Protocol for tumour-focused dose-escalated adaptive radiotherapy for the radical treatment of bladder cancer in a multicentre phase II randomised controlled trial (RAIDER): radiotherapy planning and delivery guidance.

INTRODUCTION: Daily radiotherapy delivered with radiosensitisation offers patients with muscle invasive bladder cancer (MIBC) comparable outcomes to cystectomy with functional organ preservation. Most recurrences following radiotherapy occur within the bladder. Increasing the delivered radiotherapy dose to the tumour may further improve local control. Developments in image-guided radiotherapy have allowed bladder tumour-focused 'plan of the day' radiotherapy delivery. We aim to test within a randomised multicentre phase II trial whether this technique will enable dose escalation with acceptable rates of toxicity. METHODS AND ANALYSIS: Patients with T2-T4aN0M0 unifocal MIBC will be randomised (1:1:2) between standard/control whole bladder single plan radiotherapy, standard dose adaptive tumour-focused radiotherapy or dose-escalated adaptive tumour-focused radiotherapy (DART). Adaptive tumour-focused radiotherapy will use a library of three plans (small, medium and large) for treatment. A cone beam CT taken prior to each treatment will be used to visualise the anatomy and inform selection of the most appropriate plan for treatment.Two radiotherapy fractionation schedules (32f and 20f) are permitted. A minimum of 120 participants will be randomised in each fractionation cohort (to ensure 57 evaluable DART patients per cohort).A comprehensive radiotherapy quality assurance programme including pretrial and on-trial components is instituted to ensure standardisation of radiotherapy planning and delivery.The trial has a two-stage non-comparative design. The primary end point of stage I is the proportion of patients meeting predefined normal tissue constraints in the DART group. The primary end point of stage II is late Common Terminology Criteria for Adverse Events grade 3 or worse toxicity aiming to exclude a rate of >20% (80% power and 5% alpha, one sided) in each DART fractionation cohort. Secondary end points include locoregional MIBC control, progression-free survival overall survival and patient-reported outcomes. ETHICS AND DISSEMINATION: This clinical trial is approved by the London-Surrey Borders Research Ethics Committee (15/LO/0539). The results when available will be disseminated via peer-reviewed scientific journals, conference presentations and submission to regulatory authorities. TRIAL REGISTRATION NUMBER: NCT02447549; Pre-results.

Photodynamic versus white light-guided treatment of non-muscle invasive bladder cancer: a study protocol for a randomised trial of clinical and cost-effectiveness.

INTRODUCTION: Bladder cancer is the most frequently occurring tumour of the urinary system. Ta, T1 tumours and carcinoma in situ (CIS) are grouped as non-muscle invasive bladder cancer (NMIBC), which can be effectively treated by transurethral resection of bladder tumour (TURBT). There are limitations to the visualisation of tumours with conventional TURBT using white light illumination within the bladder. Incomplete resections occur from the failure to identify satellite lesions or the full extent of the tumour leading to recurrence and potential risk of disease progression. To improve complete resection, photodynamic diagnosis (PDD) has been proposed as a method that can enhance tumour detection and guide resection. The objective of the current research is to determine whether PDD-guided TURBT is better than conventional white light surgery and whether it is cost-effective. METHODS AND ANALYSIS: PHOTO is a pragmatic multicentre randomised controlled trial (open parallel group, non-masked and superiority trial) comparing the intervention of PDD-guided TURBT with standard white light resection in newly diagnosed intermediate and high risk NMIBC within the UK National Health Service setting. Clinical effectiveness is measured with time to recurrence. Cost-effectiveness is assessed within trial via the calculation of incremental cost per recurrence avoided and incremental cost per quality-adjusted life per year gained over 3 years and over long term through a modelling exercise over patients' lifetime. ETHICS AND DISSEMINATION: Formal ethics review was undertaken with a favourable opinion, in line with UK regulatory procedures (REC reference number: 14/NE/1062). If reductions in time to recurrence is associated with long-term patient benefits, the cost-effectiveness evaluation will provide further evidence to inform adoption of the technology. Findings will be shared in lay media such as patient and charity forums and will be presented at key meetings and published in academic literature.Trial registration number ISRCTN84013636.

Cancer immunotherapy and the PD-1/PD-L1 checkpoint pathway. / Inmunoterapia contra el cáncer y la ruta del punto de control PD-1/PD-L1.

Long-term survival for patients with advanced bladder cancer is precarious, with a 5-year survival of just 5% in metastatic cases. Normally, the binding of PD-L1 to PD-1 alters the immune activity by modulating it to inhibit autoimmune diseases or chronic inflammation. However, some cancers use this route to block the immune response of the patient and continue growing. The new immunotherapy against bladder cancer aims to block the ability of tumor cells to resist patient' immune response by acting on the checkpoints of immune cells. These drugs are able to block the PD-1 receptor present on the surface of the lymphocytes, or the PD-L1 and PD-L2 ligands expressed by the cancer cells; this would prevent the binding of both blocking the immunomodulatory signal and allowing the T cells continue active against the tumor. The therapeutic target of Pembrolizumab and Nivolumab is PD-1, the receptor protein of PD-L1 in immune cells. The rest of molecules approved for different types of cancer such as Atezolizumab, Avelumab or Durvalumab act on the PD-L1 protein that is expressed in high concentrations in some cancer cells. The checkpoint inhibitors offer an effective alternative for patients for whom previously there were few options for durable responses, including those who are ineligible for cisplatin-based regimens or who are at risk of significant toxicity. This review describes the most recent data on agents that inhibit PD-L1, found on the surface of tumor cells, and PD-1 found on activated T and B cells and macrophages. Research is ongoing to further categorize responses, define ideal patient populations, and investigate combinations of checkpoint inhibitors to address multiple pathways in the functioning immune system.

Inmunoterapia contra el cáncer y la ruta del punto de control PD-1/PD-L1 / Cancer immunotherapy and the PD-1/PD-L1 checkpoint pathway

La supervivencia a largo plazo para pacientes con cáncer avanzado de vejiga es precaria, con una supervivencia a 5 años de apenas el 5% en los casos metastásicos. Normalmente, la unión de PD-L1 a PD-1 altera la actividad inmunitaria modulándola para inhibir enfermedades autoinmunes e inflamaciones crónicas. Sin embargo, algunos canceres utilizan esta vía para bloquear la respuesta inmune del paciente y continuar creciendo. La nueva inmunoterapia contra el cáncer vesical pretende bloquear la capacidad de las células tumorales para resistir a la respuesta inmune del paciente mediante la actuación sobre los puntos de control de las células inmunitarias. Dichos fármacos son capaces de bloquear el receptor PD-1 presente en la superficie de los linfocitos, o bien los ligandos PD-L1 y PD-L2 expresados por las células cancerosas, esto impediría la unión de ambos bloqueando la señal inmunomoduladora y permitiendo que las células T continúen activas contra el tumor. La diana terapéutica del Pembrolizumab y el Nivolumab, es PD-1, la proteína receptora de PD-L1 en células inmunitarias. El resto de moléculas aprobadas para distintos tipos de cáncer como Atezolizumab, Avelumab o Durvalumab actúan sobre la proteína PD-L1 que es expresada en concentraciones altas en algunas células cancerosas. Los inhibidores del punto de control ofrecen una alternativa efectiva para los pacientes para los que anteriormente había pocas opciones de respuestas duraderas, incluidos aquellos que no son elegibles para los regímenes basados en cisplatino o que están en riesgo de toxicidad significativa. Esta revisión describe los datos más recientes sobre los agentes que inhiben la PD-L1, que se encuentran en la superficie de las células tumorales, y la PD-1 que se encuentra en las células T y B activadas y los macrófagos. Se están llevando a cabo investigaciones para categorizar aún más las respuestas, definir poblaciones de pacientes ideales e investigar combinaciones de inhibidores de puntos de control para abordar múltiples vías en el funcionamiento del sistema inmunitario

Long-term survival for patients with advanced bladder cancer is precarious, with a 5-year survival of just 5% in metastatic cases. Normally, the binding of PD-L1 to PD-1 alters the immune activity by modulating it to inhibit autoimmune diseases or chronic inflammation. However, some cancers use this route to block the immune response of the patient and continue growing. The new immunotherapy against bladder cancer aims to block the ability of tumor cells to resist patient's immune response by acting on the checkpoints of immune cells. These drugs are able to block the PD-1 receptor present on the surface of the lymphocytes, or the PD-L1 and PD-L2 ligands expressed by the cancer cells; this would prevent the binding of both blocking the immunomodulatory signal and allowing the T cells continue active against the tumor. The therapeutic target of Pembrolizumab and Nivolumab is PD-1, the receptor protein of PD-L1 in immune cells. The rest of molecules approved for different types of cancer such as Atezolizumab, Avelumab or Durvalumab act on the PD-L1 protein that is expressed in high concentrations in some cancer cells. The checkpoint inhibitors offer an effective alternative for patients for whom previously there were few options for durable responses, including those who are ineligible for cisplatin-based regimens or who are at risk of significant toxicity. This review describes the most recent data on agents that inhibit PD-L1, found on the surface of tumor cells, and PD-1 found on activated T and B cells and macrophages. Research is ongoing to further categorize responses, define ideal patient populations, and investigate combinations of checkpoint inhibitors to address multiple pathways in the functioning immune system