT after BCS. METHODS: Eligible post-BCS patients who received IORT or EBRT were included in the Surveillance, Epidemiology and End Results (SEER) database from 2010 to 2018. Risk factors that affected 5-year overall survival (OS) or breast cancer specific survival (BCSS) were identified by Cox proportional hazards regression analysis. Clinical characteristics, OS, and BCSS were comparatively analyzed between the two treatment modalities. RESULTS: The survival analysis after propensity score matching confirmed that patients who received IORT (n = 2200) had a better 5-year OS than those who received EBRT (n = 2200) (p = 0.015). However, the two groups did not differ significantly in 5-year BCSS (p = 0.381). This feature persisted even after multivariate analyses that took into account numerous clinical characteristics. Although there was no significant difference in BCSS between different subgroups of patients treated with IORT or EBRT, patients over 55 years of age, with T1, N0, non-triple negative breast cancers, hormone receptor-positive, and histologic grade II showed a better OS after receiving IORT. CONCLUSION: In low-risk, early-stage breast cancer, IORT was not inferior to EBRT considering 5-year BCSS and OS. Considering the equivalent clinical outcome but less radiotoxicity, IORT might be a reasonable alternative to EBRT in highly selective patients undergoing BCS.

Salvage radiotherapy for locally recurrent cervical and endometrial carcinoma: clinical outcomes and toxicities.

BACKGROUND: The management of locally recurrent gynecological carcinoma remains a challenge due to the limited availability of data. This study aims to share our institutional experience in using definitive radiotherapy (RT) for the treatment of locally recurrent cervical and endometrial carcinoma. METHODS: The study retrospectively reviewed 20 patients in our hospital completing salvage 3D image-based HDR brachytherapy, with or without EBRT, for locally recurrent cervical and endometrial carcinoma after surgery. The Kaplan-Meier method was applied to estimate the disease-free survival (DFS) and overall survival (OS). The toxicities were assessed by CTCAEv5. RESULTS: During a median observation period of 21 months, the study reported a tumor objective response rate of 95%. The 3-year DFS and OS rates were 89.4% and 90.9%, respectively. The EBRT combined with brachytherapy achieved a median cumulative dose of 88 Gy to CTV D90. 14 patients received concurrent and/or systemic chemotherapy. Two patients suffered locoregional recurrence after salvage treatment, one of whom only received salvage brachytherapy for prior RT history. The analysis identified significant predictors for DFS, including tumor histology and FIGO stage. 5 patients observed acute grade 1-2 rectal (15%) or genitourinary (10%) toxicities. Late toxicities including grade 1-2 rectal bleeding (10%) and grade 2 pelvic fracture (5%) were seen in 3 patients. CONCLUSIONS: 3D image-guided brachytherapy combined with EBRT shows effective tumor control and acceptable toxicity profile for women with locally recurrent gynecologic cancer. The success in managing vaginal recurrence is notably influenced by histologic subtype and FIGO staging.

Hypofractionated partial breast re-irradiation in the conservative retreatment of breast cancer local recurrence.

AIM: to evaluate the outcome of partial breast re-irradiation (re-PBI) with intensity modulated RT (IMRT), using a hypofractionated scheme for breast cancer (BC) local recurrence (LR) operated on with repeat breast-conserving surgery (re-BCS). METHODS: IMRT-based re-PBI was performed using either helical or step-and-shoot modality to deliver 37.05 Gy in 13 fractions in 2.5 weeks. Cumulative incidence (CumI) of 2ndLR, toxicity, disease-free (DFS), BC specific (BCSS), and overall (OS) survival were evaluated. RESULTS: Between 5/2012 and 5/2021, 70 patients had re-PBI. Median follow-up (FU) was 6.3 years (Q1-Q3, 4.0-8.1.). Median age at 1stLR was 62. The median primary BC-1stLR interval was 12.4 years (range: 1.6-26.7). Luminal A-like 1stLR accounted for 41% of the cases and median size was 0.8 cm. During FU, 18 (26%) patients showed a subsequent event: three 2snLRs (corresponding to 8-y Cumulative rate of 4%), 3 regional nodal recurrences, 7 distant metastases, and 5 other primary tumors. At 8 years, DFS, BCSS and OS were 76%, 90%, and 90%, respectively. At multivariate analysis, Grade 3 and extensive intraductal component were independent predictors for DFS. For 51 and 46 patients, chronic toxicity and cosmesis were evaluated, respectively: 4% had grade 3 fibrosis and cosmesis was deemed good/excellent in just over 60% of the cases. CONCLUSION: Re-PBI after re-BCS represents a feasible alternative to mastectomy with regard to local control, showing an acceptable toxicity profile. A long-term FU is crucial to better understand the pattern of relapse and consolidate the position of re-PBI in clinical practice.

Investigating the Radiobiological Response to Peptide Receptor Radionuclide Therapy Using Patient-Derived Meningioma Spheroids.

Peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTA-TATE has recently been evaluated for the treatment of meningioma patients. However, current knowledge of the underlying radiation biology is limited, in part due to the lack of appropriate in vitro models. Here, we demonstrate proof-of-concept of a meningioma patient-derived 3D culture model to assess the short-term response to radiation therapies such as PRRT and external beam radiotherapy (EBRT). We established short-term cultures (1 week) for 16 meningiomas with high efficiency and yield. In general, meningioma spheroids retained characteristics of the parental tumor during the initial days of culturing. For a subset of tumors, clear changes towards a more aggressive phenotype were visible over time, indicating that the culture method induced dedifferentiation of meningioma cells. To assess PRRT efficacy, we demonstrated specific uptake of 177Lu-DOTA-TATE via somatostatin receptor subtype 2 (SSTR2), which was highly overexpressed in the majority of tumor samples. PRRT induced DNA damage which was detectable for an extended timeframe as compared to EBRT. Interestingly, levels of DNA damage in spheroids after PRRT correlated with SSTR2-expression levels of parental tumors. Our patient-derived meningioma culture model can be used to assess the short-term response to PRRT and EBRT in radiobiological studies. Further improvement of this model should pave the way towards the development of a relevant culture model for assessment of the long-term response to radiation and, potentially, individual patient responses to PRRT and EBRT.

Incidence and severity of acute radiation induced toxicities among breast cancer patients treated with adjuvant radiotherapy at a major cancer treatment center in Ghana.

BACKGROUND: Adjuvant radiotherapy after mastectomy or breast conserving surgery (BCS) is the standard of care for majority of patients with breast cancer. This is however associated with mucosal and epidermal toxicity of organs at risk (OARs). Breast cancer patients are exposed to a plethora of wrong perceptions, misinformation and myths concerning the usefulness and adverse effects of radiotherapy. There is paucity of literature on the incidence and severity of radiation-induced acute toxicities experienced by patients with breast cancer in Ghana. AIM: To assess the occurrence and severity of four main acute radiation-induced toxicities among female breast cancer patients treated with external beam radiotherapy at a major cancer treatment centre in Ghana. METHODS: Data on the occurrence of acute toxicities among patients was collected from patients' medical records, through a semi-structured questionnaire and via weekly clinical assessments. The Common Terminology Criteria for Adverse Events (CTCAE) grading scale (version 4.0) was used to grade the severity of these toxicities. Descriptive and inferential statistics using an independent two-sampled t-test (two-tailed), one-way analysis of variance (ANOVA), Pearson's Chi-square and Fisher's exact tests were performed. RESULTS: Dermatitis, fatigue, pharyngitis, and breast (chest) pain were the radiation toxicities found among the breast cancer patients undergoing treatment on the two machines. The mean predominant radiation doses associated with the onset of dermatitis, fatigue, pharyngitis, and chest pain in the breast cancer patients were 22.32 Gy, 22.48 Gy, 13.59 Gy, and 19.27 Gy respectively for treatment with a statistically significant (p = 0.0173). Radiation dermatitis was the most dominant acute radiation toxicity recorded, and its incidence and severity. The range of Fisher's p-values (0.689-0.999) between the acute radiation toxicities with both machines revealed no statistical significance. CONCLUSION: Radiation dermatitis was the dominant acute toxicity, both in incidence and severity for patients treated. There was no statistical significance in the incidence and severity of acute radiation side effects.

125I seed brachytherapy for non-central pelvic recurrence of cervical cancer after external beam radiotherapy.

OBJECTIVE: To investigate the efficacy of 125I seed brachytherapy for non-central pelvic recurrence of cervical cancer after external beam radiotherapy, and to analyze the clinical influential factors. METHODS: Between June 2015 and April 2022, 32 patients with 41 lesions were treated with 125I seed brachytherapy. The seeds were implanted under the guidance of CT and/or 3D-printed template images at a median dose of 100 Gy (range, 80-120 Gy), and the local control rate (LCR) and survival rates were calculated. We used multivariate logistic regression to identify prognosis predictors, and receiver operating characteristic (ROC) curve analysis to determine the optimal cut-off values. RESULTS: The median follow-up was 48.52 months (range, 4-86 months), and the 6-, 12-, and 24-month LCR was 88.0%, 63.2%, and 42.1%, respectively. The 1- and 2-year survival rates were 36% and 33%, respectively, and the median survival time was 13.26 months. No significant adverse events occurred. Multivariate regression analysis showed that tumor diameter, tumor stage, and LCR were independent factors influencing survival. ROC curve analysis showed that the area under the curve for tumor diameter and D90 were 0.765 and 0.542, respectively, with cut-off values of 5.3 cm and 108.5 Gy. CONCLUSIONS: The present findings indicate that 125I seed brachytherapy is feasible for treating non-central pelvic recurrence of cervical cancer after external beam radiotherapy. Further, tumor diameter < 5.3 cm and immediate postoperative D90 > 108.5 Gy were associated with better efficacy.

Graphite foils as potential skin and epithelium dosimeters at therapeutic photon energies.

This work builds upon a prior study, examining the dosimetric utility of pencil lead and thin graphitic sheets, focusing upon the measurement of skin doses within the mammographic regime. In recognizing the near soft-tissue equivalence of graphite and the earlier-observed favourable thermoluminescence yield of thin sheets of graphite, this has led to present study of 50 µm thick graphite for parameters typical of external beam fractionated radiotherapy and skin dose evaluations. The graphite layers were annealed and then stacked to form an assembly of 0.5 mm nominal thickness. Using a 6 MV photon beam and delivering doses from 2- to 60 Gy, irradiations were conducted, the assembly first forming a superficial layer to a solid water phantom and subsequently underlying a 1.5 cm bolus, seeking to circumvent the build-up to electronic equilibrium for skin treatments. Investigations were made of several dosimetric properties arising from the thermoluminescence yield of the 50 µm thick graphite slabs, in particular proportionality and sensitivity to dose. The results show excellent sensitivity within the dose range of interest, the thermoluminescence response varying with increasing depth through the stacked graphite layers, obtaining a coefficient of determination of 90%. Acknowledging there to be considerable challenge in accurately matching skin thickness with dose, the graphite sheets have nevertheless shown considerable promise as dosimeters of skin, sensitive in determination of dose from the surface of the graphite through to sub-dermal depth thicknesses.

Overall survival benefit of androgen suppression in addition to dose-escalated external beam radiotherapy for high-risk prostate cancer: Nationwide real-world data indicates a shift in men that benefit.

OBJECTIVE: To evaluate the real-world added value of androgen deprivation therapy (ADT) in addition to external beam radiotherapy (EBRT) in men with high-risk non-metastatic prostate cancer, in view of advances in radiotherapy and diagnostics. METHODS: All Dutch men diagnosed with high-risk non-metastatic prostate cancer (defined as: ≥cT2c-T3b N0M0, PSA ≥20-50 ng/ml, and/or Gleason score ≥8 (International Society of Urological Pathology [ISUP] grade ≥4)) from 2009 through 2019 and treated with EBRT with or without ADT were identified in the population-based Netherlands Cancer Registry. Propensity scores were used to match (1:1) men that received ADT to men that did not receive ADT. Subsequently, OS was compared. Analyses were also stratified by number of high-risk features, 1 (either ≥cT2c, PSA >20 ng/ml or Gleason score ≥8) versus ≥2 (out of ≥cT2c, PSA >20 ng/ml and Gleason score ≥8). RESULTS: A total of 14,773 men with high-risk non-metastatic prostate cancer were identified, 3,958 (27%) of which received EBRT alone. After matching, 3,427 men remained in both groups and baseline characteristics were well-balanced. After a median follow-up of 92 months, OS was better in men treated with EBRT and ADT compared to men treated with EBRT alone (10-year OS: 66.4% versus 61.8%; HR 0.88 [95%CI: 0.80-0.96]). There was no statistically significant difference in OS in the subgroup of men with only 1 high-risk feature (10-year OS 67.7% versus 64.9%; HR 0.95 [95%CI: 0.85-1.07]). CONCLUSIONS: In a contemporary cohort of men treated for high-risk non-metastatic prostate cancer with EBRT, an OS benefit of adding ADT was only observed in men with at least 2 high-risk features. These results suggest that improvements in diagnostics and treatment in recent decades have resulted in a stage shift of men benefiting from the addition of ADT to EBRT.

Dose-intensified stereotactic body radiotherapy for painful vertebral metastases: A randomized phase 3 trial.

BACKGROUND: The purpose of this randomised study was to determine whether dose-intensified stereotactic body radiotherapy (SBRT) for painful vertebral metastases results in increased rates of pain improvement compared with conventional external beam radiotherapy (cEBRT) (control) 6 months after treatment. METHODS: This randomized, controlled phase 3 trial was conducted between November 2016 and January 2023, when it was stopped early. Patients were eligible if they were aged 18 years or older; had one or two painful, stable, or potentially unstable vertebral metastases; and had a life expectancy of 1 year or longer according to the investigator's estimates. Patients received 48.5 grays (Gy) in 10 fractions (with epidural involvement) or 40 Gy in five fractions (without epidural involvement) in the SBRT group and 30 Gy in 10 fractions or 20 Gy in five fractions in the cEBRT group, respectively. The primary end point was an improvement in the pain score at the treated site by at least 2 points (on a visual analog scale from 0 to 10 points) at 6-month follow-up. Data were analyzed on an intention-to-treat and per-protocol basis. RESULTS: Of 214 patients who were screened for eligibility, 63 were randomized 1:1 between SBRT (33 patients with 36 metastases) and cEBRT (30 patients with 31 metastases). The median age of all patients was 66 years, and 40 patients were men (63.5%). In the intention-to-treat analysis, the 6-month proportion of patients who had metastases with pain reduction by 2 or more points was significantly higher in the SBRT group versus the control group (69.4% vs. 41.9%, respectively; two-sided p = .02). Changes in opioid medication intake relative to baseline were nonsignificant between the groups. No differences were observed in vertebral compression fracture or adverse event rates between the groups. CONCLUSIONS: Dose-intensified SBRT improved pain score more effectively than cEBRT at 6 months.

A Japanese multi-institutional phase II study of moderate hypofractionated intensity-modulated radiotherapy with image-guided technique for prostate cancer.

BACKGROUND: The aim of this multi-institutional phase II study was to confirm the safety and the potential efficacy of moderately hypofractionated intensity-modulated radiotherapy (IMRT) with prostate-based image-guidance for Japanese patients. METHODS: Patients with low- or intermediate-risk localized prostate cancer were eligible. Patients with a part of high risk (having only one of the following factors, cT3a, 20 < PSA ≤ 30, or GS = 8 or 9) were also included. Hypofractionated IMRT using daily image-guided technique with prostate matching was performed with a total dose of 70 Gy in 28 fractions. Neoadjuvant hormonal therapy for 4-8 months was mandatory for patients with intermediate or high-risk prostate cancer. RESULTS: From 20 institutions, 134 patients enrolled. The median follow-up was 5.16 years (range, 1.43-6.47 years). The number of patients with low, intermediate, and high-risk prostate cancer was 20, 80, and 34, respectively. The 5-year overall, biochemical failure-free, and clinical failure-free survival was 94.5%, 96.0%, and 99.2%, respectively. The 5-year biochemical failure-free survival for patients with low-, intermediate-, and high-risk disease was 94.1%, 97.4%, and 93.9%, respectively. The incidences of grade 2 gastrointestinal (GI) and genitourinary (GU) late toxicities at 5 years were 5.3% and 5.3%, respectively. There are no acute or late toxicities ≥ grade 3. Of 124 patients who were followed for up to 5 years, the grade 2 late GU or GI toxicities were 10.5% (90% confidence intervals, 6.3-16.2%, p = 0.0958). CONCLUSION: The safety and efficacy of moderately hypofractionated IMRT with prostate-based image-guidance was confirmed among Japanese patients with prostate cancer.

Methodological guide for assessing the carbon footprint of external beam radiotherapy: A single-center study with quantified mitigation strategies.

Background and purposes: Data on the carbon footprint of external beam radiotherapy (EBRT) are scarce. Reliable and exhaustive data, including a detailed carbon inventory, are needed to determine effective mitigation strategies. Materials and methods: This study proposes a methodology for calculating the carbon footprint of EBRT and applies it to a single center. Mitigation strategies are derived from the carbon inventory, and their potential reductions are quantified whenever possible. Results: The average emission per treatment and fraction delivered was 489 kg CO2eq and 27 kg CO2eq, respectively. Patient transportation (43 %) and the construction and maintenance of linear accelerators (LINACs) and scanners (17 %) represented the most significant components. Electricity, the only energy source used, accounted for only 2 % of emissions.Derived mitigation strategies include a data deletion policy (reducing emissions in 30 years by 12.5 %), geographical appropriateness (-12.2 %), transportation mode appropriateness (-9.3 %), hypofractionation (-5.9 %), decrease in manufacturers' carbon footprint (-5.2 %), and an increase in machine durability (-3.5 %). Conclusion: Our findings indicate that a significant reduction in the carbon footprint of a radiotherapy unit can be achieved without compromising the quality of care.This study provides a methodology and a starting point for comparison and proposes and quantifies mitigation strategies, paving the way for others to follow.

Long-Term Survival of a Patient With Anaplastic Thyroid Carcinoma Treated With Hypofractionated Radiotherapy: A Case Report.

Anaplastic thyroid carcinoma, a rare type of primary thyroid cancer, is one of the most aggressive neoplasms with a poor prognosis. Many cases are in the advanced stage at the time of the initial visit, and curative treatment is impossible. Because of the highly radioresistant nature of anaplastic thyroid carcinoma, this condition cannot be properly controlled with conventional radiotherapy. Herein, we report the case of a patient with anaplastic thyroid carcinoma who underwent hypofractionated radiotherapy, attained a complete response, and is still alive more than 10 years after treatment with no evidence of disease. To overcome the high radioresistance of anaplastic thyroid carcinoma, we administered 50 Gy in 10 fractions three times a week. Furthermore, we administered paclitaxel and carboplatin sequentially before and after radiotherapy. Consequently, the patient completed treatment and reached a complete response. He is still alive more than 10 years after treatment with no evidence of disease or severe adverse events. Hypofractionated radiation therapy may provide good control of locally advanced anaplastic thyroid carcinoma.

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.

Combining Surgery, Radiotherapy, and Topical Chemotherapy to Prevent Primary Orbital Exenteration for Atypical Caruncular Melanoma: A Case Report.

Introduction: This case report demonstrates the possibility of successful eye and vision-sparing therapy for caruncular melanoma. Case Presentation: We present an atypical presentation of a caruncular melanoma. After excisional biopsy, residual flat conjunctival melanosis resolved using topical chemotherapy (5-fluorouracil), which was well tolerated. Relapse of the melanoma was treated with external beam radiotherapy, but the tumor grew despite treatment. Eighteen months after complete excision of the relapsed melanoma, the patient remains tumor-free while the eye and its function remain preserved. Conclusion: This case report suggests that aggressive eye-sparing therapy for caruncular melanoma combining surgery, adjuvant topical chemotherapy, and external beam radiotherapy, can be an alternative for primary orbital exenteration.

Toxicity of external beam accelerated partial-breast irradiation (APBI) in adjuvant therapy of early-stage breast cancer: prospective randomized study.

BACKGROUND: Accelerated partial breast irradiation (APBI) is an alternative breast-conserving therapy approach where radiation is delivered in less time compared to whole breast irradiation (WBI), resulting in improved patient convenience, less toxicity, and cost savings. This prospective randomized study compares the external beam APBI with commonly used moderate hypofractionated WBI in terms of feasibility, safety, tolerance, and cosmetic effects. METHODS: Early breast cancer patients after partial mastectomy were equally randomized into two arms- external APBI and moderate hypofractionated WBI. External beam technique using available technical innovations commonly used in targeted hypofractionated radiotherapy to minimize irradiated volumes was used (cone beam computed tomography navigation to clips in the tumor bed, deep inspiration breath hold technique, volumetric modulated arc therapy dose application, using flattening filter free beams and the six degrees of freedom robotic treatment couch). Cosmetics results and toxicity were evaluated using questionnaires, CTCAE criteria, and photo documentation. RESULTS: The analysis of 84 patients with a median age of 64 years showed significantly fewer acute adverse events in the APBI arm regarding skin reactions, local and general symptoms during a median follow-up of 37 months (range 21-45 months). A significant difference in favor of the APBI arm in grade ≥ 2 late skin toxicity was observed (p = 0.026). Late toxicity in the breast area (deformation, edema, fibrosis, and pain), affecting the quality of life and cosmetic effect, occurred in 61% and 17% of patients in WBI and APBI arms, respectively. The cosmetic effect was more favorable in the APBI arm, especially 6 to 12 months after the radiotherapy. CONCLUSION: External APBI demonstrated better feasibility and less toxicity than the standard regimen in the adjuvant setting for treating early breast cancer patients. The presented study confirmed the level of evidence for establishing the external APBI in daily clinical practice. TRIAL REGISTRATION: NCT06007118.

Brachytherapy: The urologist opinion.

Prostate cancer remains a prevalent concern worldwide, necessitating continual advancements in treatment modalities. This abstract explores the role of brachytherapy as a viable and effective option in the management of prostate cancer. Brachytherapy involves the implantation of radioactive sources directly into the prostate, providing a localized dose of radiation. n recent studies and clinical trials, brachytherapy has demonstrated promising outcomes, particularly in terms of disease control and patient outcomes. The treatment's ability to deliver a concentrated intraprostatic dose, often in combination with external beam radiotherapy, has shown favorable results. Furthermore, brachytherapy's impact on disease-free survival and its potential in reducing urinary and bowel toxicity have been subjects of investigation. This abstract delves into the technical aspects, patient outcomes, and emerging trends in brachytherapy for prostate cancer. By examining the current literature and research findings, we aim to shed light on the evolving role of brachytherapy in the comprehensive management of prostate cancer, emphasizing its potential as a valuable therapeutic option.