Intra-prostatic recurrences after radiotherapy with focal boost: Location and dose mapping in the FLAME trial.

INTRODUCTION: The FLAME trial demonstrated that the dose to the gross tumor volume (GTV) is associated with tumour control in prostate cancer patients. This raises the question if dose de-escalation to the remaining prostate gland can be considered. Therefore, we investigated if intraprostatic recurrences occur at the location of the GTV and which dose was delivered at that location. MATERIALS AND METHODS: For FLAME trial patients with an intra-prostatic recurrence, we collected pre-treatment images, GTV delineations, dose distributions and post-recurrence images. Pre-treatment images were registered to the post-recurrence images (PSMA-PET CT). An overlap between GTV and PSMA-PET activity was considered an intra-prostatic recurrence at the location of the primary tumor. RESULTS: Twenty eight out of 535 patients in the FLAME trial had an intra-prostatic recurrence. Its location could be determined for 24 patients. One patient recurred in the prostate gland outside the GTV. The median D98% to the GTV was 76.5 Gy (range: 73.3-86.5 Gy). Only one patient with a recurrence in the GTV received a substantial focal boost of 86.5 Gy. The D98% of all remaining patients was < 81 Gy. CONCLUSION: Intra-prostatic recurrences of intermediate- and high-risk prostate cancer patients treated with radiotherapy appeared predominantly at the location of the primary tumor. All but one patient did not receive a high dose to the GTV. Intra-prostatic failure is likely a consequence of the undertreatment of the primary tumor rather than the undertreatment of the remaining prostate gland.

Selecting a PRO-CTCAE-based subset for patient-reported symptom monitoring in prostate cancer patients: a modified Delphi procedure.

BACKGROUND: Clinician-based reporting of adverse events leads to underreporting and underestimation of the impact of adverse events on prostate cancer patients. Therefore, interest has grown in capturing adverse events directly from patients using the Patient-Reported Outcomes (PROs) version of the Common Terminology Criteria for Adverse Events (CTCAE). We aimed to develop a standardized PRO-CTCAE subset tailored to adverse event monitoring in prostate cancer patients. MATERIALS AND METHODS: We used a mixed-method approach based on the 'phase I guideline for developing questionnaire modules' by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life group, including a literature review, and interviews with patients (n = 30) and health care providers (HCPs, n = 16). A modified Delphi procedure was carried out to reach consensus on the final subset selected from the complete PRO-CTCAE item library. RESULTS: Fourteen multidisciplinary HCPs and 12 patients participated in the Delphi rounds. Ninety percent agreed on the final subset, consisting of: 'ability to achieve and maintain erection', 'decreased libido', 'inability to reach orgasm', 'urinary frequency', 'urinary urgency', 'urinary incontinence', 'painful urination', 'fecal incontinence', 'fatigue', 'hot flashes', 'feeling discouraged', 'sadness', and 'concentration'. From 16 articles identified in the literature review, the following adverse events for which no PRO-CTCAE items are available, were included to the recommendation section: 'nocturia', 'blood and/or mucus in stool', 'hemorrhoids', 'hematuria', 'cystitis', 'neuropathy', and 'proctitis'. CONCLUSIONS: The obtained PRO-CTCAE-subset can be used for multidisciplinary adverse event monitoring in prostate cancer care. The described method may guide development of future PRO-CTCAE subsets.

Urinary incontinence and erectile dysfunction in patients with localized or locally advanced prostate cancer: A nationwide observational study.

BACKGROUND: Although urinary adverse events after treatment of prostate cancer (CaP) are common, population-based studies on functional outcomes are scarce. The aim of this study is to evaluate the occurrence of urinary incontinence (UI) and erectile dysfunction (ED) in daily clinical practice using a nationwide Dutch cohort of patients with localized or locally advanced CaP. BASIC PROCEDURES: Patients were invited to complete the EPIC-26 questionnaire before treatment (baseline) and at 12 and 24 months after diagnosis. We calculated the mean EPIC-26 domain scores, stratified by treatment modality (i.e., radical prostatectomy, external radiotherapy, and no active treatment), and the proportions of patients with UI (defined as ≥ 2 pads per day) and ED (defined as erections not firm enough for sexual intercourse). Logistic regression modeling was used to explore the factors related to UI and ED after surgery. MAIN FINDINGS: In total 1,759 patients participated in this study. Patients undergoing radical prostatectomy experienced clinically relevant worsening in the urinary incontinence domain. After excluding patients who reported UI at baseline, 15% of patients with prostatectomy reported UI 24 months after diagnosis. Only comorbidity was associated with UI in surgically treated patients. Regardless of treatment, patients reported a clinically significant reduced sexual functioning over time. Before treatment, 54% of patients reported ED. Among the 46% remaining patients, 87% of patients treated with radical prostatectomy reported ED 24 months after diagnosis, 41% after radiotherapy, and 46% in patients without active treatment. Bilateral nerve-sparing surgery was the only factor associated with ED after 24 months. PRINCIPAL CONCLUSIONS: UI and ED frequently occur in patients with localized and locally advanced CaP, in particular after radical prostatectomy. The higher occurrence rate of UI and ED, compared with clinical trial participants, supports the importance of real-world data, which can be used for local treatment recommendations and patient information, but also to evaluate effects of future initiatives, such as treatment centralization and research aimed at improving functional outcomes.

Superior efficacy of neoadjuvant chemotherapy and radical cystectomy in cT3-4aN0M0 compared to cT2N0M0 bladder cancer.

In this study, we compared complete pathological downstaging (pCD, ≤(y)pT1N0) and overall survival (OS) in patients with cT2 versus cT3-4aN0M0 UC of the bladder undergoing radical cystectomy (RC) with or without neoadjuvant chemo- (NAC) or radiotherapy (NAR). A population-based sample of 5,517 patients, who underwent upfront RC versus NAC + RC or NAR + RC for cT2-4aN0M0 UC between 1995-2013, was identified from the Netherlands Cancer Registry. Data were retrieved from individual patient files and pathology reports. pCD-rates were compared using Chi-square tests and OS was estimated by Kaplan-Meier analyses. Multivariable analyses were conducted to determine odds (OR) and hazard ratios (HR) for pCD-status and OS, respectively. We included 4,504 (82%) patients with cT2 and 1,013 (18%) with cT3-4a UC. Median follow-up was 9.2 years. In cT2 UC, pCD-rate was 25% after upfront RC versus 43% (p < 0.001) and 33% (p = 0.130) after NAC + RC and NAR + RC, respectively. In cT3-4a UC, pCD-rate was 8% after upfront RC versus 37% (p < 0.001) and 16% (p = 0.281) after NAC + RC and NAR + RC, respectively. In cT2 UC, 5-year OS was 57% and 51% for NAC + RC and upfront RC, respectively (p = 0.135), whereas in cT3-4a UC, 5-year OS was 55% for NAC + RC versus 36% for upfront RC (p < 0.001). In multivariable analysis for OS, NAC was beneficial in cT3-4a UC (HR: 0.67, 95%CI 0.51-0.89) but not in cT2 UC (HR: 0.91, 95%CI 0.72-1.15). NAR did not influence OS. In conclusion, NAC + RC was associated with superior pCD compared to RC alone and NAR + RC. Superior OS for NAC + RC compared to RC alone was especially evident in cT3-4a disease.

MRI-guided prostate adaptive radiotherapy - A systematic review.

Dose escalated radiotherapy improves outcomes for men with prostate cancer. A plateau for benefit from dose escalation using EBRT may not have been reached for some patients with higher risk disease. The use of increasingly conformal techniques, such as step and shoot IMRT or more recently VMAT, has allowed treatment intensification to be achieved whilst minimising associated increases in toxicity to surrounding normal structures. To support further safe dose escalation, the uncertainties in the treatment target position will need be minimised using optimal planning and image-guided radiotherapy (IGRT). In particular the increasing usage of profoundly hypo-fractionated stereotactic therapy is predicated on the ability to confidently direct treatment precisely to the intended target for the duration of each treatment. This article reviews published studies on the influences of varies types of motion on daily prostate position and how these may be mitigated to improve IGRT in future. In particular the role that MRI has played in the generation of data is discussed and the potential role of the MR-Linac in next-generation IGRT is discussed.

Brachytherapy after external beam radiotherapy and limited surgery preserves bladders for patients with solitary pT1-pT3 bladder tumors.

BACKGROUND: Several French, Belgian and Dutch radiation oncologists have reported good results with the combination of limited surgery after external beam radiotherapy (EBRT) followed by brachytherapy in early-stage muscle-invasive bladder cancer. PATIENTS AND METHODS: Data from 12 of 13 departments which are using this approach have been collected retrospectively, in a multicenter database, resulting in 1040 patients: 811 males and 229 females with a median age of 66 years, range 28-92 years. Results were analyzed according to tumor stage and diameter, histology grade, age and brachytherapy technique, continuous low-dose rate (CLDR) and pulsed dose rate (PDR). RESULTS: At 1, 3 and 5 years, the local recurrence-free probability was 91%, 80% and 75%, metastasis-free probability was 91%, 80% and 74%, disease-free probability was 85%, 68% and 61% and overall survival probability was 91%, 74% and 62%, respectively. The differences in the outcome between the contributing departments were small. After multivariate analysis, the only factor influencing the local control rate was the brachytherapy technique. Toxicity consisted mainly of 24 fistula, 144 ulcers/necroses and 93 other types. CONCLUSIONS: EBRT followed by brachytherapy, combined with limited surgery, offers excellent results in terms of bladder sparing for selected groups of patients suffering from bladder cancer.

Symptomatic brain metastases from small-cell carcinoma of the urinary bladder: The Netherlands Cancer Institute experience and literature review.

BACKGROUND: The incidence of symptomatic brain metastases in small-cell carcinoma of the urinary bladder (SCBC) is unknown. This precludes advice about prophylactic cranial irradiation (PCI). PATIENTS AND METHODS: The medical records of all patients with SCBC seen at The Netherlands Cancer Institute from 1993 to 2009 (n = 51) were reviewed. Limited disease (LD) was defined as any pT, cN0₋1, and cM1. Patients with LD were offered bladder-preserving treatment involving combined chemoradiotherapy. Patients with extensive disease (ED) were treated with palliative chemotherapy. PCI was not applied in any patient. RESULTS: Among 39 patients with LD, median disease-specific survival was 35 months. Four developed symptomatic brain metastases after a median follow-up of 15 months (range 3-24) and were treated with whole-brain radiotherapy. No patient with ED developed symptomatic brain metastases during a median follow-up of 6 months. The reported incidence of brain metastases in SCBC in the literature ranges between 0% and 40%. On the basis of all reported series, the pooled estimate of the cumulative incidence of brain metastases is 10.5% (95% confidence interval 7.5% to 14.1%). CONCLUSIONS: The incidence of symptomatic brain metastases from SCBC is significantly lower than that from small-cell lung cancer. Therefore, we do not routinely advise PCI in patients with SCBC.

[New developments in the treatment of muscle-invasive bladder cancer]. / Nieuwe ontwikkelingen in de behandeling van spierinvasief blaascarcinoom.

Muscle-invasive bladder cancer is an important oncological problem. When no distant metastases are detected, a radical cystectomy is the standard treatment. In recent years new developments in the treatment of the disease have been explored. These developments comprise new surgical techniques such as neobladder construction using the patient's intestinal tissue, sexuality-preserving surgery and robot-assisted surgery. Furthermore, indications for perioperative chemotherapy are discussed. Finally, bladder-sparing approaches are described: brachytherapy and chemo-radiation.

Survival after bladder-preservation with brachytherapy versus radical cystectomy; a single institution experience.

OBJECTIVE: To evaluate the long-term survival following brachytherapy and following cystectomy of patients with invasive bladder cancer treated in our institution. PATIENTS AND METHODS: Between 1988 and 2000 108 patients with solitary, organ confined T1-T2 invasive bladder cancer of < or = 5 cm were treated with a transurethral resection, and a course of external beam radiotherapy (30 Gy) followed by 40 Gy brachytherapy. The overall and disease specific survival rates of these patients are compared with those of 77 patients with T1-T2 invasive bladder cancer treated with cystectomy between 1988-2003. RESULTS: The 5/10 year overall survival rates were 62%/50% after brachytherapy and 67%/58% after cystectomy (p = 0.67). The 5/10 year disease specific survival rates were 73%/67% after brachytherapy and 72%/72% after cystectomy (p = 0.28). When adjusted for age, multiplicity, T-stage, N-stage and grade, the 5/10 year overall survival rates were 65%/53% after brachytherapy and 62%/51% after cystectomy, respectively. The adjusted disease specific survival rates were 75%/70% after brachytherapy and 66%/66% after cystectomy. CONCLUSIONS: This study does not provide evidence regarding survival against the use of bladder preservation with brachytherapy for patients with solitary, T1-T2 invasive bladder cancer of < or = 5 cm diameter, seeking bladder-sparing alternatives to radical cystectomy.

[Good results of bladder-preserving treatment in poorly differentiated and invasive bladder carcinoma using interstitial Iridium-192 radiotherapy]. / Goede resultaten van blaassparende behandeling bij slecht gedifferentieerde en invasieve blaascarcinomen met behulp van interstitiële Iridium-192-radiotherapie.

OBJECTIVE: The analyse the efficacy and safety of conservative treatment for T1G3 and T2-T3a bladder carcinoma. DESIGN: Retrospective. SETTING: National Cancer Institute/Anthoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands. METHODS: Between 1987 and 1994 (7 years) 63 patients with T1G3 or T2-T3a tumours < 5 cm diameter were treated with a combined approach consisting of a transurethral resection, a course of external irradiation (30 Gy in 15 fractions) to the bladder and an Iridium-192 implant procedure. RESULTS: After a mean follow-up of 4.2 years (range 3 months to 7.2 years) 42 patients were alive without tumour. Fourteen patients died from bladder cancer and 4 patients died from intercurrent disease. Three patients were alive with non-curable cancer. Nine patients had an isolated bladder relapse. Seven of these could be salvaged with cystectomy (3 patients) or transurethral resection (4 patients). Eight patients developed distant metastases only and 7 patients distant metastases combined with bladder recurrence. The 5 year actuarial survival was 66%. Acute and late morbidity was limited and mainly related to the surgical procedure. CONCLUSION: Bladder conservation using Iridium-192 implantation is an effective and safe procedure and in selected group of patients with bladder cancer it is a good alternative to radical cystectomy.

[Usefulness of ambulatory EEG in detecting critical and intercritical events in patients with epilepsy or with suspected epilepsy]. / Utilità dell'EEG dinamico nel riconoscimento di eventi critici e intercritici in pazienti epilettici o con sospetta epilessia.

Ambulatory EEGs (EEGAs) were recorded in 251 patients. In 91 of these patients there was a suspicion of having epileptic seizures, in 117 a diagnosis of epilepsy was already established, in 43 the withdrawal of antiepileptic drugs was envisaged being apparently free from seizures for years. The EEGA showed epileptogenic abnormalities in 31% of patients of the first group. This percentage was not far from the one obtained with standard EEG (EEGS) recordings. In the second group, a divergence was found, as for the classification of seizures, between the ictal events actually recorded on the EEGA and the definition of seizures based on clinical information. Furthermore ictal events recorded by the EEGA were less frequent than one would have anticipated according to the seizure frequency asserted by the patients. In the third group the EEGA disclosed the persistence of epileptic seizures, mostly represented by diffuse spike and wave discharges, in about 30% of the patients. Finally, comparison of the results obtained by the EEGA with those obtained by the EEGS in all patients suggested that the two recording techniques are complementary.

Ethosuximide alters intrathalamic and thalamocortical synchronizing mechanisms: a possible explanation of its antiabsence effect.

Effects of systemic administration of a single dose (50 mg/kg) of ethosuximide (ESM) on extracellularly recorded thalamic (nucleus centralis lateralis, CL; nucleus reticularis, RE) and cortical neurons and on cortical EEG activity of acute cats, have been studied. In intact animals ESM led to: (a) desynchronization of cortical EEG activity; (b) reduction of cortical recruiting responses to 6 Hz stimulation of nucleus centralis medialis (CeM); (c) increased firing rate of CL units; and (d) reduction of incremental responses (IRs) of CL neurons to CeM stimulation. In midbrain reticular formation (MRF)-lesioned animals, ESM induced: (a) reduction of cortical spindle waves; (b) increment of their intraburst frequency; (c) reduction of the IR of CL neurons to 3 and 6 Hz CeM stimulation; (d) shortening of the inhibitory period following each response; and (e) no increment of spontaneous firing rate of CL units. Moreover, ESM led to important changes in the spontaneous activity of RE neurons: spike barrages, typical of these neurons in MRF-lesioned animals, became less frequent and of longer duration, being also constituted by longer interspike intervals. However, responses of RE neurons to low frequency CeM stimulation, when present, did not show any incremental phenomenon and appeared unchanged after ESM. Responses of cortical neurons to paired stimuli, applied with different interstimulus intervals, to nucleus ventralis posterolateralis or in animals with isolated cortex, to subcortical white matter, disclosed a reduction of the cortical inhibitory period following the response to the conditioning stimulus. These data suggest that ESM exerts a moderate diffuse anti-inhibitory action at both cortical and thalamic levels and an activating effect on MRF, which could also be accomplished through disinhibition. The reduction of the inhibitory phases in thalamic nuclei would alter spontaneous intrathalamic synchronizing mechanisms, leading to a decreased effectiveness of thalamocortical volleys, which are believed to be fundamental for the appearance of cortical spike and wave discharges. This hypothesis would therefore explain the specific efficacy of ESM against absence seizures.