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BACKGROUND AND OBJECTIVE: We assessed the safety of atezolizumab in unselected patients (including understudied populations typically excluded from clinical trials) with pretreated urinary tract carcinoma (UTC). The prespecified final analysis updates previously reported safety and efficacy data. METHODS: The single-arm prospective SAUL study (NCT02928406) enrolled 1004 patients with locally advanced/metastatic urothelial/non-urothelial UTC that had progressed during/after one to three prior treatment lines for advanced UTC (or <12 mo after [neo]adjuvant therapy). Broad eligibility criteria allowed enrollment of patients with complex comorbidities approximating the real-world setting. Patients received atezolizumab 1200 mg every 3 wk until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included duration of response and overall survival (OS). KEY FINDINGS AND LIMITATIONS: The treated cohort included 10% of patients with poor performance status, 5% with creatinine clearance <30 ml/min, and 4% with autoimmune disease. At median follow-up of 55 mo, median atezolizumab duration was 2.8 mo (range 0-62); 68 patients (7%) continued atezolizumab for >4 yr. Treatment-related grade ≥3 adverse events occurred in 16% of patients (death in 1%); 8% discontinued atezolizumab for adverse events. Median OS was 8.6 mo (95% confidence interval 7.8-9.7) and 136 patients (14%) had OS longer than 4 yr. Limitations include the small sample size for some subgroups of special interest. CONCLUSIONS AND CLINICAL IMPLICATIONS: Long-term safety and efficacy data continue to show a benefit of atezolizumab in unselected patients with UTC. Remarkably, 14% of patients lived for >4 yr after starting atezolizumab. These results can inform multidisciplinary team discussions and treatment decision-making for patients with UTC with complex comorbidities. PATIENT SUMMARY: The SAUL study looked at how well tolerated a drug called atezolizumab was in patients with urinary tract cancer who had already received up to three previous treatments for their cancer, including people who are usually not included in clinical trials because of other medical conditions. The length of survival after starting treatment was also assessed. Overall, the results show that atezolizumab was well tolerated. People for whom other therapies had failed lived for about 8.6 months on average after starting treatment, and 14% of the patients were still alive after 4 years.
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AIMS: To resolve the ongoing controversy surrounding the impact of teratoma (TER) in the primary among patients with metastatic testicular non-seminomatous germ-cell tumours (NSGCT). PATIENTS AND METHODS: Using the International Germ Cell Cancer Collaborative Group (IGCCCG) Update Consortium database, we compared the survival probabilities of patients with metastatic testicular GCT with TER (TER) or without TER (NTER) in their primaries corrected for known prognostic factors. Progression-free survival (5y-PFS) and overall survival at 5 years (5y-OS) were estimated by the Kaplan-Meier method. RESULTS: Among 6792 patients with metastatic testicular NSGCT, 3224 (47%) had TER in their primary, and 3568 (53%) did not. In the IGCCCG good prognosis group, the 5y-PFS was 87.8% in TER versus 92.0% in NTER patients (p = 0.0001), the respective 5y-OS were 94.5% versus 96.5% (p = 0.0032). The corresponding figures in the intermediate prognosis group were 5y-PFS 76.9% versus 81.6% (p = 0.0432) in TER and NTER and 5y-OS 90.4% versus 90.9% (p = 0.8514), respectively. In the poor prognosis group, there was no difference, neither in 5y-PFS [54.3% in TER patients versus 55.4% (p = 0.7472) in NTER], nor in 5y-OS [69.4% versus 67.7% (p = 0.3841)]. NSGCT patients with TER had more residual masses (65.3% versus 51.7%, p < 0.0001), and therefore received post-chemotherapy surgery more frequently than NTER patients (46.8% versus 32.0%, p < 0.0001). CONCLUSION: Teratoma in the primary tumour of patients with metastatic NSGCT negatively impacts on survival in the good and intermediate, but not in the poor IGCCCG prognostic groups.
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Neoplasias Embrionárias de Células Germinativas , Seminoma , Teratoma , Neoplasias Testiculares , Masculino , Humanos , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/terapia , Prognóstico , Teratoma/terapia , Fatores de Risco , Estudos RetrospectivosRESUMO
BACKGROUND: BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours. METHODS: RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median). PRIMARY ENDPOINT: invasive loco-regional control (ILRC); secondary overall survival. FINDINGS: Hypoxia affected overall survival (HR = 1.30; 95% CI 0.99-1.70; p = 0.062): more uncertainty for ILRC (HR = 1.29; 95% CI 0.82-2.03; p = 0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n = 90, HR 1.69; 95% CI 0.99-2.89 p = 0.057) but not conventional (n = 207, HR 0.70; 95% CI 0.28-1.80, p = 0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n = 51; HR 14.2; 95% CI 1.7-119; p = 0.015) but not conventional (n = 24, HR 1.04; 95% CI 0.07-15.5, p = 0.978) radiotherapy. INTERPRETATION: Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial. FUNDING: Cancer Research UK, NIHR, MRC.
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Hipóxia , Mitomicina , Humanos , Intervalo Livre de Doença , Fracionamento da Dose de Radiação , Biomarcadores , Resultado do TratamentoRESUMO
BACKGROUND: Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) inhibitor approved for the treatment of locally advanced or metastatic urothelial carcinoma in adults with susceptible FGFR3/2 alterations who have progression after platinum-containing chemotherapy. The effects of erdafitinib in patients with FGFR-altered metastatic urothelial carcinoma who have progression during or after treatment with checkpoint inhibitors (anti-programmed cell death protein 1 [PD-1] or anti-programmed death ligand 1 [PD-L1] agents) are unclear. METHODS: We conducted a global phase 3 trial of erdafitinib as compared with chemotherapy in patients with metastatic urothelial carcinoma with susceptible FGFR3/2 alterations who had progression after one or two previous treatments that included an anti-PD-1 or anti-PD-L1. Patients were randomly assigned in a 1:1 ratio to receive erdafitinib or the investigator's choice of chemotherapy (docetaxel or vinflunine). The primary end point was overall survival. RESULTS: A total of 266 patients underwent randomization: 136 to the erdafitinib group and 130 to the chemotherapy group. The median follow-up was 15.9 months. The median overall survival was significantly longer with erdafitinib than with chemotherapy (12.1 months vs. 7.8 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.47 to 0.88; P = 0.005). The median progression-free survival was also longer with erdafitinib than with chemotherapy (5.6 months vs. 2.7 months; hazard ratio for progression or death, 0.58; 95% CI, 0.44 to 0.78; P<0.001). The incidence of grade 3 or 4 treatment-related adverse events was similar in the two groups (45.9% in the erdafitinib group and 46.4% in the chemotherapy group). Treatment-related adverse events that led to death were less common with erdafitinib than with chemotherapy (in 0.7% vs. 5.4% of patients). CONCLUSIONS: Erdafitinib therapy resulted in significantly longer overall survival than chemotherapy among patients with metastatic urothelial carcinoma and FGFR alterations after previous anti-PD-1 or anti-PD-L1 treatment. (Funded by Janssen Research and Development; THOR ClinicalTrials.gov number, NCT03390504.).
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Anticorpos Monoclonais Humanizados , Antineoplásicos , Carcinoma de Células de Transição , Receptores de Fatores de Crescimento de Fibroblastos , Neoplasias da Bexiga Urinária , Adulto , Humanos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Docetaxel/efeitos adversos , Docetaxel/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêuticoRESUMO
Background: Erdafitinib is indicated for the treatment of adults with locally advanced/metastatic urothelial carcinoma and susceptible FGFR3/2 alterations progressing on/after one or more lines of prior platinum-based chemotherapy. Objective: To better understand the frequency and management of select treatment-emergent adverse events (TEAEs) to enable optimal fibroblast growth factor receptor inhibitor (FGFRi) treatment. Design setting and participants: Longer-term efficacy and safety results of the BLC2001 (NCT02365597) trial in patients with locally advanced and unresectable or metastatic urothelial carcinoma were studied. Intervention: Erdafitinib schedule of 8 mg/d continuous in 28-d cycles, with uptitration to 9 mg/d if serum phosphate level was <5.5 mg/dl and no significant TEAEs occurred. Outcome measurements and statistical analysis: Adverse events were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The Kaplan-Meier methodology was used for the cumulative incidence of the first onset of TEAEs by grade. Time to resolution of TEAEs was summarized descriptively. Results and limitations: At data cutoff, the median treatment duration was 5.4 mo among 101 patients receiving erdafitinib. Select TEAEs (total; grade 3) were hyperphosphatemia (78%; 2.0%), stomatitis (59%; 14%), nail events (59%; 15%), non-central serous retinopathy (non-CSR) eye disorders (56%; 5.0%), skin events (55%; 7.9%), diarrhea (55%; 4.0%), and CSR (27%; 4.0%). Select TEAEs were mostly of grade 1 or 2, and were managed effectively with dose modifications, including dose reductions or interruptions, and/or supportive concomitant therapies, resulting in few events leading to treatment discontinuation. Further work is needed to determine whether management is generalizable to the nonprotocol/general population. Conclusions: Identification of select TEAEs and appropriate management with dose modification and/or concomitant therapies resulted in improvement or resolution of most TEAEs in patients, allowing for continuation of FGFRi treatment to ensure maximum benefit. Patient summary: Early identification and proactive management are warranted to mitigate or possibly prevent erdafitinib side effects to allow for maximum drug benefit in patients with locally advanced or metastatic bladder cancer.
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BACKGROUND/PURPOSE: This work evaluated the suitability of MR derived sequences for use in online adaptive RT workflows on a 1.5 Tesla (T) MR-Linear Accelerator (MR Linac). MATERIALS/METHODS: Non-patient volunteers were recruited to an ethics approved MR Linac imaging study. Participants attended 1-3 imaging sessions in which a combination of DIXON, 2D and 3D volumetric T1 and T2 weighted images were acquired axially, with volunteers positioned using immobilisation devices typical for radiotherapy to the anatomical region being scanned. Images from each session were appraised by three independent reviewers to determine optimal sequences over six anatomical regions: head and neck, female and male pelvis, thorax (lung), thorax (breast/chest wall) and abdomen. Site specific anatomical structures were graded by the perceived ability to accurately contour a typical organ at risk. Each structure was independently graded on a 4-point Likert scale as 'Very Clear', 'Clear', 'Unclear' or 'Not visible' by observers, consisting of radiographers (therapeutic and diagnostic) and clinicians. RESULTS: From July 2019 to September 2019, 18 non-patient volunteers underwent 24 imaging sessions in the following anatomical regions: head and neck (n=3), male pelvis (n=4), female pelvis (n=5), lung/oesophagus (n=5) abdomen (n=4) and chest wall/breast (n=3). T2 sequences were the most preferred for perceived ability to contour anatomy in both male and female pelvis. For all other sites T1 weighted DIXON sequences were most favourable. CONCLUSION: This study has determined the preferential sequence selection for organ visualisation, as a pre-requisite to our institution adopting MR-guided radiotherapy for a more diverse range of disease sites.
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Radioterapia Guiada por Imagem , Radioterapia de Intensidade Modulada , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Aceleradores de Partículas , Planejamento da Radioterapia Assistida por ComputadorRESUMO
BACKGROUND: Recurrence is common after neoadjuvant chemotherapy and radical treatment for muscle-invasive bladder cancer. We investigated the effect of adding nintedanib to neoadjuvant chemotherapy on response and survival in muscle-invasive bladder cancer. METHODS: NEOBLADE was a parallel-arm, double-blind, randomised, placebo-controlled, phase 2 trial of neoadjuvant gemcitabine and cisplatin chemotherapy with nintedanib or placebo in locally advanced muscle-invasive bladder cancer. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0-1, were recruited from 15 hospitals in the UK. Patients were randomly assigned (1:1) to nintedanib or placebo using permuted blocks with random block sizes of two or four, stratified by centre and glomerular filtration rate. Treatments were allocated using an interactive web-based system, and patients and investigators were masked to treatment allocation throughout the study. Patients received oral nintedanib (150 mg or 200 mg twice daily for 12 weeks) or placebo, in addition to usual neoadjuvant chemotherapy with intravenous gemcitabine 1000 mg/m2 on days 1 and 8 and intravenous cisplatin 70 mg/m2 on day 1 of a 3-weekly cycle. The primary endpoint was pathological complete response rate, assessed at cystectomy or at day 8 of cyclde 3 (plus or minus 7 days) if cystectomy did not occur. Primary analyses were done in the intention-to-treat population. The trial is registered with EudraCT, 2012-004895-01, and ISRCTN, 56349930, and has completed planned recruitment. FINDINGS: Between Dec 4, 2014, and Sept 3, 2018, 120 patients were recruited and were randomly allocated to receive nintedanib (n=57) or placebo (n=63). The median follow-up for the study was 33·5 months (IQR 14·0-44·0). Pathological complete response in the intention-to-treat population was reached in 21 (37%) of 57 patients in the nintedanib group and 20 (32%) of 63 in the placebo group (odds ratio [OR] 1·25, 70% CI 0·84-1·87; p=0·28). Grade 3 or worse toxicities were observed in 53 (93%) of 57 participants who received nintedanib and 50 (79%) of 63 patients in the placebo group (OR 1·65, 95% CI 0·74-3·65; p=0·24). The most common grade 3 or worse adverse events were thromboembolic events (17 [30%] of 57 patients in the nintedanib group vs 13 [21%] of 63 patients in the placebo group [OR 1·63, 95% CI 0·71-3·76; p=0·29]) and decreased neutrophil count (22 [39%] in the nintedanib group vs seven [11%] in the placebo group [5·03, 1·95-13·00; p=0·0006]). 45 treatment-related serious adverse events occurred in the nintedanib group and 43 occurred in the placebo group. One treatment-related death occurred in the placebo group, which was due to myocardial infarction. INTERPRETATION: The addition of nintedanib to chemotherapy was safe but did not improve the rate of pathological complete response in muscle-invasive bladder cancer. FUNDING: Boehringer Ingelheim.
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Cisplatino , Neoplasias da Bexiga Urinária , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/efeitos adversos , Desoxicitidina/análogos & derivados , Método Duplo-Cego , Feminino , Humanos , Indóis , Masculino , Músculos , Terapia Neoadjuvante/efeitos adversos , Neoplasias da Bexiga Urinária/tratamento farmacológico , GencitabinaRESUMO
PURPOSE: Survival in stage I seminoma is almost 100%. Computed tomography (CT) surveillance is an international standard of care, avoiding adjuvant therapy. In this young population, minimizing irradiation is vital. The Trial of Imaging and Surveillance in Seminoma Testis (TRISST) assessed whether magnetic resonance images (MRIs) or a reduced scan schedule could be used without an unacceptable increase in advanced relapses. METHODS: A phase III, noninferiority, factorial trial. Eligible participants had undergone orchiectomy for stage I seminoma with no adjuvant therapy planned. Random assignment was to seven CTs (6, 12, 18, 24, 36, 48, and 60 months); seven MRIs (same schedule); three CTs (6, 18, and 36 months); or three MRIs. The primary outcome was 6-year incidence of Royal Marsden Hospital stage ≥ IIC relapse (> 5 cm), aiming to exclude increases ≥ 5.7% (from 5.7% to 11.4%) with MRI (v CT) or three scans (v 7); target N = 660, all contributing to both comparisons. Secondary outcomes include relapse ≥ 3 cm, disease-free survival, and overall survival. Intention-to-treat and per-protocol analyses were performed. RESULTS: Six hundred sixty-nine patients enrolled (35 UK centers, 2008-2014); mean tumor size was 2.9 cm, and 358 (54%) were low risk (< 4 cm, no rete testis invasion). With a median follow-up of 72 months, 82 (12%) relapsed. Stage ≥ IIC relapse was rare (10 events). Although statistically noninferior, more events occurred with three scans (nine, 2.8%) versus seven scans (one, 0.3%): 2.5% absolute increase, 90% CI (1.0 to 4.1). Only 4/9 could have potentially been detected earlier with seven scans. Noninferiority of MRI versus CT was also shown; fewer events occurred with MRI (two [0.6%] v eight [2.6%]), 1.9% decrease (-3.5 to -0.3). Per-protocol analyses confirmed noninferiority. Five-year survival was 99%, with no tumor-related deaths. CONCLUSION: Surveillance is a safe management approach-advanced relapse is rare, salvage treatment successful, and outcomes excellent, regardless of imaging frequency or modality. MRI can be recommended to reduce irradiation; and no adverse impact on long-term outcomes was seen with a reduced schedule.
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Seminoma , Neoplasias Testiculares , Quimioterapia Adjuvante , Seguimentos , Humanos , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Estadiamento de Neoplasias , Orquiectomia , Seminoma/tratamento farmacológico , Seminoma/terapia , Neoplasias Testiculares/diagnóstico por imagem , Neoplasias Testiculares/cirurgiaRESUMO
BACKGROUND: Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, was shown to be clinically active and tolerable in patients with advanced urothelial carcinoma and prespecified FGFR alterations in the primary analysis of the BLC2001 study at median 11 months of follow-up. We aimed to assess the long-term efficacy and safety of the selected regimen of erdafitinib determined in the initial part of the study. METHODS: The open-label, non-comparator, phase 2, BLC2001 study was done at 126 medical centres in 14 countries across Asia, Europe, and North America. Eligible patients were aged 18 years or older with locally advanced and unresectable or metastatic urothelial carcinoma, at least one prespecified FGFR alteration, an Eastern Cooperative Oncology Group performance status of 0-2, and progressive disease after receiving at least one systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy or were ineligible for cisplatin. The selected regimen determined in the initial part of the study was continuous once daily 8 mg/day oral erdafitinib in 28-day cycles, with provision for pharmacodynamically guided uptitration to 9 mg/day (8 mg/day UpT). The primary endpoint was investigator-assessed confirmed objective response rate according to Response Evaluation Criteria In Solid Tumors version 1.1. Efficacy and safety were analysed in all treated patients who received at least one dose of erdafitinib. This is the final analysis of this study. This study is registered with ClinicalTrials.gov, NCT02365597. FINDINGS: Between May 25, 2015, and Aug 9, 2018, 2328 patients were screened, of whom 212 were enrolled and 101 were treated with the selected erdafitinib 8 mg/day UpT regimen. The data cutoff date for this analysis was Aug 9, 2019. Median efficacy follow-up was 24·0 months (IQR 22·7-26·6). The investigator-assessed objective response rate for patients treated with the selected erdafitinib regimen was 40 (40%; 95% CI 30-49) of 101 patients. The safety profile remained similar to that in the primary analysis, with no new safety signals reported with longer follow-up. Grade 3-4 treatment-emergent adverse events of any causality occurred in 72 (71%) of 101 patients. The most common grade 3-4 treatment-emergent adverse events of any cause were stomatitis (in 14 [14%] of 101 patients) and hyponatraemia (in 11 [11%]). There were no treatment-related deaths. INTERPRETATION: With longer follow-up, treatment with the selected regimen of erdafitinib showed consistent activity and a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma and prespecified FGFR alterations. FUNDING: Janssen Research & Development.
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Carcinoma de Células de Transição/tratamento farmacológico , Pirazóis/uso terapêutico , Quinoxalinas/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Idoso , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Coriorretinopatia Serosa Central/induzido quimicamente , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Seguimentos , Humanos , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Pirazóis/efeitos adversos , Quinoxalinas/efeitos adversos , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologiaRESUMO
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.
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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 MR-Linac 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.
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Aceleradores de Partículas , Planejamento da Radioterapia Assistida por Computador , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema de Registros , Adulto JovemRESUMO
PURPOSE: Atezolizumab is an established treatment option for pretreated urothelial carcinoma, demonstrating efficacy in phase II/III trials. The SAUL study enrolled a broader patient population to determine safety and efficacy in underrepresented subgroups. MATERIALS AND METHODS: Patients with metastatic urinary tract carcinoma received atezolizumab 1,200 mg every 3 weeks until disease progression, unacceptable toxicity, loss of clinical benefit, or patient/physician decision. The primary endpoint was safety. Efficacy was a secondary endpoint. Analyses by programmed cell death ligand-1 (PD-L1) status, age, Eastern Cooperative Oncology Group performance status (ECOG PS) and renal impairment were prespecified; post hoc analyses explored outcomes by tumor location. RESULTS: A total of 1,004 patients were enrolled. Subgroup analyses in patients with older age, renal impairment, or upper tract urothelial carcinoma showed safety and efficacy similar to those in patients without these characteristics. Patients with ECOG PS 2 had clinical features typically associated with aggressive disease; median overall survival was 2.3 months versus 10.0 months in patients with ECOG PS0/1. Patients with PD-L1 expression on ≥5% of tumor-infiltrating immune cells tended to have better outcomes than those with <5% PD-L1 expression, although conclusions on the relative efficacy of atezolizumab cannot be drawn from this single-arm study. CONCLUSIONS: The understudied populations included in the SAUL study had similar outcomes to those in more selected populations included in phase II/III trials of atezolizumab, except for those with ECOG PS 2. Age ≥80 years and/or creatinine clearance <30 ml/minute does not preclude administration of atezolizumab; however, treatment risk versus benefit must be carefully assessed in patients with ECOG PS 2.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Determinação de Ponto Final , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
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 3,543 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.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Idoso , Humanos , Cooperação Internacional , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/mortalidade , Neoplasias Embrionárias de Células Germinativas/patologia , Prognóstico , Neoplasias Testiculares/mortalidade , Neoplasias Testiculares/patologia , Adulto JovemRESUMO
PURPOSE: The classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major advance in the management of germ-cell tumors, but relies on data of only 660 patients with seminoma treated between 1975 and 1990. We re-evaluated this classification in a database from a large international consortium. MATERIALS AND METHODS: Data on 2,451 men with metastatic seminoma treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Australia, Europe, and North America. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS) calculated from day 1 of treatment. Variables at initial presentation were evaluated for their prognostic impact. Results were validated in an independent validation set of 764 additional patients. RESULTS: Compared with the initial IGCCCG classification, in our modern series, 5-year PFS improved from 82% to 89% (95% CI, 87 to 90) and 5-year OS from 86% to 95% (95% CI, 94 to 96) in good prognosis, and from 67% to 79% (95% CI, 70 to 85) and 72% to 88% (95% CI, 80 to 93) in intermediate prognosis patients. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good prognosis patients with LDH above 2.5× upper limit of normal had a 3-year PFS of 80% (95% CI, 75 to 84) and a 3-year OS of 92% (95% CI, 88 to 95) versus 92% (95% CI, 90 to 94) and 97% (95% CI, 96 to 98) in the group with lower LDH. CONCLUSION: PFS and OS in metastatic seminoma significantly improved in our modern series compared with the original data. The original IGCCCG classification retains its relevance, but can be further refined by adding LDH at a cutoff of 2.5× upper limit of normal as an additional adverse prognostic factor.
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Seminoma/mortalidade , Neoplasias Testiculares/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Cooperação Internacional , L-Lactato Desidrogenase/metabolismo , Masculino , Metástase Neoplásica , Prognóstico , Seminoma/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/patologiaRESUMO
At the Canadian Testis Cancer Workshop, the multidisciplinary management of testis cancer care was discussed. The two-day workshop involved urologists, medical and radiation oncologists, pathologists, radiologists, physician's assistants, residents, fellows, nurses, patients, and patient advocacy group members.This review summarizes the discussion regarding clinical dilemmas in local and regional testis cancer. We present cases that highlight the need for a coordinated approach to individualize care. Overarching themes include the importance of a multidisciplinary approach to testis cancer, willingness to involve a high-volume experienced center, and given that the oncological outcomes are excellent, a reminder that clinical decisions need to prioritize selecting a strategy with the least treatment-related morbidity when safe.
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The choice of first-line therapy for patients with metastatic urothelial cancer (mUC) is based on cisplatin-eligibility and programmed death-ligand 1 (PD-L1) status. For patients with mUC who are ineligible for cisplatin and with low PD-L1 expression, chemotherapy-based regimens are the only approved first-line option. In a Phase I/II trial of the chemotherapy-free regimen, bempegaldesleukin (BEMPEG; NKTR-214) plus nivolumab, patients with locally advanced or mUC experienced tumor responses regardless of baseline PD-L1 expression (objective response rates: 50 and 45% in patients with PD-L1-positive and -negative tumors, respectively). The Phase II PIVOT-10 study (NCT03785925), evaluates efficacy and safety of first-line BEMPEG plus nivolumab in cisplatin-ineligible patients with locally advanced or mUC. Most patients will have low PD-L1 expression. Primary end point: objective response rates (including complete response).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Projetos de Pesquisa , Neoplasias Urológicas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais , Cisplatino/administração & dosagem , Humanos , Interleucina-2/administração & dosagem , Interleucina-2/análogos & derivados , Terapia de Alvo Molecular , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Nivolumabe/administração & dosagem , Polietilenoglicóis/administração & dosagem , Prognóstico , Neoplasias Urológicas/diagnóstico , Neoplasias Urológicas/etiologia , Neoplasias Urológicas/mortalidadeRESUMO
Purpose: MR-guided Radiation Therapy (MRgRT) allows for high-precision radiotherapy under real-time MR visualization. This enables margin reduction and subsequent dose escalation which may lead to higher tumor control and less toxicity. The Unity MR-linac (Elekta AB, Stockholm, Sweden) integrates a linear accelerator with a 1.5T diagnostic quality MRI and an online adaptive workflow. A prospective international registry was established to facilitate the evidence-based implementation of the Unity MR-linac into clinical practice, to systemically evaluate long-term outcomes, and to aid further technical development of MR-linac-based MRgRT. Methods and Results: In February 2019, the Multi-OutcoMe EvaluatioN of radiation Therapy Using the MR-linac study (MOMENTUM) started within the MR-linac Consortium. The MOMENTUM study is an international academic-industrial partnership between several hospitals and industry partner Elekta. All patients treated on the MR-linac are eligible for inclusion in MOMENTUM. For participants, we collect clinical patient data (e.g., patient, tumor, and treatment characteristics) and technical patient data which is defined as information generated on the MR-linac during treatment. The data are captured, pseudonymized, and stored in an international registry at set time intervals up to two years after treatment. Patients can choose to provide patient-reported outcomes and consent to additional MRI scans acquired on the MR-linac. This registry will serve as a data platform that supports multicenter research investigating the MR-linac. Rules and regulations on data sharing, data access, and intellectual property rights are summarized in an academic-industrial collaboration agreement. Data access rules ensure secure data handling and research integrity for investigators and institutions. Separate data access rules exist for academic and industry partners. This study is registered at ClinicalTrials.gov with ID: NCT04075305 (https://clinicaltrials.gov/ct2/show/NCT04075305). Conclusion: The multi-institutional MOMENTUM study has been set up to collect clinical and technical patient data to advance technical development, and facilitate evidenced-based implementation of MR-linac technology with the ultimate purpose to improve tumor control, survival, and quality of life of patients with cancer.
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At the Canadian Testis Cancer Workshop, the rationale and feasibility of regionalization of testis cancer care were discussed. The two-day workshop involved urologists, medical and radiation oncologists, pathologists, radiologists, physician's assistants, residents and fellows, and nurses, as well as patients and patient advocacy groups.This review summarizes the discussion and recommendations of one of the central topics of the workshop - the centralization of testis cancer in Canada. It was acknowledged that non-guideline-concordant care in testis cancer occurs frequently, in the range of 18-30%. The National Health Service in the U.K. stipulates various testis cancer care modalities be delivered through supra-regional network. All cases are reviewed at a multidisciplinary team meeting and aspects of care can be delivered locally through the network. In Germany, no such network exists, but an insurance-supported online second opinion network was developed that currently achieves expert case review in over 30% of cases. There are clear benefits to regionalization in terms of survival, treatment morbidity, and cost. There was agreement at the workshop that a structured pathway for diagnosis and treatment of testis cancer patients is required.Regionalization may be challenging in Canada because of geography; independent administration of healthcare by each province; physicians fearing loss of autonomy and revenue; patient unwillingness to travel long distances from home; and the inability of the larger centers to handle the ensuing increase in volume. We feel the first step is to identify the key performance indicators and quality metrics to track the quality of care received. After identifying these metrics, implementation of a "networks of excellence" model, similar to that seen in sarcoma care in Ontario, could be effective, coupled with increased use of health technology, such as virtual clinics and telemedicine.
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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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Adolescente , Adulto , Bleomicina/administração & dosagem , Carboplatina/administração & dosagem , Cisplatino/administração & dosagem , Etoposídeo/administração & dosagem , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Prognóstico , Taxa de Sobrevida , Vincristina/administração & dosagem , Adulto JovemRESUMO
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< 0.001]; overall FACT-B TOTAL score -8.22 [-10.76 to -5.68, p< 0.01]), recovering to baseline at 6 months and remaining similar to baseline subsequently. There was no significant difference between randomised groups at any time point. CONCLUSIONS: Immediately following (chemo)radiotherapy, a significant proportion of patients report declines in HRQoL, which improve to baseline after 6 months. Two-thirds of patients report stable or improved HRQoL on long-term follow-up. There is no evidence of impairment in HRQoL resulting from the addition of chemotherapy. PATIENT SUMMARY: Quality of life of bladder cancer patients treated with radiotherapy±chemotherapy deteriorates during treatment, but improves to at least pretreatment levels within 6 months. Addition of chemotherapy to radiotherapy does not affect patient-reported quality of life.