RESUMO
BACKGROUND: The KEYNOTE-057 trial evaluated activity and safety of pembrolizumab in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer who were ineligible for or declined radical cystectomy. In cohort A (patients with carcinoma in situ, with or without papillary tumours) of the KEYNOTE-057 study, pembrolizumab monotherapy led to a complete response rate of 41% at 3 months, and 46% of responders maintained a response lasting at least 12 months. Here, we evaluate pembrolizumab monotherapy in cohort B of patients with papillary tumours without carcinoma in situ. METHODS: KEYNOTE-057 is a single-arm, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. Cohort B eligible patients were aged 18 years and older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had BCG-unresponsive high-risk non-muscle-invasive bladder cancer with papillary tumours (high-grade Ta or any-grade T1) without carcinoma in situ. Transurethral resection of bladder tumour within 12 weeks of first pembrolizumab dose was required. Patients received pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 35 cycles. Primary endpoint was 12-month disease-free survival of high-risk non-muscle-invasive bladder cancer or progressive disease as assessed by cystoscopy, cytology, and central pathology and radiology review. Activity was assessed in all patients who received at least one dose of the study drug and had a baseline evaluation. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing. FINDINGS: Between April 12, 2016, and June 17, 2021, 132 patients (104 [79%] men and 28 [21%] women) who had received a median of ten (IQR 9-15) previous BCG instillations were enrolled into cohort B of the study. Patients received a median of 10 cycles (IQR 6-27) of pembrolizumab. At data cutoff date, Oct 20, 2022, median follow-up was 45·4 months (IQR 36·4-59·3) and five (4%) of 132 patients remained on treatment. The 12-month disease-free survival was 43·5% (95% CI 34·9-51·9). Treatment-related adverse events occurred in 97 (73%) of 132 patients; 19 (14%) had a grade 3 or 4 treatment-related adverse event; the most common grade 3 or 4 treatment-related adverse events were colitis (in three [2%] patients) and diarrhoea (in two [2%]). 17 (13%) of 132 patients experienced serious treatment-related adverse events, of which colitis (three patients [2%]) was most common. No treatment-related deaths occurred. INTERPRETATION: Pembrolizumab monotherapy showed antitumour activity and manageable toxicity in patients with BCG-unresponsive high-risk Ta or T1 bladder cancer without carcinoma in situ and could potentially be a suitable treatment option for patients who decline or are ineligible for radical cystectomy. Findings will need to be confirmed in a randomised controlled trial. FUNDING: Merck Sharp & Dohme.
Assuntos
Anticorpos Monoclonais Humanizados , Vacina BCG , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Masculino , Feminino , Idoso , Vacina BCG/uso terapêutico , Vacina BCG/administração & dosagem , Vacina BCG/efeitos adversos , Pessoa de Meia-Idade , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma in Situ/tratamento farmacológico , Carcinoma in Situ/patologia , Invasividade Neoplásica , Idoso de 80 Anos ou mais , Neoplasias não Músculo Invasivas da BexigaRESUMO
BACKGROUND: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only. METHODS: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or Tany N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual. FINDINGS: Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related. INTERPRETATION: Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma. FUNDING: US National Institutes of Health National Cancer Institute and Bristol Myers Squibb.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Nefrectomia , Nivolumabe , Humanos , Nivolumabe/administração & dosagem , Nivolumabe/uso terapêutico , Nivolumabe/efeitos adversos , Carcinoma de Células Renais/cirurgia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/mortalidade , Masculino , Feminino , Neoplasias Renais/cirurgia , Neoplasias Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/mortalidade , Pessoa de Meia-Idade , Idoso , Canadá , Quimioterapia Adjuvante , Estadiamento de Neoplasias , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagemRESUMO
PURPOSE OF REVIEW: This review focuses on special populations poorly represented in current evidence-based practice for metastatic renal cell carcinoma (mRCC). This includes the elderly and frail, patients on immunosuppression or with autoimmune diseases, patients with brain, liver, and/or bone metastases, and RCC with sarcomatoid features. RECENT FINDINGS: Certain populations are poorly represented in current trials for mRCC. Patients with central nervous system (CNS) metastases are often excluded from first-line therapy trials. Modern doublet systemic therapy appears to benefit patients with bone or liver metastases, but data supporting this conclusion is not robust. Post-hoc analyses on patients with sarcomatoid differentiation have shown improved response to modern doublet therapy over historical treatments. The elderly are underrepresented in current clinical trials, and most trials exclude all but high-performing (nonfrail) patients, though true frailty is likely poorly captured using the current widely adopted indices. It is difficult to make conclusions about the efficacy of modern therapy in these populations from subgroup analyses. Data from trials on other malignancies in patients with autoimmune diseases or solid organ transplant recipients on immunosuppression suggest that immune checkpoint inhibitors (ICIs) may still have benefit, though at the risk of disease flare or organ rejection. The efficacy of ICIs has not been demonstrated specifically for RCC in this group of patients. SUMMARY: The elderly, frail, and immunosuppressed, those with tumors having aggressive histologic features, and patients with brain, bone, and/or liver metastases represent the populations least understood in the modern era of RCC treatment.
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Doenças Autoimunes , Carcinoma de Células Renais , Neoplasias Renais , Neoplasias Hepáticas , Idoso , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Encéfalo , Neoplasias Hepáticas/tratamento farmacológicoRESUMO
PURPOSE OF REVIEW: The purpose of this review is to highlight the most recent changes in the management of advanced renal cell carcinoma, a complicated and ever-changing field of research. RECENT FINDINGS: A recent meta-analysis examining combination therapy favors nivolumab plus cabozantinib as the overall survival leader in doublet therapy. Initial results on the first ever trial of triplet therapy have demonstrated improved progression-free survival over current standard of care. The hypoxia-inducible factor-2α (HIF-2α) inhibitor belzutifan is FDA approved for patients with von Hippel-Lindau disease and is currently being investigated in patients with nonhereditary renal cell carcinoma. The new glutamate synthesis inhibitor, telaglenastat, perhaps confers synergistic benefit when combined with everolimus, but combination with cabozantinib was not so effective. Dual mammalian target of rapamycin (mTOR) inhibition with sapanisertib does not appear to be an effective therapeutic option. New biomarkers and targets are actively being investigated. Four recent trials examining alternative agents to pembrolizumab in the adjuvant setting did not demonstrate an improvement in recurrence-free survival. Cytoreductive nephrectomy in the combination therapy era is supported by retrospective data; clinical trials are recruiting patients. SUMMARY: The last year ushered in novel approaches of varying success for managing advanced renal cell carcinoma, including triplet therapy, HIF-2α inhibitors, metabolic pathway inhibitors, and dual mTOR inhibitors. Pembrolizumab remains the only modern therapy available in the adjuvant setting, and the waters surrounding cytoreductive nephrectomy are still murky.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Estudos Retrospectivos , Neoplasias Renais/tratamento farmacológico , Fatores de Transcrição Hélice-Alça-Hélice BásicosRESUMO
OBJECTIVES: Our study aimed to determine the publication rates of podium presentations from the 2017 and 2018 Society of Gynecologic Oncology (SGO) Annual Meetings; and to examine rates and predictors of oral presentations that resulted in publication. METHODS: We reviewed podium presentations given at the 2017 and 2018 SGO Annual Meetings. Abstracts were evaluated for publication from January 1, 2017 to March 30, 2020 and January 1, 2018 to June 30, 2021, respectively, to allow for a 3 year period of publication. RESULTS: In 2017 and 2018, 43 of 75 (57.3%) and 47 of 83 (56.6%) podium presentations were published within 3 years, respectively. No significant difference was found between the mean time to publication within 3 years (13.0 months vs 14.1 months for 2017 and 2018, respectively; p=0.96). Similarly, the mean difference of journal impact factors between both years did not reach significance (6.57 and 10.7 for 2017 and 2018, respectively; p=0.09). The median impact factor (IF) was 4.54 (range: 40.3) and 4.62 (range: 70.7) in 2017 and 2018, respectively. Of the presentations published, 53.4% (2017) and 38.3% (2018) appeared in the journal Gynecologic Oncology. Significant positive correlations for the likelihood of publication were determined among the following: funding status (r=0.93) including funding involving National Institutes for Health (r=0.91) or pharmaceutical (r=0.95), clinical trial study design (r=0.94), and pre-clinical research (r=0.95) (all p<0.005). CONCLUSIONS: At the 2017 and 2018 SGO Annual Meetings 57% of podium presentations were published in a peer-reviewed journal within 3 years. Publication in peer-reviewed journals is crucial for timely distribution of clinical information to the medical community.
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Projetos de Pesquisa , Sociedades Médicas , Humanos , FemininoRESUMO
Reprogramming the tumor microenvironment to increase immune-mediated responses is currently of intense interest. Patients with immune-infiltrated "hot" tumors demonstrate higher treatment response rates and improved survival. However, only the minority of tumors are hot, and a limited proportion of patients benefit from immunotherapies. Innovative approaches that make tumors hot can have immediate impact particularly if they repurpose drugs with additional cancer-unrelated benefits. The seasonal influenza vaccine is recommended for all persons over 6 mo without prohibitive contraindications, including most cancer patients. Here, we report that unadjuvanted seasonal influenza vaccination via intratumoral, but not intramuscular, injection converts "cold" tumors to hot, generates systemic CD8+ T cell-mediated antitumor immunity, and sensitizes resistant tumors to checkpoint blockade. Importantly, intratumoral vaccination also provides protection against subsequent active influenza virus lung infection. Surprisingly, a squalene-based adjuvanted vaccine maintains intratumoral regulatory B cells and fails to improve antitumor responses, even while protecting against active influenza virus lung infection. Adjuvant removal, B cell depletion, or IL-10 blockade recovers its antitumor effectiveness. Our findings propose that antipathogen vaccines may be utilized for both infection prevention and repurposing as a cancer immunotherapy.
Assuntos
Imunoterapia/métodos , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/uso terapêutico , Injeções Intralesionais , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Linfócitos B , Fatores de Transcrição de Zíper de Leucina Básica/genética , Linfócitos T CD8-Positivos/imunologia , Humanos , Imunidade Celular , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana , Interleucina-10 , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Repressoras/genética , Estações do Ano , Pele , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Esqualeno/administração & dosagem , Microambiente Tumoral/efeitos dos fármacos , VacinaçãoRESUMO
AbstractThe American Urological Association (AUA) and American College of Surgeons (ACS) codes of professionalism require surgeons to disclose the specific roles and responsibilities of trainees to patients during the informed consent process. The objective of this study is to analyze how these requirements are met by urology training programs. An anonymous electronic survey was distributed to the program directors (PDs) of the 143 Accreditation Council for Graduate Medical Education urology residency programs in the United States in 2021. Information was collected regarding program demographics, aspects of the program's consent process, and the disclosure to patients of the role and participation of residents in their surgery. There were 49 responses to the survey (34.3% response rate). Nearly 70 percent of PDs reported that attending physicians lead the consent process. The topics covered during consent discussion include possible complications (25%), expected recovery time (23%), length of the surgery (22%), the people involved (18%), and their specific roles (7%). Many PDs do not explicitly discuss trainee involvement (48.8%) or when a resident is to perform the majority of the case (87.8%). The majority of PDs (78.8%) communicate medical student involvement, but 73.2 percent reported having a patient decline participation of a trainee after describing their role. Despite the AUA and ACS codes of professionalism, many urologists do not disclose resident involvement in surgery to patients. Further discussions are needed to explore how to better balance resident education and patient autonomy.
Assuntos
Internato e Residência , Urologia , Humanos , Estados Unidos , Educação de Pós-Graduação em Medicina , Inquéritos e Questionários , Consentimento Livre e EsclarecidoRESUMO
PURPOSE OF REVIEW: The genomic and immunologic profiling of renal cell carcinoma (RCC) has provided the impetus for advancements in systemic treatments using combination therapy - either with immune check point inhibitor (ICI)â+âICI or with ICIâ+âtargeted therapy. This approach has been examined in several landmark trials, treating both clear cell (ccRCC) and nonclear cell (nccRCC) histologies. In this review, we highlight systemic therapy advancements made in this new decade, the 2020s. RECENT FINDINGS: Targeting the programmed death receptor 1/PD-L1 pathway has created more tolerable and effective immunotherapy regimens, expanding the applications of ICIs. These new applications, paired with trial data, include ICI monotherapy in nccRCC and adjuvant pembrolizumab in resected, high-risk RCC. In addition, ICIâ+âICI and ICIâ+âTKI combination therapy have demonstrated oncologic efficacy in advanced ccRCC and sarcomatoid RCC. Similar progress has been noted regarding new targeted therapies. Along the hypoxia inducible factor pathway, belzutifan has received FDA approval in von Hippel-Lindau-associated RCC. In addition, in papillary RCC, agents such as cabozantinib target the MET proto-oncogene pathway and have demonstrated impressive oncologic outcomes. SUMMARY: The 2020s utilize the molecular profiling of advanced RCC as a scaffold for recent trials in immunotherapy and targeted therapies. Going forward, emphasizing patient-reported outcomes and careful clinical trial construction remain critical to improve systemic therapy in RCC.
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Antineoplásicos , Carcinoma de Células Renais , Neoplasias Renais , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Humanos , Imunoterapia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologiaRESUMO
PURPOSE: Retroperitoneal lymph node dissection (RPLND) for men with clinical stage (CS) I or II testicular nonseminomatous germ cell tumor (NSGCT) has both staging and therapeutic implications. We aimed to investigate the impact of lymph node count (LNC) on outcome after primary RPLND for men with CS I or II NSGCT using a nationally representative data set. MATERIALS AND METHODS: A retrospective analysis of men who received a primary RPLND for CS I or II NSGCT was performed using the National Cancer Database. The Kaplan-Meier method was used to determine overall survival (OS) according to LNC. Logistic regression analyses were used to identify factors associated with LNC >20 and factors predictive of lymph node-positive (pN+) disease after primary RPLND. RESULTS: Of 1,376 men who comprised our analytical cohort, 50.1% and 49.9% had 1-20 lymph nodes (LNs) and >20 LNs removed, respectively. Five-year OS rates were 96.4% and 99.1% for men with 1-20 and >20 LNs resected, respectively (p=0.004). A higher proportion of men with >20 LNs removed were treated at academic centers, had private insurance, presented with higher AJCC (American Joint Committee on Cancer) CS and were more likely to have pN+ disease, compared to those with 1-20 LNs removed. Factors significantly associated with pN+ disease after RPLND include higher AJCC CS and LNC (per 10-count increase). CONCLUSIONS: Higher LNC after primary RPLND significantly increases the likelihood of identifying pN+ disease and is associated with improved OS. Our data support the therapeutic implications of a thoroughly performed RPLND in the primary setting.
Assuntos
Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Humanos , Excisão de Linfonodo/métodos , Linfonodos/patologia , Linfonodos/cirurgia , Masculino , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Embrionárias de Células Germinativas/cirurgia , Espaço Retroperitoneal/patologia , Estudos Retrospectivos , Neoplasias Testiculares/patologia , Resultado do TratamentoRESUMO
PURPOSE: The American Urological Association (AUA) Annual Meeting serves as the premier platform for presenting unpublished research in urology. Among selected abstracts, podium presentations represent the most impactful submissions. While podium presentations receive a large audience through conference attendance and social media posts, it is unclear how often they manifest as publications in peer-reviewed journals. MATERIALS AND METHODS: Podium presentations from the 2017 AUA Annual Meeting were reviewed. Abstracts were assessed for publication between January 1, 2015 and May 31, 2020 allowing for a 3-year window of publication and accounting for publications prior to the submission deadline. Abstract authors were individually searched with key terms being added sequentially until <30 results were generated in PubMed®. Abstracts were deemed published if at least 1 author and 1 conclusion matched a manuscript. Publication rate, time to publication, and 2019 journal impact factor were collected. Statistical analysis was performed by linear and logistic regression. RESULTS: Of 872 podium presentations, 453 (51.9%) were published within 3 years. Median time from submission to publication was 12.5 months (IQR: 7.5-20.5). The number of articles published at 1, 2 and 3 years from submission was 203, 368 and 430, respectively. The median journal impact factor of publications was 3.2 (IQR: 2.0-5.8). Oncology studies (OR=1.21 [95% CI: 0.91-1.60], p=0.186) had similar rates of publication compared to non-oncology studies. CONCLUSIONS: While AUA podium presentations disseminate valuable data, approximately half were not published in peer-reviewed journals within 3 years. Therefore, care must be taken when promoting findings or adopting new practices based on these presentations alone.
Assuntos
Congressos como Assunto , Editoração/estatística & dados numéricos , Sociedades Médicas , Urologia , Humanos , Fatores de Tempo , Estados UnidosRESUMO
BACKGROUND: To investigate the effects of the U.S. Preventive Services Task Force's (USPSTF) 2012 recommendation against prostate-specific antigen (PSA)-based screening for prostate cancer on survival disparities based on insurance status. Prior to the USPSTF's 2012 screening recommendation, previous studies found that insured patients with prostate cancer had better outcomes than uninsured patients. METHODS: Using the SEER 18 database, we examined prostate cancer-specific survival (PCSS) based on diagnostic time period and insurance status. Patients were designated as belonging to the pre-USPSTF era if diagnosed in 2010-2012 or post-USPSTF era if diagnosed in 2014-2016. PCSS was measured with the Kaplan-Meier method, while disparities were measured with the Cox proportional hazards model. RESULTS: During the pre-USPSTF era, uninsured patients experienced worse PCSS compared to insured patients (adjusted HR 1.256, 95% CI 1.037-1.520, p = 0.020). This survival disparity was no longer observed during the post-USPSTF era as a result of decreased PCSS among insured patients combined with unchanged PCSS among uninsured patients (adjusted HR 0.946, 95% CI 0.642-1.394, p = 0.780). CONCLUSIONS: Although the underlying reasons are not clear, the USPSTF's 2012 PSA screening recommendation may have hindered insured patients from being regularly screened for prostate cancer and selectively led to worse outcomes for insured patients without affecting the survival of uninsured patients.
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Antígeno Prostático Específico , Neoplasias da Próstata , Detecção Precoce de Câncer , Humanos , Masculino , Modelos de Riscos Proporcionais , Próstata , Neoplasias da Próstata/diagnóstico , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Standard treatment for high-risk non-muscle-invasive bladder cancer is transurethral resection of bladder tumour followed by intravesical BCG immunotherapy. However, despite high initial responses rates, up to 50% of patients have recurrence or become BCG-unresponsive. PD-1 pathway activation is implicated in BCG resistance. In the KEYNOTE-057 study, we evaluated pembrolizumab, a PD-1 inhibitor, in BCG-unresponsive non-muscle-invasive bladder cancer. METHODS: We did this open-label, single-arm, multicentre, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. In cohort A of the trial, adults aged 18 years or older with histologically confirmed BCG-unresponsive carcinoma in situ of the bladder, with or without papillary tumours, with an Eastern Cooperative Oncology Group performance status of 0-2, and who were ineligible for or declined radical cystectomy were enrolled. All enrolled patients were assigned to receive pembrolizumab 200 mg intravenously every 3 weeks for up to 24 months or until centrally confirmed disease persistence, recurrence, or progression; unacceptable toxic effects; or withdrawal of consent. The primary endpoint was clinical complete response rate (absence of high-risk non-muscle-invasive bladder cancer or progressive disease), assessed by cystoscopy and urine cytology approximately 3 months after the first dose of study drug. Patient follow-ups were done every 3 months for the first 2 years and every 6 months thereafter for up to 5 years. Efficacy was assessed in all patients who received at least one dose of the study drug and met BCG-unresponsive criteria. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing. FINDINGS: Between Dec 9, 2015, and April 1, 2018, we screened 334 patients for inclusion. 186 patients did not meet inclusion criteria, and 47 patients were assigned to cohort B (patients with BCG-unresponsive high grade Ta or any grade T1 papillary disease without carcinoma in situ; results will be reported separately). 101 eligible patients were enrolled and assigned to receive pembrolizumab. All 101 patients received at least one dose of the study drug and were included in the safety analysis. Five patients had disease that did not meet the US Food and Drug Administration definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore not included in the efficacy analysis (n=96). Median follow-up was 36·4 months (IQR 32·0-40·7). 39 (41%; 95% CI 30·7-51·1) of 96 patients with BCG-unresponsive carcinoma in situ of the bladder with or without papillary tumours had a complete response at 3 months. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients; the most common were arthralgia (in two [2%] patients) and hyponatraemia (in three [3%] patients). Serious treatment-related adverse events occurred in eight (8%) patients. There were no deaths that were considered treatment related. INTERPRETATION: Pembrolizumab monotherapy was tolerable and showed promising antitumour activity in patients with BCG-unresponsive non-muscle-invasive bladder cancer who declined or were ineligible for radical cystectomy and should be considered a a clinically active non-surgical treatment option in this difficult-to-treat population. FUNDING: Merck Sharp & Dohme.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Vacina BCG/uso terapêutico , Carcinoma in Situ/tratamento farmacológico , Carcinoma Papilar/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma in Situ/imunologia , Carcinoma in Situ/patologia , Carcinoma Papilar/imunologia , Carcinoma Papilar/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologiaRESUMO
BACKGROUND: Although renal cell carcinoma (RCC) is believed to have a strong hereditary component, there is a paucity of published guidelines for genetic risk assessment. A panel of experts was convened to gauge current opinions. METHODS: A North American multidisciplinary panel with expertise in hereditary RCC, including urologists, medical oncologists, clinical geneticists, genetic counselors, and patient advocates, was convened. Before the summit, a modified Delphi methodology was used to generate, review, and curate a set of consensus questions regarding RCC genetic risk assessment. Uniform consensus was defined as ≥85% agreement on particular questions. RESULTS: Thirty-three panelists, including urologists (n = 13), medical oncologists (n = 12), genetic counselors and clinical geneticists (n = 6), and patient advocates (n = 2), reviewed 53 curated consensus questions. Uniform consensus was achieved on 30 statements in specific areas that addressed for whom, what, when, and how genetic testing should be performed. Topics of consensus included the family history criteria, which should trigger further assessment, the need for risk assessment in those with bilateral or multifocal disease and/or specific histology, the utility of multigene panel testing, and acceptance of clinician-based counseling and testing by those who have experience with hereditary RCC. CONCLUSIONS: In the first ever consensus panel on RCC genetic risk assessment, 30 consensus statements were reached. Areas that require further research and discussion were also identified, with a second future meeting planned. This consensus statement may provide further guidance for clinicians when considering RCC genetic risk assessment. LAY SUMMARY: The contribution of germline genetics to the development of renal cell carcinoma (RCC) has long been recognized. However, there is a paucity of guidelines to define how and when genetic risk assessment should be performed for patients with known or suspected hereditary RCC. Without guidelines, clinicians struggle to define who requires further evaluation, when risk assessment or testing should be done, which genes should be considered, and how counseling and/or testing should be performed. To this end, a multidisciplinary panel of national experts was convened to gauge current opinion on genetic risk assessment in RCC and to enumerate a set of recommendations to guide clinicians when evaluating individuals with suspected hereditary kidney cancer.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Consenso , Testes Genéticos , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Medição de RiscoRESUMO
PURPOSE OF REVIEW: As molecular profiling of renal cell carcinoma (RCC) continues to elucidate novel targets for nonclear cell histologies, understanding the landscape of these targets is of utmost importance. In this review, we highlight the genomic landscape of nonclear cell RCC and its implications for current and future systemic therapies. RECENT FINDINGS: Several genomic studies have described the mutational burden among nonclear cell histologies. These studies have highlighted the importance of MET in papillary RCC and led to several clinical trials evaluating the efficacy of MET inhibitors for papillary RCC. The success of immune checkpoint inhibitors, such as ipilimumab and nivolumab, in clear cell RCC has led to ongoing trials evaluating these novel therapeutics in nonclear cell RCC. SUMMARY: Genomic profiling has allowed for the evaluation of novel targets for nonclear cell RCC. This evolving therapeutic landscape is being explored in promising, ongoing trials that have the potential for changing how nonclear cell RCC is managed.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Perfilação da Expressão Gênica , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
PURPOSE OF REVIEW: Pheochromocytoma and paraganglioma (PPGLs) are neuroendocrine tumors with diverse clinical presentations. PPGLs can be sporadic but often are associated with various syndromes, which can have variable clinical presentations. A thorough workup is therefore critical for staging, treatment, and follow-up. Imaging is an essential part of the workup and diagnosis of PPGLs. RECENT FINDINGS: Improvements in cross-sectional imaging with radionuclides have increased specificity and sensitivity for identifying and treating PPGLs. Furthermore, a variety of targets on PPGLs has allowed for optimal imaging with radionuclides that can be used for staging and treatment. Currently, radionuclides are being evaluated for staging and treatment of PPGLs. Developing novel radionuclides that can identify disease sites and target them simultaneously provides a potential for improving survival and outcomes in patients with PPGLs. Given the clinical diversity among PPGLs, expanding the therapeutic arsenal against locally advanced or metastatic PPGLs can allow clinicians to evaluate and treat PPGLs thoroughly.
Assuntos
Paraganglioma , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Neoplasias das Glândulas Suprarrenais/terapia , Humanos , Imageamento por Ressonância Magnética , Paraganglioma/diagnóstico , Paraganglioma/diagnóstico por imagem , Paraganglioma/terapia , Feocromocitoma/diagnóstico , Feocromocitoma/diagnóstico por imagem , Feocromocitoma/terapia , Cintilografia , Compostos Radiofarmacêuticos/uso terapêutico , Síndrome , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: In May 2012, the US Preventive Services Task Force (USPSTF) recommended against prostate-specific antigen (PSA)-based screening for prostate cancer (PCa), assigning it a grade D. This decision then was modified in 2018 to a grade C for men aged 55 to 69 years. The authors hypothesized that changes in screening practices would reduce survival outcomes for both Black and White men but maintain racial discrepancies in outcomes. METHODS: Using the Surveillance, Epidemiology, and End Results database, the authors examined PCa-specific survival based on race and year of diagnosis. The period between January 2010 and December 2012 was categorized as the pre-USPSTF era, whereas the period between January 2014 and December 2016 was classified as the post-USPSTF era. The year 2013 was considered the transition year and was excluded from the analysis. RESULTS: A total of 49,388 men were identified in the pre-USPSTF era who were diagnosed with PCa, approximately 83.7% of whom were White and 16.3% of whom were Black. In the post-USPSTF era, a total of 41,829 men were diagnosed with PCa, approximately 82.7% of whom were White and 17.3% of whom were Black. When compared with the pre-USPSTF era, men diagnosed in the post-USPSTF era were found to have more adverse clinical features. In the pre-USPSTF era, White men were less likely to die of PCa than Black men. This survival disparity between White and Black men was no longer observed in the post-USPSTF era. CONCLUSIONS: In men diagnosed with PCa between 2014 and 2016, a survival disparity between White and Black men was not observed due to a decrease in survival among White men while the survival of Black men remained steady.
Assuntos
Programas de Rastreamento/métodos , Neoplasias da Próstata/mortalidade , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Detecção Precoce de Câncer , Humanos , Calicreínas/análise , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/análise , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Fatores Raciais , Programa de SEER , Estados Unidos , População Branca/estatística & dados numéricosRESUMO
BACKGROUND: Stage III renal cell carcinoma (RCC) encompasses both lymph node-positive (pT1-3N1M0) and lymph node-negative (pT3N0M0) disease. However, prior institutional studies have indicated that among patients with stage III disease, those with lymph node disease have worse oncologic outcomes and experience survival that is similar to that of patients with American Joint Committee on Cancer (AJCC) stage IV disease. The objective of the current study was to validate these findings using a large, nationally representative sample of patients with kidney cancer. METHODS: Patients with AJCC stage III or stage IV RCC were identified using the National Cancer Data Base (NCDB). Patients were categorized as having lymph node-positive stage III (pT1-3N1M0), lymph node-negative stage III (pT3N0M0), or stage IV metastatic (pT1-3 N0M1) disease. Cox proportional hazards models compared outcomes while adjusting for comorbidities. Kaplan-Meier estimates illustrated relative survival when comparing staging groups. RESULTS: A total of 8988 patients met the inclusion criteria, with 6587 patients classified as having lymph node-negative stage III disease, 2218 as having lymph node-positive stage III disease, and 183 as having stage IV disease. Superior survival was noted among patients with lymph node-negative stage III disease, but similar survival was noted between patients with lymph node-positive stage III and stage IV RCC, with 5-year survival rates of 61.9% (95% confidence interval [95% CI], 60.3%-63.4%), 22.7% (95% CI, 20.6%-24.9%), and 15.6% (95% CI, 11.1%-23.8%), respectively. CONCLUSIONS: Current RCC staging systems group pT1-3N1M0 and pT3N0M0 disease as stage III disease. However, the results of the current validation study suggest the need for further stratification and even placement of patients with pT1-3N1M0 disease into the stage IV category. Staging that accurately reflects oncologic prognosis may help clinicians better counsel and select patients who might derive the most benefit from lymphadenectomy, adjuvant systemic therapy, more rigorous imaging surveillance, and clinical trial participation.
Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Linfonodos/patologia , Adulto , Idoso , Carcinoma de Células Renais/mortalidade , Distribuição de Qui-Quadrado , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Estatísticas não Paramétricas , Taxa de Sobrevida , Fatores de TempoRESUMO
PURPOSE OF REVIEW: As the biology of metastatic renal cell carcinoma (mRCC) continues to be elucidated, novel treatments focused around immunotherapies and targeted therapies will continue to emerge. In this review, we will highlight recent treatment advances and their implications for surgical and systemic therapy. RECENT FINDINGS: Several new treatments, including the tyrosine kinase inhibitor cabozantinib, the combination of a programmed cell death protein 1 antibody (nivolumab) with a cytotoxic T-lymphocyte-associated antigen 4 antibody (ipilimumab), and the combination of axitinib with pembrolizumab or avelumab have been approved by the US Food and Drug Administration as first-line therapy for the treatment of mRCC. Although promising survival benefits have been seen with these new therapies, careful patient selection is still critical. SUMMARY: The introduction of novel therapies and the investigation of combinatorial therapies have shifted the treatment paradigm for advanced RCC. Present trials have provided promising data that could lead to further therapeutic advances.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/cirurgia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/cirurgia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/patologia , Quimioterapia Adjuvante , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Procedimentos Cirúrgicos de Citorredução/métodos , Humanos , Neoplasias Renais/patologia , Terapia Neoadjuvante , Metástase Neoplásica , Inibidores de Proteínas Quinases/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Patients with high-risk renal cell carcinoma (RCC) experience high rates of recurrence despite definitive surgical resection. Recent trials of adjuvant tyrosine kinase inhibitor therapy have provided conflicting efficacy results at the cost of significant adverse events. PD-1 blockade via monoclonal antibodies has emerged as an effective disease-modifying treatment for metastatic RCC. There is emerging data across other solid tumors of the potential efficacy of neoadjuvant PD-1 blockade, and preclinical evidence supporting a neoadjuvant over adjuvant approach. PROSPER RCC is a Phase III, randomized trial evaluating whether perioperative nivolumab increases recurrence-free survival in patients with high-risk RCC undergoing nephrectomy. The neoadjuvant component, intended to prime the immune system for enhanced efficacy, distinguishes PROSPER from other purely adjuvant studies and permits highly clinically relevant translational studies.