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Postoperative pancreatic fistula remains the leading cause of significant morbidity after pancreatoduodenectomy for pancreatic ductal adenocarcinoma. Preoperative chemoradiotherapy has been described to reduce the risk of postoperative pancreatic fistula, but randomized trials on neoadjuvant treatment in pancreatic ductal adenocarcinoma focus increasingly on preoperative chemotherapy rather than preoperative chemoradiotherapy. This study aimed to investigate the impact of preoperative chemotherapy and preoperative chemoradiotherapy on postoperative pancreatic fistula and other pancreatic-specific surgery related complications on a nationwide level. All patients after pancreatoduodenectomy for pancreatic ductal adenocarcinoma were included in the mandatory nationwide prospective Dutch Pancreatic Cancer Audit (2014–2020). Baseline and treatment characteristics were compared between immediate surgery, preoperative chemotherapy, and preoperative chemoradiotherapy. The relationship between preoperative chemotherapy, chemoradiotherapy, and clinically relevant postoperative pancreatic fistula (International Study Group of Pancreatic Surgery grade B/C) was investigated using multivariable logistic regression analyses. Overall, 2,019 patients after pancreatoduodenectomy for pancreatic ductal adenocarcinoma were included, of whom 1,678 underwent immediate surgery (83.1%), 192 (9.5%) received preoperative chemotherapy, and 149 (7.4%) received preoperative chemoradiotherapy. Postoperative pancreatic fistula occurred in 8.3% of patients after immediate surgery, 4.2% after preoperative chemotherapy, and 2.0% after preoperative chemoradiotherapy (P =.004). In multivariable analysis, the use of preoperative chemoradiotherapy was associated with reduced risk of postoperative pancreatic fistula (odds ratio, 0.21; 95% confidence interval, 0.03–0.69; P =.033) compared with immediate surgery, whereas preoperative chemotherapy was not (odds ratio, 0.59; 95% confidence interval, 0.25–1.25; P =.199). Intraoperatively hard, or fibrotic pancreatic texture was most frequently observed after preoperative chemoradiotherapy (53% immediate surgery, 62% preoperative chemotherapy, 77% preoperative chemoradiotherapy, P <.001). This nationwide analysis demonstrated that in patients undergoing pancreatoduodenectomy for pancreatic ductal adenocarcinoma, only preoperative chemoradiotherapy, but not preoperative chemotherapy, was associated with a reduced risk of postoperative pancreatic fistula. [Display omitted] [ABSTRACT FROM AUTHOR]

The necessity of the staging laparoscopy in patients with pancreatic cancer is still debated. The objective of this study was to assess the yield of staging laparoscopy for detecting occult metastases in patients with resectable or borderline resectable pancreatic cancer. This was a post-hoc analysis of the randomized controlled PREOPANC trial in which patients with resectable or borderline resectable pancreatic cancer were randomized between preoperative chemoradiotherapy or immediate surgery. Patients assigned to preoperative treatment underwent a staging laparoscopy prior to preoperative treatment according to protocol, to avoid unnecessary chemoradiotherapy in patients with occult metastatic disease. Of the 246 included patients, 7 did not undergo surgery. A staging laparoscopy was performed in 133 patients (55.6%) and explorative laparotomy in 106 patients (44.4%). At staging laparoscopy, occult metastases were detected in 13 patients (9.8%); 12 liver metastases and 1 peritoneal metastasis. At direct explorative laparotomy, occult metastases were found in 9 patients (8.5%); 6 with liver metastases, 1 with peritoneal metastases, and 2 with metastases at multiple sites. One patient had peritoneal metastases at exploration after a negative staging laparoscopy. Patients with occult metastases were more likely to receive palliative chemotherapy if found with staging laparoscopy compared to laparotomy (76.9% vs. 30.0%, p = 0.040). Staging laparoscopy detected occult metastases in about 10% of patients with resectable or borderline resectable pancreatic cancer. These patients were more likely to receive palliative systemic chemotherapy compared to patients in whom occult metastases were detected with laparotomy. A staging laparoscopy is recommended before planned resection. [ABSTRACT FROM AUTHOR]

Ultrasonography of the diaphragm in the zone of apposition has become increasingly popular to evaluate muscle thickness and thickening fraction. However, measurements in this anatomical location are frequently hindered by factors that constrain physical accessibility or that alter diaphragm position. Therefore, other anatomical positions at the chest wall for transducer placement are used, but the variability in diaphragm thickness across the dome has not been systematically studied. The aim of this study was to evaluate anatomical variation of diaphragm thickness in 46 healthy volunteers on three ventrodorsal lines and two craniocaudal positions on these three lines. The intraclass correlation coefficient (ICC) for diaphragm thickness in the craniocaudal direction on the mid-axillary line was significantly higher than those on the posterior axillary and midclavicular lines, suggesting it had the lowest variability (ICCmidaxillary = .89, 95% confidence interval [CI]: 0.83-0.93, ICCposterior axillary = 0.74, 95% CI: 0.62-0.85, ICCmidclavicular = 0.62, 95% CI: 0.43-0.47, p < 0.05). Average diaphragm thickness was comparable on the posterior axillary and midaxillary lines and substantially larger on the midclavicular line (1.24 mm [1.06-1.47], 1.27 mm [1.10-1.42] and 2.32 [1.97-2.70], p < 0.01). We conclude that the normal diaphragm has a large variability in thickness, especially in the ventrodorsal direction. Variability in craniocaudal position is the lowest at the midaxillary line, which therefore appears to be the preferred site for diaphragm thickness measurement. [ABSTRACT FROM AUTHOR]

Hematopoietic recovery between cycles of chemotherapy is critical for treatment continuation and outcome. Hematopoietic recovery is frequently defined based on neutrophil and platelet counts. Although this is clinically meaningful, we are intrigued by the possibility that 'hidden' incomplete recovery of other lineages and uncommitted progenitors after chemotherapy may have significant consequences. To this end, we exposed young adult mice to three rounds of chemotherapy (Fluorouracil, Cytarabine or Doxorubicin), at 21-day intervals to allow full quantitative hematopoietic recovery between cycles and prior to endpoint analyses (Sigurdsson, Blood adv., 2020). Despite rapid and complete recovery of total nucleated cell counts and platelets, we observed striking and persistent differences in hematopoiesis in chemotherapy-exposed mice. These included myeloid bias, anaemia and thrombocytosis, strongly resembling natural ageing. Having previously shown that HSC ageing coincides with decreased mitochondrial activity (Mansell, Cell Stem Cell, 2021), we herein kinetically modelled the metabolic response of HSCs to chemotherapy. Strikingly, we found a lack of metabolic recovery specific to HSCs in terms of mitochondrial content and mitochondrial membrane potential (ΔΨm). This metabolically deflated state coincides with decreased function upon competitive transplantation, evident by reduced and myeloid-biased engraftment. To test whether the lack of mitochondrial recovery is causative of this HSC dysfunction, we pharmacologically targeted mitochondria using mitoquinol (Mito-Q). Strategic Mito-Q treatments did indeed result in accelerated bone marrow recovery and rescued B-lymphopoiesis upon transplantation. We conclude that chemotherapy exposure induces premature hematopoietic ageing that is relevant and may be rescued through strategic use of mitochondrial-targeted treatments. [ABSTRACT FROM AUTHOR]

Whereas neoadjuvant chemo(radio)therapy is increasingly used in pancreatic cancer, it is currently not recommended for other periampullary (non-pancreatic) cancers. This has important implications for the relevance of the preoperative diagnosis for pancreatoduodenectomy. This retrospective multicentre cohort study aimed to determine the frequency of clinically relevant misdiagnoses in patients undergoing pancreatoduodenectomy for pancreatic or other periampullary cancer. Data from all consecutive patients who underwent a pancreatoduodenectomy between 2014 and 2018 were obtained from the prospective Dutch Pancreatic Cancer Audit. The preoperative diagnosis as concluded by the multidisciplinary team (MDT) meeting was compared with the final postoperative diagnosis at pathology to determine the rate of clinically relevant misdiagnosis (defined as missed pancreatic cancer or incorrect diagnosis of pancreatic cancer). In total, 1244 patients underwent pancreatoduodenectomy of whom 203 (16%) had a clinically relevant misdiagnosis preoperatively. Of all patients with a final diagnosis of pancreatic cancer, 13% (87/679) were preoperatively misdiagnosed as distal cholangiocarcinoma (n = 41, 6.0%), ampullary cancer (n = 27, 4.0%) duodenal cancer (n = 16, 2.4%), or other (n = 3, 0.4%). Of all patients with a final diagnosis of periampullary (non-pancreatic) cancer, 21% (116/565) were preoperatively incorrectly diagnosed as pancreatic cancer. Accuracy of preoperative diagnosis was 84% for pancreatic cancer, 71% for distal cholangiocarcinoma, 73% for ampullary cancer and 73% for duodenal cancer. A prediction model for the preoperative likelihood of pancreatic cancer (versus other periampullary cancer) prior to pancreatoduodenectomy demonstrated an AUC of 0.88. This retrospective multicentre cohort study showed that 16% of patients have a clinically relevant misdiagnosis that could result in either missing the opportunity of neoadjuvant chemotherapy in patients with pancreatic cancer or inappropriate administration of neoadjuvant chemotherapy in patients with non-pancreatic periampullary cancer. A preoperative prediction model is available on www.pancreascalculator.com. [ABSTRACT FROM AUTHOR]

Background: In the Emergency Department, lactate measurement is a useful tool to risk-stratify critically ill patients. However, it is unclear whether arterial or peripheral venous lactate levels can be used interchangeably for this purpose. In this systematic review, we provide an overview of studies investigating the agreement between arterial and peripheral venous lactate levels in the Emergency Department.Methods: PubMed, Embase, the Cochrane Central Register of Controlled Trials/Wiley, Web of Science/Clarivate Analytics, and references of selected articles were assessed for all studies comparing arterial and peripheral venous lactate levels in adult patients in the emergency department. Two reviewers independently screened all potentially relevant titles and abstracts for eligibility using a standardized data-worksheet.Results: Nine studies were included. Peripheral venous lactate levels tend to be higher than arterial lactate levels with mean differences ranging from 0.18 mmol/l to 1.06 mmol/l. Importantly, poorer agreement occurs in hyperlactatemia. At a cut-of level of 1.6 mmol/l, peripheral venous lactate can rule out arterial hyperlactatemia with a sensitivity between 94% and 100%. At a cut off value of 2 mmol/l, sensitivities of 97% and 100% were found.Conclusion: Agreement between arterial and peripheral venous lactate is poor in hyperlactatemia, making peripheral venous lactate an unreliable parameter to use interchangeably in the ED. In clinical practice, peripheral venous lactate can be used as a screening tool to rule out arterial hyperlactatemia at a cut-off value of 2 mmol/l. However, hyperlactatemia should be confirmed using arterial sampling in case of a peripheral venous lactate level > 2 mmol/l. [ABSTRACT FROM AUTHOR]

Objective Overt hypothyroidism confers an increased risk of non-alcoholic fatty liver disease (NAFLD). The liver plays a crucial role in the metabolism of cholesterol and triglycerides; thyroid hormones interact on hepatic lipid homeostasis. Thyroid function within the euthyroid range affects a number of health issues, including atherosclerosis development and biochemical markers of increased cardiovascular risk. However, the association of thyroid hormones with NAFLD in euthyroid subjects has not been unequivocally established. We therefore determined associations of thyroid hormone parameters with NAFLD among euthyroid subjects. Methods The study was conducted in the Lifelines Cohort Study, a population-based cohort study of participants living in the North of the Netherlands. Only euthyroid subjects (thyroid-stimulating hormone (TSH) 0.5–4.0 mU/L, free thyroxine (FT4) 11–19.5 pmol/L and free triiodothyronine (FT3) 4.4–6.7 pmol/L) older than 18 years were included. Exclusion criteria were participants with excessive alcohol use, known hepatitis or cirrhosis, liver functions ≥ three times the upper limit, current cancer, non-white ancestry, previous or current use of thyroid medication and current use of lipid or glucose lowering medication. A priori defined liver biochemistry, thyroid function parameters and metabolic syndrome (MetS) were studied. NAFLD was defined by using the validated Fatty Liver Index (FLI); FLI ≥ 60 was categorized as NAFLD. A P < 0.01 was considered significant. Results FLI ≥ 60 was found in 4274 (21.1%) of 20,289 individuals (62.1% male, median age 46 years) with increased prevalence of MetS ( P < 0.0001). In age- and sex-adjusted analysis FLI ≥ 60 was independently associated with a higher FT3 (OR 1.34, 95% CI 1.29–1.39, per SD increment, P < 0.0001) and a lower FT4 (OR 0.73, 95% CI 0.70–0.75, P < 0.0001) but not by TSH. The strongest association was found for the FT3/FT4 ratio (OR 1.44, 95% CI 1.39–1.49, P < 0.0001). These associations remained similar after additional adjustment for the presence of MetS. In subjects with enlarged waist circumference, TSH and FT4 were lower while FT3 was higher, resulting in an increased FT3/FT4 ratio ( P < 0.0001). Conclusions Euthyroid subjects with suspected NAFLD are characterized by higher FT3, lower FT4 and higher FT3/FT4 ratio, probably consequent to central obesity. [ABSTRACT FROM AUTHOR]

Purpose Patients with breast cancer may develop dental problems due to treatment. We examined the prevalence of their dental care use and needs, compared the prevalence of use with that of the general population, and examined which factors predict patients' dental care use. Methods Patients with primary breast cancer completed a questionnaire at 6 and 15 months post-diagnosis. Medical data were retrieved from medical records. The prevalence of dental care use and needs was examined with descriptive analyses. Associations between predictors and dental care use were examined with multivariate analyses. Results Twenty-one percent of 746 participants visited their dentist at least once in the past three months at 6 months, and 23% at 15 months post-diagnosis. The estimated percentage of women with at least one contact with their dentist in 12 months was low compared to the general female population (31.9% versus 79.5%). One to two percent of the respondents wanted more contact. Having dental care insurance (odds ratio 1.80; 95% CI, 1.08–3.00), chemotherapy (odds ratio 1.93; 95% CI, 1.21–3.06), and clinical distress 6 months post-diagnosis (odds ratio 2.53; 95% CI, 1.70–3.79) predicted use of dental care 9 months later. Conclusions Up to 15 months post-diagnosis, breast cancer patients' dental care use is lower than warranted. Oncologists and cancer nurses are recommended to inform patients about dental risks, and to encourage them – particularly those without insurance – to visit their dentist. Occurrence of dental problems should be monitored, especially in patients who receive chemotherapy or who are clinically distressed. [ABSTRACT FROM AUTHOR]

Objectives Low-normal thyroid function within the euthyroid range may influence plasma lipoprotein levels. Associations between variation in thyroid function and pre-β-high density lipoproteins (pre-β-HDL), i.e. lipid-poor or lipid free HDL particles that act as initial acceptor of cell-derived cholesterol, are unknown. We determined relationships of plasma pre-β-HDL with thyroid function in euthyroid subjects with and without type 2 diabetes mellitus (T2DM). Design and Subjects TSH, free T4, plasma (apo)lipoproteins, pre-β-HDL, pre-β-HDL formation (pre-β-HDL generation during incubation with lecithin:cholesterol acyltransferase being inhibited) and phospholipid transfer protein (PLTP) activity were measured in fasting plasma from 72 T2DM and 82 non-diabetic subjects. Results TSH was similar and free T4 was slightly higher ( P < 0.05) in T2DM vs. non-diabetic subjects. HDL cholesterol and apoA-I were lower, whereas pre-β-HDL (expressed as % of apoA-I), triglycerides and PLTP activity were higher in T2DM ( P < 0.05 to P < 0.001). In T2DM, pre-β-HDL formation (in apoA-I concentration and in % of apoA-I) was positively related to free T4, PLTP activity, total cholesterol and triglycerides ( P < 0.05 for each). Multivariable linear regression analyses, adjusted for age, sex, PLTP activity, total cholesterol and triglycerides, demonstrated that pre-β-HDL formation was positively related to free T4 (in apoA-I concentration: β = 0.278, P = 0.014; in % of apoA-I: β = 0.343, P = 0.003) in T2DM, but not in non-diabetic subjects (both P > 0.30; interaction terms: both P < 0.05). Conclusions Variations in thyroid function within the euthyroid range may influence the metabolism of pre-β-HDL in T2DM. [ABSTRACT FROM AUTHOR]

Objectives Low-normal thyroid function may relate to increases in plasma cholesterol and triglycerides, but effects on lipoprotein subfractions are largely unknown. Associations of alterations in lipoprotein metabolism and functionality with low-normal thyroid function could be more pronounced in Type 2 diabetes mellitus (T2DM). We determined relationships of plasma lipids and lipoprotein subfractions with thyroid-stimulating hormone (TSH) and free thyroxine (free T 4 ) in euthyroid subjects, and assessed whether such relationships are modified in the context of T2DM. Design and methods TSH, free T 4 , (apo)lipoproteins and lipoprotein subfractions (nuclear magnetic resonance spectroscopy) were measured after an overnight fast in 61 T2DM subjects and 52 non-diabetic subjects. Results TSH and free T 4 were similar in T2DM and non-diabetic subjects. Plasma triglycerides, large very low density (VLDL) particles, VLDL size and small low density lipoprotein (LDL) particles were increased, whereas high density lipoprotein (HDL) cholesterol was decreased in T2DM subjects ( p ≤ 0.05 for each). Age-, sex-, and diabetes status-adjusted multivariable linear regression analysis demonstrated that plasma triglycerides were associated positively with TSH (β = 0.196, p = 0.039). Large VLDL particles (β = − 0.215, p = 0.020) and VLDL size were inversely associated with free T 4 (β = − 0.285, p < 0.001). These relationships were not significantly modified by diabetes status (interaction terms: p > 0.10 for each). In all subjects combined, LDL and HDL subfraction characteristics were not significantly related to thyroid function status. Conclusions Low-normal thyroid function may confer increased plasma triglycerides, large VLDL particles and increased VLDL particle size. These relationships are not to a major extent modified in the context of T2DM. [ABSTRACT FROM AUTHOR]

Summary Background If treatment of the axilla is indicated in patients with breast cancer who have a positive sentinel node, axillary lymph node dissection is the present standard. Although axillary lymph node dissection provides excellent regional control, it is associated with harmful side-effects. We aimed to assess whether axillary radiotherapy provides comparable regional control with fewer side-effects. Methods Patients with T1–2 primary breast cancer and no palpable lymphadenopathy were enrolled in the randomised, multicentre, open-label, phase 3 non-inferiority EORTC 10981-22023 AMAROS trial. Patients were randomly assigned (1:1) by a computer-generated allocation schedule to receive either axillary lymph node dissection or axillary radiotherapy in case of a positive sentinel node, stratified by institution. The primary endpoint was non-inferiority of 5-year axillary recurrence, considered to be not more than 4% for the axillary radiotherapy group compared with an expected 2% in the axillary lymph node dissection group. Analyses were by intention to treat and per protocol. The AMAROS trial is registered with ClinicalTrials.gov , number NCT00014612 . Findings Between Feb 19, 2001, and April 29, 2010, 4823 patients were enrolled at 34 centres from nine European countries, of whom 4806 were eligible for randomisation. 2402 patients were randomly assigned to receive axillary lymph node dissection and 2404 to receive axillary radiotherapy. Of the 1425 patients with a positive sentinel node, 744 had been randomly assigned to axillary lymph node dissection and 681 to axillary radiotherapy; these patients constituted the intention-to-treat population. Median follow-up was 6·1 years (IQR 4·1–8·0) for the patients with positive sentinel lymph nodes. In the axillary lymph node dissection group, 220 (33%) of 672 patients who underwent axillary lymph node dissection had additional positive nodes. Axillary recurrence occurred in four of 744 patients in the axillary lymph node dissection group and seven of 681 in the axillary radiotherapy group. 5-year axillary recurrence was 0·43% (95% CI 0·00–0·92) after axillary lymph node dissection versus 1·19% (0·31–2·08) after axillary radiotherapy. The planned non-inferiority test was underpowered because of the low number of events. The one-sided 95% CI for the underpowered non-inferiority test on the hazard ratio was 0·00–5·27, with a non-inferiority margin of 2. Lymphoedema in the ipsilateral arm was noted significantly more often after axillary lymph node dissection than after axillary radiotherapy at 1 year, 3 years, and 5 years. Interpretation Axillary lymph node dissection and axillary radiotherapy after a positive sentinel node provide excellent and comparable axillary control for patients with T1–2 primary breast cancer and no palpable lymphadenopathy. Axillary radiotherapy results in significantly less morbidity. Funding EORTC Charitable Trust. [ABSTRACT FROM AUTHOR]

The EORTC Breast Cancer Group (BCG), created in 1962, is a multidisciplinary group involving surgeons, medical oncologists, radiation oncologists, pathologists, basic scientists, and clinical research fellows. Currently, more than 80 member's institutions across Europe are participating in the group studies. The main goal of the BCG is to conduct high-quality international clinical trials covering all areas of breast cancer care: from loco-regional to systemic disease control, and from in situ carcinoma to metastatic disease. Over 50 years, the BCG has performed dozens of clinical studies including several thousands of patients. Many practice-changing trials and major achievements were conducted optimizing local control, improving systemic therapy in early and metastatic breast cancer, pioneering work in clinical-translational trials and collaboration within intergroup trials. The strategic plan of the BCG for future research includes three distinct albeit overlapping areas: loco-regional therapy, (neo-)adjuvant systemic therapy, trials in the metastatic setting, and niche population studies. For each of these areas the group has considered the prevailing EORTC strategy of focusing on practice-changing studies and translational research, with an emphasis on niche trials. During five decades, the BCG has successfully performed a series of practice-changing trials enrolling several thousands of patients. These studies have contributed to the clinical knowledge on the treatment of breast cancer and have influenced clinical practice and breast cancer patients' outcome worldwide. [ABSTRACT FROM AUTHOR]

Abstract: The EORTC Breast Cancer Group (BCG), created in 1962, is a multidisciplinary group involving surgeons, medical oncologists, radiation oncologists, pathologists, basic scientists, and clinical research fellows. Currently, more than 80 member''s institutions across Europe are participating in the group studies. The main goal of the BCG is to conduct high-quality international clinical trials covering all areas of breast cancer care: from loco-regional to systemic disease control, and from in situ carcinoma to metastatic disease. Over 50 years, the BCG has performed dozens of clinical studies including several thousands of patients. Many practice-changing trials and major achievements were conducted optimizing local control, improving systemic therapy in early and metastatic breast cancer, pioneering work in clinical-translational trials and collaboration within intergroup trials. The strategic plan of the BCG for future research includes three distinct albeit overlapping areas: loco-regional therapy, (neo-)adjuvant systemic therapy, trials in the metastatic setting, and niche population studies. For each of these areas the group has considered the prevailing EORTC strategy of focusing on practice-changing studies and translational research, with an emphasis on niche trials. During five decades, the BCG has successfully performed a series of practice-changing trials enrolling several thousands of patients. These studies have contributed to the clinical knowledge on the treatment of breast cancer and have influenced clinical practice and breast cancer patients'' outcome worldwide. [Copyright &y& Elsevier]

Abstract: Background: Effective diagnosis and treatment of patients with hilar cholangiocarcinoma (HCCA) is based on the synergy of endoscopists, interventional radiologists, radiotherapists and surgeons. This report summarizes the multidisciplinary experience in management of HCCA over a period of two decades at the Academic Medical Center in Amsterdam, with emphasis on surgical outcome. Methods: From 1988 until 2003, 117 consecutive patients underwent resection on the suspicion of HCCA. Preoperative work-up included staging laparoscopy, preoperative biliary drainage, assessment of volume/function of future remnant liver and radiation therapy to prevent seeding metastases. More aggressive surgical approach combining hilar resection with extended liver resection was applied as of 1998. Outcomes of resection including actuarial 5-year survival were assessed. Results: Eighteen patients (15.3%) appeared to have a benign lesion on microscopical examination of the specimen, leaving 99 patients with histologically proven HCCA. These 99 patients were analysed according to three 5-year time periods of resection, i.e. period 1 (1988–1993, n =45), 2 (1993–1998, n =25) and 3 (1998–2003, n =29). The rate of R0 resections increased and actuarial five-year survival significantly improved from 20±5% for the periods 1 and 2, to 33±9% in period 3 (p <0.05). Postoperative morbidity and mortality in the last period were 68% and 10%, respectively. Conclusion: Extended surgical resection resulted in increased rate of R0 resections and significantly improved survival. Candidates for resection should be considered by a specialized, multidisciplinary team. [Copyright &y& Elsevier]

Summary: Background: We did a randomised phase 3 trial assessing the benefit of addition of long-term androgen suppression with a luteinising-hormone-releasing hormone (LHRH) agonist to external irradiation in patients with prostate cancer with high metastatic risk. In this report, we present the 10-year results. Methods: For this open-label randomised trial, eligible patients were younger than 80 years and had newly diagnosed histologically proven T1–2 prostatic adenocarcinoma with WHO histological grade 3 or T3–4 prostatic adenocarcinoma of any histological grade, and a WHO performance status of 0–2. Patients were randomly assigned (1:1) to receive radiotherapy alone or radiotherapy plus immediate androgen suppression. Treatment allocation was open label and used a minimisation algorithm with institution, clinical stage of the disease, results of pelvic-lymph-node dissection, and irradiation fields extension as minimisation factors. Patients were irradiated externally, once a day, 5 days a week, for 7 weeks to a total dose of 50 Gy to the whole pelvis, with an additional 20 Gy to the prostate and seminal vesicles. The LHRH agonist, goserelin acetate (3·6 mg subcutaneously every 4 weeks), was started on the first day of irradiation and continued for 3 years; cyproterone acetate (50 mg orally three times a day) was given for 1 month starting a week before the first goserelin injection. The primary endpoint was clinical disease-free survival. Analysis was by intention to treat. The trial is registered at ClinicalTrials.gov, number NCT00849082. Findings: Between May 22, 1987, and Oct 31, 1995, 415 patients were randomly assigned to treatment groups and were included in the analysis (208 radiotherapy alone, 207 combined treatment). Median follow-up was 9·1 years (IQR 5·1–12·6). 10-year clinical disease-free survival was 22·7% (95% CI 16·3–29·7) in the radiotherapy-alone group and 47·7% (39·0–56·0) in the combined treatment group (hazard ratio [HR] 0·42, 95% CI 0·33–0·55, p<0·0001). 10-year overall survival was 39·8% (95% CI 31·9–47·5) in patients receiving radiotherapy alone and 58·1% (49·2–66·0) in those allocated combined treatment (HR 0·60, 95% CI 0·45–0·80, p=0·0004), and 10-year prostate-cancer mortality was 30·4% (95% CI 23·2–37·5) and 10·3% (5·1–15·4), respectively (HR 0·38, 95% CI 0·24–0·60, p<0·0001). No significant difference in cardiovascular mortality was noted between treatment groups both in patients who had cardiovascular problems at study entry (eight of 53 patients in the combined treatment group had a cardiovascular-related cause of death vs 11 of 63 in the radiotherapy group; p=0·60) and in those who did not (14 of 154 vs six of 145; p=0·25). Two fractures were reported in patients allocated combined treatment. Interpretation: In patients with prostate cancer with high metastatic risk, immediate androgen suppression with an LHRH agonist given during and for 3 years after external irradiation improves 10-year disease-free and overall survival without increasing late cardiovascular toxicity. Funding: AstraZeneca; Ligue Nationale Contre le Cancer (France), through the EORTC Charitable Trust. [Copyright &y& Elsevier]