X. Maldonado

High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial

BACKGROUND The optimum duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains undefined. We aimed to determine whether long-term androgen deprivation was superior to short-term androgen deprivation when combined with high-dose radiotherapy. METHODS In this open-label, multicentre, phase 3 randomised controlled trial, patients were recruited from ten university hospitals throughout Spain. Eligible patients had clinical stage T1c-T3b N0M0 prostate adenocarcinoma with intermediate-risk and high-risk factors according to 2005 National Comprehensive Cancer Network criteria. Patients were randomly assigned (1:1) using a computer-generated randomisation schedule to receive either 4 months of androgen deprivation combined with three-dimensional conformal radiotherapy at a minimum dose of 76 Gy (range 76-82 Gy; short-term androgen deprivation group) or the same treatment followed by 24 months of adjuvant androgen deprivation (long-term androgen deprivation group), stratified by prostate cancer risk group (intermediate risk vs high risk) and participating centre. Patients assigned to the short-term androgen deprivation group received 4 months of neoadjuvant and concomitant androgen deprivation with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy (flutamide 750 mg per day or bicalutamide 50 mg per day) was added during the first 2 months of treatment. Patients assigned to long-term suppression continued with the same luteinising hormone-releasing hormone analogue every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02175212. FINDINGS Between Nov 7, 2005, and Dec 20, 2010, 178 patients were randomly assigned to receive short-term androgen deprivation and 177 to receive long-term androgen deprivation. After a median follow-up of 63 months (IQR 50-82), 5-year biochemical disease-free survival was significantly better among patients receiving long-term androgen deprivation than among those receiving short-term treatment (90% [95% CI 87-92] vs 81% [78-85]; hazard ratio [HR] 1·88 [95% CI 1·12-3·15]; p=0·01). 5-year overall survival (95% [95% CI 93-97] vs 86% [83-89]; HR 2·48 [95% CI 1·31-4·68]; p=0·009) and 5-year metastasis-free survival (94% [95% CI 92-96] vs 83% [80-86]; HR 2·31 [95% CI 1·23-3·85]; p=0·01) were also significantly better in the long-term androgen deprivation group than in the short-term androgen deprivation group. The effect of long-term androgen deprivation on biochemical disease-free survival, metastasis-free survival, and overall survival was more evident in patients with high-risk disease than in those with low-risk disease. Grade 3 late rectal toxicity was noted in three (2%) of 177 patients in the long-term androgen deprivation group and two (1%) of 178 in the short-term androgen deprivation group; grade 3-4 late urinary toxicity was noted in five (3%) patients in each group. No deaths related to treatment were reported. INTERPRETATION Compared with short-term androgen deprivation, 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy improved biochemical control and overall survival in patients with prostate cancer, particularly those with high-risk disease, with no increase in late radiation toxicity. Longer follow-up is needed to determine whether men with intermediate-risk disease benefit from more than 4 months of androgen deprivation. FUNDING Spanish National Health Investigation Fund, AstraZeneca.

Prognostic implications of epilepsy in glioblastomas.

OBJECTIVES The role of seizures and antiepileptic treatments associated with glioblastoma is a current topic of discussion. The objective of this study is to characterize and establish implications of epilepsy associated with glioblastoma. PATIENTS AND METHODS We retrospectively analyzed the medical history, focused on epileptic features of 134 histologically diagnosed glioblastoma over a period of 4 years. RESULTS The sample group had an average age of 56 years and 66% were male. Complete tumor resection was performed in 66% and 64.2% received further radio-oncologic treatment. The average survival rate was 12.4 months and 11.5% survived to 5 years. Epileptic seizures were the presentation symptom in 27% of cases and 51% suffered seizures during the disease, 26% become drug-resistant. Focal evolving to a bilateral convulsive seizures were the most frequent type. Epileptic seizures at presentation independently predicted longer survival (p<0.001). Furthermore, a history of epilepsy or seizures during disease improved survival. Late onset seizures, recurrences or status epilepticus during the course of the disease indicated tumor progression or the final stages of life. Prophylactic antiepileptic drugs did not prevent seizures. Similarly, there was no difference in survival between patients who did not use antiepileptic drugs and those using valproate or levetiracetam. Patients under 60 years, full oncologic treatment and secondary glioblastomas were factors that improved survival (p<0.001). CONCLUSION Previous history of epilepsy or the onset of seizures as a presentation symptom in glioblastomas predict longer survival. Half of patients have seizures during the course of the disease. Antiepileptic drugs alone do not increase survival in glioblastoma patients.

31Phosphorus magnetic resonance spectroscopy in the assessment of head and neck tumors.

PURPOSE 31Phosphorus magnetic resonance spectroscopy (31P-MRS) provides biochemical information in a noninvasive way. The aim of this work was: (a) to characterize the 31P spectrum of advanced head and neck tumors, and (b) to evaluate the spectral changes after treatment and to correlate them with the pathologic response. METHODS AND MATERIALS A total of 20 patients diagnosed with advanced head and neck tumors and 7 healthy controls participated in the study. The tumor mass and its contralateral side were studied by means of 31P-MRS before and after treatment. Neck muscles of a control group were also studied. RESULTS Tumors presented ratios of phosphomonoesters (PME), phosphodiesters (PDE), and inorganic phosphate (Pi) with respect to the adenosine triphosphate (ATP), significantly higher and a PCr (phosphocreatine)/ATP ratio lower than the neck muscle of volunteers or the contralateral side. The PDE/ATP and PME/ATP ratio values obtained before therapy were similar, independent of the later response to treatment. However, when there was a complete response, the ratios measured after treatment were decreased. CONCLUSION These results show the existence of significant differences between the 31phosphorus spectrum of tumors and neck muscle, but also between the tumors and their contralateral sides. Moreover, 31P-MRS is able to detect metabolic changes after a complete response. These results suggest that 31P-MRS would be useful in the evaluation of the clinical response of head and neck tumors.

Uroncor consensus statement: Management of biochemical recurrence after radical radiotherapy for prostate cancer: From biochemical failure to castration resistance.

Management of patients who experience biochemical failure after radical radiotherapy with or without hormonal therapy is highly challenging. The clinician must not only choose the type of treatment, but also the timing and optimal sequence of treatment administration. When biochemical failure occurs, numerous treatment scenarios are possible, thus making it more difficult to select the optimal approach. Moreover, rapid and ongoing advances in treatment options require that physicians make decisions that could impact both survival and quality of life. The aim of the present consensus statement, developed by the Urological Tumour Working Group (URONCOR) of the Spanish Society of Radiation Oncology (SEOR), is to provide cancer specialists with the latest, evidence-based information needed to make the best decisions for the patient under all possible treatment scenarios. The structure of this consensus statement follows the typical development of disease progression after biochemical failure, with the most appropriate treatment recommendations given for each stage. The consensus statement is organized into three separate chapters, as follows: biochemical failure with or without local recurrence and/or metastasis; progression after salvage therapy; and treatment of castration-resistant patients.

Improving Survival of Medulloblastoma: Results in Two Groups of Patients

This retrospective study compares the results obtained in 56 children with medulloblastoma treated with two different protocols at our center between 1975 and 1990. Since 1985 we have been enrolled in the medulloblastoma SIOP II protocol in which we have entered 27 patients. These patients from the SIOP group (SG) and the 29 children treated before 1985, the historical group (HG). When the two groups were compared for age and sex distribution, no differences were found; however, prognostic factors were worse in the HG than in SG: 21 versus 15 T3-T4 and 13 versus 8 high-risk, respectively. The relapse rate was 63% for the HG and 39% for the SG. Five-year disease-free survival was 31% for the HG and 56% for the SG (p = 0.037). Five-year survival was 52 and 70%, respectively (p = 0.055). When SG and HG were compared by stratifying for tumor size, surgical resection and the risk variable, better disease-free survival was obtained in SG than in HG. In a multivariate analysis, the HG and the high-risk proved to be variable independent predictors of poor survival. We observe an increase in survival in our patients with medulloblastoma.

Targeting fibroblast growth factor receptors and immune checkpoint inhibitors for the treatment of advanced bladder cancer: New direction and New Hope

Bladder cancer is one of the leading causes of death in Europe and the United States. About 25% of patients with bladder cancer have advanced disease (muscle-invasive or metastatic disease) at presentation and are candidates for systemic chemotherapy. In the setting of metastatic disease, use of cisplatin-based regimens improves survival. However, despite initial high response rates, the responses are typically not durable leading to recurrence and death in the vast majority of these patients with median overall survival of 15months and a 5-year survival rate of ⩽10%. Furthermore, unfit patients for cisplatin have no standard of care for first line therapy in advance disease Most second-line chemotherapeutic agents tested have been disappointing. Newer targeted drugs and immunotherapies are being studied in the metastatic setting, their usefulness in the neoadjuvant and adjuvant settings is also an intriguing area of ongoing research. Thus, new treatment strategies are clearly needed. The comprehensive evaluation of multiple molecular pathways characterized by The Cancer Genome Atlas project has shed light on potential therapeutic targets for bladder urothelial carcinomas. We have focused especially on emerging therapies in locally advanced and metastatic urothelial carcinoma with an emphasis on immune checkpoints inhibitors and FGFR targeted therapies, which have shown great promise in early clinical studies.

Role of Immunotherapy in Castration-Resistant Prostate Cancer (CRPC)

Initial therapy for metastatic prostate cancer consists of androgenic suppression. However, this is only a palliative treatment with an effective duration that usually lasts 12–24 months. Historically, castration‐resistant prostate cancer (CRPC) had been considered a chemoresistant tumour. In 2004, docetaxel received USA Food and Drug Administration approval as a first‐line treatment for metastatic prostate cancer, after two independent phase III trials showed an increased survival benefit. Recently, five new drugs have shown increased survival in CRPC: sipuleucel‐T (assymptomatic or minimally symptomatic), abiraterone acetate (before and after docetaxel), cabazitaxel (after docetaxel), MDV3100 (after docetaxel) and radium‐223 (not suitable for docetaxel or after docetaxel). The identification of antigens in normal prostate tissue or prostate cancer that are recognised by immune effectors cells has resulted in several new studies based on immunotherapy. Prostate cancer disease provides a test system to determine the efficacy of vaccines for different reasons. This cancer is a tumour that grows relatively slowly. Recurrence is often diagnosed early (with many patients presenting only with biochemical progression), there is a biological marker that can predict prognosis and outcome (PSA doubling time), various specific antigens have been identified and characterised, and vaccines can be used with a good safety profile combined with anti‐androgen therapy, chemotherapy, or radiotherapy. Here we provide a review of the main important immune treatments in CRPC.

The influence of metabolic syndrome on prostate cancer risk detection and its aggressiveness.

226 Background: Metabolic syndrome (MS) is a frequent pathological condition that increase cardiovascular risk and mortality. MS is frequently diagnosed in adult men who are at risk of prostate cancer (PC). Some studies have postulated a relationship between MS and overall oncogenesis, however no information exist in relation to PC. The objective of this study was to analyze the impact of MS on PC detection risk and PC aggressiveness. METHODS A group of 2408 men were consecutively subjected to prostate biopsy for cause, PSA >4 ng/mL (64.4%), abnormal DRE (9%) or both (26.6%). Median PSA was 7.0 ng/mL (0.7-1279) and median age 68 years (46-86). MS was evaluated according to the ATPIII criteria (three or more conditions: waist circumference >102 cm, triglyceride level >150 mg/dL, high density lipoprotein level <40 mg/dL, fasting glucosa level >110 ng/dL and blood pressure >130/85 mmHg. Men on lipid-lowering medications, hypoglicemiants and antihypertensives were classified as positive for the respective criterion. We took at least 10 cores in PB, plus 1 to 8 additional cores depending on age and prostate volume according to a modified Viennas nomogram. Overall PC detection rate was 35.2% and high grade (HG) rate (Gleason score >7) 28.3%. Binary logistic regression and contingence analysis were performed and odds ratios (OR) calculated to analyze the strength of relationships. RESULTS The overall prevalence of MS was 61.5% (1480/2408). Multivariate analysis showed that MS was not an independent predictor of PC however MS was an independent predictor of HGPC. The rate of PC was 34.3% in men with MS (508 of 1480) and 36.6% in men without MS (340/928), p=0.255. OR: 0.904 (95%CI 0.762-1.073). The rate of HGPC was 33.1% among the PCs detected in men with MS and 21.2% among the PCs detected in men without MS, p <0.001, OR 1.839 (95%IC 1.337-2.531). CONCLUSIONS MS does not seem to increase the risk of prostate cancer detection in men subjected to PB for cause. However, we have detected an increase of the aggressiveness among PCs detected in men with MS.

Effect of chronic treatment of combined statins and aspirin on the risk of prostate cancer detection.

185 Background: The role of chronic treatment (ChT) with statins and aspirin on prostate cancer (PC) carcinogenesis is controversial. Both drugs are frequently used in adult men who are at risk of PC, and many of them receive both drugs simultaneously. The impact of the combined treatment (CT) with statins and aspirin on PC risk has never been reported. We proposed to explore the influence of ChT with statins and aspirin in the PC risk detection and their aggressiveness. METHODS 2408 men were consecutively biopsied for cause: PSA > 4 ng/mL (64.4%), abnormal DRE (9%) or both (26.6%). ChT with statins and aspirin (>1 year) was controlled. Median age was 68 years (46-86) and median PSA 7.0 ng/mL (0.7-1279). At least 10 cores, plus 1 to 8 additional cores, were obtained. The PC detection rate was 35.2% and the Gleason score was < 7 in 20.8%, 7 in 50.9% and > 7 (HGPC) in 28.3%. Multivariate and univariate analysis were done and OR calculated to analyze the strength of the relationships. RESULTS 440 men (18.3%) were receiving statins alone (SA), 160 (6.6%) aspirin alone (AA), and 304 (12.6%) both drugs simultaneously. Multivariate analysis showed that CT was the only independent predictor of a reduced risk of PC detection, p=0.025, (OR 0.589, 95%CI 0.370-0-936). PC was detected in 552 of 1502 men (36.7%) not receiving statins or aspirin, 34.5% (152/440) receiving SA, 40% (64/160) receiving AA, and in 26.3% (80/304) receiving statins and aspirin simultaneously. Related to cancer aggressiveness, multivariate analysis showed that combined treatment predicted significantly an increased risk of HGPC, p=0.013, (OR 2.672, 95%CI 1.226-5.825). HGPC was detected in 136 of 552 (24.6%) PCs detected in men not receiving statins or aspirin, in 40 of 152 (26.3%) PCs detected in men receiving SA, in 24 of 64 (37.7%) PCs detected in men receiving AA, and in 40 of 80 (50%) PCs detected in men receiving statins and aspirin simultaneously. CONCLUSIONS This study suggests that ChT with the combination of statins and aspirin reduce significantly the risk of PC detection in men subjected to prostate biopsy for cause. However, this reduction of PC detection is accompanied by a significant increase of PC aggressiveness.

Fluorouracil and High-dose Leucovorin with Radiotherapy as Adjuvant Therapy for Rectal Cancer: Results of a Phase II Study

The purpose of this phase II study was to evaluate the efficacy and toxicity of fluorouracil and high-dose leucovorin (5-FU/LV) with pelvic irradiation as adjuvant therapy for patients with macroscopical resected rectal or recto-sigmoid cancer. Following surgery for stages II-III primary (52) or recurrent rectal cancer (4), 56 patients received 8 cycles of 5-FU/LV and pelvic irradiation. 5-FU doses were 200 mgr/m2 for cycles 2-3 and 300 mgr/m2 for cycles 1 and 4-8. LV doses remained fixed at 200 mgr/m2. Pelvic radiation was started in the third week, between the first and second cycle. The total dose was 50.4 Gy. No severe complications had been recorded. The incidence of grade 3 diarrhea was 19%. Three patients presented leukopenia grade 3 (5%). In 44 patients (78%) the planned treatment could be administered. The median follow-up was 40 months (range 22-66). Seven patients had a local relapse (13%) and 6 developed distant metastasis (10%). The 3-year disease-free survival was 72% and the overall survival was 76%. These preliminary results show that combined post-operative 5-FU/LV and pelvic radiotherapy are well tolerated and present a reasonable local control and survival rates. This adjuvant treatment should be evaluated in randomized trials.