Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial.

BACKGROUND: STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. METHODS: We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. RESULTS: Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69-0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). CONCLUSIONS: The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden.

Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC + AAP versus SOC + DocP. Method: Recruitment to SOC + DocP and SOC + AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC + AAP, and HR > 1 favours SOC + DocP. Results: A total of 566 consenting patients were contemporaneously randomised: 189 SOC + DocP and 377 SOC + AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1.16 (95% CI 0.82-1.65); failure-free survival HR = 0.51 (95% CI 0.39-0.67); progression-free survival HR = 0.65 (95% CI 0.48-0.88); metastasis-free survival HR = 0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR = 1.02 (0.70-1.49); and symptomatic skeletal events HR = 0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC + DocP, and 40%, 7% and 1% SOC + AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.

Safety and efficacy of low doses of diclofenac on acute pain in the emergency setting.

Diclofenac is the most widely prescribed non-steroidal anti-inflammatory drug worldwide. Data collected during the last 10 years reported a dose-duration dependent increasing of cardiovascular risk associated with the use of diclofenac, supporting the evidence of a close association with the degree of COX-2 inhibition achieved in vivo. Nevertheless, the amplitude of cardiovascular risk associated with the administration of diclofenac at low doses and for the short-term duration is still poorly defined. Indeed, data did not show a clear and strong increasing of the risk for daily doses of 75 and of 50 mg. Concerning duration, while the identification of a safe temporal window is less defined, some studies reported an absence or a very low risk when the exposure is shorter than 30 days. Today, new low-dosage diclofenac formulations are available, allowing to reduce the systemic exposure, the degree of COX-2 inhibition and possibly the risk of occurrence of cardiovascular events. This is the reason why those new formulations may represent the ideal drug for the management of pain in the emergency setting.

Diagnostic and therapeutic approach to acute pulmonary embolism in an emergency department.

Pulmonary embolism (PE) is the obstruction of the pulmonary arteries by the dislodging and embolization of thrombotic material coming in most cases from the deep veins of the leg. PE is a relatively common disease with an estimated annual incidence up to 37 cases diagnosed per 100,000 persons it is the third cause of death in the United States. Clinical signs and symptoms are non specific and in the 70% of cases there isn't a correct diagnosis. The aim of this review is to summarize the state of the art of the diagnostic and treatment algorithms of PE in the evidence based medicine in order to minimize the "clinician gestalt" by the only guide for the early diagnosis and treatment of the disease. A correct diagnosis based on pre test probability, the use of computed tomographic pulmonary angiography, early anticoagulation/fibrinolysis started in the Emergency Department can change the natural history of the disease. In perspective, a combined approach of localyzed fibrinolysis and mechanical fragmentation could improve the overall outcome of these patients.

[Sublingually administered captopril versus nifedipine in hypertension emergencies]. / Captopril versus nifedipina somministrati per via sublinguale nelle emergenze ipertensive.

Aim of the study was to assess the effectiveness and tolerability of sublingual captopril (SLC) versus sublingual nifedipine (SLN) in treating hypertensive emergencies. During hypertensive crises (systolic blood pressure exceeding 200 mmHg and diastolic blood pressure exceeding 115 mmHg) forty hypertensive patients received either 25 mg of SLC or 10 mg of SLN in a randomized single blind fashion. Blood pressure and heart rate were then controlled after 5, 10, 15, 20, 30, 45, 60, 120 min. and, in 18 cases, up to the 8th hour from the administration. Our results showed: 1) a satisfactory control of the hypertensive crises in 80% of patients treated with SLC with a significant blood pressure reduction after 10 min. (13/8 mmHg, p less than 0.02), while the maximum hypotensive effect was achieved after 30 min. (52/36 mmHg, p less than 0.001); SLN was able to reduce blood pressure in 90% of all the cases, with a significant reduction after 5 min. (15/11 mmHg, p less than 0.02) and hypotensive peak after 20 min (57/38 mmHg, p greater than 0.001); 2) no significant differences for hypotensive effectiveness between the two groups, but with SLC having a mildly delayed onset of action when compared to SLN; 3) antihypertensive effect lasting for about 6 hours in patients treated with SLC and blood pressure progressively raising after 4 hours in patients who received SLN; 4) a significant correlation between blood pressure reduction and blood pressure before drug administration in both groups; a significant correlation between pretreatment PRA and antihypertensive effect in the SLC group. We conclude that both drugs are effective and useful in treating hypertensive emergencies. Anyway we think that in severe forms SLN should be preferred for the shorter time preceding onset of action.

[The relationship between high-density lipoproteins, thromboxane B2 and arteriosclerosis in a case of primary hypoalphalipoproteinemia]. / Rapporto tra lipoproteine ad alta densità, trombossano B2 ed arteriosclerosi in un caso di ipoalfalipoproteinemia primitiva.

Data in the literature suggest that cases of hypoalphalipoproteinemia involve an increase in thromboxane B2 (TXB2) together with an increased risk of atherosclerosis. A recent detailed examination of a 32-year-old man revealed clinical and biochemical features strongly indicative of that pathology. The case presented several unusual features: marked infiltration of the skin and mesenteric lymph nodes by histiocytic lipids with sufficient hyperplasia to induce acute intestinal occlusion combined with an in vivo TXB2 generation curve, subsequently inhibited by aspirin, that was comparable to the curves of the control subjects. Furthermore there were no signs of early atherosclerotic damage so that it was possible to postulate the hypothesis that despite the 50% drop in alpha-lipoprotein levels, they were still sufficient to ensure normal turnover of the other lipoproteins so that, however complex the clinical condition, it was an incomplete expression of a phenotype.

[Usefulness of sublingual captopril in hypertensive emergencies. Preliminary results]. / Utilità del captopril sublinguale nelle emergenze ipertensive. Risultati preliminari.

The aim of this study, whose preliminary findings are reported, is to evaluate the efficacy of captopril, administered by a sublingual route, in the treatment of hypertensive emergencies. Captopril has been given by this route to 20 hypertensive patients while these had an ongoing hypertensive crisis (defined as a systolic arterial pressure above 200 mmHg associated with a diastolic arterial pressure above 115 mmHg). Arterial pressure has been measured after 5, 20, 10, 15, 30, 45, 60 and 120 min. For 8 patients it has been measured until the eighth hour. Results were the following: a satisfactory control of hypertensive crisis in 85% of patients, as stated by a slight but significant drop of arterial pressure after 10 min (15/10 mmHg; p less than 0.05) and by a maximum antihypertensive effect after 30 min (57/39 mmHg; p less than 0.001); an antihypertensive effect was evident until 6 hours after the administration of the drug; a positive correlation between the antihypertensive effect and pretreatment levels of arterial pressure and plasma renin activity; drug was free from relevant side effects; sublingual captopril can be considered an efficacious, easy to use and valuable tool in the treatment of hypertensive emergencies.