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High-dose radiotherapy in patients with high-risk prostate cancers treated with long-term androgen deprivation therapy (GETUG AFU 18): a randomised, phase 3 trial.

BACKGROUND: For patients with high-risk prostate cancer, the role of dose-escalated radiotherapy in combination with long-term androgen deprivation treatment (ADT) is controversial, without any demonstrated benefit on cancer-specific or overall survival. We aimed to evaluate the effect of a 10 Gy dose increase, from 70 Gy to 80 Gy, on progression-free survival in men with high-risk prostate cancer. METHODS: In this multicentre, open-label, randomised, phase 3 trial, we enrolled patients with high-risk prostate cancer, defined as prostate-specific antigen of 20 ng/mL or more, Gleason score of at least 8, or clinical stage T3-T4, from 25 centres in France. Participants were randomly assigned (1:1) by minimisation, stratified by centre and previous pelvic lymph node dissection, to receive prostate-targeted dose-escalated external beam radiotherapy (80 Gy; 2 Gy per fraction for 8 weeks) or standard-dose external beam radiotherapy (70 Gy; 2 Gy per fraction for 7 weeks), combined with long-term ADT. Neither the participants nor the investigators were masked to the allocated treatment. The primary endpoint was 5-year progression-free survival defined as the time from randomisation to first biochemical (defined as prostate-specific antigen >nadir plus 2 ng/mL) or clinical (ie, local, regional, or metastatic) disease progression, analysed in the intention-to-treat population, with 197 events required. 5-year progression-free survival was the prespecified endpoint, and 10-year progression-free survival was additionally reported (post hoc) in view of the low number of events at 5 years. The trial is registered at ClinicalTrials.gov, NCT00967863, and is complete. FINDINGS: Between April 6, 2009, and Jan 24, 2013, 505 patients with high-risk prostate cancer were enrolled; 250 were assigned to receive dose-escalated radiotherapy (80 Gy) and 255 to receive standard dose radiotherapy (70 Gy). All participants were male and ethnicity data were not collected. At a median follow-up of 9&#xb7;5 years (IQR 8&#xb7;5-10&#xb7;3), 5-year progression-free survival was 91&#xb7;4% (95% CI 87&#xb7;0-94&#xb7;4) in the dose-escalation group versus 88&#xb7;1% (83&#xb7;2-91&#xb7;6) in the control group, and 10-year progression-free survival was 83&#xb7;6% (77&#xb7;8-88&#xb7;0) versus 72&#xb7;2% (65&#xb7;3-78&#xb7;0; stratified HR 0&#xb7;56, 95% CI 0&#xb7;40-0&#xb7;78, p<0&#xb7;0001). Grade 3 or worse adverse events assessed at 6 months (acute toxicity) were observed in 60 (24%) of patients in the dose-escalation group and 62 (25%) in the control group. The most frequent grade 3 or worse adverse events were sexual disorders (28 [11%] in the dose-escalation group vs 20 [8%] in the control group) and bladder or urethra disorders (12 [5%] vs 19 [8%]). Adverse events assessed at 5 years (late toxicity) occurred in 118 (70%) of 168 in the dose-escalation group and 122 (73%) of 168 in the control group; grade 3 or worse late toxicities occurred in 19 (8%) participants in the dose-escalated radiotherapy group versus 17 (7%) participants in the control group. The most common late grade 3 adverse event was bladder or urethra disorders (seven [4%] vs three [2%], respectively). Serious adverse events occurred in nine (4%) patients in the dose escalation group and nine (4%) in the control group; none were considered to be treatment related. There were no treatment-related deaths. INTERPRETATION: For patients with high-risk prostate cancer, radiotherapy at a total dose of 80 Gy, in combination with long-term ADT, improved progression-free survival and could be a potential option in this situation. However, given the low number of events, further research is needed to consolidate and confirm the benefit in dose-escalation in prostate cancer-specific survival and overall survival. FUNDING: French National Cancer Institute and AstraZeneca.

Aged

Robust optimisation for photon radiotherapy: A scoping review of models, paradigms, and reporting.

BACKGROUND AND PURPOSE: Robust optimisation offers an alternative to conventional margin-based photon radiotherapy planning by explicitly modelling uncertainty, but practice is variable and not standardised. MATERIALS AND METHODS: A scoping review was conducted to map robust optimisation for photon external beam radiotherapy. Electronic searches of Scopus, PubMed and Google Scholar (2000-2025, English language) identified planning studies that incorporated modelled uncertainties into the optimisation process and reported at least one robustness-related outcome. Data were charted on clinical context, uncertainty models, optimisation paradigms, robustness metrics and evidence for clinical implementation. RESULTS: Seventy-one studies were included. Most investigated prostate, breast or lung cancer and used intensity-modulated radiotherapy or volumetric-modulated arc therapy in commercial or research treatment planning systems. Scenario-based worst-case (minimax) optimisation was the dominant paradigm in clinically oriented work, while chance-constrained, conditional value at-risk, distributionally robust and adaptive formulations were confined to small methodological series. Uncertainty modelling focused mainly on rigid set-up error; fewer studies incorporated respiratory motion, inter-fraction anatomical change, dose-calculation uncertainty or biological variation. Robustness was evaluated with diverse scenario-based dose-volume metrics, probabilistic coverage measures, composite robustness indices and, less often, biological endpoints. Direct clinical implementation reports were scarce. CONCLUSION: Robust photon planning is technically feasible and generally maintains or improves target coverage and organ sparing compared with margin-based planning. However, heterogeneity in uncertainty models, optimisation configuration and robustness reporting limits comparison and synthesis. Pragmatic minimum standards are proposed to support future consensus and wider clinical adoption.

Humans

Reduced Length of ADT and ARTA With XRT in High-Risk Prostate Cancer (RELAX): A Randomised Controlled Trial.

AIM: To assess the efficacy of a short, intensified regimen of androgen deprivation therapy (ADT) and androgen receptor-targeted agent (ARTA) with curative-intent external beam radiotherapy (XRT) for high-risk prostate cancer (HRPCa) staged with prostate specific membrane antigen (PSMA) imaging. MATERIALS AND METHODS: The RELAX (Reduced Length of ADT and ARTA with XRT in high-risk prostate cancer) trial is a multicentre, phase II randomised non-inferiority trial comparing 9 months of ADT and 6 months of ARTA against the standard 24-month ADT, with definitive dose-escalated hypofractionated pelvic radiotherapy for PSMA-staged non-metastatic HRPCa. The primary endpoint is 5-year disease-free survival (DFS), defined from randomisation to first biochemical or clinico-radiological recurrence or any-cause death. Secondary endpoints include biochemical failure-free survival, metastasis-free survival, overall survival, testosterone recovery, treatment-related adverse effects, and patient-reported outcomes. Participants are monitored with serial serum PSA and testosterone levels, CTCAE and PRO-CTCAE assessments, and PSMA-PETCT at recurrence. The non-inferiority margin is set at 10% absolute difference from an expected 5-year DFS of 85% in the standard arm, with intention-to-treat analysis. The trial is ethics board approved and funded by institutional intramural grant, and registered on clinicaltrials.gov (NCT06818682). RESULTS: The planned accrual of 206 participants commenced in February 2025, with nearly a third of enrolment completed till date. CONCLUSION: The RELAX trial incorporates contemporary standards of PSMA-based staging, dose-escalated hypofractionated radiotherapy, and ARTA for HRPCa. The results are expected to inform the efficacy of a shorter, intensified androgen suppression strategy against the prevailing standard of long-term ADT for these patients.

Humans

Novel insights into retinoblastoma: From oncogenic circuitry to precision diagnosis and eye-preserving therapies.

Retinoblastoma (RB) represents the most common primary intraocular malignancy in childhood and stands as a paradigm for translating molecular oncology into precision clinical management. This review synthesizes the comprehensive evolution in the understanding and treatment of RB. First, we deconstruct the intricate oncogenic circuitry that extends far beyond Knudson's classic "two-hit" RB1 inactivation model, describing non-classical MYCN-driven pathogenesis, multi-layered epigenetic reprogramming (including chromatin, RNA and histone changes), and distinct histological subtypes with defined clinical correlates, such as the favorable-prognosis cavitary RB. Single-cell genomics has elucidated the cellular origin from cone precursor cells and intratumoral heterogeneity. Risk stratification has been refined through well-defined classification systems, from the therapy-guiding International Intraocular Retinoblastoma Classification (IIRC) to the comprehensive American Joint Committee on Cancer Tumor-Node-metastasis (AJCC TNM) staging. Furthermore, the diagnostic paradigm has advanced from conventional anatomical imaging to liquid biopsies, enabling non-invasive molecular staging and monitoring via tumor-derived cell-free DNA analysis. Concurrently, the therapeutic landscape has undergone a radical shift, moving from enucleation and external-beam radiotherapy to an era dominated by local sight-preserving strategies. We provide a critical synthesis of the evidence for intravenous chemotherapy and the transformative role of super-selective intra-arterial chemotherapy (IAC), and describe essential randomized controlled trials, technical innovations, and optimized drug regimens. Finally, we explore emerging targeted molecular therapies and future directions. By integrating cutting-edge molecular insights with robust, high-level clinical evidence, this review offers the framework for achieving patient and eye survival as well as vision preservation in children with Retinoblastoma.

Intra-arterial chemotherapy

Carcinoma of the prostate: local control with external beam radiation therapy.

Local clinical control of the primary disease was evaluated in 209 patients with stage C adenocarcinoma of the prostate treated with definitive external beam radiation therapy and followed for a minimum of 2 years. Of these patients 92 per cent required no further prostatic operations for obstruction. Prostatectomy before therapy did not necessarily prevent later prostatic obstruction from occurring. Of 129 patients who had only a needle biopsy before irradiation 90 per cent had improvement of the obstructive and/or irritative symptoms as tumor regression occurred with therapy and these patients did not require a later prostatic operation for obstruction. Stricture formation occurred in 8 per cent of the patients and was not influenced by the type of preirradiation prostatic operation done. If transurethral resection was reuqired after irradiation it was technically more difficult but the morbidity was acceptable. The incidence of hematuria and incontinence was far less than that reported in non-irradiated patients with this disease. Most tumors exhibited a down-grading effect after irradiation. There were no deaths attributable to the treatment. Over-all, 83 per cent of the 209 patients had no urinary complaints after completion of therapy. From a urological viewpoint, good clinical local control is achieved in the patient with stage C adenocarcinoma of the prostate treated with external beam radiation therapy.

Adenocarcinoma

The ultrastructural changes of prostate adenocarcinoma following external beam radiation therapy.

Ultrastructural studies were done to determine the effects of radiation therapy on prostatic adenocarcinoma. Twenty patients were included in the study: 6 with benign hyperplasia, 4 with untreated adenocarcinoma and 10 with adenocarcinoma who had received radiation therapy. Benign and malignant ultrastructural characteristics were established. On the basis of these characteristics 6 of the 10 radiated prostates were believed to have tumor cells present after therapy. Of the remaining 4 patients 3 had ultrastructural changes suggesting radiation effects and a possibly altered malignant potential.

Adenocarcinoma

External small-field irradiation of cervical carcinoma with linear accelerator.

Since 1966, 125 patients with carcinoma of the uterine cervix were treated with a 6 MV roentgen beam from a linear accelatro. The pelvis was irradiated with 60 Gy followed by 30 to 45 Gy to a small volume using a lateral pendulum. The small-field irradiation was performed using a new beam-directing device consisting of a rod with a central pivot. Favourable results were achieved, despite the fact that most of the patients had advanced carcinoma.

Female

Dose distribution in 42 MV roentgen irradiation of cervical carcinoma.

The dose distribution obtained with two different techniques for external irradiation of cervical carcinoma is described. The dose to the central area is somewhat higher with the multiple beam technique compared with the newly introduced shielding block technique. The difference between the calculated CRE values for the two techniques is small. When the shielding block is not placed over the area corresponding to the position of the applicators from the previous intracavitary treatment the considerable difference in absorbed dose between the two techniques does not correspond to the difference in the calculated CRE values. A comparison of the relative distributions laterally, in total dose and CRE, shows that for central volumes the relative CRE is much higher than the relative dose, when the normalization is made at the pelvic wall.

Absorption

Results of treating stage III carcinoma of the breast by primary radiation therapy.

One hundred sixteen patients with stage III carcinoma of the breast were treated by primary radiation therapy. The 5-year actuarial survival and relapse-free survival were 25% and 22%, respectively. The 5-year actuarial probability of local tumor control for the entire group was 64%. In patients undergoing an excisional biopsy and an interstitial implant of the primary tumor area, local control was 100%. In patients who had either an excisional biopsy or an implant, the 5-year actuarial probability of local control was 77% and 76%, respectively. In contrast, in patients having neither an excisional biopsy nor an implant, local control was only 41%. In patients receiving a total dose of greater than 6000 rad, from external beam treatment or from external beam plus an interstitial implant, the local control was 78% compared to 39% in patients receiving a total dose of less than 6000 rad. Forty-one patients received some form of adjuvant therapy. Both local control and relapse-free survival were improved in patients receiving chemotherapy as the sole adjuvant and in patients receiving chemotherapy combined with an endocrine ablative procedure. However, patients treated with only an endocrine ablative procedure had no improvement in survival nor in local control. These results indicate that primary radiation therapy can provide local control in a high proportion of patients with stage III carcinoma of the breast and suggest that chemotherapy is effective in improving both local control and survival in these patients.

Adult

Limited epithelial carcinoma of the ovary treated with curative intent by the intraperitoneal installation of radiocolloids.

Between January 1960 and September 1972, 104 patients with limited epithelial carcinoma of the ovary received intraperitoneal radiocolloid. Fifty-six of these patients also received external beam radiation therapy to the pelvis (pelvic RT). Five-year actuarial no-evidence-of-disease survival rates were 95% for stage Iai, 82% for Iaii, 73% for Ib, 67% for Ic, 67% for IIa, 67% for IIb without gross residual tumor (GRT), 25% for IIb with GRT, and 50% for III with minimal or no GRT. The addition of pelvic RT following radiocolloid could not be shown to affect survival of patients with Stage I and IIa tumors. Small bowel complications were related to the use of pelvic RT, however, occurring in 2.2% of patients treated with radiocolloid alone and 24% of patients treated with colloid and pelvic RT (p less than 0.005). In patients who underwent abdominal surgery following treatment of ovarian cancer, no excessive complication rate was observed. We conclude that for patients with stages Iaii through IIa, postoperative radiocolloid appears to provide the greatest chance of survival with the least chance of complication. For patients with Stage IIb and III lesions in whom there is minimal or no GRT, radiocolloid followed by pelvic RT produced survival rates comparable or superior to any other form of postoperative therapy.

Adult