Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma.

BACKGROUND: The role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery is not clear. METHODS: In a phase 3, multicenter, double-blind, randomized, controlled trial, we assigned patients with muscle-invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed. The primary end points were disease-free survival among all the patients (intention-to-treat population) and among patients with a tumor programmed death ligand 1 (PD-L1) expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary end point. RESULTS: A total of 353 patients were assigned to receive nivolumab and 356 to receive placebo. The median disease-free survival in the intention-to-treat population was 20.8 months (95% confidence interval [CI], 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo (hazard ratio for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 74.5% and 55.7%, respectively (hazard ratio, 0.55; 98.72% CI, 0.35 to 0.85; P<0.001). The median survival free from recurrence outside the urothelial tract in the intention-to-treat population was 22.9 months (95% CI, 19.2 to 33.4) with nivolumab and 13.7 months (95% CI, 8.4 to 20.3) with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77.0% with nivolumab and 62.7% with placebo (hazard ratio for recurrence outside the urothelial tract or death, 0.72; 95% CI, 0.59 to 0.89). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 75.3% and 56.7%, respectively (hazard ratio, 0.55; 95% CI, 0.39 to 0.79). Treatment-related adverse events of grade 3 or higher occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. Two treatment-related deaths due to pneumonitis were noted in the nivolumab group. CONCLUSIONS: In this trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population and among patients with a PD-L1 expression level of 1% or more. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 274 ClinicalTrials.gov number, NCT02632409.).

Treatment patterns, survival, and healthcare utilisation and costs in patients with locally advanced and metastatic bladder cancer in Denmark 2015-2020.

BACKGROUND: Treatment patterns in locally advanced and metastatic urothelial bladder cancer (La/mUBC) is changing, but little is known about current treatment patterns, survival, and costs of these patients. Our aim was to describe treatment patterns, survival, and healthcare utilisation/costs in Danish La/mUBC patients in a routine clinical care setting. METHODS: Registry-based nationwide cohort study including all bladder cancer patients aged 18 years or older with a La/mUBC tumour in the pathology register and a concomitant bladder cancer diagnosis in the Danish National Patient Registry in the period 2015-2020. We categorised the patients according to (1) La/mUBC at time of first bladder cancer diagnosis (de novo La/mUBC) and (2) non-invasive or localised muscle-invasive bladder cancer at time of diagnosis which had progressed to La/mUBC. All patients were included at date of pathology-confirmed La/mUBC. Follow-up ended 30 September 2022. RESULTS: We identified 1278 patients (69% men) with La/mUBC and no other previous cancer. Of these, 212 (17%) had de novo La/mUBC, while 1066 (83%) had progressed to La/mUBC. Median age was 72 years. Patients were followed for a median of 13.0 months (interquartile range 4.7;32.0). During follow-up, 651 (51%) patients started first-line treatment, of these, 285 progressed to second-line treatment, and 112 also started third-line treatment. Median survival was 13.0 months from La/mUBC diagnosis, 12.1 months from start of first-line treatment, 9.8 months from start of second-line treatment, and 8.6 months from start of third-line treatment. The mean number of days admitted to hospital was 3.47, 3.97, and 4.07 per month following initiation of first-line, second-line, and third-line treatment, respectively. CONCLUSION: Patients with La/mUBC have a poor prognosis, and in routine clinical care only around half of the patients received systemic anti-cancer treatment suggesting an unmet need for novel treatments. The overall costs only increased slightly from first to third-line treatment.

Dose comparison of robustly optimized intensity modulated proton therapy (IMPT) vs IMRT and VMAT photon plans for testicular seminoma.

BACKGROUND: Patients with stage II seminoma have traditionally been treated with photons to the retroperitoneal and iliac space, which leads to a substantial dose bath to abdominal and pelvic organs at risk (OAR). As these patients are young and with excellent prognosis, reducing dose to OAR and thereby the risk of secondary cancer is of utmost importance. We compared IMPT to opposing IMRT fields and VMAT, assessing dose to OAR and both overall and organ-specific secondary cancer risk. MATERIAL AND METHODS: A comparative treatment planning study was conducted on planning CT-scans from ten patients with stage II seminoma, treated with photons to a 'dog-leg' field with doses ranging from 20 to 25 Gy and a 10 Gy sequential boost to the metastatic lymph node(s). Photon plans were either 3-4 field IMRT (Eclipse) or 1-2 arc VMAT (Pinnacle). Proton plans used robust (5 mm; 3.5%) IMPT (Eclipse), multi field optimization with 3 posterior fields supplemented by 2 anterior fields at the level of the iliac vessels. Thirty plans were generated. Mean doses to OARs were compared for IMRT vs IMPT and VMAT vs IMPT. The risk of secondary cancer was calculated according to the model described by Schneider, using excess absolute risk (EAR, per 10,000 persons per year) for body outline, stomach, duodenum, pancreas, bowel, bladder and spinal cord. RESULTS: Mean doses to all OARs were significantly lower with IMPT except similar kidney (IMRT) and spinal cord (VMAT) doses. The relative EAR for body outline was 0.59 for IMPT/IMRT (p < .05) and 0.33 for IMPT/VMAT (p < .05). Organ specific secondary cancer risk was also lower for IMPT except for pancreas and duodenum. CONCLUSION: Proton therapy reduced radiation dose to OAR compared to both IMRT and VMAT plans, and potentially reduce the risk of secondary cancer both overall and for most OAR.

Treatment of muscle-invasive urothelial cancer with nivolumab (CheckMate 274 study): a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a paper published in a medical journal that describes the results of a study called CheckMate 274. This study looked at a new treatment for muscle-invasive urothelial cancer, a type of cancer found in the urinary tract that has spread from the inner lining of the urinary tract or bladder and into the surrounding muscle wall where it can then spread to other parts of the body. The standard treatment for muscle-invasive urothelial cancer is surgery to remove affected parts of the urinary tract. However, cancer returns in more than half of people after this surgery. Adjuvant therapy is given to people after surgery with muscle-invasive urothelial cancer with a goal to reduce the risk of the cancer coming back; however, at the time this study started, there was no standard adjuvant treatment. WHAT HAPPENED IN THE STUDY?: In the CheckMate 274 study, researchers compared nivolumab with a placebo as an adjuvant treatment for people with muscle-invasive urothelial cancer. The aim of the study was to understand how well nivolumab worked to reduce the chance of the cancer returning after surgery. The study also looked at what side effects (unwanted or unexpected results or conditions that are possibly related to the use of a medication) people had with treatment. WHAT DO THE RESULTS MEAN?: The results showed that people who received nivolumab versus placebo: Survived longer before the cancer was detected again, including people who had programmed death ligand-1 (shortened to PD-L1) on their cancer cells. Survived longer before a secondary cancer outside of the urinary tract was detected. Experienced no differences in health-related quality of life (the impact of the treatment on a person's mental and physical health). Had similar side effects to the people who received nivolumab in other studies. Clinical Trial Registration: NCT02632409 (ClinicalTrials.gov).

Adverse health behaviours in long-term testicular cancer survivors: a Danish nationwide study.

BACKGROUND: Treatment for disseminated testicular cancer increases the risk of secondary malignancy and cardiovascular disease. The risk of developing these serious adverse effects may be positively affected by healthy living. The purpose of this study was to identify health behaviours with possible influence on late effects that could be targets for intervention. MATERIAL AND METHODS: In this cross-sectional study, testicular cancer survivors diagnosed in the period 1984-2007 from the Danish Testicular Cancer database completed a questionnaire on health behaviours (2014-2016). We estimated prevalence of smoking, alcohol consumption, sedentary lifestyle and overweight. Prevalence ratios described with 95% confidence intervals of adverse health behaviours were stratified by treatment modalities and compared to a reference population by means of logistic regression with adjustment for sociodemographic confounders. RESULTS: In total, 2395 testicular cancer survivors (surveillance, 1175; chemotherapy, 897; radiotherapy, 323), median time since diagnosis 19 years, and 65,289 noncancer males were included, questionnaire response rates were 60% and 54%, respectively. There were more current smokers (prevalence ratio; 1.14, 95% confidence interval (CI): 1.03-1.26) and patients with body mass index above 25 kg/m2 (prevalence ratio; 1.10, 95% CI: 1.01-1.20) among testicular cancer survivors than in the reference population. Testicular cancer survivors reported less sedentary lifestyle (prevalence ratio; 95% CI: 0.74, 0.64-0.85) and everyday drinkers were fewer (prevalence ratio; 0.79, 95% CI: 0.68-0.92) than in the reference population. CONCLUSION: We identified smoking cessation as primary target for intervention studies in testicular cancer survivors. The effect of smoking cessation interventions as part of treatment should be investigated. Whether drug-based intervention is effective in minimising the risk of exposure to conventional risk factors for cardiovascular disease is also of interest.

Ten years of experience with MRI follow-up of testicular cancer stage I: a retrospective study and an MRI protocol with DWI.

INTRODUCTION: Patients with testicular cancer (TC) are mainly young and survival rates are high. MRI has several times been proposed to replace CT in follow-up of this patient group to reduce image-related radiation exposure. However, current evidence is scarce for the use of MRI in this context. AIMS: First, to retrospectively evaluate the ability of MRI of the retroperitoneum and pelvis to detect relapse in patients with TC stage I. Second, to present a relevant MRI protocol of the retroperitoneum and pelvis with diffusion weighted imaging (DWI). MATERIAL AND METHODS: A retrospective analysis of written radiology reports compared to clinical data from clinical practice from 2010 to 2018. The cohort consists of 2487 MRIs of the retroperitoneum and pelvis in 759 patients with TC stage I (524 seminoma (69.0%), 235 non-seminoma (31.0%)), including 102 patients (13.4%) with confirmed relapse. Confirmed relapse was defined when treatment was initiated for metastatic TC. RESULTS: Ninety-five patients had a relapse in the MRI scan field during follow-up. MRI of the retroperitoneum and pelvis showed a high sensitivity of 93.8% and a high specificity of 97.4% for detecting TC relapse. The sensitivity for detecting relapse ≥10 mm in short axis lymph node diameter was 100%. The negative predictive value was 99.7%, the positive predictive value was 59.9% and the accuracy was 97.3%. CONCLUSIONS: MRI of the retroperitoneum and pelvis constitutes a safe alternative to CT in follow-up of patients with TC stage I with both a high sensitivity and a high specificity. We present a robust MRI protocol with DWI and estimate that MRI follow-up of TC stage I can be easily implemented in most modern radiology departments. Registration: Conducted with permission from the Danish Data Protection Agency (1-16-02-323-16) and the Danish Health Authority.

Safety and Activity of Sorafenib in Addition to Vinflunine in Post-Platinum Metastatic Urothelial Carcinoma (Vinsor): Phase I Trial.

LESSONS LEARNED: First trial to report safety and activity of the microtubule inhibitor vinflunine plus the tyrosine kinase inhibitor sorafenib in post-platinum metastatic urothelial cancer (mUC) patients.A recommended phase II dose was identified for the treatment combination of vinflunine plus sorafenib, with main adverse events including fatigue, febrile neutropenia, neutropenia, hypertension, and hyponatremia.An overall response rate of 41% to second-line vinflunine plus sorafenib treatment in patients with platinum-resistant mUC was confirmed. BACKGROUND: Platinum-progressive metastatic urothelial carcinoma (mUC) is a clinical challenge. The tyrosine kinase inhibitor sorafenib has demonstrated varied activity in mUC. This trial was designed to examine safety and activity of vinflunine plus sorafenib in mUC. METHODS: In addition to standard dose of vinflunine (320 or 280 mg/m2), patients received sorafenib (400, 600, or 800 mg/day), in a 3 + 3 dose-escalation phase I design. RESULTS: Twenty-two patients (median age 62.5 years) were included. Five patients received vinflunine 320 mg/m2 and 17 received 280 mg/m2. The maximum tolerated dose (MTD) of sorafenib with vinflunine 280 mg/m2 was 600 mg, and with vinflunine 320 mg/m2 it was not determined, owing to toxicity. Adverse events (AEs) grades 3 + 4 consisted of neutropenia (6 patients), febrile neutropenia (5), and hyponatremia (5). The overall response rate (ORR) in the efficacy-evaluable patients was 41% (7 of 17), all partial responses evaluated by RECIST version 1.1. Median overall survival (OS) was 7.0 months (1.8-41.7). CONCLUSION: The defined recommended phase II dose (RPTD) was vinflunine 280 mg/m2 plus sorafenib 400 mg. Sorafenib was too toxic in combination with vinflunine 320 mg/m2. The ORR of 41% to this second-line combination treatment of mUC is noteworthy and supports further trials.

Sexual Function in a Nationwide Cohort of 2,260 Survivors of Testicular Cancer after 17 Years of Followup.

PURPOSE: Evidence on the long-term impact of testicular cancer treatment on sexual function is not clear. Our aim was to estimate the effect of testicular cancer treatment on the risk of sexual dysfunction in long-term survivors of testicular cancer. MATERIALS AND METHODS: We performed a cross-sectional study of 2,260 long-term survivors of testicular cancer with a median followup of 17 years (IQR 12-24), including 1,098 who underwent orchiectomy alone (surveillance), 788 treated with bleomycin, etoposide and cisplatin alone or post-chemotherapy retroperitoneal surgery, 300 treated with abdominal radiotherapy and 74 who received more than 1 line of treatment. Sexual function was evaluated by the IIEF-15 (International Index of Erectile Function-15) questionnaire. Results were compared between treatment groups using logistic regression analysis with the results on each of the 5 IIEF-15 dimensions as the outcome and treatment as exposure using surveillance as the referent. RESULTS: The risk of erectile dysfunction was increased in all treatment groups compared to surveillance, including bleomycin, etoposide and cisplatin alone (OR 1.5, 95% CI 1.0-2.1, p <0.05), bleomycin, etoposide and cisplatin with post-chemotherapy surgery (OR 2.1, 95% CI 1.4-3.4, p <0.005), radiotherapy (OR 1.7, 95% CI 1.1-2.5, p <0.05) and more than 1 line of treatment (OR 3.2, 95% CI 1.6-6.3, p <0.005). Orgasmic dysfunction was associated with radiotherapy, bleomycin, etoposide and cisplatin with post-chemotherapy surgery and more than 1 line of treatment. CONCLUSIONS: Treatment with bleomycin, etoposide and cisplatin, radiotherapy and more than 1 treatment line increased the risk of erectile dysfunction in long-term survivors of testicular cancer compared to surveillance. Patients should be informed about this as part of the information on treatment related late effects.

Limited post-chemotherapy retroperitoneal resection of residual tumour in non-seminomatous testicular cancer: complications, outcome and quality of life.

BACKGROUND: Resection of residual masses after chemotherapy plays a crucial role in management of patients with germ cell tumours (GCTs). The extent of surgery is controversial and we present the experiences from Aarhus University Hospital over a 20-year period. The aim was to evaluate survival, complications, working ability and quality of life (QOL) following a limited surgical procedure performed to resect residual masses in non-seminomatous testicular cancer patients after chemotherapy. MATERIAL AND METHODS: A consecutive patient cohort of 109 patients having surgery between 1993 and 2013 was investigated. Hospital records were reviewed and complications were graded according to the Clavien-Dindo classification. QOL data were assessed in a cross-sectional analysis using the European Organisation for Research and Treatment of Cancer (EORTC), QLQ-C30 version 3.0. Patients were matched 1:1 with controls to evaluate the influence of surgical resection on the QOL. RESULTS: With a median follow-up of 10.3 years, 11 relapses in retroperitoneum were recorded in 10 patients (9%), and four patients (5%) died of disease progression. The majority of relapses in patients considered having no evidence of disease (NED) after primary retroperitoneal surgery occurred 10 + years after treatment and was outside the field of the elective lymph node dissection. Twenty-seven (44%) grade I, 15 (24%) grade II, 7 (11%) grade IIIa and 13 (21%) grade IIIb complications were recorded. No grade IV and V complications were observed. Twenty-three patients (20%) reported loss of antegrade ejaculation. We found no significant differences between patients and controls regarding QOL. CONCLUSION: The survival outcome and complication rate are favourable and are comparable to studies involving full and modified template lymph node dissection. We find that limited resection constitutes an applicable and safe procedure. Limited surgical resection did not influence the patients' long-term QOL. Longer follow-up might be considered.

Surveillance versus adjuvant radiotherapy for patients with high-risk stage I seminoma.

BACKGROUND: The optimal treatment strategy for patients with clinical stage I (CS-1) seminoma is controversial. The objective of the current study was to evaluate the outcomes for patients considered to be at high risk of disease recurrence with a tumor size ≥6 cm. Patients were treated with either adjuvant radiotherapy (RT) or followed with surveillance. METHODS: From the Danish Testicular Cancer database, the authors identified 473 patients with CS-1 seminoma with a tumor size ≥6 cm. Of these, 254 patients underwent adjuvant RT and 219 were followed with surveillance. Cumulative incidence function was applied to estimate the risk of disease recurrence, risk of second malignant neoplasm, and risk of receiving >1 line of treatment. Survival of the 2 groups was compared with the log-rank test and Cox model including age at diagnosis. RESULTS: No significant differences were found with regard to overall survival or risk of a second malignant neoplasm. Patients undergoing adjuvant RT received more treatments per patient than patients followed with surveillance, but there was no significant difference noted with regard to the risk of receiving >1 line of treatment. The 10-year cumulative incidence of disease recurrence was 32% versus 2.8%, respectively, for patients followed with surveillance and adjuvant RT. In patients followed with surveillance who developed disease recurrence, there was a high incidence of second recurrences after RT. CONCLUSIONS: The 10-year overall survival was found to be similar irrespective of primary treatment. Adjuvant RT was found to effectively reduce the rate of disease recurrence but resulted in the overtreatment of approximately two-thirds of the patients. The high incidence of second disease recurrences after RT in the patients followed with surveillance needs be addressed in future studies. Cancer 2017;123:1212-1218. © 2016 American Cancer Society.

Results from a Phase I Study of Lapatinib with Gemcitabine and Cisplatin in Advanced or Metastatic Bladder Cancer: EORTC Trial 30061.

BACKGROUND/OBJECTIVE: Lapatinib is a potent HER1 and HER2 inhibitor. Gemcitabine-cisplatin (GC) is a standard chemotherapy regimen for advanced/metastatic bladder cancer. This phase I study examined the safety of lapatinib in combination with GC in patients with bladder cancer. The primary aim was to determine the maximum tolerated dose (MTD) of lapatinib in combination with GC. METHODS: A 3 + 3 dose escalation protocol was used with lapatinib at 750, 1,000 and then 1,250 mg. It was dosed daily with gemcitabine (1,000 mg/m2 on days 1, 8 and 15) and cisplatin (70 mg/m2 on day 2) every 28 days. In all, 18 patients with a median age of 63 years (range 50-77) were included; 3/6, 3/5 and 6/7 patients received lapatinib at 750, 1,000 and 1,250 mg, combined with GC, in cohorts 1, 2 and 3, respectively. RESULTS: No dose-limiting toxicities (DLTs) were observed in cohort 1 or 2 (3 patients each); in cohort 3 (2 × 3 patients), 1 of the 6 patients presented DLTs (grade 4, treatment-related febrile neutropenia and renal failure). Twelve patients received 6 cycles. CONCLUSIONS: Lapatinib at 750-1,250 mg combined with GC appears safe and tolerable. The MTD of lapatinib combined with GC in bladder cancer was 1,250 mg.

Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial.

BACKGROUND: Patients with muscle-invasive urothelial carcinoma of the bladder have poor survival after cystectomy. The EORTC 30994 trial aimed to compare immediate versus deferred cisplatin-based combination chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder. METHODS: This intergroup, open-label, randomised, phase 3 trial recruited patients from hospitals across Europe and Canada. Eligible patients had histologically proven urothelial carcinoma of the bladder, pT3-pT4 disease or node positive (pN1-3) M0 disease after radical cystectomy and bilateral lymphadenectomy, with no evidence of any microscopic residual disease. Within 90 days of cystectomy, patients were centrally randomly assigned (1:1) by minimisation to either immediate adjuvant chemotherapy (four cycles of gemcitabine plus cisplatin, high-dose methotrexate, vinblastine, doxorubicin, and cisplatin [high-dose MVAC], or MVAC) or six cycles of deferred chemotherapy at relapse, with stratification for institution, pT category, and lymph node status according to the number of nodes dissected. Neither patients nor investigators were masked. Overall survival was the primary endpoint; all analyses were by intention to treat. The trial was closed after recruitment of 284 of the planned 660 patients. This trial is registered with ClinicalTrials.gov, number NCT00028756. FINDINGS: From April 29, 2002, to Aug 14, 2008, 284 patients were randomly assigned (141 to immediate treatment and 143 to deferred treatment), and followed up until the data cutoff of Aug 21, 2013. After a median follow-up of 7.0 years (IQR 5.2-8.7), 66 (47%) of 141 patients in the immediate treatment group had died compared with 82 (57%) of 143 in the deferred treatment group. No significant improvement in overall survival was noted with immediate treatment when compared with deferred treatment (adjusted HR 0.78, 95% CI 0.56-1.08; p=0.13). Immediate treatment significantly prolonged progression-free survival compared with deferred treatment (HR 0.54, 95% CI 0.4-0.73, p<0.0001), with 5-year progression-free survival of 47.6% (95% CI 38.8-55.9) in the immediate treatment group and 31.8% (24.2-39.6) in the deferred treatment group. Grade 3-4 myelosuppression was reported in 33 (26%) of 128 patients who received treatment in the immediate chemotherapy group versus 24 (35%) of 68 patients who received treatment in the deferred chemotherapy group, neutropenia occurred in 49 (38%) versus 36 (53%) patients, respectively, and thrombocytopenia in 36 (28%) versus 26 (38%). Two patients died due to toxicity, one in each group. INTERPRETATION: Our data did not show a significant improvement in overall survival with immediate versus deferred chemotherapy after radical cystectomy and bilateral lymphadenectomy for patients with muscle-invasive urothelial carcinoma. However, the trial is limited in power, and it is possible that some subgroups of patients might still benefit from immediate chemotherapy. An updated individual patient data meta-analysis and biomarker research are needed to further elucidate the potential for survival benefit in subgroups of patients. FUNDING: Lilly, Canadian Cancer Society Research.

Cognitive impairment and potential biological and psychological correlates of neuropsychological performance in recently orchiectomized testicular cancer patients.

OBJECTIVE: The aim of this study was to determine the prevalence of cognitive impairment (CI) in newly diagnosed and orchiectomized testicular cancer (TC) patients prior to systemic treatment, and to explore biological and psychological correlates. METHODS: Sixty-six TC patients were compared with 25 healthy men on neuropsychological tests and a measure of cognitive complaints. CI status and a global composite score (representing overall neuropsychological performance) were calculated for each participant. Possible psychological (depression, anxiety, stress, and post-traumatic stress symptoms) and biological (cortisol, IL-6, TNF-α, and CRP) correlates and predictors of patients' cognitive functioning were explored. RESULTS: TC patients had lower scores on 6 out of 11 neuropsychological outcomes (p < 0.01) in processing speed, attention, and working memory, verbal learning and memory, and verbal fluency. Prevalence of CI among TC patients was 58%, significantly exceeding the frequency in healthy men (p < 0.01). Patients' cortisol levels predicted overall neuropsychological performance (p = 0.04). Cognitive complaints were associated with IL-6 (p = 0.02) and all psychological distress measures (p < 0.001). CONCLUSIONS: The prevalence of CI in recently orchiectomized TC patients was unexpectedly high with patients performing more poorly than healthy controls on a majority of neuropsychological outcomes. Cortisol is a potential predictor of neuropsychological performance in TC patients prior to cytotoxic treatment.

Intra-fractional bladder motion and margins in adaptive radiotherapy for urinary bladder cancer.

BACKGROUND: The bladder is a tumour site well suited for adaptive radiotherapy (ART) due to large inter-fractional changes, but it also displays considerable intra-fractional motion. The aim of this study was to assess target coverage with a clinically applied method for plan selection ART and to estimate population-based and patient-specific intra-fractional margins, also relevant for a future re-optimisation strategy. MATERIAL AND METHODS: Nine patients treated in a clinical phase II ART trial of daily plan selection for bladder cancer were included. In the library plans, 5 mm isotropic margins were added to account for intra-fractional changes. Pre-treatment and weekly repeat magnetic resonance imaging (MRI) series were acquired in which a full three-dimensional (3D) volume was scanned every second min for 10 min (a total of 366 scans in 61 series). Initially, the bladder clinical target volume (CTV) was delineated in all scans. The t = 0 min scan was then rigidly registered to the planning computed tomography (CT) and plan selections were simulated using the CTV_0 (at t = 0 min). To assess intra-fractional motion, coverage of the CTV_10 (at t = 10 min) was quantified using the applied PTV. Population-based margins were calculated using the van Herk margin recipe while patient-specific margins were calculated using a linear model. RESULTS: For 49% of the cases, the CTV_10 extended more than 5 mm outside the CTV_0. However, in 58 of the 61 cases (97%) CTV_10 was covered by the selected PTV. Population-based margins of 14 mm Sup/Ant, 9 mm Post and 5 mm Inf/Lat were sufficient to cover the bladder. Using patient-specific margins, the overlap between PTV and bowel-cavity was reduced from 137 cm(3) with the plan selection strategy to 24 cm(3). CONCLUSION: In this phase II ART trial, 5 mm isotropic margin for intra-fractional motion was sufficient even though considerable intra-fractional motion was observed. In online re-optimised ART, population-based margin can be applied although patient-specific margins are preferable.

Cognitive impairment in testicular cancer survivors 2 to 7 years after treatment.

PURPOSE: The aim of the present study was to determine the prevalence of cognitive impairment (CI) in a group of testicular (TC) survivors by comparing their neuropsychological test scores with normative data and to assess their performance in specific cognitive domains. METHODS: Seventy-two TC survivors were evaluated 2 to 7 years post-treatment with a neuropsychological test battery that assessed multiple cognitive domains-attention and working memory, processing speed, verbal fluency, learning and memory, and executive functioning. Test scores were compared with normative data, and CI status was calculated for each participant. RESULTS: In group-level analyses, survivors exhibited significantly impaired scores on a majority (9/12) of the neuropsychological outcomes (p < 0.01). In individual-level analyses, 62.5 % of the survivors were classified as having CI, significantly exceeding the expected normative frequency of 25 % (binomial test: p < 0.001). In particular, CI was observed in multiple outcomes related to verbal learning and memory (29 to 33 % of participants), visual learning and memory (14-28 %), processing speed (8-24 %), executive functioning (17 %), and attention and working memory (4-15 %). No association was found between treatment modality (surgery ± chemotherapy) and CI. CONCLUSIONS: The prevalence of CI in TC survivors was unexpectedly high, with survivors performing significantly worse than expected on a majority of the neuropsychological outcomes. While the findings are preliminary in nature, they still have important implications for the diagnosis and treatment of CI in TC survivors.

A comparison of morbidity following conformal versus intensity-modulated radiotherapy for urinary bladder cancer.

BACKGROUND: In radiotherapy (RT) of urinary bladder cancer, the use of intensity-modulated RT (IMRT) opens for sparing of considerable intestinal volumes. The purpose of the present study was to investigate the acute and late toxicities following either conformal RT (CRT) or IMRT for bladder cancer, and to correlate the toxicities to dose-volume parameters. MATERIAL AND METHODS: The study included 116 consecutively treated patients with muscle-invasive bladder cancer who received either CRT (n = 66) or IMRT (n = 50) during 2007-2010. Acute side effects were retrospectively collected whereas late effects were assessed by a cross-sectional evaluation by telephone interview of 44 recurrence-free patients. Acute and late toxicities were scored according to the Common Terminology Criteria for Adverse Event (CTCAE) version 3.0. RESULTS: Acute diarrhoea grade ≥ 2 was more frequent in patients treated by CRT (56%) compared to IMRT (30%) (p = 0.008). Logistic regression analysis showed a correlation between acute diarrhoea and bowel cavity dose-volume parameters in the 10-50 Gy range. Severe late toxicity (grade ≥ 3) was recorded in 10% of the total cohort, with no statistical difference between the IMRT and CRT groups. CONCLUSION: Patients treated with IMRT for bladder cancer had significantly less acute diarrhoea compared to those treated with CRT, but there was no significant difference in late morbidity between the groups. The risk of acute diarrhoea was related to the volume of bowel irradiated.

Normal tissue sparing in a phase II trial on daily adaptive plan selection in radiotherapy for urinary bladder cancer.

UNLABELLED: Background: Patients with urinary bladder cancer often display large changes in the shape and size of their bladder target during a course of radiotherapy (RT), making adaptive RT (ART) appealing for this tumour site. We are conducting a clinical phase II trial of daily plan selection-based ART for bladder cancer and here report dose-volume data from the first 20 patients treated in the trial. MATERIAL AND METHODS: All patients received 60 Gy in 30 fractions to the bladder; in 13 of the patients the pelvic lymph nodes were simultaneously treated to 48 Gy. Daily patient set-up was by use of cone beam computed tomography (CBCT) guidance. The first 5 fractions were delivered with large, population-based (non-adaptive) margins. The bladder contours from the CBCTs acquired in the first 4 fractions were used to create a patient-specific library of three plans, corresponding to a small, medium and large size bladder. From fraction 6, daily online plan selection was performed, where the smallest plan covering the bladder was selected prior to each treatment delivery. A total of 600 treatment fractions in the 20 patients were evaluated. RESULTS: Small, medium and large size plans were used almost equally often, with an average of 10, 9 and 11 fractions, respectively. The median volume ratio of the course-averaged PTV (PTV-ART) relative to the non-adaptive PTV was 0.70 (range: 0.46-0.89). A linear regression analysis showed a 183 cm(3) (CI 143-223 cm(3)) reduction in PTV-ART compared to the non-adaptive PTV (R(2) = 0.94). CONCLUSION: Daily adaptive plan selection in RT of bladder cancer results in a considerable normal tissue sparing, of a magnitude that we expect will translate into a clinically significant reduction of the treatment-related morbidity.

Postchemotherapy Retroperitoneal Lumpectomy in Patients with Nonseminoma Testicular Cancer: A Nationwide Study.

BACKGROUND AND OBJECTIVE: Optimal treatment outcomes in patients with metastatic nonseminoma testicular cancer are achieved with chemotherapy and subsequent surgery in cases with residual tumor. In Denmark, postchemotherapy retroperitoneal lumpectomy (RPLP) is performed in patients with residual tumors >1 cm. There is a need to clarify whether this surgical method provides acceptable treatment results. Our objective was to describe morbidity and oncological outcomes of postchemotherapy RPLP. METHODS: This was a retrospective population-based multicenter study including patients with nonseminoma testicular cancer and postchemotherapy RPLP performed in Denmark between 1990 and 2015. A total of 219 patients were eligible, with median follow-up of 19 yr. Postoperative complications were evaluated according to the Clavien-Dindo classification. The cumulative incidence of recurrence inside or outside the borders of a bilateral surgical template, progression-free survival (PFS), and overall survival estimates were calculated using the Kaplan-Meier method. KEY FINDINGS AND LIMITATIONS: After median follow-up of 19 yr, 31/219 patients (14%) experienced a surgical complication, of which 5% were Clavien-Dindo grade ≥III. In total, 37 patients experienced a recurrence. The 5-yr, 10-yr, and 20-yr cumulative risk of recurrence inside a bilateral template was 4.3%, 5.9%, and 5.9%, respectively. The 10-yr PFS rate was 83% and the 10-yr overall survival rate was 96%. The main limitation of the study is the retrospective design. CONCLUSIONS AND CLINICAL IMPLICATIONS: With few patients experiencing a major postoperative complication and a 10-yr cumulative rate of 5.9% for recurrence inside a bilateral surgical template, postchemotherapy RPLP appears to be a safe alternative to template surgery for disseminated nonseminoma. PATIENT SUMMARY: We looked at minimal surgery to remove tumor tissue remaining after chemotherapy in patients with testicular cancer. We found a low frequency of complications, tumor recurrence, and death.

Use of Risk Factors To Select Adjuvant Therapy Versus Surveillance for Testicular Nonseminoma and Seminoma Germ Cell Tumors.

New risk factors associated with relapse of stage I testicular cancer have been identified. These new factors reflect the risk of recurrence much better than previous parameters and can be used to assess the possible effect of adjuvant chemotherapy.