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Over the past half century, advancements in treatment have led to cures in an overwhelming majority of patients with testicular germ cell tumors. Astute clinical decision-making, informed by the abundant data from published clinical trials, is essential for achieving a cure whenever possible and minimizing the toxicity of treatment. Important remaining challenges include reducing the risk of secondary malignancies and other late effects of chemotherapy and radiation therapy, and developing curative treatments for patients with cancer that is refractory to current therapies. This article reviews the current treatment landscape and highlights recent discoveries in diagnosis and staging, emerging biomarkers for disease, and treatment for relapsed/refractory disease. Treatment algorithms for testis cancer are complex and clinicians should apply them carefully, not only to optimize shortterm, disease-related outcomes, but also to maximize long-term survival and quality of life.
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Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Masculino , Humanos , Qualidade de Vida , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Testiculares/patologia , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/etiologiaRESUMO
BACKGROUND: Checkpoint inhibitor therapy is a standard of care for patients with metastatic renal cell carcinoma. Treatment options after checkpoint inhibitor therapy include vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitors, although no prospective data regarding their use in this setting exist. Axitinib is a VEGF-R inhibitor with clinical data supporting increased activity with dose titration. We aimed to investigate the activity of dose titrated axitinib in patients with metastatic renal cell carcinoma who were previously treated with checkpoint inhibitor. METHODS: We did a multicentre, phase 2 trial of axitinib given on an individualised dosing algorithm. Patients at least 18 years of age with histologically or cytologically confirmed locally recurrent or metastatic renal cell carcinoma with clear cell histology, a Karnofsky Performance Status of 70% or more, and measurable disease who received checkpoint inhibitor therapy as the most recent treatment were eligible. There was no limit on number of previous therapies received. Patients received oral axitinib at a starting dose of 5 mg twice daily with dose titration every 14 days in 1 mg increments (ie, 5 mg twice daily to 6 mg twice daily, up to 10 mg twice daily maximum dose) if there was no axitinib-related grade 2 or higher mucositis, diarrhoea, hand-foot syndrome, or fatigue. If one or more of these grade 2 adverse events occurred, axitinib was withheld for 3 days before the same dose was resumed. Dose reductions were made if recurrent grade 2 adverse events despite treatment breaks or grade 3-4 adverse events occurred. The primary outcome was progression-free survival. Analyses were done per protocol in all patients who received at least one dose of axitinib. Recruitment has been completed and the trial is ongoing. This trial is registered with ClincalTrials.gov, number NCT02579811. FINDINGS: Between Jan 5, 2016 and Feb 21, 2018, 40 patients were enrolled and received at least one dose of study treatment. With a median follow-up of 8·7 months (IQR 3·7-14·2), the median progression-free survival was 8·8 months (95% CI 5·7-16·6). Fatigue (83%) and hypertension (75%) were the most common all-grade adverse events. The most common grade 3 adverse event was hypertension (24 patients [60%]). There was one (3%) grade 4 adverse event (elevated lipase) and no treatment-related deaths occurred. Serious adverse events that were likely related to therapy occurred in eight (20%) patients; the most common were dehydration (n=4) and diarrhoea (n=2). INTERPRETATION: Individualised axitinib dosing in patients with metastatic renal cell inoma previously treated with checkpoint inhibitors did not meet the prespecified threshold for progression free survival, but these data show that this individualised titration scheme is feasible and has robust clinical activity. These prospective results warrant consideration of axitinib in this setting. FUNDING: Pfizer.
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Antineoplásicos/administração & dosagem , Axitinibe/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Idoso , Algoritmos , Antineoplásicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Axitinibe/efeitos adversos , Carcinoma de Células Renais/secundário , Desidratação/induzido quimicamente , Diarreia/induzido quimicamente , Fadiga/induzido quimicamente , Feminino , Humanos , Hipertensão/induzido quimicamente , Ipilimumab/uso terapêutico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Intervalo Livre de Progressão , Critérios de Avaliação de Resposta em Tumores Sólidos , RetratamentoRESUMO
Three experts discussed changes in the 8th edition of the AJCC Cancer Staging Manual and challenges regarding these changes for staging of breast cancer, testicular cancer, and head and neck cancer, respectively. In general, the staging changes for breast cancer and for human papillomavirus-positive oropharyngeal cancer were hailed as improvements, but the changes for testicular cancer were questioned as to their clinical relevance. Better studies are needed to improve staging for human papillomavirus-negative oropharyngeal cancer.
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Neoplasias da Mama/diagnóstico , Neoplasias de Cabeça e Pescoço/diagnóstico , Estadiamento de Neoplasias , Guias de Prática Clínica como Assunto , Neoplasias Testiculares/diagnóstico , Feminino , Humanos , Masculino , Estadiamento de Neoplasias/métodos , Estadiamento de Neoplasias/normasRESUMO
Partnering with patients who reject our recommended treatment: how to understand what our patients are going through.
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Relações Médico-Paciente , Humanos , Recusa do Paciente ao Tratamento , Neoplasias/terapia , Neoplasias/psicologiaRESUMO
Clinical trials for immunotherapy-based regimens in metastatic renal cell carcinoma (mRCC) have extensive inclusion and exclusion criteria. We investigated the clinical outcomes in a real-world cohort of patients who would not have met the criteria for inclusion in front-line mRCC trials. Patients treated with ipilimumab/nivolumab and axitinib/pembrolizumab for front-line mRCC were identified and divided into clinical trial eligible (CTE) and clinical trial ineligible (CTI) cohorts based on key inclusion or exclusion criteria from their respective Phase-3 registration trials. Clinical outcomes were compared in CTE and CTI cohorts. A total of 62 patients treated with axitinib/pembrolizumab and 103 treated with ipilimumab/nivolumab were identified. The International Metastatic RCC Database Consortium (IMDC) criteria were similar across CTE and CTI patients in axitinib/pembrolizumab and ipilimumab/nivolumab cohorts. In the axitinib/pembrolizumab cohort (n = 62), 24 (39%) patients were CTI. The major reasons for the ineligibility were lab abnormalities (n = 11), histology (n = 9), and brain metastases (n = 3). There was no significant difference in response rates (P = 0.08). The median progression-free survival (PFS) was numerically longer in CTE patients (28 vs 12 months; P = 0.09). The overall survival (OS) was higher in the CTE patients (P = 0.02). In the ipilimumab/nivolumab cohort (n = 103), 59 (57%) were CTI. The most common reasons for ineligibility were brain metastases (n = 18), lab abnormalities (n = 16), and histology (n = 16). There was no significant difference in response rates (P = 0.22). However, PFS (P = 0.003) and OS (P < 0.0001) were higher in the CTE patients. In conclusion, many real-world patients are ineligible for RCC clinical trials and had worse outcomes when compared to trial-eligible patients. Additional treatment options are needed for these patients, as well as strategies to include them in prospective trials.
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INTRODUCTION: The combination of ipilimumab/nivolumab is approved for patients with treatment-naïve, intermediate-, and poor-risk metastatic renal cell carcinoma (mRCC), but duration of therapy and safety/efficacy of reinduction at progression is unknown. A phase II trial of intermittent ipilimumab/nivolumab with reinduction at progression was conducted (NCT03126331). PATIENTS AND METHODS: Patients with treatment-naïve mRCC were treated with induction ipilimumab/nivolumab followed by up to 24 weeks of maintenance nivolumab. Patients who achieved a complete response (CR) or partial response (PR) were eligible for inclusion and entered a treatment-free observation period. Patients were restaged every 12 weeks. Patients with no disease progression (PD) remained off therapy. Upon PD, patients were re-challenged with 2 doses of ipilimumab/nivolumab every 3 weeks. Study objectives were to estimate success rate of observation in patients who achieve a CR/PR, and to assess toxicity in patients undergoing reinduction. The study accrued slower than expected and was closed prior to the anticipated accrual goal of 20 patients. RESULTS: Nine patients were included; 89% male, median age 57, 67% clear-cell histology, and 78% intermediate-risk by IMDC criteria. Response to ipilimumab/nivolumab followed by nivolumab maintenance prior to enrollment was 33% CR and 67% PR. Most (78%) patients have remained off therapy, with a median treatment-free interval (TFI) of 34.3 months (range, 8.7-41.8). Two patients had PD off therapy and received 2 cycles of reinduction ipilimumab and nivolumab. No grade 3 or greater toxicities occurred with reinduction. Both patients developed PD at their first scans after reinduction. CONCLUSION: This prospective study demonstrates that patients with a radiographic response to ipilimumab/nivolumab can have prolonged treatment-free intervals. Further studies of de-escalation strategies are warranted. TRIAL REGISTRATION: NCT03126331 [Date of registration 4/27/2017; https://clinicaltrials.gov/ct2/show/NCT03126331].
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INTRODUCTION: As most patients with metastatic urothelial carcinoma (mUC) will be treated with immune checkpoint inhibitors (ICI), familiarity with their associated immune-related adverse events (irAEs) is critical. We describe the characteristics and outcomes of ICI-treated mUC patients who experienced irAEs requiring treatment interruption (TI) or permanent discontinuation. MATERIALS AND METHODS: ICI-treated mUC patients who developed grade ≥2 irAEs were reviewed. Clinical-, treatment-, and toxicity-related data were evaluated. Toxicity was graded per common terminology for categorization of adverse events v5.0. Cohorts were divided into patients who underwent ICI rechallenge and those who required permanent ICI discontinuation. Time to treatment interruption (TTI), time to next treatment, and duration of clinical benefit were assessed descriptively. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier methodology. RESULTS: Of 200 ICI-treated mUC patients at Cleveland Clinic between October 2015 and October 2020, 16 (8%) experienced ≥ grade 2 irAEs necessitating TI. Median TTI among all patients was 6.5 months (range, 1-19). Eleven patients (69%) required corticosteroids. ICI were held and rechallenged in 10 patients (62%) and permanently discontinued in 6 patients (38%). Of the 10 ICI-rechallenged patients, 7 (70%) experienced another irAE upon rechallenge with median time to irAE recurrence of 2.9 months (range, 0.1-10.9); 3 (30%) eventually discontinued ICI due to recrudescent irAEs. Four (40%) of the 10 ICI-rechallenged patients received subsequent therapy. Five (83%) of the 6 patients who permanently discontinued ICI demonstrated durable clinical benefit off therapy with median duration of clinical benefit 17.7 months (range, 14.2-55.2). Two-year OS was 40% (95% CI: 19%-86%) in the ICI rechallenge cohort and 67% (95% CI: 38%-100%) in the permanent discontinuation cohort. CONCLUSION: ICI-treated mUC patients who developed irAEs requiring TI had a high rate of subsequent irAEs upon ICI rechallenge. Importantly, patients who permanently discontinued ICI due to irAE demonstrated durable clinical benefit off treatment.
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Antineoplásicos Imunológicos , Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Interrupção do Tratamento , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/induzido quimicamente , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos RetrospectivosRESUMO
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in the Journal of Clinical Oncology, to patients seen in their own clinical practice.Optimal treatment of patients with testicular germ cell tumors requires a coordinated multidisciplinary approach, so that surgery, chemotherapy, and, when appropriate, radiation therapy can be integrated into a coherent and comprehensive treatment plan. Nonseminomatous germ cell tumors (NSGCT) are often a mixture of teratoma and cancer (choriocarcinoma, embryonal carcinoma, seminoma, and/or yolk sac tumor). While the cancers are highly sensitive to and often cured by chemotherapy, teratoma is resistant to chemotherapy and radiation therapy and generally must be resected surgically to be successfully treated. Therefore, the standard of care for metastatic NSGCT is to resect all resectable residual masses after chemotherapy. If such resection reveals only teratoma and/or necrosis/fibrosis, then patients are put on a surveillance schedule to monitor for relapse. If viable cancer is found and there are positive margins or 10% or more of any of the residual masses consists of viable cancer, then two cycles of adjuvant chemotherapy should be considered.
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Neoplasias Embrionárias de Células Germinativas , Teratoma , Neoplasias Testiculares , Masculino , Humanos , Adulto , Adolescente , Recidiva Local de Neoplasia , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/cirurgia , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Teratoma/tratamento farmacológicoRESUMO
BACKGROUND: The current treatment of metastatic renal cell carcinoma (mRCC) with vascular endothelial growth factor (VEGF)-targeted agents is continuous therapy until progression of disease (PD) or unacceptable toxicity. Chronic mild to moderate toxicity and risk of long-term toxicity ensue for some patients. It is hypothesized that patients with an initial response to treatment can maintain disease control off all therapy for a period of time. METHODS: A retrospective study of patients with mRCC who initiated VEGF-targeted therapy between January 2004 and December 2009 at The Cleveland Clinic Foundation, Cleveland, Ohio, or Institut Gustave-Roussy, Villejuif, France, was conducted. Patients had achieved RECIST (Response Evaluation Criteria in Solid Tumors)-defined stable disease or better on therapy, and were then taken off all therapy for reasons not including disease progression. Patient, disease, and therapy characteristics were recorded. The primary objective was progression-free survival (PFS), measured as the time from discontinuation of therapy to RECIST-defined PD. RESULTS: Forty patients were identified. After a median follow-up of 29.7 months (range, 4.2 to 84.7 months), 25 patients (63%) had PD off therapy (median PFS, 10.0 months; range, 1.4-27.2 months). Among these patients, 8 (32%) had progression in sites that were not previously involved with disease. Heng risk group (hazard ratio, 2.49; 95% confidence interval, 1.19-5.22; P = .011) and achievement of a complete response prior to discontinuing therapy (hazard ratio, 0.20; 95% confidence interval, 0.04-0.86; P = .025) were independent predictors of PFS in a multivariable Cox proportional hazards model. CONCLUSIONS: A select subset of mRCC patients achieving stable disease or better on VEGF-targeted therapy can be observed off all therapy. Further prospective investigation is warranted.
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Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Suspensão de Tratamento , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/secundário , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Fatores de TempoRESUMO
Despite efforts to embrace diversity, women and members of racial, ethnic, and gender minority groups continue to experience bias, inequities, microaggressions, and unwelcoming atmospheres in the workplace. Specifically, women in oncology have lower promotion rates and less financial support and mentorship, and they are less likely to hold leadership positions. These experiences are exceedingly likely at the intersection of identities, leading to decreased satisfaction, increased burnout, and a higher probability of leaving the workforce. Microaggressions have also been associated with depression, suicidal thoughts, and other health and safety issues. Greater workplace diversity and equity are associated with improved financial performance; greater productivity, satisfaction, and retention; improved health care delivery; and higher-quality research. In this article, we provide tools and steps to promote equity in the oncology workplace and achieve cultural change. We propose the use of tailored approaches and tools, such as active listening, for individuals to become microaggression upstanders; we also propose the implementation of education, evaluation, and transparent policies to promote a culture of equity and diversity in the oncology workplace.
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Microagressão , Oncologistas , Etnicidade , Feminino , Humanos , Grupos Minoritários , Grupos RaciaisRESUMO
BACKGROUND: Given that training is integral to providing constructive peer feedback, we examined the impact of a regularly reinforced, structured peer assessment method on student-reported feedback abilities throughout a two-year preclinical Communication Skills course. METHODS: Three consecutive 32-student medical school classes were introduced to the Observation-Reaction-Feedback method for providing verbal assessment during Year 1 Communication Skills orientation. In biweekly small-group sessions, students received worksheets reiterating the method and practiced giving verbal feedback to peers. Periodic questionnaires evaluated student perceptions of feedback delivery and the Observation-Reaction-Feedback method. RESULTS: Biweekly reinforcement of the Observation-Reaction-Feedback method encouraged its uptake, which correlated with reports of more constructive, specific feedback. Compared to non-users, students who used the method noted greater improvement in comfort with assessing peers in Year 1 and continued growth of feedback abilities in Year 2. Comfort with providing modifying feedback and verbal feedback increased over the two-year course, while comfort with providing reinforcing feedback and written feedback remained similarly high. Concurrently, student preference for feedback anonymity decreased. CONCLUSIONS: Regular reinforcement of a peer assessment framework can increase student usage of the method, which promotes the expansion of self-reported peer feedback skills over time. These findings support investigation of analogous strategies in other medical education settings. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40670-021-01242-w.
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BACKGROUND: Prostate-specific antigen screening is controversial. In 2008, the United States Preventive Services Task Force recommended against screening men aged ≥ 75 years, and in 2012, expanded this to include all men. The impact of these changes continues to unfold. We hypothesized that these screening changes could delay the diagnosis of advanced prostate cancer. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results database was used to identify men (age, 55-69 years) diagnosed with prostate cancer in 2004 to 2008 (group 1), 2009 to 2012 (group 2), and 2013 to 2015 (group 3). Groups reflect United States Preventive Services Task Force guideline changes. Descriptive statistics were used to present baseline statistics and the number of patients diagnosed in aforementioned groups. Data was adjusted for population growth. RESULTS: A total of 328,586 men were identified (group 1, 135,625; group 2, 117,979; group 3, 74,982). The average number of men diagnosed annually with N1M0 (group 1, 381; group 2, 477; group 3, 660) and M1 (group 1, 523; group 2, 761; group 3, 1037) disease increased. With group 1 as control, there was a decrease in the incidence of localized disease (group 2, 9.2%; group 3, 33.2%). However, the incidence of N1M0 (group 2, 5.3%; group 3, 30.1%) and M1 disease (group 2, 22.6%; group 3, 49.2%) increased. Separate analyses of patients (age 50-75 years) and African Americans showed similar trends. CONCLUSION: With each recommendation, there was increased incidence of de novo metastatic prostate cancer. The sequelae of advanced disease include financial, emotional, and physical burden. Future studies are needed to identify screening strategies that reduce the risk of developing metastatic disease without over-diagnosing indolent cancers.
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Detecção Precoce de Câncer , Neoplasias da Próstata , Comitês Consultivos , Negro ou Afro-Americano , Idoso , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Antígeno Prostático Específico , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Despite treatment with abiraterone acetate and prednisone (AA/P), most patients with metastatic hormone sensitive prostate cancer (mHSPC) will develop castration-resistant disease (metastatic castration-resistant prostate cancer [mCRPC]). The early identification of who will progress on AA/P is limited. OBJECTIVE: This study investigates the role of prostate surface antigen (PSA) kinetics as a predictor of progression in mHSPC patients treated with AA/P. PATIENTS AND METHODS: All patients with mHSPC who initiated androgen deprivation therapy (ADT) and AA/P from June 2017 to February 2019 at the Cleveland Clinic were eligible. PSA-mCRPC was defined as a PSA rise at two consecutive time points. Patients were followed until first mCRPC or last contact after AA/P. Patterns of PSA change were evaluated using a longitudinal mixed model at time 0, 3, 6, 9, and 12 months from AA/P initiation. The association between PSA profile at 3 months and PSA-mCRPC was examined using survival analysis. Radiographic progression (Rad-mCRPC) was also analyzed. RESULTS: A total of 130 men with follow-up were included. The median (interquartile range [IQR]) follow-up time was 15.3 (10.5, 22.5) months. Eighty-two percent were Caucasian (median age 68.5 years); participants had a median (IQR) PSA of 16.8 (5.3, 48.0) ng/mL. Half of the patients had de novo disease, and 46.2% had high-risk disease (61% had a Gleason score ≥ 8, 16% had visceral disease, and 54% had three or more bony lesions). The greatest PSA percentage reduction from baseline after AA/P initiation occurred at the first 3 months (median 98.3%). The reduction at 6-12 months from baseline was small (99.7-100%). Patients without PSA-mCRPC had a significantly greater 3-month reduction of PSA values compared to patients who developed PSA-mCRPC (p interaction = 0.0002). 50.8% of patients were able to achieve a non-detectable PSA (median 13.1 months). PSA-mCRPC (n = 20) was observed from 4 to 24 months after AA/P, with the majority of events occurring within the first 12 months. Patients with PSA < 0.3 ng/mL (12-month PSA-mCRPC-free 94.5% vs. 69.4%, p = 0.0004) or a ≥ 98% reduction (94.9% vs. 68.0%, p = 0.0002) at 3 months had better PSA-mCRPC-free survival compared to their counterparts. Absolute reduction at 3 months was not associated with PSA-mCRPC. Similar PSA patterns were seen in those who had Rad-mCRPC compared to no Rad-mCRPC (p interaction < 0.05). CONCLUSION: The degree of PSA decline at 3 months predicted serologic progression to mCRPC. Those who developed castration-resistant disease had higher PSA and a lower percentage reduction by 3 months. Tracking early PSA pattern changes may alert clinicians to poor treatment effect and potential progression; they should consider frequent PSA measurement and imaging, as well as the initiation of sequential therapy.
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Androstenos/uso terapêutico , Antígenos de Superfície/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Prednisona/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Androstenos/farmacologia , Humanos , Masculino , Prednisona/farmacologia , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Myeloid-derived suppressor cells (MDSCs) were linked to pathologic stage in bladder urothelial carcinoma (UC). Neutrophil lymphocyte ratio (NLR) is an inflammatory biomarker with a prognostic role in metastatic (m)UC. OBJECTIVE: We hypothesized that MDSC levels correlate with NLR and overall survival (OS) in mUC. PATIENTS AND METHODS: MDSCs were measured in blood samples from patients with mUC in fresh unfractionated whole blood (WB) and peripheral blood mononuclear cells (PBMC) by flow cytometry and defined as LinloCD33+/HLADR- (Total MDSC). MDSC subsets were defined as polymorphonuclear (PMN-MDSC: CD15+/CD14-), monocytic (M-MDSC: CD15-/CD14+), and uncommitted (UNC-MDSC: CD15-/CD14-). MDSC populations were presented as a percentage of live nucleated blood cells. Spearman's rank correlation assessed correlations between MDSC and NLR. Kaplan-Meier curves and log-rank test estimated OS from the time of MDSC collection to last follow-up or date of death. RESULTS: Of the 76 patients, 78% were men and 43% were never smokers with a median age of 69 years (range 31-83); 72% had pure UC and 76% had lower tract UC. Prior therapies included intravesical therapy (22%), neoadjuvant chemotherapy (30%), cystectomy or nephroureterectomy (55%). Median follow-up for all patients was 12 months (0.6-36.5). PMN-MDSC was the predominant subset in WB and PBMC. There was significant correlation between individual MDSC subsets in WB and PBMC (p ≤ 0.001). Both WB UNC-MDSC/PMN-MDSC ratios (rho = - 0.27, p = 0.03) and PBMC UNC-MDSC/PMN-MDSC (rho = - 0.28, p = 0.02) were negatively correlated with NLR. Median OS was 17.7 months (95% CI: 11.0-NE). Overall 1-year and 3-year survival rates were 0.60 (95% CI 0.49-0.73) and 0.15 (95% CI 0.03-0.67), respectively. Higher WB UNC-MDSC levels (HR 3.78, p = 0.0022) and higher NLR (HR 2.6, p = 0.0179) were associated with shorter OS. CONCLUSIONS: Specific MDSC subsets correlate with NLR. Higher WB UNC-MDSC levels and higher NLR were negative prognostic factors. Given the feasibility of serial blood draws, dynamic assessment of MDSC over time and further validation with longer follow-up are warranted.
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Linfócitos/metabolismo , Células Supressoras Mieloides/metabolismo , Neutrófilos/metabolismo , Neoplasias Urológicas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Neoplasias Urológicas/mortalidade , Neoplasias Urológicas/patologiaRESUMO
A MESSAGE FROM ASCO'S PRESIDENT: Shortly before I was elected President of ASCO, I attended the 65th birthday party of a current patient. She had been diagnosed 10 years earlier with metastatic breast cancer and hadn't been sure she wanted to move forward with further treatment. With encouragement, she elected to participate in a clinical trial of an investigational drug that is now widely used to treat breast cancer. Happily, here we were, celebrating with her now-married daughters, their husbands, and three beautiful grandchildren, ages 2, 4, and 8. Such is the importance of clinical trials and promising new therapies.Clinical research is about saving and improving the lives of individuals with cancer. It's a continuing story that builds on the efforts of untold numbers of researchers, clinicians, caregivers, and patients. ASCO's Clinical Cancer Advances report tells part of this story, sharing the most transformative research of the past year. The report also includes our latest thinking on the most urgent research priorities in oncology.ASCO's 2020 Advance of the Year-Refinement of Surgical Treatment of Cancer-highlights how progress drives more progress. Surgery has played a fundamental role in cancer treatment. It was the only treatment available for many cancers until the advent of radiation and chemotherapy. The explosion in systemic therapies since then has resulted in significant changes to when and how surgery is performed to treat cancer. In this report, we explore how treatment successes have led to less invasive approaches for advanced melanoma, reduced the need for surgery in renal cell carcinoma, and increased the number of patients with pancreatic cancer who can undergo surgery.Many research advances are made possible by federal funding. With the number of new US cancer cases set to rise by roughly a third over the next decade, continued investment in research at the national level is crucial to continuing critical progress in the prevention, screening, diagnosis, and treatment of cancer.While clinical research has translated to longer survival and better quality of life for many patients with cancer, we can't rest on our laurels. With ASCO's Research Priorities to Accelerate Progress Against Cancer, introduced last year and updated this year, we've identified the critical gaps in cancer prevention and care that we believe to be most pressing. These priorities are intended to guide the direction of research and speed progress.Of course, the effectiveness or number of new treatments is meaningless if patients don't have access to them. High-quality cancer care, including clinical trials, is out of reach for too many patients. Creating an infrastructure to support patients is a critical part of the equation, as is creating connections between clinical practices and research programs. We have much work to do before everyone with cancer has equal access to the best treatments and the opportunity to participate in research. I know that ASCO and the cancer community are up for this challenge.Sincerely,Howard A. "Skip" Burris III, MD, FACP, FASCOASCO President, 2019-2020.
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Oncologia/métodos , Neoplasias/terapia , Difusão de Inovações , Previsões , Humanos , Oncologia/tendências , Neoplasias/diagnóstico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Nivolumab is approved for mRCC patients who have received prior anti-angiogenic therapy but the duration of therapy required for sustained clinical benefit is unknown. A phase II clinical trial to investigate the feasibility of intermittent nivolumab dosing was conducted. METHODS: Patients ≥18 years of age with mRCC who were previously treated with at least one antiangiogenic therapy were eligible. Patients were treated with nivolumab for twelve weeks. Patients who had RECIST PD were removed from the trial. Patients who did not initially achieve ≥10% reduction in tumor burden (TB) continued nivolumab per standard of care. Patients with ≥10% TB reduction entered a treatment-free observation phase with re-imaging every 12 weeks. Nivolumab was restarted in patients with a ≥ 10% TB increase and again held with TB reduction ≥10%. This intermittent nivolumab dosing continued until RECIST PD while on nivolumab. The primary objective was feasibility of intermittent nivolumab, defined as the proportion of patients eligible for intermittent therapy who elect to receive intermittent nivolumab. Intermittent nivolumab would be considered "feasible" if the acceptance rate was ≥80%. Forty patients provides > 95% power with 0.05 type I error, assuming a null acceptance rate of 50%. With the approval of the combination of ipilimumab/nivolumab (April 2018) in front-line mRCC, this cohort was closed prior to completed pre-planned approval. RESULTS: Of the 14 patients enrolled, 13 (93%) were male with a median age 65. All had a prior nephrectomy and 12 (86%) were intermediate-risk by IMDC criteria. Five patients (36%) met the criteria for the intermittent phase of the trial (median TB decrease 46%) and all agreed to intermittent therapy. With a median follow-up of 48 weeks, only one patient restarted therapy. The four remaining patients have a sustained response for a median of 34 weeks (range, 16-53) off therapy. No patients developed RECIST PD while off therapy. CONCLUSIONS: This prospective experience of intermittent nivolumab dosing in mRCC supports further investigation of intermittent immunotherapy dosing strategies in RCC. TRIAL REGISTRATION: NCT03126331 (Intermittent Nivolumab in Metastatic Renal Cell Carcinoma Patients; Date of registration 4/27/2017; https://clinicaltrials.gov/ct2/show/NCT03126331 ).
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Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Nivolumabe/administração & dosagem , Idoso , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Quimioterapia Adjuvante/métodos , Esquema de Medicação , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Rim/diagnóstico por imagem , Rim/efeitos dos fármacos , Rim/imunologia , Rim/cirurgia , Neoplasias Renais/imunologia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Nefrectomia , Intervalo Livre de Progressão , Estudos Prospectivos , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologiaRESUMO
BACKGROUND: Nivolumab is approved for the treatment of refractory metastatic renal cell carcinoma. Patterns and predictors of progressive disease (PD) on nivolumab, and outcomes in such patients are lacking. METHODS: A retrospective analysis of patients (pts) with metastatic clear cell renal cell carcinoma (ccRCC) who received nivolumab at Cleveland Clinic (2015-2017) was performed. PD was defined per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or clinical progression as per treating physician. Univariate analyses (UVA) and multivariate analyses (MVA) were used to identify clinical and laboratory markers as potential predictors of progression-free survival (PFS). RESULTS: Ninety patients with mean age of 65, 74% men, and 83% good or intermediate International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group were included. Median number of prior systemic treatments was 2 (range, 1-6). Median overall survival (OS) and PFS were 15.8 and 4.4 months, respectively. Fifty-seven patients (63%) had PD and 44% of patients with radiographic PD had new organ sites of metastases with brain (8/23, 35%) being the most common. Twelve patients received treatment beyond progression (TBP), and among 6 patients with available data, 3 (50%) had any tumor shrinkage (2 pts. with 17% shrinkage, one pt. with 29% shrinkage). Of 57 patients with PD, 28 patients (49%) were able to initiate subsequent treatment, mainly with axitinib and cabozantinib, while 40% of patients were transitioned to hospice after PD. In MVA, a higher baseline Neutrophil-to-Lymphocyte ratio (NLR) (HR, 1.86; 95% CI, 1.05-3.29; p = 0.033) was associated with an increased risk of progression, whereas higher (> 0.1 k/uL) baseline eosinophil count was associated with a lower risk of progression (HR, 0.54; 95% CI, 0.30-0.98; p = 0.042). CONCLUSION: Brain was the most common site of PD in patients treated with nivolumab, and only half of patients progressing on nivolumab were able to initiate subsequent treatment. The risk of PD increased with a higher baseline NLR and reduced with a higher baseline eosinophil count.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Nivolumabe/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Carcinoma de Células Renais/patologia , Progressão da Doença , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Metástase Neoplásica , Nivolumabe/farmacologiaRESUMO
BACKGROUND: Neoadjuvant chemotherapy (NAC) has been increasingly adopted in the management of high-grade upper tract urothelial carcinoma (UTUC), largely extrapolating from level I evidence in urothelial carcinoma of the bladder. Studies examining pathologic outcomes in patients with UTUC receiving NAC are mostly limited to retrospective, single-center studies with limited sample size, with results of a phase II trial recently presented. Hypothesizing that NAC is associated with improved pathologic response (PR), we compared pathologic outcomes in patients with high-grade UTUC who did and did not receive NAC before extirpative surgery. PATIENTS AND METHODS: A total of 6174 patients with nonmetastatic, high-grade UTUC who underwent extirpative surgery from 2006 to 2014 were identified from the National Cancer Database. Patients were stratified by NAC status. PR was defined as pathologic stage less than clinical stage. Univariate and multivariable logistic regression analysis was employed to identify predictors of PR. RESULTS: Two hundred sixty (4.2%) patients received NAC. A higher incidence of PR was observed in patients receiving NAC (25.2% vs. 1.8%; P < .001), with complete PR observed in 6.1% of patients receiving NAC and 0.4% of patients undergoing surgery alone. NAC (odds ratio [OR], 19.8; 95% confidence interval [CI], 11.8-33.5), nonwhite race (OR, 3.2; 95% CI, 1.7-6.3), and ureteral tumor location (OR, 1.6; 95% CI, 1.02-2.6) were independently associated with PR. CONCLUSIONS: Examining a large national cancer registry, we observed a higher incidence of PR in patients with UTUC receiving NAC, validating findings of prior studies. Our findings support consideration of NAC in high grade UTUC. Prospective trials will better define the impact of NAC on pathologic and survival outcomes.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células de Transição/patologia , Neoplasias Renais/patologia , Nefrectomia , Neoplasias Ureterais/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/terapia , Feminino , Humanos , Rim/patologia , Rim/cirurgia , Neoplasias Renais/terapia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Gradação de Tumores , Estudos Prospectivos , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Resultado do Tratamento , Ureter/patologia , Ureter/cirurgia , Neoplasias Ureterais/terapiaRESUMO
T cell infiltration in tumors has been investigated as a biomarker of response to checkpoint inhibitors. Neo-adjuvant studies in renal cell carcinoma (RCC) may provide a unique opportunity to compare T cell infiltration in a pretreatment renal mass biopsy to a posttreatment nephrectomy specimen, and thus evaluate the effects of immune checkpoint inhibitors. However, there are no data regarding the association of T cell infiltration in matched biopsy and nephrectomy samples without intervening treatment. Understanding this association will inform investigation of this potential biomarker in future studies.Matched biopsy and nephrectomy samples (without intervening systemic therapy) were identified from patients with nonmetastatic RCC. Selected tissue sections from biopsy and nephrectomy samples were reviewed and marked for intratumoral lymphocytes by a pathologist. Immunohistochemistry (IHC) was utilized to stain for T cell markers (CD3, CD4, and CD8). Intratumoral staining was then quantified in the tissue sections as counts per total tumor area surveyed. Spearman correlation (r) was used to measure associations.Thirty matched pairs were investigated. The median interval between biopsy and nephrectomy was 2.8 (0.2-87.7) months. Clear cell was the most common histology (29/30; 97%). There was a statistically significant positive correlation between the frequency of CD3 and CD8 T cells between matched biopsy and nephrectomy samples (râ=â0.39; Pâ=â.036 and râ=â0.38; Pâ=â.041, respectively).The frequencies of CD8+ T cells in matched biopsy and nephrectomy samples in RCC in the absence of intervening treatment have been characterized and show a positive correlation between matched biopsy and nephrectomy samples.
Assuntos
Linfócitos T CD8-Positivos/citologia , Carcinoma de Células Renais/imunologia , Neoplasias Renais/imunologia , Linfócitos do Interstício Tumoral/citologia , Adulto , Idoso , Biomarcadores Tumorais , Biópsia , Carcinoma de Células Renais/cirurgia , Pontos de Checagem do Ciclo Celular/imunologia , Feminino , Humanos , Imunidade Celular , Imuno-Histoquímica , Rim/imunologia , Neoplasias Renais/cirurgia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Nefrectomia , Estatísticas não Paramétricas , Adulto JovemRESUMO
BACKGROUND: We assessed the clinical outcomes of patients with oligoprogressive renal cell carcinoma (mRCC) treated with stereotactic radiosurgery (SRS), stratified by changing or continuing systemic treatment. PATIENTS AND METHODS: Ninety-five consecutive patients with clear cell mRCC who had undergone SRS to the central nervous system (CNS) or spine during systemic treatment were divided into 3 cohorts: those who continued the same systemic therapy (STAY), those who changed systemic treatment after SRS (SWITCH), and patients with progression outside the SRS sites, who also changed systemic treatment (PD-SYS). The primary outcome was treatment duration after SRS, defined as the interval between SRS and discontinuation of the current systemic therapy for the STAY group and discontinuation of the first subsequent therapy in the SWITCH and PD-SYS groups. RESULTS: Local control with SRS was achieved in 85% of the patients. The most common systemic treatment at SRS included anti-vascular endothelial growth factor (67%), mammalian target of rapamycin (14%), and programmed cell death protein 1 inhibitors (9%). The median treatment duration for the STAY group was 5.2 months (95% confidence interval [CI], 3.5-6.9) compared with 5.0 months (95% CI, 4.3-5.7) for the SWITCH group (P = .549) and 3.1 months (95% CI, 1.7-4.5) for the PD-SYS group (P = .07, compared with all other patients). No difference in median overall survival was found for the STAY and SWITCH groups (24.2 vs. 27.1 months; P = .381) but was significantly longer than that for the PD-SYS group (P = .025). CONCLUSION: The decision to continue the same systemic therapy at SRS to treat CNS or spinal lesions did not compromise the clinical outcomes of patients with oligoprogressive mRCC.