High-dose radiotherapy and risk-adapted androgen deprivation in localised prostate cancer (DART 01/05): 10-year results of a phase 3 randomised, controlled trial.

BACKGROUND: The optimal duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains controversial. The DART 01/05 trial was designed to determine whether long-term androgen deprivation is superior to short-term androgen deprivation when combined with high-dose radiotherapy. The 5-year results showed that 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy significantly improved biochemical control, metastasis, and overall survival, especially in patients with high-risk disease. In this report, we present the 10-year final results of the trial. METHODS: This open-label, phase 3, randomised, controlled trial was done in ten hospitals in Spain. The eligibility criteria included patients aged 18 years or older with histologically confirmed T1c to T3, N0, and M0 adenocarcinoma of the prostate, according to the 2002 classification of the American Joint Committee on Cancer, with intermediate-risk and high-risk factors, prostate-specific antigen (PSA) less than 100 ng/mL, and a Karnofsky performance score of at least 70%. Patients were randomly assigned (1:1) to receive 4 months of neoadjuvant and concomitant short-term androgen deprivation (STAD) plus high-dose radiotherapy (minimum dose 76 Gy; median dose 78 Gy) or to receive the same treatment followed by 24 months of adjuvant long-term androgen deprivation (LTAD), via a randomisation scheduled generated by Statistical Analysis Software programme (version 9.1) and an interactive web response system. Patients assigned to the STAD group received 4 months of neoadjuvant and concomitant androgen deprivation (oral flutamide 750 mg per day or oral bicalutamide 50 mg per day) with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy was added during the first 2 months of treatment. Patients assigned to LTAD continued with goserelin every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival at 5 years. For this 10-year study we analysed overall survival, metastasis-free survival, biochemical disease-free survival, and cause-specific survival. Analysis was by intention to treat. This trial is closed and is registered at ClinicalTrials.gov (NCT02175212) and in the EU Clinical Trials Register (EudraCT 2005-000417-36). FINDINGS: Between Nov 7, 2005, and Dec 20, 2010, 355 patients were enrolled. One patient in the STAD group withdrew from the trial, hence 354 participants were randomly assigned to STAD (n=177) or LTAD (n=177). The median follow-up was 119·4 months (IQR 100·6-124·3). The 10-year biochemical disease-free survival for LTAD was 70·2% (95% CI 63·1-77·3) and for STAD was 62·3% (54·9-69·7; hazard ratio [HR] 0·84; 95% CI 0·50-1·43; p=0·52). At 10 years, overall survival was 78·4% (72·1-84·8) for LTAD and 73·3% (66·6-80·0) for STAD (HR 0·84; 95% CI 0·55-1·27; p=0·40), and metastasis-free survival was 76·0% (69·4-82·7) for LTAD and 70·9% (64·0-77·8) for STAD (HR 0·90; 95% CI, 0·37-2·19; p=0·81). For the subgroup of high-risk patients, the 10-year biochemical disease-free survival was 67·2% (57·2-77·2) for LTAD and 53·7% (43·3-64·1) for STAD (HR 0·90; 95% CI 0·49-1·64; p=0·73), the 10-year overall survival was 78·5% (69·6-87·3) for LTAD and 67·0% (57·3-76·7) for STAD (HR 0·58; 95% CI 0·33-1·01; p=0·054), and the 10-year metastasis-free survival was 76·6% (95% CI 67·6-85·6) for LTAD and 65·0% (55·1-74·8) for STAD (HR 0·89; 95% CI 0·33-2·43; p=0·82). Only 11 (3%) of 354 patients died from prostate cancer, all of them in the high-risk subgroup (five in the LTAD group and six in the STAD group). 76 (21%) patients died from other causes (mainly second malignancies in 31 [9%] and cardiovascular disease in 21 [6%]). No treatment-related deaths were observed. INTERPRETATION: After an extended 10-year follow-up, we were unable to support the significant benefit of LTAD reported at 5 years. However, the magnitude of the benefit was clinically relevant in high-risk patients. Intermediate-risk patients treated with high-dose radiotherapy do not benefit from LTAD. A biological characterisation with the inclusion of genomic testing is needed in the decision-making process. FUNDING: Grupo de Investigación en Oncología Radioterápica and Sociedad Española de Oncología Radioterápica, the National Health Investigation Fund, and AstraZeneca.

A Pilot, Phase II, Randomized, Open-Label Clinical Trial Comparing the Neurotoxicity of Three Dose Regimens of Nab-Paclitaxel to That of Solvent-Based Paclitaxel as the First-Line Treatment for Patients with Human Epidermal Growth Factor Receptor Type 2-Negative Metastatic Breast Cancer.

BACKGROUND: This study aimed to characterize the neurotoxicity of three different regimens of nab-paclitaxel compared with a standard regimen of solvent-based (sb) paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer based on the Total Neurotoxicity Score (TNS), a tool specifically developed to assess chemotherapy-induced neurotoxicity. MATERIALS AND METHODS: This was a randomized, open-label study testing 4-week cycles of 80 mg/m2 sb-paclitaxel (PACL80/w) on days 1, 8, and 15; 100 mg/m2 nab-paclitaxel on days 1, 8, and 15 (NAB100/w); 150 mg/m2 nab-paclitaxel on days 1, 8, and 15 (NAB150/w); and 150 mg/m2 nab-paclitaxel on days 1 and 15 (NAB150/2w). In addition to the TNS, neuropathy was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). Tumor response and quality of life were also evaluated. RESULTS: Neurotoxicity, as evaluated by the TNS, did not significantly differ between the sb-paclitaxel group and any of the nab-paclitaxel groups. The frequency of (any grade) polyneuropathy, as measured by the NCI-CTCAE, was lower in the PACL80/w (n = 7, 50%) and NAB150/2w (n = 10, 62.5%) groups than in the NAB100/w (n = 13, 81.3%) or NAB150/w (n = 11, 78.6%) group. Although the differences were not statistically significant, compared with the other groups, in the NAB150/w group, the time to occurrence of grade ≥2 polyneuropathy was shorter, and the median time to recovery from grade ≥2 polyneuropathy was longer. Dose delays and reductions due to neurotoxicity and impact of neurotoxicity on the patients' experience of symptoms and functional limitations was greater with NAB150/w. Among the seven polymorphisms selected for genotyping, the variant alleles of EPHA5-rs7349683, EPHA6-rs301927, and EPHA8-rs209709 were associated with an increased risk of paclitaxel-induced neuropathy. CONCLUSION: The results of this exploratory study showed that, regardless of the dose, nab-paclitaxel did not differ from sb-paclitaxel in terms of neurotoxicity as evaluated with the TNS. However, results from NCI-CTCAE, dose delays and reductions, and functional tools consistently indicate that NAB150/w regimen is associated with a greater risk of chemotherapy-induced neuropathy. Thus, our results question the superiority of the TNS over NCI-CTCAE for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and potentially supported by pharmacogenetic analysis. Registry: EudraCT, 2012-002361-36; NCT01763710 IMPLICATIONS FOR PRACTICE: The results of this study call into question the superiority of the Total Neurotoxicity Score over the National Cancer Institute Common Terminology Criteria for Adverse Events for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context and suggest that a regimen of 150 mg/m2 nab-paclitaxel administered on days 1, 8, and 15 is associated with a greater risk of chemotherapy-induced neuropathy and hematological toxicity compared with other lower-dose nab-paclitaxel regimens or a standard regimen of solvent-based paclitaxel. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and could benefit from pharmacogenetics analysis.

Antireflux ureteral stent proof of concept assessment after minimally invasive treatment of obstructive uropathy in animal model.

OBJECTIVES: To assess the efficacy of a new anti-reflux intraureteral stent design in a swine model after minimally invasive treatment of ureteral stricture to reduce ureteral stent morbidity, previous to manufacture this design in a biodegradable fashion. METHODS: Twenty-eight female pigs were included. The study began with a cystoscopic, nephrosonographic and contrast fluoroscopic assessment. Afterwards, obstructive uropathy model in right ureter was created. Obstruction was confirmed 6 weeks later and animals were randomly distributed into 2 groups. Group I underwent laser endopyelotomy and Group-II laparoscopic pyeloplasty A 3Fr anti-reflux intraureteral stent was placed 6 weeks. Follow-up evaluations were performed at 3-6 weeks. The final follow-up was completed at 5 months and included the aforementioned diagnostic methods and pathological study. RESULTS: None of the study animals showed any vesicoureteral reflux signs or ureteral orifice injury. There were no urinomas or ureteric fistulas. The dislodgement rate was 10.7%. After 6 weeks of stenting, 71.4% of ureters showed ureteral peristalsis below the stent, and 100% at the final follow-up. After pathological assessment, no differences were shown at UPJ and healing in the incised area was correct in both groups. CONCLUSIONS: The new stent design avoids vesicoureteral reflux and bladder trigone irritation, consequently might reduce morbidity associated with double pigtail ureteral stents. This study also shows that it is only necessary temporary scaffolding the incised ureteral segment and not the entire length of the ureter after minimally invasive surgery. It is also necessary to manufacture this design in a biodegradable material, thus avoiding its removal.

Antireflux ureteral stent proof of concept assessment after minimally invasive treatment of obstructive uropathy in animal model / Evaluación preliminar de un catéter ureteral antirreflujo tras el tratamiento minimamente invasivo de la uropatia obstructiva en modelo animal

OBJECTIVES: To assess the efficacy of a new anti-reflux intraureteral stent design in a swine model after minimally invasive treatment of ureteral stricture to reduce ureteral stent morbidity, previous to manufacture this design in a biodegradable fashion. METHODS: Twenty-eight female pigs were included. The study began with a cystoscopic, nephrosonographic and contrast fluoroscopic assessment. Afterwards, obstructive uropathy model in right ureter was created. Obstruction was confirmed 6 weeks later and animals were randomly distributed into 2 groups. Group I underwent laser endopyelotomy and Group-II laparoscopic pyeloplasty A 3Fr anti-reflux intraureteral stent was placed 6 weeks. Follow-up evaluations were performed at 3-6 weeks. The final follow-up was completed at 5 months and included the aforementioned diagnostic methods and pathological study. RESULTS: None of the study animals showed any vesicoureteral reflux signs or ureteral orifice injury. There were no urinomas or ureteric fistulas. The dislodgement rate was 10.7%. After 6 weeks of stenting, 71.4% of ureters showed ureteral peristalsis below the stent, and 100% at the final follow-up. After pathological assessment, no differences were shown at UPJ and healing in the incised area was correct in both groups. CONCLUSIÓN: The new stent design avoids vesicoureteral reflux and bladder trigone irritation, consequently might reduce morbidity associated with double pigtail ureteral stents. This study also shows that it is only necessary temporary scaffolding the incised ureteral segment and not the entire length of the ureter after minimally invasive surgery. It is also necessary to manufacture this design in a biodegradable material, thus avoiding its removal

OBJETIVOS: Evaluar un nuevo diseño de catéter intraureteral-antirreflujo en modelo porcino tras el tratamiento mínimamente invasivo de estenosis ureterales. MÉTODOS: Se emplearon 28 ejemplares de la especie porcina. El estudio se inicia con la evaluación cistoscópica, nefrosonográfica y fluoroscópica de la vía urinaria. Posteriormente, se procede a la creación del modelo de estenosis en el uréter derecho. La obstrucción se confirma 6 semanas después y los animales son distribuidos aleatoriamente en dos grupos homogeneos. El Grupo-I, fue tratado mediante endopielotomía láser, y el Grupo-II mediante una pieloplastia laparoscópica. En ambos grupos se coloca durante 6 semanas, un catéter ureteral antirreflujo de 3Fr. Los seguimientos de los animales del estudio se realizaron a las 3-6 semanas. Con un seguimiento final a los 5 meses, que incluye un estudio anatomopatológico. RESULTADOS: Ninguno de los animales del estudio mostró reflujo vesicoureteral o signos de lesión en el orificio ureteral. No se produjeron ni fístulas ni urinomas. La tasa de migración alcanzó un 10,7%. Tras 6 semanas de cateterización el 71,4% de los uréteres mostraron peristaltismo ureteral distal y un 100% a los 5 meses. Tras el estudio anatomopatológico, no se evidencian diferencias en la zona de la unión pieloureteral y la cicatrización fue correcta en ambos grupos. CONCLUSIONES: El nuevo catéter ureteral impide el reflujo vesicoureteral y la irritación del trígono vesical, por lo que previsiblemente podría reducir la morbilidad asociada a los catéteres ureterales. El estudio también muestra que solo es necesaria la cateterización temporal del segmento incidido y no de todo el uréter. Evidentemente es necesario desarrollar este nuevo diseño en su versión biodegradable, para su empleo clínico futuro

Description and validation of realistic and structured endourology training model.

PURPOSE: The aim of the present study was to validate a model of training, which combines the use of non-biological and ex vivo biological bench models, as well as the modelling of urological injuries for endourological treatment in a porcine animal model. MATERIAL AND METHODS: A total of 40 participants took part in this study. The duration of the activity was 16 hours. The model of training was divided into 3 levels: level I, concerning the acquisition of basic theoretical knowledge; level II, involving practice with the bench models and level III, concerning practice in the porcine animal model. First, trainees practiced with animals without using a model of injured (ureteroscopy, management of guide wires and catheters under fluoroscopic control) and later practiced in lithiasic animal model. During the activity, an evaluation of the face and content validity was conducted, as well as constructive validation provided by the trainees versus experts. Evolution of the variables during the course within each group was analysed using the Student's t test for paired samples, while comparisons between groups, were performed using the Student's t test for unpaired samples. RESULTS: The assessments of face and content validity were satisfactory. The constructive validation, "within one trainee" shows that were statistical significant differences between the first time the trainees performed the tasks in the animal model and the last time, mainly in the knowledge of procedure and Holmium laser lithotripsy cathegories. At the beginning of level III, there are also statistical significant differences between trainee's scores and the expert's scores. CONCLUSIONS: This realistic Endourology training model allows the acquisition of knowledge and technical and non-technical skills as evidenced by the face, content and constructive validity. Structured use of bench models (biological and non biological) and animal model simulators increase the endourological basic skills.

The role of the clinical research coordinator--data manager--in oncology clinical trials.

BACKGROUND: The purpose of this study was to determine the standard tasks performed by clinical research coordinators (CRCs) in oncology clinical trials. METHODS: Forty-one CRCs were anonymously surveyed, using a four-page self-administered questionnaire focused on demographics, qualifications, and professional experience. The survey questions on responsibilities consisted of an ad-hoc 32-item questionnaire where respondents had to rate the frequency of involvement in the listed activities using a 3-point scale. We defined as "standard" a task that was rated as "in all or nearly all trials" by at least half of the respondents. RESULTS: A response rate of 90% (37 out of 41) was achieved after two mailings. Less than half of the respondents had received additional training in oncology, clinical research or Good Clinical Practices (GCP). Overall, all standard tasks performed by CRCs were in the category of "monitoring activities" (those usually performed by a Clinical Research Associate "CRA") and included patient registration/randomization, recruitment follow-up, case report form completion, collaboration with the CRA, serious adverse events reporting, handling of investigator files, and preparing the site for and/or attending audits. CONCLUSIONS: CRCs play a key role in the implementation of oncology clinical trials, which goes far beyond mere data collection and/or administrative support, and directly contributes to the gathering of good quality data.