Search

BC2001, the largest randomised trial of bladder-sparing treatment for muscle-invasive bladder cancer (MIBC), demonstrated improvement in locoregional control by adding fluorouracil and mitomycin C to radiotherapy (James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477-88). There are limited data on long-term recurrence risk.To determine whether benefit of adding chemotherapy to radiotherapy for MIBC is maintained in the long term.A phase 3 randomised controlled 2 × 2 factorial trial was conducted. Between 2001 and 2008, 458 patients with T2-T4a N0M0 MIBC were enrolled; 360 were randomised to radiotherapy (178) or chemoradiotherapy (182), and 218 were randomised to standard whole-bladder radiotherapy (108) or reduced high-dose-volume radiotherapy (111). The median follow-up time was 9.9 yr. The trial is registered (ISRCTN68324339).Radiotherapy: 55 Gy in 20 fractions over 4 wk or 64 Gy in 32 fractions over 6.5 wk; concurrent chemotherapy: 5-fluorouracil and mitomycin C.Locoregional control (primary endpoint), invasive locoregional control, toxicity, rate of salvage cystectomy, disease-free survival (DFS), metastasis-free survival (MFS), bladder cancer-specific survival (BCSS), and overall survival. Cox regression was used. The analysis of efficacy outcomes was by intention to treat.Chemoradiotherapy improved locoregional control (hazard ratio [HR] 0.61 [95% confidence interval {CI} 0.43-0.86], p = 0.004) and invasive locoregional control (HR 0.55 [95% CI 0.36-0.84], p = 0.006). This benefit translated, albeit nonsignificantly, for disease-related outcomes: DFS (HR 0.78 [95% CI 0.60-1.02], p = 0.069), MFS (HR 0.78, [95% CI 0.58-1.05], p = 0.089), overall survival (HR = 0.88 [95% CI 0.69-1.13], p = 0.3), and BCSS (HR 0.79 [95% CI 0.59-1.06], p = 0.11). The 5-yr cystectomy rate was 14% (95% CI 9-21%) with chemoradiotherapy versus 22% (95% CI 16-31%) with radiotherapy alone (HR 0.54, [95% CI 0.31-0.95], p = 0.034). No differences were seen between standard and reduced high-dose-volume radiotherapy.Long-term findings confirm the benefit of adding concomitant 5-fluorouracil and mitomycin C to radiotherapy for MIBC.We looked at long-term outcomes of a phase 3 clinical trial testing radiotherapy with or without chemotherapy for patients with invasive bladder cancer. We concluded that the benefit of adding chemotherapy to radiotherapy was maintained over 10 yr.

Redacted protocol for supplementary files

Table S1. Canadian tissue microarray, histology and relapse rate details. Table S2. Univariate, stratified and multivariate models for prognostic ability of VI, CXCL12 expression. Table S3. Multivariate analyses; alternative models. Figure S1: Kaplan-Meier relapse-free survival curves in combined TE08 and TE22 trial cohorts with (n=190) and without FFPE (n=501). Figure S2: Relapse-free rate by CXCL12 intensity (

Supplementary data from Clinical and Genome-wide Analysis of Cisplatin-induced Tinnitus Implicates Novel Ototoxic Mechanisms

Supplementary Figure 4 shows pharmacokinetic parameters for guadecitabine and decitabine in the dose escalation phase

Purpose:Preclinical data indicate that DNA methyltransferase inhibition will circumvent cisplatin resistance in various cancers.Patient and Methods:SPIRE comprised a dose-escalation phase for incurable metastatic solid cancers, followed by a randomized dose expansion phase for neoadjuvant treatment of T2–4a N0 M0 bladder urothelial carcinoma. The primary objective was a recommended phase II dose (RP2D) for guadecitabine combined with gemcitabine and cisplatin. Treatment comprised 21-day gemcitabine and cisplatin cycles (cisplatin 70 mg/m2, i.v., day 8 and gemcitabine 1,000 mg/m2, i.v., days 8 + 15). Guadecitabine was injected subcutaneously on days 1–5, within escalation phase cohorts, and to half of 20 patients in the expansion phase. Registration ID: ISRCTN 16332228.Results:Within the escalation phase, dose-limiting toxicities related predominantly to myelosuppression requiring G-CSF prophylaxis from cohort 2 (guadecitabine 20 mg/m2, days 1–5). The most common grade ≥3 adverse events in 17 patients in the dose-escalation phase were neutropenia (76.5%), thrombocytopenia (64.7%), leukopenia (29.4%), and anemia (29.4%). Addition of guadecitabine to gemcitabine and cisplatin in the expansion phase resulted in similar rates of severe hematologic adverse events, similar cisplatin dose intensity, but modestly reduced gemcitabine dose intensity. Radical treatment options after chemotherapy were not compromised. Pharmacodynamics evaluations indicated guadecitabine maximal target effect at the point of cisplatin administration. Pharmacokinetics were consistent with prior data. No treatment-related deaths occurred.Conclusions:The guadecitabine RP2D was 20 mg/m2, days 1–5, in combination with gemcitabine and cisplatin and required GCSF prophylaxis. Gene promoter methylation pharmacodynamics are optimal with this schedule. Addition of guadecitabine to gemcitabine and cisplatin was tolerable, despite some additional myelosuppression, and warrants further investigation to assess efficacy.

Purpose:Cisplatin, a commonly used chemotherapeutic, results in tinnitus, the phantom perception of sound. Our purpose was to identify the clinical and genetic determinants of tinnitus among testicular cancer survivors (TCS) following cisplatin-based chemotherapy.Experimental Design:TCS (n = 762) were dichotomized to cases (moderate/severe tinnitus; n = 154) and controls (none; n = 608). Logistic regression was used to evaluate associations with comorbidities and SNP dosages in genome-wide association study (GWAS) following quality control and imputation (covariates: age, noise exposure, cisplatin dose, genetic principal components). Pathway over-representation tests and functional studies in mouse auditory cells were performed.Results:Cisplatin-induced tinnitus (CisIT) significantly associated with age at diagnosis (P = 0.007) and cumulative cisplatin dose (P = 0.007). CisIT prevalence was not significantly greater in 400 mg/m2-treated TCS compared with 300 (P = 0.41), but doses >400 mg/m2 (median 580, range 402–828) increased risk by 2.61-fold (P < 0.0001). CisIT cases had worse hearing at each frequency (0.25–12 kHz, P < 0.0001), and reported more vertigo (OR = 6.47; P < 0.0001) and problems hearing in a crowd (OR = 8.22; P < 0.0001) than controls. Cases reported poorer health (P < 0.0001) and greater psychotropic medication use (OR = 2.4; P = 0.003). GWAS suggested a variant near OTOS (rs7606353, P = 2 × 10−6) and OTOS eQTLs were significantly enriched independently of that SNP (P = 0.018). OTOS overexpression in HEI-OC1, a mouse auditory cell line, resulted in resistance to cisplatin-induced cytotoxicity. Pathway analysis implicated potassium ion transport (q = 0.007).Conclusions:CisIT associated with several neuro-otological symptoms, increased use of psychotropic medication, and poorer health. OTOS, expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells.

Purpose: Up to 50% of patients diagnosed with stage I nonseminomatous germ cell tumors (NSGCTs) harbor occult metastases. Patients are managed by surveillance with chemotherapy at relapse or adjuvant treatment up front. Late toxicities from chemotherapy are increasingly recognized. Based on a potential biologic role in germ cells/tumors and pilot data, our aim was to evaluate tumor expression of the chemokine CXCL12 alongside previously proposed markers as clinically useful biomarkers of relapse.Experimental Design: Immunohistochemistry for tumor expression of CXCL12 was assessed as a biomarker of relapse alongside vascular invasion, histology (percentage embryonal carcinoma), and MIB1 staining for proliferation in formalin-fixed paraffin-embedded orchidectomy samples from patients enrolled in the Medical Research Council's TE08/22 prospective trials of surveillance in stage I NSGCTs.Results: TE08/TE22 trial patients had a 76.4% 2-year relapse-free rate, and both CXCL12 expression and percentage embryonal carcinoma provided prognostic value independently of vascular invasion (stratified log rank test P = 0.006 for both). There was no additional prognostic value for MIB1 staining. A model using CXCL12, percentage embryonal carcinoma, and VI defines three prognostic groups that were independently validated.Conclusions: CXCL12 and percentage embryonal carcinoma both stratify patients' relapse risk over and above vascular invasion alone. This is anticipated to improve the stratification of patients and identify high-risk cases to be considered for adjuvant therapy. Clin Cancer Res; 22(5); 1265–73. ©2015 AACR.

Supplementary Tables and Methods

Supplementary Figure 1 shows a schematic of the treatment cycle

Supplementary Figure 2 shows CONSORT diagrams for both phases of the trial

Supplementary Figure 3 shows promotor methylation status for the indicated genes in cfDNA

Purpose: High-field magnetic resonance-linear accelerators (MR-Linacs), linear accelerators combined with a diagnostic magnetic resonance imaging (MRI) scanner and online adaptive workflow, potentially give rise to novel online anatomic and response adaptive radiation therapy paradigms. The first high-field (1.5T) MR-Linac received regulatory approval in late 2018, and little is known about clinical use, patient tolerability of daily high-field MRI, and toxicity of treatments. Herein we report the initial experience within the MOMENTUM Study (NCT04075305), a prospective international registry of the MRLinac Consortium. Methods and Materials: Patients were included between February 2019 and October 2020 at 7 institutions in 4 countries. We used descriptive statistics to describe the patterns of care, tolerability (the percentage of patients discontinuing their course early), and safety (grade 3-5 Common Terminology Criteria for Adverse Events v.5 acute toxicity within 3 months after the end of treatment). Results: A total 943 patients participated in the MOMENTUM Study, 702 of whom had complete baseline data at the time of this analysis. Patients were primarily male (79%) with a median age of 68 years (range, 22-93) and were treated for 39 different indications. The most frequent indications were prostate (40%), oligometastatic lymph node (17%), brain (12%), and rectal (10%) cancers. The median number of fractions was 5 (range, 1-35). Six patients discontinued MR-Linac treatments, but none due to an inability to tolerate repeated high-field MRI. Of the 415 patients with complete data on acute toxicity at 3 month follow-up, 18 (4%) patients experienced grade 3 acute toxicity related to radiation. No grade 4 or 5 acute toxicity related to radiation was observed. Conclusions: In the first 21 months of our study, patterns of care were diverse with respect to clinical utilization, body sites, and radiation prescriptions. No patient discontinued treatment due to inability to tolerate daily high-field MRI scans, and the acute radiation toxicity experience was encouraging. (c) 2021 Published by Elsevier Inc.

Background Retroperitoneal lymph node dissection (RPLND) is essential for the treatment of metastatic germ cell tumours of the testis. Recommendations on the referral and management of complex urological cancers in the UK includes centralisation of services to regional centres. Objective To review contemporary PC-RPLND outcomes at a high-volume centre with a complex case-mix, and compare with national registry data. Design, setting, and participants We retrospectively reviewed the medical records of PC-RPLNDs performed for germ cell tumours at our centre between July 2012 and September 2018. Outcome measurements and statistical analysis Primary outcomes were Clavien 3+ complications, histology, rates of positive margin, relapse, in-field recurrences, and mortality. Secondary outcomes were blood loss, operation time, blood transfusion, adjuvant procedures, length of stay, and lymph node count. Surgical and histological outcomes of all RPLNDs for testicular cancers were compared with national RPLND registry data. For statistical difference, χ2 testing was used. Results and limitations A total of 178 procedures were performed, including 31 (17%) redo RPLNDs. Clavien 3+ complications occurred in 11 (7%). Histological findings in non-redo cases were the following: necrosis 24%, teratoma 62%, viable germ cell tumour 11%, and dedifferentiated cancers 3%. Rates of positive margin, relapse, and in-field recurrence were 11%, 17%, and 2%, respectively. Overall survival was 89% at a median of 36 mo. The median blood loss was 650 ml (350, 1250), with a transfusion rate of 8%. Nephrectomy, vascular reconstruction, and visceral resection was required in 12%, 6%, and 3% respectively. The median inpatient stay was 6 d (5, 8) and the median node count was 35 (20, 37). A comparison of all RPLNDs with national data showed no statistical difference in primary outcomes. Our blood transfusion rate was significantly lower (12% vs 21%, χ2 [1, N = 322] = 4.296, p = 0.038). Conclusions Centralisation led to high quality of RPLND in UK. Within that, our series (the largest in the UK) demonstrates no significant difference in outcomes despite higher complexity cases. Our blood transfusion rates are in fact lower than national figures. Complex RPLNDs should be performed in high-volume centres where possible. Patient summary In the UK, retroperitoneal lymph node dissections (RPLND) are centralised to specialist centres and the quality of surgery is high, with low complications and good histological outcomes. When compared to national data, we found no significant difference in the majority of outcomes from our high-volume centre despite our complex case-mix., Take Home Message This is the largest postchemotherapy retroperitoneal lymph node dissection (RPLND) series in the UK. Centralisation has led to a high standard of RPLNDs nationally, lower proportion of RPLNDs performed for necrosis only, and the evolution of high-volume centres. The benefits of high volume centres are the following: no significant difference in the majority of outcomes despite the higher proportion of complex cases and a reduced blood transfusion rate; transfusion is linked to poorer oncological outcomes in a number of malignancies.

Background Late relapse (LR) of nonseminomatous germ cell tumour (NSGCT) is uncommon, with limited data published. LR is defined as relapse occurring after a disease-free interval of 2 yr. Objective To review features of NSGCT LR in a UK tertiary centre. Design, setting, and participants A total of 3064 patients were referred from January 2005 to December 2017. We identified patients who experienced LR after initial pathology demonstrated NSGCT and reviewed data for their original and LR presentation and management. Outcome measurements and statistical analysis Outcomes included time to LR measured from the date of diagnosis, and overall survival. This was assessed using Cox proportional Hazards modelling, with stratification or adjustment for potential confounders. Results and limitations We identified 101 patients with LR; the median time to LR was 96 mo. Forty-three patients (42.6%) experienced relapse after 10 yr. Univariable log-rank testing revealed that the median time to LR was significantly shorter for patients who had not received induction chemotherapy (iCTx; 54 mo, 95% confidence interval [CI] 48–108) than for those who did (112 mo, 95% CI 84–186; p = 0.04). Patients who had received iCTx were less likely to have elevated tumour markers (36% vs 46%) and more likely to undergo initial surgical resection at LR compared to CTx-naïve patients. Postpubertal teratoma (PPT), yolk sac, and dedifferentiated elements predominated for patients with iCTx exposure, whereas active GCT or fibrosis predominated in postchemotherapy resections for CTx-naïve patients at LR. Forty-one men underwent postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) as part of their initial treatment for metastatic disease. Of these, 20 experienced LR in the retroperitoneum, with 18 undergoing repeat RPLND as part of their LR management. Fifteen of the repeat RPLND histopathology specimens had a PPT component. There have been 23 deaths overall; survival was worse for patients presenting with symptoms (13/36, 33%) and those receiving CTx and no surgery (10/17, 59%) at LR. Conclusions When LR of NSGCT occurs, it is frequently after an extended interval and is later among patients with prior iCTx, with PPT predominating. The high frequency of LR within the retroperitoneum following PC-RPLND reinforces the need for good-quality PC-RPLND. Patient summary We reviewed data for patients who had a late relapse of testicular cancer. We found that patients who did not receive chemotherapy as the first treatment for their initial diagnosis had a shorter time to relapse. Our results highlight the importance of long-term follow-up for testicular cancer., Take Home Message Late recurrence of nonseminomatous germ cell tumours most frequently occurs more than 10 yr after the initial diagnosis.

Purpose: Small cell carcinoma of the bladder (SCCB) is rare, accounting for less than 1% of all bladder carcinomas. It is aggressive, and outcomes are poor as a result of its early metastatic spread. Owing to its rarity, there are limitations on data to propose standardized management pathways. Methods and Materials: We conducted a retrospective analysis of patients presenting with pure or predominant-histology SCCB to 26 institutions in the United Kingdom between 2006 and 2016. The data cutoff date was February 1, 2018. We report patient characteristics, treatment received, and subsequent clinical outcomes. Results: A total of 409 eligible patients were included. Among these, 306 (74.8%) were male, the median age was 71 years (range, 35-96 years), and 189 patients (46.2%) had pure-histology SCCB. At data cutoff, 301 patients (73.6%) had died. The median overall survival (OS) was 15.9 months (95% CI, 13.2-18.7 months). Two hundred patients (48.9%) were confirmed to have bladder-confined disease (N0, M0), with a median OS of 28.3 months (95% CI, 20.9-35.8 months), versus a median OS of 12.7 months (95% CI, 10.9-14.6 months) for the 172 patients (42.1%) with confirmed N1-3 and/or M1 disease (hazard ratio [HR], 2.03; 95% CI, 1.58-2.60; P < .001). A total of 247 patients (61.5%) received primary chemotherapy, with a median OS of 21.6 months (95% CI, 15.5-27.6 months), versus a median OS of 9.1 months (95% CI, 5.4-12.8 months) in patients who did not receive primary chemotherapy (HR, 0.46; 95% CI, 0.37-0.59; P < .001). Choice of chemotherapy agent did not alter outcomes. For those with bladder-confined disease, 61 (30.5%) underwent cystectomy, and 104 (52.0%) received radiation therapy. Survival outcomes were similar for both cystectomy and radiation therapy. Only 6 patients (1.5%) were identified as having brain metastases at any time point. Conclusions: To our knowledge, this is the largest retrospective study of all-stage SCCB to date. Patients have a poor prognosis overall, but survival is improved in those able to receive chemotherapy and with organ-confined disease. Brain metastases are rare.

Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

PURPOSE: Hypofractionated radiation therapy can be used to treat patients with muscle-invasive bladder cancer unable to have radical therapy. Toxicity is a key concern, but adaptive plan-of the day (POD) image-guided radiation therapy delivery could improve outcomes by minimizing the volume of normal tissue irradiated. The HYBRID trial assessed the multicenter implementation, safety, and efficacy of this strategy.METHODS: HYBRID is a Phase II randomized trial that was conducted at 14 UK hospitals. Patients with T2-T4aN0M0 muscle-invasive bladder cancer unsuitable for radical therapy received 36 Gy in 6 weekly fractions, randomized (1:1) to standard planning (SP) or adaptive planning (AP) using a minimization algorithm. For AP, a pretreatment cone beam computed tomography (CT) was used to select the POD from 3 plans (small, medium, and large). Follow-up included standard cystoscopic, radiologic, and clinical assessments. The primary endpoint was nongenitourinary Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 (≥G3) toxicity within 3 months of radiation therapy. A noncomparative single stage design aimed to exclude ≥30% toxicity rate in each planning group in patients who received ≥1 fraction of radiation therapy. Local control at 3-months (both groups combined) was a key secondary endpoint.RESULTS: Between April 15, 2014, and August 10, 2016, 65 patients were enrolled (SP, n = 32; AP, n = 33). The median follow-up time was 38.8 months (interquartile range [IQR], 36.8-51.3). The median age was 85 years (IQR, 81-89); 68% of participants (44 of 65) were male; and 98% of participants had grade 3 urothelial cancer. In 63 evaluable participants, CTCAE ≥G3 nongenitourinary toxicity rates were 6% (2 of 33; 95% confidence interval [CI], 0.7%-20.2%) for the AP group and 13% (4 of 30; 95% CI, 3.8%-30.7%) for the SP group. Disease was present in 9/48 participants assessed at 3 months, giving a local control rate of 81.3% (95% CI, 67.4%-91.1%).CONCLUSIONS: POD adaptive radiation therapy was successfully implemented across multiple centers. Weekly ultrahypofractionated 36 Gy/6 fraction radiation therapy is safe and provides good local control rates in this older patient population.

PURPOSE The classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) plays a pivotal role in the management of metastatic germ cell tumors but relies on data of patients treated between 1975 and 1990. MATERIALS AND METHODS Data on 9,728 men with metastatic nonseminomatous germ cell tumors treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Europe, North America, and Australia. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS). The survival estimates were updated for the current era. Additionally, a novel prognostic model for PFS was developed in 3,542 patients with complete information on potentially relevant variables. The results were validated in an independent data set. RESULTS Compared with the original IGCCCG publication, 5-year PFS remained similar in patients with good prognosis with 89% (87%-91%) versus 90% (95% CI, 89 to 91), but the 5-year OS increased from 92% (90%-94%) to 96% (95%-96%). In patients with intermediate prognosis, PFS remained similar with 75% (71%-79%) versus 78% (76%-80%) and the OS increased from 80% (76%-84%) to 89% (88%-91%). In patients with poor prognosis, the PFS increased from 41% (95% CI, 35 to 47) to 54% (95% CI, 52 to 56) and the OS from 48% (95% CI, 42 to 54) to 67% (95% CI, 65 to 69). A more granular prognostic model was developed and independently validated. This model identified a new cutoff of lactate dehydrogenase at a 2.5 upper limit of normal and increasing age and presence of lung metastases as additional adverse prognostic factors. An online calculator is provided ( https://www.eortc.org/IGCCCG-Update ). CONCLUSION The IGCCCG Update model improves individual prognostication in metastatic nonseminomatous germ cell tumors. Increasing age and lung metastases add granularity to the original IGCCCG classification as adverse prognostic factors.

Background BC2001 demonstrated improved local control with the addition of chemotherapy to radiotherapy in 360 patients with muscle-invasive bladder cancer. Objective To establish whether such benefit remained in BC2001 patients who received prior neoadjuvant chemotherapy. Design, setting, and participants A total of 117 patients (33%) received neoadjuvant chemotherapy and were randomised to radiotherapy with (48%) or without (52%) concomitant chemotherapy. Patients were recruited between August 2001 and April 2008 from 28 UK centres. Intervention Platinum-based neoadjuvant chemotherapy, followed by radiotherapy with (cRT) or without (RT) synchronous 5-fluorouracil and mitomycin-C. Outcome measurements and statistical analysis Toxicity, locoregional control (LRC), overall survival (OS), and quality of life (QoL) were measured. Results and limitations Of the patients, 74% received gemcitabine plus cisplatin or carboplatin. Compliance rates with full-dose radiotherapy were cRT 93% and RT 92%. An excess of grade ≥3 toxicities while on (chemo)radiation occurred for cRT 33% versus RT 22%, although nonstatistically significant (p = 0.16). With 110 mo median follow-up for survival (interquartile range 96–123), cRT showed improved LRC though not statistically significant (adjusted hazard ratio [aHR] = 0.64, 95% confidence interval [CI] 0.33–1.23, p = 0.18). No differences in OS (aHR = 0.95, 95% CI 0.57–1.57, p = 0.8) were observed. No significant detriment in QoL was observed between cRT and RT in this subgroup of patients. Conclusions Neoadjuvant chemotherapy does not compromise the delivery of radical curative treatment. Although underpowered due to a small sample size, the benefit of chemoradiotherapy to improve local control in this group of patients receiving neoadjuvant chemotherapy is consistent with that observed in the main trial. Although a nonsignificant excess of toxicity was observed, there was no evidence of impaired QoL. Patient summary Chemotherapy before radical chemo(radiotherapy) is feasible and well tolerated.

Highlights • Prostate and oligometastases patients were most common first sites treated. • Conventional professional roles and responsibilities will evolve in the future. • Thresholds for on-line adaptive radiotherapy remain undefined., Background and purpose The uptake of new technologies has varied internationally and there have often been barriers to implementation. On-line adaptive radiotherapy (ART) promises to improve patient outcome. This survey focuses on the implementation phase of delivering ART and professional roles and responsibilities currently involved in the workflow and changes which may be expected in the future. Materials and methods A 38 question survey included aspects on current practice; professional responsibilities; benefits and barriers; and decision making and responsibilities. For the purposes of the questionnaire and paper, ART was considered where tumour and /or organs at risk were contoured and re-planning was performed on-line. The questionnaire was electronically distributed via radiotherapy networks. Results Nineteen international responses were received. Europe (n = 11), United States of America (n = 4); Canada (n = 2), Australia (n = 1) and Hong Kong (n = 1). The majority of centres started using ART in either 2018 (n = 7) or 2019 (n = 6). Four centres started treating with ART between 2015 and 2017, and the first was in 2014. Centres initially treated prostate and oligometastases patients, expanding to treat prostate, oligometastases, pancreas and rectum. The majority of centres were working in conventional roles, however moving towards radiographers taking more responsibility in contouring organs at risk (OAR), target and dosimetry. The three most important criteria chosen by medical doctors to determine if ART should be used were overall gross anatomy changes of target and OAR, target not covered by planning target volume (PTV) and OAR close to the high dose area. There was no clear consensus on the minimum improvement in dose to target or reduction in dose to OAR to warrant adaption. Conclusion On-line ART has been implemented successfully internationally. Initial practice maintains conventional professional roles and responsibilities, however there is trend to changing roles for the future. There is little consensus regarding the triggers of adaption.

Objectives To assess the efficacy and tolerability of the dual EGFR/VEGFR inhibitor, vandetanib, in combination with carboplatin and gemcitabine in the first line treatment of patients with advanced urolthelial cancer (UC) who were unsuitable for cisplatin. Patients and methods From 2011 and 2014, 82 patients were randomised from 16 hospitals across the UK into the TOUCAN double‐blind, placebo‐controlled randomised phase II receiving six 21‐day cycles of intravenous carboplatin (AUC 4.5 day 1) and gemcitabine (1000mg/m2 days 1,8) in combination with either oral vandetanib 100mg or placebo (once daily). Progression‐free survival (PFS – primary endpoint), adverse events (AEs), tolerability and feasibility of use, objective response rate and overall survival (OS) were evaluated. Intention‐to‐treat and per protocol analyses were used to analyse the primary endpoint. Results Eighty‐two patients were randomised 1:1 to vandetanib (n=40) or placebo (n=42). 25 patients (30%) completed 6 cycles of all allocated treatment. Toxicity ≥grade 3 was experienced in 80% (n=32) and 76% (n=32) of patients on vandetanib and placebo arms respectively. Median PFS was 6.8 and 8.8 months for vandetanib and placebo arms, respectively (HR=1.07, 95% CI 0.65‐1.76, p=0.71); median OS was 10.8 vs 13.8 months (HR=1.41, 95% CI 0.79‐2.52, p=0.88); and radiological response rates were 50% and 55%. Conclusion There is no evidence that vandetanib improves clinical outcome in this setting. Our data do not support its adoption as the regimen of choice for first line treatment in UC patients who were unfit for cisplatin.

While most testicular germ cell tumours (TGCTs) exhibit exquisite sensitivity to platinum chemotherapy, ~10% are platinum resistant. To gain insight into the underlying mechanisms, we undertake whole exome sequencing and copy number analysis in 40 tumours from 26 cases with platinum-resistant TGCT, and combine this with published genomic data on an additional 624 TGCTs. We integrate analyses for driver mutations, mutational burden, global, arm-level and focal copy number (CN) events, and SNV and CN signatures. Albeit preliminary and observational in nature, these analyses provide support for a possible mechanistic link between early driver mutations in RAS and KIT and the widespread copy number events by which TGCT is characterised., Most testicular germ-cell tumours are exquisitely sensitive to platinum-based chemotherapies, but little is known about why 10% are resistant. Here, the authors explore the potential underlying mechanisms by probing the genomic landscape of platinum-resistant disease.

Background Up to 50% of men with poor prognosis, non-seminoma germ cell tumours (GCTs) die with standard BEP (bleomycin, etoposide and cisplatin) chemotherapy. An intensive regimen, CBOP/BEP (carboplatin, bleomycin, vincristine and cisplatin/BEP), met response targets in a randomised, phase II trial (74% complete response or partial response marker negative, 90% confidence interval (CI) 61%–85%). Aim To assess long-term outcomes and late toxicity associated with CBOP/BEP. Methods Patients with poor prognosis extracranial GCT were randomised to 4xBEP or CBOP/BEP (2xCBOP, 2xBO, 3xBEP with 15,000iu of bleomycin). Low-dose, stabilising chemotherapy before entry was permitted. Response rates (primary outcome) were reported previously. Here, we report secondary outcomes: progression-free survival (PFS), overall survival (OS) and late toxicity. Prognostic factors and the impact of marker decline are assessed in exploratory analysis. Results Eighty-nine patients (43 CBOP/BEP) were randomised. After median 63 months follow-up, 3-year PFS is 55.7% (95% CI: 39.7%, 69.0%) for CBOP/BEP and 38.7% (95% CI: 24.7%, 52.4%) for BEP (hazard ratio [HR]: 0.59 (0.33, 1.06), p = 0.079). Three-year OS is 65.0% (48.8%, 77.2%) and 58.5% (43.0%, 71.2%), respectively (HR: 0.79 (0.41, 1.52), p = 0.49). Twelve-month toxicity was affected by subsequent treatments, with no clear differences between arms. Stabilising chemotherapy was associated with poorer PFS (HR: 2.09 (1.14, 3.81), p = 0.017), whereas unfavourable marker decline, in 60 (70%) patients, was not. Conclusion Although not powered for PFS, results for CBOP/BEP are promising. Impact on OS was less clear (and will be affected by subsequent therapy). Further study in an international phase III trial is warranted. Trial registration ISRCTN 53643604., Highlights • Intensive induction chemotherapy met response targets in poor prognosis germ cell tumours. • Three-year progression-free survival was 56% for CBOP/BEP and 39% for BEP. • Impact on survival was less clear and will be affected by subsequent therapy. • Further study in an international phase III trial is warranted.

Background Standard management in the UK for high-risk stage 1 nonseminoma germ cell tumours of the testis (NSGCTT) is two cycles of adjuvant bleomycin, etoposide (360 mg/m2), and cisplatin (BE360P) chemotherapy, or surveillance. Objective To test whether one cycle of BE500P achieves similar recurrence rates to two cycles of BE360P. Design, setting, and participants A total of 246 patients with vascular invasion–positive stage 1 NSGCTT or combined seminoma + NSGCTT were centrally registered in a single-arm prospective study. Intervention One cycle comprising bleomycin 30000 IU on days 1, 8, and 15, etoposide 165 mg/m2 on days 1–3, and cisplatin 50 mg/m2 on days 1–2, plus antibacterial and granulocyte colony stimulating factor prophylaxis. Outcome measurements and statistical analysis The primary endpoint was 2-yr malignant recurrence (MR); the aim was to exclude a rate of ≥5%. Participants had regular imaging and tumour marker (TM) assessment for 5 yr. Results and limitations The median follow-up was 49 mo (interquartile range 37–60). Ten patients with rising TMs at baseline were excluded. Four patients had MR at 6, 7, 13, and 27 mo; all received second-line chemotherapy and surgery and three remained recurrence-free at 5 yr. The 2-yr MR rate was 1.3% (95% confidence interval 0.3–3.7%). Three patients developed nonmalignant recurrences with localised teratoma differentiated, rendered disease-free after surgery. Grade 3–4 febrile neutropenia occurred in 6.8% of participants. Conclusions BE500P is safe and the 2-yr MR rate is consistent with that seen following two BE360P cycles. The 111 study is the largest prospective trial investigating one cycle of adjuvant BE500P in high-risk stage 1 NSGCTT. Adoption of one cycle of BE500P as standard would reduce overall exposure to chemotherapy in this young population. Patient summary Removing the testicle fails to cure many patients with high-risk primary testicular cancer since undetectable cancers are often present elsewhere. A standard additional treatment in Europe is two cycles of chemotherapy to eradicate these. This trial shows one cycle has few adverse effects and comparable outcomes to those seen with two cycles., Take Home Message The 111 trial aimed to exclude a 2-yr recurrence rate of >5% with adjuvant one cycle of bleomycin, etoposide (500 mg/m2), and cisplatin (BE500Px1) in stage 1, high-risk nonseminomatous germ cell testis tumours. This was achieved, with 1.3% malignant recurrences among 236 cases. BE500Px1 should replace BE360Px2 as standard care for such patients.

Background BC2001, the largest randomised trial of bladder-sparing treatment for muscle-invasive bladder cancer, demonstrated improvement of local control and bladder cancer–specific survival from the addition of concomitant 5-fluorouracil and mitomycin C to radiotherapy. Objective To determine the impact of treatment on the health-related quality of life (HRQoL) of BC2001 participants. Design, setting, and participants 458 UK patients with T2-T4a N0 M0 transitional cell carcinoma of the bladder. Intervention Patients were randomised to the chemotherapy comparison (radiotherapy, 178, or chemoradiotherapy, 182); and/or to the radiotherapy comparison (standard, 108, or reduced high-dose volume radiotherapy, 111). Outcome measurements and statistical analysis Patients completed Functional Assessment of Cancer Therapy—Bladder (FACT-BL) questionnaires at baseline, end of treatment (EoT), and 6, 12, 24, 36, 48, and 60 months after radiotherapy. The primary endpoint was change from baseline in the bladder cancer subscale (BLCS) at 12 months. Results and limitations Data were available for 331 (92%) and 204 (93%) participants at baseline and for 192 (54%) and 114 (52%) at 12 months for the chemotherapy and radiotherapy comparisons, respectively. HRQoL declined at EoT (BLCS –5.06 [99% confidence interval: –6.12 to –4.00, p

Background Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonistplus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial.Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m 2 (60 mg/m 2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues.Findings Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7.4 months (IQR 3.5-13.9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4.1 months [95% CI 3.3-4.8] vs 2.8 months [2.6-2.9]; HR 0.696 [95% CI 0.573-0.845]; p=0.0002). Median overall survival was 9.4 months (95% CI 7.9-11.4) in the ramucirumab group versus 7.9 months (7.0-9.3) in the placebo group (stratified HR 0.887 [95% CI 0.724-1.086]; p=0.25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group.Interpretation Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

To provide new information on factors associated with discrepancies between patient-reported and audiometrically defined hearing loss (HL) in adult-onset cancer survivors after cisplatin-based chemotherapy (CBCT) and to comprehensively investigate risk factors associated with audiometrically defined HL.A total of 1410 testicular cancer survivors (TCS) ≥6 months post-CBCT underwent comprehensive audiometric assessments (0.25 to 12 kHz) and completed questionnaires. HL severity was defined using American Speech-Language-Hearing Association criteria. Multivariable multinomial regression identified factors associated with discrepancies between patient-reported and audiometrically defined HL and multivariable ordinal regression evaluated factors associated with the latter.Overall, 34.8% of TCS self-reported HL. Among TCS without tinnitus, those with audiometrically defined HL at only extended high frequencies (EHFs) (10 to 12 kHz) (17.8%) or at both EHFs and standard frequencies (0.25 to 8 kHz) (23.4%) were significantly more likely to self-report HL than those with no audiometrically defined HL (8.1%) [odds ratio (OR) = 2.48; 95% confidence interval (CI), 1.31 to 4.68; and OR = 3.49; 95% CI, 1.89 to 6.44, respectively]. Older age (OR = 1.09; 95% CI, 1.07 to 1.11, p0.0001), absence of prior noise exposure (OR = 1.40; 95% CI, 1.06 to 1.84, p = 0.02), mixed/conductive HL (OR = 2.01; 95% CI, 1.34 to 3.02, p = 0.0007), no hearing aid use (OR = 5.64; 95% CI, 1.84 to 17.32, p = 0.003), and lower education (OR = 2.12; 95% CI, 1.23 to 3.67, p = 0.007 for high school or less education versus postgraduate education) were associated with greater underestimation of audiometrically defined HL severity, while tinnitus was associated with greater overestimation (OR = 4.65; 95% CI, 2.64 to 8.20 for a little tinnitus, OR = 5.87; 95% CI, 2.65 to 13.04 for quite a bit tinnitus, and OR = 10.57; 95% CI, 4.91 to 22.79 for very much tinnitus p0.0001). Older age (OR = 1.13; 95% CI, 1.12 to 1.15, p0.0001), cumulative cisplatin dose (300 mg/m2, OR = 1.47; 95% CI, 1.21 to 1.80, p = 0.0001), and hypertension (OR = 1.80; 95% CI, 1.28 to 2.52, p = 0.0007) were associated with greater American Speech-Language-Hearing Association-defined HL severity, whereas postgraduate education (OR = 0.58; 95% CI, 0.40 to 0.85, p = 0.005) was associated with less severe HL.Discrepancies between patient-reported and audiometrically defined HL after CBCT are due to several factors. For survivors who self-report HL but have normal audiometric findings at standard frequencies, referral to an audiologist for additional testing and inclusion of EHFs in audiometric assessments should be considered.