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PURPOSE: The purpose of this study was to evaluate the clinical benefits of nivolumab with/without ipilimumab combined with stereotactic body radiotherapy (SBRT) in patients with pretreated metastatic biliary tract cancer (mBTC). PATIENTS AND METHODS: The study was a phase 2 randomized trial with Simon's optimal two-stage design requiring 36 evaluable patients per group after second stage. Sixty-one patients were included from September 2018 to January 2022 and randomized (1:1) to receive SBRT (15 Gy × 1 on day 1 to a primary or metastatic lesion) and nivolumab (3 mg/kg intravenously on day 1 and every 2 weeks) with/without ipilimumab (1 mg/kg intravenously on day 1 and every 6 weeks). Primary endpoint was clinical benefit rate (CBR), defined as the percentage of patients with complete response, partial response, or stable disease. Decision to continue accrual into the second stage depended on the CBR from the first stage. RESULTS: Forty-two patients received SBRT/nivolumab/ipilimumab with a CBR of 31.0% [95% confidence interval (CI), 17.6-47.1]. Five patients (11.9%) achieved partial response with median duration of 4.4 months (range, 1.1-21.5). Nineteen patients received SBRT/nivolumab. This group was closed after the initial stage based on a CBR of 10.5% (95% CI, 1.3-33.1). Adverse events were graded with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Grade ≥3 treatment-related adverse events occurred in 13 (31%) and 3 (16%) patients in the SBRT/nivolumab/ipilimumab and SBRT/nivolumab groups, respectively. One patient died from immune-related hepatitis in the SBRT/nivolumab/ipilimumab group. CONCLUSIONS: Combining SBRT, nivolumab, and ipilimumab is well tolerated, feasible, and shows response in a subgroup of patients with mBTC.
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Neoplasias del Sistema Biliar , Ipilimumab , Nivolumab , Radiocirugia , Humanos , Radiocirugia/métodos , Radiocirugia/efectos adversos , Nivolumab/administración & dosificación , Nivolumab/uso terapéutico , Femenino , Masculino , Neoplasias del Sistema Biliar/patología , Neoplasias del Sistema Biliar/terapia , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/mortalidad , Ipilimumab/administración & dosificación , Ipilimumab/uso terapéutico , Anciano , Persona de Mediana Edad , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano de 80 o más Años , Terapia CombinadaRESUMEN
BACKGROUND AND PURPOSE: The SOFT trial is a prospective, multicenter, phase 2 trial investigating magnetic resonance (MR)-guided stereotactic ablative radiotherapy (SABR) for abdominal, soft tissue metastases in patients with oligometastatic disease (OMD) (clinicaltrials.gov ID NCT04407897). We present the primary endpoint analysis of 1-year treatment-related toxicity (TRAE). MATERIALS AND METHODS: Patients with up to five oligometastases from non-hematological cancers were eligible for inclusion. A risk-adapted strategy prioritized fixed organs at risk (OAR) constraints over target coverage. Fractionation schemes were 45-67.5 Gy in 3-8 fractions. The primary endpoint was grade ≥ 4 TRAE within 12 months post-SABR. The association between the risk of gastrointestinal (GI) toxicity and clinical and dosimetric parameters was tested using a normal tissue complication probability model. RESULTS: We included 121 patients with 147 oligometastatic targets, mainly located in the liver (41 %), lymph nodes (35 %), or adrenal glands (14 %). Nearly half of all targets (48 %, n = 71) were within 10 mm of a radiosensitive OAR. No grade 4 or 5 TRAEs, 3.5 % grade 3 TRAEs, and 43.7 % grade 2 TRAEs were reported within the first year of follow-up. We found a significant association between grade ≥ 2 GI toxicity and the parameters GI OAR D0.1cc, D1cc, and D20cc. CONCLUSION: In this phase II study of MR-guided SABR of oligometastases in the infra-diaphragmatic region, we found a low incidence of toxicity despite half of the lesions being within 10 mm of a radiosensitive OAR. GI OAR D0.1cc, D1cc, and D20cc were associated with grade ≥ 2 GI toxicity.
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Neoplasias , Radiocirugia , Humanos , Estudios Prospectivos , Fraccionamiento de la Dosis de Radiación , Radiocirugia/efectos adversosRESUMEN
BACKGROUND: Interleukin-6 blockade and radiation combined with immunotherapy may modulate the tumour microenvironment to overcome immune resistance. We assessed the efficacy of ipilimumab, nivolumab, and tocilizumab combined with stereotactic body radiotherapy (SBRT) in patients with refractory pancreatic cancer (PC). METHODS: Patients with PC who had progressive disease (PD) or intolerance to gemcitabine- or fluorouracil-containing regimens were enrolled in Part A of the two-part, single-centre, phase 2 study (NCT04258150). SBRT with 15 Gy was administered on day one of the first cycle. Ipilimumab was administered (1 mg/kg every 6 weeks) for a maximum of two infusions. Nivolumab (6 mg/kg) and tocilizumab (8 mg/kg) were given every four weeks until the PD or unacceptable toxicity, or for up to one year. The primary end-point was the objective response rate, with a threshold of 15%. RESULTS: Twenty-six patients were enrolled and treated between April 17, 2020, and January 25, 2021. The median follow-up time at the time of data cutoff (February 7, 2022) was 4.9 months (interquartile range 2.1-7.7). No responses were observed. Five patients (19%; 95% confidence intervals [CI], 7-39) achieved a stable disease. The median progression-free survival was 1.6 months (95% CI 1.4-1.7), and the median overall survival was 5.3 months (95% CI 2.3-8.0). Overall, 19 (73%) experienced adverse events related to the treatment including two (8%) with grade 3 or higher events. CONCLUSION: The combination of ipilimumab, nivolumab, tocilizumab, and SBRT in patients with PC did not meet the prespecified criteria for expansion for full accrual.
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Neoplasias Pancreáticas , Radiocirugia , Humanos , Nivolumab/efectos adversos , Ipilimumab/efectos adversos , Radiocirugia/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Pancreáticas/tratamiento farmacológico , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
Background and purpose: The Ethos system has enabled online adaptive radiotherapy (oART) by implementing an automated treatment planning system (aTPS) for both intensity-modulated radiotherapy (IMRT) and volumetric modulated arc radiotherapy (VMAT) plan creation. The purpose of this study is to evaluate the quality of aTPS plans in the pelvic region. Material and Methods: Sixty patients with anal (n = 20), rectal (n = 20) or prostate (n = 20) cancer were retrospectively re-planned with the aTPS. Three IMRT (7-, 9- and 12-field) and two VMAT (2 and 3 arc) automatically generated plans (APs) were created per patient. The duration of the automated plan generation was registered. The best IMRT-AP and VMAT-AP for each patient were selected based on target coverage and dose to organs at risk (OARs). The AP quality was analyzed and compared to corresponding clinically accepted and manually generated VMAT plans (MPs) using several clinically relevant dose metrics. Calculation-based pre-treatment plan quality assurance (QA) was performed for all plans. Results: The median total duration to generate the five APs with the aTPS was 55 min, 39 min and 35 min for anal, prostate and rectal plans, respectively. The target coverage and the OAR sparing were equivalent for IMRT-APs and VMAT-MPs, while VMAT-Aps.demonstrated lower target dose homogeneity and higher dose to some OARs. Both conformity and homogeneity index were equivalent (rectal) or better (anal and prostate) for IMRT-APs compared to VMAT-MPs. All plans passed the patient-specific QA tolerance limit. Conclusions: The aTPS generates plans comparable to MPs within a short time-frame which is highly relevant for oART treatments.
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PURPOSE: To evaluate the clinical benefit of nivolumab with or without ipilimumab in combination with stereotactic body radiotherapy (SBRT) in patients with refractory metastatic pancreatic cancer (mPC). METHODS: Between November 2016 and December 2019, patients with refractory mPC were randomly assigned 1:1 to SBRT of 15 Gy with nivolumab or nivolumab/ipilimumab stratified by performance status (ClinicalTrials.gov identifier: NCT02866383). The primary end point was the clinical benefit rate (CBR), defined as the percentage of patients with complete or partial response (PR) or stable disease, according to RECIST 1.1. Simon's 2-stage phase II optimal design was used independently for both arms, with CBR determining expansion to the second stage. Secondary end points included safety, response rate, duration of response, progression-free survival, and overall survival. Exploratory analyses included biomarkers related to the benefits. RESULTS: Eighty-four patients (41 SBRT/nivolumab and 43 SBRT/nivolumab/ipilimumab) received at least one dose of study treatment. CBR was 17.1% (8.0 to 30.6) for patients receiving SBRT/nivolumab and 37.2% (24.0 to 52.1) for SBRT/nivolumab/ipilimumab. PR was observed in one patient receiving SBRT/nivolumab and lasted for 4.6 months. Six patients receiving SBRT/nivolumab/ipilimumab achieved a PR with a median duration of response of 5.4 months (4.2 to not reached). Grade 3 or higher treatment-related adverse events occurred in 10 (24.4%) and 13 (30.2%) patients in the SBRT/nivolumab and SBRT/nivolumab/ipilimumab groups, respectively. Programmed cell death ligand-1 expression by tumor proportion score or combined positivity score of ≥ 1% was not associated with clinical benefits. On-treatment decreased serum interleukin-6, interleukin-8, and C-reactive protein levels were associated with better overall survival. CONCLUSION: Clinically meaningful antitumor activity and favorable safety profiles were demonstrated after treatment with SBRT/nivolumab/ipilimumab in patients with refractory mPC. However, the contribution from SBRT is unknown. Further studies are warranted.
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Neoplasias Pancreáticas , Radiocirugia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteína C-Reactiva , Humanos , Interleucina-6 , Interleucina-8 , Ipilimumab/efectos adversos , Ligandos , Nivolumab/efectos adversos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/radioterapia , Radiocirugia/efectos adversosRESUMEN
BACKGROUND AND PURPOSE: Online adaptive radiotherapy (oART) potentially reduces the dose to organs at risk (OARs) as the planning target volume (PTV) margins are reduced compared to a non-adaptive approach (non-ART). This study evaluates the feasibility and dosimetric impact of cone-beam computed tomography (CBCT)-guided oART of urinary bladder cancer for the first patients treated, using patient-specific margins. MATERIALS AND METHODS: Sixteen consecutive patients with muscle-invasive bladder cancer received two or more (median = 23) fractions as oART, and remaining fractions as non-ART. The non-ART fractions were delivered with standard population-based margins, while reduced patient-specific margins based on intra-fractional variations extracted from 2-4 fractions were applied to the primary PTV (PTV-T) during the oART fractions. Target volume and coverage, and dose to OARs were compared between non-ART and oART plans, and the oART procedure time was recorded. RESULTS: In total, 297/512 fractions were delivered as oART with full re-optimization to the anatomy of the day. The median (interquartile range, IQR) oART procedure time, measured from the end of CBCT generation to completion of plan review, and quality assurance was 13.9 (11.9;16.6) min. The median (IQR) volume reduction in PTV-T volume was 33.9 (24.2;45.0)%, comparing oART and non-ART plans, resulting in median (IQR) reductions in bowel bag V45Gy of 18.8 (12.7;27.9)% and rectum V50Gy of 70.7 (35.9;94.8)%. By re-optimizing the plan to the daily anatomy, full target coverage was achieved at all oART fractions. CONCLUSIONS: oART resulted in large reductions in treatment volumes and doses to OARs, compared to non-ART, while ensuring target coverage. This indicates potential reductions in gastrointestinal toxicity.
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Radioterapia Guiada por Imagen , Radioterapia de Intensidad Modulada , Neoplasias de la Vejiga Urinaria , Tomografía Computarizada de Haz Cónico/métodos , Humanos , Órganos en Riesgo , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia Guiada por Imagen/métodos , Radioterapia de Intensidad Modulada/métodos , Neoplasias de la Vejiga Urinaria/radioterapiaRESUMEN
PURPOSE: The purpose of this study was to evaluate our 2 years' experience with single-isocenter, non-coplanar, volumetric modulated arc therapy (VMAT) for brain metastasis (BM) stereotactic radiosurgery (SRS). METHODS: A total of 202 patients treated with the VMAT SRS solution were analyzed retrospectively. Plan quality was assessed for 5â¯mm (120) and 2.5â¯mm (high-definition, HD) central leaf width multileaf collimators (MLCs). For BMs at varying distances from the plan isocenter, the geometric offset from the ideal position for two image-guided radiotherapy workflows was calculated. In the workflow with ExacTrac (BrainLAB, München, Germany; WET), patient positioning errors were corrected at each couch rotation. In the workflow without ExacTrac (W-noET), only the initial patient setup correction was considered. The dose variation due to rotational errors was simulated for multiple-BM plans with the HD-MLC. RESULTS: Plan conformity and quality assurance were equivalent for plans delivered with the two MLCs while the HD-MLC plans provided better healthy brain tissue (BmP) sparing. 95% of the BMs had residual intrafractional setup errors ≤â¯2â¯mm for WET and 68% for WnoET. For small BM (≤1â¯cc) situated >3â¯cm from the plan isocenter, the dose received by 95% of the BM decreased in median (interquartile range) by 6.3% (2.8-8.8%) for a 1-degree rotational error. CONCLUSION: This study indicates that the HD-MLC is advantageous compared to the 120-MLC for sparing healthy brain tissue. When a 2-mm margin is applied, WnoET is sufficient to ensure coverage of BM situated ≤â¯3â¯cm of the plan isocenter, while for BM further away, WET is recommended.
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Neoplasias Encefálicas , Radioterapia de Intensidad Modulada , Neoplasias Encefálicas/secundario , Humanos , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador , Estudios RetrospectivosRESUMEN
BACKGROUND AND PURPOSE: Studies have demonstrated the potential of online adaptive radiotherapy (oART). However, routine use has been limited due to resource demanding solutions. This study reports on experiences with oART in the pelvic region using a novel cone-beam computed tomography (CBCT)-based, artificial intelligence (AI)-driven solution. MATERIAL AND METHODS: Automated pre-treatment planning for thirty-nine pelvic cases (bladder, rectum, anal, and prostate), and one hundred oART simulations were conducted in a pre-clinical release of Ethos (Varian Medical Systems, Palo Alto, CA). Plan quality, AI-segmentation accuracy, oART feasibility and an integrated calculation-based quality assurance solution were evaluated. Experiences from the first five clinical oART patients (three bladder, one rectum and one sarcoma) are reported. RESULTS: Auto-generated pre-treatment plans demonstrated similar planning target volume (PTV) coverage and organs at risk doses, compared to institution reference. More than 75% of AI-segmentations during simulated oART required none or minor editing and the adapted plan was superior in 88% of cases. Limitations in AI-segmentation correlated to cases where AI model training was lacking. The five first treated patients complied well with the median adaptive procedure duration of 17.6 min (from CBCT acceptance to treatment delivery start). The treated bladder patients demonstrated a 42% median primary PTV reduction, indicating a 24%-30% reduction in V45Gy to the bowel cavity, compared to non-ART. CONCLUSIONS: A novel commercial oART solution was demonstrated feasible for various pelvic sites. Clinically acceptable AI-segmentation and auto-planning enabled adaptation within reasonable timeslots. Possibilities for reduced PTVs observed for bladder cancer indicated potential for toxicity reductions.
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PURPOSE: Pembrolizumab, a programmed death 1 inhibitor, demonstrated promising single-agent activity in untreated patients with various cancer types. The phase II KEYNOTE-427 study evaluated efficacy and safety of single-agent pembrolizumab in treatment-naive patients with advanced clear cell renal cell carcinoma (ccRCC; cohort A) and advanced non-ccRCC (cohort B). Results of cohort A are reported. METHODS: In this open-label, single-arm phase II study, patients with advanced ccRCC received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. The primary end point was objective response rate by RECIST, version 1.1. RESULTS: In the total population (N = 110), median time from enrollment to data cutoff was 35.9 (range, 29.5-40.3) months. Objective response rate was 36.4% with four (3.6%) complete responses and 36 (32.7%) partial responses; disease control rate was 58.2% (95% CI, 48.4 to 67.5). Most patients (68.2%) had a decrease in target lesions, including 30.9% with a reduction ≥ 60%. Median duration of response was 18.9 (range, 2.3-37.6+) months; 64.1% of responders had a response ≥ 12 months (Kaplan-Meier). Median progression-free survival was 7.1 months (95% CI, 5.6 to 11.0). Median overall survival was not reached; 12-month and 24-month overall survival rates were 88.2% and 70.8%, respectively. Durable responses were observed across all International Metastatic RCC Database Consortium categories. Grade 3-5 treatment-related adverse events were reported in 30.0% of patients, of which colitis and diarrhea were most frequent. CONCLUSION: Single-agent pembrolizumab showed promising antitumor activity as a first-line treatment in patients with advanced ccRCC, with durable responses across International Metastatic RCC Database Consortium categories. Safety and tolerability profile of pembrolizumab monotherapy was comparable to what has been previously described in other tumor types.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/patología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados no Aleatorios como Asunto , Pronóstico , Tasa de SupervivenciaRESUMEN
BACKGROUND: The extent to which response and survival benefits with immunotherapy-based regimens persist informs optimal first-line treatment options. We provide long-term follow-up in patients with advanced renal cell carcinoma (aRCC) receiving first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the phase 3 CheckMate 214 trial. Survival, response, and safety outcomes with NIVO+IPI versus SUN were assessed after a minimum of 42 months of follow-up. METHODS: Patients with aRCC were enrolled from October 16, 2014, through February 23, 2016. Patients stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk and region were randomized to nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks for four doses, followed by nivolumab (3 mg/kg) every 2 weeks; or SUN (50 mg) once per day for 4 weeks (6-week cycle). Primary endpoints: overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) per independent radiology review committee in IMDC intermediate-risk/poor-risk patients. Secondary endpoints: OS, PFS, and ORR in the intention-to-treat (ITT) population and safety. Favorable-risk patient outcomes were exploratory. RESULTS: Among ITT patients, 550 were randomized to NIVO+IPI (425 intermediate/poor risk; 125 favorable risk) and 546 to SUN (422 intermediate/poor risk; 124 favorable risk). Among intermediate-risk/poor-risk patients, OS (HR, 0.66; 95% CI, 0.55-0.80) and PFS (HR, 0.75; 95% CI, 0.62-0.90) benefits were observed, and ORR was higher (42.1% vs 26.3%) with NIVO+IPI versus SUN. In ITT patients, both OS benefits (HR, 0.72; 95% CI, 0.61-0.86) and higher ORR (39.1% vs 32.6%) were observed with NIVO+IPI versus SUN. In favorable-risk patients, HR for death was 1.19 (95% CI, 0.77-1.85) and ORR was 28.8% with NIVO+IPI versus 54.0% with SUN. Duration of response was longer (HR, 0.46-0.54), and more patients achieved complete response (10.1%-12.8% vs 1.4%-5.6%) with NIVO+IPI versus SUN regardless of risk group. The incidence of treatment-related adverse events was consistent with previous reports. CONCLUSIONS: NIVO+IPI led to improved efficacy outcomes versus SUN in both intermediate-risk/poor-risk and ITT patients that were maintained through 42 months' minimum follow-up. A complete response rate >10% was achieved with NIVO+IPI regardless of risk category, with no new safety signals detected in either arm. These results support NIVO+IPI as a first-line treatment option with the potential for durable response. TRIAL REGISTRATION NUMBER: NCT02231749.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Ipilimumab/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Nivolumab/uso terapéutico , Sunitinib/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Femenino , Estudios de Seguimiento , Humanos , Ipilimumab/farmacología , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Nivolumab/farmacología , Sunitinib/farmacología , Análisis de SupervivenciaRESUMEN
BACKGROUND AND PURPOSE: In radiotherapy, treatment response is generally evaluated many weeks after end of the treatment course. If the treatment outcome could be predicted during radiotherapy better tumour control could be achieved through timely adaptation of the treatment strategy. In this study intra-treatment change based on the diffusion MRI outlined viable tumour volume (VTV) was assessed and compared to the standard GTV to study their outcome prediction capacity. MATERIALS AND METHODS: Thirty-eight brain metastases from twenty-one cancer patients were analysed in this prospective trial. Diffusion and structural MRI was acquired on a 1 T machine before, during, and at follow-up 2-3 months after radiotherapy. The VTV was defined as a region with high cellularity using high b-value diffusion MRI scans. Further, the diffusivity of the VTV was derived as the apparent diffusion coefficient (ADC). Treatment outcome was determined using RECIST defined bounds in the T1W MRI follow-up scan. Longitudinal statistical analysis was performed using a linear mixed effect model. RESULTS: The GTV declined in both responding and non-responding (significantly) tumours with inseparable rates during radiotherapy. The VTV volume fraction reduced significantly in the responding tumours only. The ADC of the VTV increased significantly in responding metastases whereas it decreased in non-responding metastases. Furthermore, no association between baseline tumour size or primary disease and outcome was observed. CONCLUSION: GTV size change during radiotherapy is not a reliable predictor of outcome in brain metastases. On the other hand, change in the volume fraction of VTV and diffusivity of VTV shows ability to stratify treatment outcome.
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Neoplasias Encefálicas , Imagen de Difusión por Resonancia Magnética , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/radioterapia , Humanos , Imagen por Resonancia Magnética , Estudios Prospectivos , Carga TumoralRESUMEN
BACKGROUND: In the phase 3 METEOR trial, cabozantinib improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) versus everolimus in patients with advanced renal cell carcinoma (RCC), after prior antiangiogenic therapy. METHODS: Outcomes were evaluated for subgroups defined by prior therapy with sunitinib or pazopanib as the only prior VEGFR inhibitor, or prior anti-PD-1/PD-L1 therapy. RESULTS: For the prior sunitinib subgroup (N = 267), median PFS for cabozantinib versus everolimus was 9.1 versus 3.7 months (HR 0.43, 95% CI 0.32-0.59), ORR was 16% versus 3%, and median OS was 21.4 versus 16.5 months (HR 0.66, 95% CI 0.47-0.93). For the prior pazopanib subgroup (N = 171), median PFS for cabozantinib versus everolimus was 7.4 versus 5.1 months (HR 0.67, 95% CI 0.45-0.99), ORR was 19% versus 4%, and median OS was 22.0 versus 17.5 months (HR 0.66, 95% CI 0.42-1.04). For prior anti-PD-1/PD-L1 therapy (N = 32), median PFS was not reached for cabozantinib versus 4.1 months for everolimus (HR 0.22, 95% CI 0.07-0.65), ORR was 22% versus 0%, and median OS was not reached versus 16.3 months (HR 0.56, 95% CI 0.21-1.52). CONCLUSIONS: Cabozantinib was associated with improved clinical outcomes versus everolimus in patients with advanced RCC, irrespective of prior therapy, including checkpoint inhibitor therapy.
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Inhibidores de la Angiogénesis/uso terapéutico , Anilidas/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Everolimus/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Piridinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Indazoles , Masculino , Persona de Mediana Edad , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Sunitinib/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Interleukin-2 (IL2)-based immunotherapy is curative for a small subset of patients with metastatic renal-cell carcinoma (mRCC). Preclinical data suggests that bevacizumab (BEV), a humanized anti-VEGF monoclonal antibody, has potential immunomodulatory effects by permitting efficient natural killer (NK) cell-mediated killing and by reverting immune suppression. PATIENT AND METHODS: We performed a randomized phase II study comparing IL2/IFN (interferon)/BEV with IL2/IFN in favourable/intermediate-risk mRCC patients. One hundred and eighteen patients received IFN 3 MIU subcutaneously (sc) daily and IL2 2.4 MIU/m2 sc twice daily, 5 days per week for two consecutive weeks every 28-day-cycle, for 9 months; or supplemented with BEV 10 mg/kg, every 2 weeks intravenously (iv) until progression, unacceptable toxicity, or 1 year following no evidence of disease (NED). Primary end point was progression-free survival (PFS). RESULTS: Baseline characteristics were well-balanced between the two arms; metastasis-free interval <1 year (75 versus 76%); prior nephrectomy (85 versus 86%); MSKCC favourable/intermediate-risk group (51/49 versus 52%/48%); three or more disease sites (41 versus 44%), respectively. The median PFS was 8.0 mo (95% CI, 4.2-11.9) with IL2/IFN/BEV and 8.1 mo (95% CI, 5.1-11.0) with IL2/IFN, p = .73. There was no difference in secondary endpoints, IL2/IFN/BEV versus IL2/IFN; median time-to-treatment failure (7.4 versus 5.6 mo, p = .54), response rate (44.1 versus 28.8%, p = .13), surgery of residual disease (17.0 versus 17.0%, p = 1.0), patients achieving NED (3.4 versus 8.5%, p = .44), and median overall survival (30.3 versus 34.1 mo, p = .39), respectively. TKI post progression was well-balanced (85 versus 78%). No new/unexpected toxicity was observed. Most common Grade 3/4 adverse events for IL2/IFN/BEV and IL2/IFN were fatigue (64 versus 61%), flu-like symptoms (37 versus 41%) and thrombosis (6.8 versus 18.6%, p = .01), respectively. CONCLUSIONS: The addition of BEV to IL-2/IFN did not add efficacy in mRCC. (ClinicalTrials.gov, NCT01274273.).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Adulto , Anciano , Bevacizumab/administración & dosificación , Bevacizumab/efectos adversos , Carcinoma de Células Renales/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Interleucina-2/administración & dosificación , Interleucina-2/efectos adversos , Interleucina-2/análogos & derivados , Estimación de Kaplan-Meier , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Resultado del TratamientoRESUMEN
An imaging biomarker for early prediction of treatment response potentially provides a non-invasive tool for better prognostics and individualized management of the disease. Radiotherapy (RT) response is generally related to changes in gross tumor volume manifesting months later. In this prospective study we investigated the apparent diffusion coefficient (ADC), perfusion fraction and pseudo diffusion coefficient derived from diffusion weighted MRI as potential early biomarkers for radiotherapy response of brain metastases. It was a particular aim to assess the optimal time point for acquiring the DW-MRI scan during the course of treatment, since to our knowledge this important question has not been addressed directly in previous studies. Twenty-nine metastases (N = 29) from twenty-one patients, treated with whole-brain fractionated external beam RT were analyzed. Patients were scanned with a 1 T MRI system to acquire DW-, T2*W-, T2W- and T1W scans, before start of RT, at each fraction and at follow up two to three months after RT. The DW-MRI parameters were derived using regions of interest based on high b-value images (b = 800 s mm-2). Both volumetric and RECIST criteria were applied for response evaluation. It was found that in non-responding metastases the mean ADC decreased and in responding metastases it increased. The volume based response proved to be far more consistently predictable by the ADC change found at fraction number 7 and later, compared to the linear response (RECIST). The perfusion fraction and pseudo diffusion coefficient did not show sufficient prognostic value with either response assessment criteria. In conclusion this study shows that the ADC derived using high b-values may be a reliable biomarker for early assessment of radiotherapy response for brain metastases patients. The earliest response stratification can be achieved using two DW-MRI scans, one pre-treatment and one at treatment day 7-9 (equivalent to 21 Gy).
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Neoplasias Encefálicas/secundario , Imagen de Difusión por Resonancia Magnética/métodos , Anciano , Neoplasias Encefálicas/radioterapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Perfusión , Pronóstico , Estudios ProspectivosRESUMEN
BACKGROUND: Several biomarkers of treatment efficacy have been associated with a better prognosis in patients with metastatic renal cell carcinoma (mRCC). The prognostic significance of biomarkers in the early treatment phase is unclear. MATERIAL AND METHODS: In a complete national cohort of mRCC patients receiving first-line tyrosine kinase inhibitors (TKI) or interleukin-2 based immunotherapy (IT) from 2006 to 2010, overall survival (OS) was analysed for baseline International mRCC Database Consortium (IMDC) classification factors and on-treatment time-dependent biomarkers obtained day 1 each cycle week 4-12 after treatment initiation with multivariate analysis and bootstrap validation. RESULTS: A total of 735 patients received first-line TKI (59%) or IT (41%). Median OS was overall 14.0 months and 33.4, 18.5, and 5.8 months for baseline IMDC favourable, intermediate, and poor risk groups, respectively (p < 0.0001). Systolic blood pressure ≥140 mmHg, neutrophils < lower level of normal (LLN), platelets < LLN, sodium ≥ LLN, and LDH ≤1.5 times upper level of normal after treatment initiation were significantly associated with favourable OS independent of baseline IMDC risk group in multivariate analyses stratified for TKI and IT (p ≤ 0.04). Concordance (C)-index for IMDC classification alone was 0.625 (95% CI 0.59-0.66) and combined with the five-factor biomarker profile 0.683 (95% CI 0.64-0.72). For patients with good (3-5 factors) and poor (0-2 factors) biomarker profile median OS were 23.5 and 9.6 months, respectively (p < 0.0001). Adding the five-factor biomarker profile significantly improved prognostication in IMDC intermediate (25.7 vs. 12.0 months, p < 0.0001) and poor (12.8 vs. 6.4 months, p < 0.0001) risk groups. A trend was seen in IMDC favourable risk group (38.9 vs. 28.7 months, p = 0.112). CONCLUSION: On-treatment hypertension, neutropenia, thrombocytopenia, LDH below 1.5 times upper level of normal, and normal sodium, obtained week 4-12 of treatment, are independent biomarkers of favourable outcome in mRCC, independent of treatment type.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/análisis , Carcinoma de Células Renales/secundario , Neoplasias Renales/patología , Anciano , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/metabolismo , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/metabolismo , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Tasa de SupervivenciaRESUMEN
BACKGROUND: Although diffusion-weighted magnetic resonance imaging (DW-MRI) is widely used in radiation therapy (RT) response studies, no standard of delineating the region of interest (ROI) exists. In this retrospective study, we evaluate the effect of four ROI strategies on the apparent diffusion coefficients (ADC) in patients receiving palliative RT to brain metastases. MATERIAL AND METHODS: Twenty-two metastases from nine patients, treated with whole-brain irradiation (30 Gy in 10 fractions) were analyzed. Patients were scanned with a 1T MR system to acquire DW- (eight b-values), T2*W-, T2W- and T1W scans, before start of RT (pre-RT) and at the 9th/10th fraction (end-RT). The following ROI strategies were applied. ROIb800 and ROIb0: Entire tumor volume visible on DW(b = 800 s/mm(2)) and DW(b = 0 s/mm(2)) images, respectively. ROIb800vi: Viable tumor volume based on DW(b = 800 s/mm(2)). ROIb800rep: ROIb800 from pre-RT scan replicated to end-RT scan. Delineations were aided by co-registered T1W, T2W and T2*W images. ADC was estimated with two mono-exponential fits and one bi-exponential fit. RESULTS: Differences in absolute ADC values were non-significant across ROI strategy independent of fitting method, while significantly different between fitting methods. Evaluation of individual metastases showed that ROI strategies disagreed on the relative ADC change (from pre-RT to end-RT) in 13 of the 22 metastases when all fitting methods were added up. CONCLUSION: The ROI strategies have an effect on the relative ADC change, which may be important for the assessment of individual patient's response to RT and the interpretation of the current literature.
Asunto(s)
Neoplasias Encefálicas/radioterapia , Imagen de Difusión por Resonancia Magnética , Difusión/efectos de la radiación , Determinación de Punto Final/métodos , Cuidados Paliativos , Anciano , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/secundario , Fraccionamiento de la Dosis de Radiación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Teóricos , Estudios Retrospectivos , Resultado del Tratamiento , Carga TumoralRESUMEN
BACKGROUND: Limited data exist on the economic consequences of implementing targeted therapy (TT) for metastatic renal cell carcinoma (RCC) in a real-world setting. OBJECTIVE: To analyze health care and productivity costs for TT implementation in a national cohort of patients. DESIGN, SETTING, AND PARTICIPANTS: Costs were measured per patient per year during a 2-yr follow-up during 2002-2005 (immunotherapy only) and 2006-2009 (TT implementation). All Danish patients with a diagnosis code for RCC and a procedure code for TT or immunotherapy were linked to the Danish National Patient Registry (contains information on all contacts with primary and secondary health sector). Health care and productivity costs were retrieved from the Danish case-mix system and Coherent Social Statistics, respectively. Drug costs were calculated separately from procedure codes and retail prices. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Generalized linear models were used to analyze costs adjusted for age, gender, and civil status. RESULTS AND LIMITATIONS: A total of 439 patients were included for 2006-2009 and 192 for 2002-2005. Comparison of the health care cost per patient per year between 2006-2009 and 2002-2005 revealed lower inpatient costs (11 899 vs 19 944, adjusted relative risk [RR] 0.64), higher outpatient costs (14 308 vs 6209, RR 2.39), lower radiotherapy costs (194 vs 633, RR 0.31), higher radiology costs (676 vs 191, RR 3.73), and higher separately calculated drug costs (12 040 vs 3103, RR 3.82, all p<0.001) for the former. Total health care costs per patient per year did not significantly differ (27 676 vs 27 856, RR 1.05, p=0.5) between the two periods. Income from employment did not significantly differ between 2006-2009 and 2002-2005 (RR 1.11, p=0.11) and costs associated with loss of productivity were 7852 and 8265, respectively. CONCLUSIONS: A different pattern of health care costs were observed but total health care costs per patient per year did not significantly differ after implementation of TT for patients with mRCC. PATIENT SUMMARY: In this nationwide study, we found changes in the pattern of health care costs for patients with metastatic kidney cancer after implementation of targeted therapy compared to an immunotherapy control period; however, total health care costs and income from employment were without significant changes.
Asunto(s)
Inhibidores de la Angiogénesis/economía , Antineoplásicos/economía , Carcinoma de Células Renales/economía , Costos de la Atención en Salud , Factores Inmunológicos/economía , Neoplasias Renales/economía , Inhibidores de Proteínas Quinasas/economía , Sistema de Registros , Adulto , Anciano , Anciano de 80 o más Años , Atención Ambulatoria/economía , Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos/uso terapéutico , Bevacizumab/economía , Bevacizumab/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/secundario , Costos y Análisis de Costo , Dinamarca , Costos de los Medicamentos , Eficiencia , Empleo/economía , Everolimus/economía , Everolimus/uso terapéutico , Femenino , Fluorouracilo/economía , Fluorouracilo/uso terapéutico , Hospitalización/economía , Humanos , Factores Inmunológicos/uso terapéutico , Indoles/economía , Indoles/uso terapéutico , Interferón-alfa/economía , Interferón-alfa/uso terapéutico , Interleucina-2/economía , Interleucina-2/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia/tratamiento farmacológico , Niacinamida/análogos & derivados , Niacinamida/economía , Niacinamida/uso terapéutico , Compuestos de Fenilurea/economía , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirroles/economía , Pirroles/uso terapéutico , Radiografía/economía , Radioterapia/economía , Sirolimus/análogos & derivados , Sirolimus/economía , Sirolimus/uso terapéutico , Sorafenib , SunitinibRESUMEN
The EGF receptor (EGFR) is expressed in most cases of anal carcinomas. Anecdotal benefit from EGFR-targeted therapy has been reported in anal cancer and a negative correlation with Kirsten Ras (KRAS) mutation status has been proposed. The purpose of this retrospective study was to investigate the frequency and the prognostic value of KRAS and BRAF mutations in a large cohort of patients with anal cancer. One hundred and ninety-three patients with T1-4N0-3M0-1 anal carcinoma were included in the study. Patients were treated with curative (92%) or palliative intent (8%) between January 2000 and January 2010. KRAS mutations were detected using Therascreen(®)KRAS real-time PCR assay (Qiagen) and V600E or V600D/K BRAF mutations were uncovered using Pyrosequencing. The frequency of KRAS and BRAF mutations was low; KRAS mutations were detected in 1.6% and BRAF mutations in 4.7% of the biopsies. No impact of KRAS or BRAF status on survival was found. In conclusion, both KRAS and BRAF mutations are rare in anal cancer. The low frequency of KRAS mutations support protocols exploring EGFR-targeted therapy in patients with metastatic anal cancer, while treatment with BRAF inhibitors might be relevant for only a very few patients.
Asunto(s)
Neoplasias del Ano/patología , Carcinoma de Células Escamosas/patología , Carcinoma Verrugoso/patología , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Ano/genética , Carcinoma de Células Escamosas/genética , Carcinoma Verrugoso/genética , Estudios de Cohortes , ADN de Neoplasias/química , ADN de Neoplasias/genética , Femenino , Histocitoquímica , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutación/genética , Modelos de Riesgos Proporcionales , Proteínas Proto-Oncogénicas p21(ras) , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios RetrospectivosRESUMEN
PURPOSE: Carcinomas of the anal canal are strongly associated with the human papillomavirus (HPV). Expression of p16 is used as a surrogate marker of HPV infection. In a retrospective study, we evaluated HPV genotyping and p16 expression as prognostic markers of overall survival (OS) and disease-specific survival (DSS) in patients diagnosed with American Joint Committee on Cancer (AJCC) stages I to III carcinoma of the anal canal. PATIENTS AND METHODS: HPV genotyping polymerase chain reaction (high-risk subtypes 16, 18, 31, 33, 45, 52, and 58) and immunohistochemical expression of p16 were analyzed by using paraffin-embedded tumor biopsies from 143 anal carcinomas. The patients were treated with combined chemoradiotherapy or radiotherapy alone. RESULTS: HPV16 was detected in 81.0% of the tumors, followed by HPV33 (5.1%), HPV18 (2.2%), and HPV58 (0.7%). p16 positivity was found in 92.9% of the tumors. In univariable survival analysis, HPV positivity was significantly correlated with improved OS (74% v 52%; P=.036) and DSS (84% v 52%; P=.002), and p16 positivity was significantly correlated with improved OS (76% v 30%; P<.001) and DSS (85% v 30%; P<.001). In multivariable COX analysis that included HPV status, p16 status, sex, T stage, N stage, and treatment, p16 positivity remained an independent prognostic factor for OS (hazard ratio [HR], 0.07; 95% CI, 0.01 to 0.61; P=.016) and DSS (HR, 0.07; 95% CI, 0.01 to 0.53; P=.011). CONCLUSION: p16 positivity is an independent prognostic factor for OS and DSS in patients with AJCC stages I to III carcinoma of the anal canal.