RESUMEN
Alofanib is a small-molecule allosteric extracellular FGFR2 inhibitor. We report safety and preliminary efficacy from the first-in-human phase 1b study of alofanib in heavily pretreated patients with advanced gastric cancer. The standard dose-escalation design 3+3 aimed to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Alofanib was administered daily intravenously 5 days on, 2 days off. There were five dose levels (50-350 mg/m2). All patients received alofanib until disease progression or unacceptable toxicity. 21 patients were enrolled. Patients were predominantly male (71%), 67% had 2 and more metastatic sites, including liver metastases (43%), 19% had ECOG PS 2, and were heavily pretreated (86% had previous 2 and more treatment lines). During dose escalation, no dose-limiting toxicities were observed, and MTD was not defined. 15 (71.4%) patients had at least one adverse event associated with the treatment (TRAE). Grade 3 or higher TRAEs were observed in 6 patients (28.6%). The most common TRAEs included reactions immediately after administration, diarrhea, thrombocytopenia, arthralgia, and headache. The median progression-free survival and overall survival was 3.63 (95% CI 1.58-5.68) and 7.0 (95% CI 3.82-10.18) months, respectively. The 6- and 12-month overall survival rates were 57.1% and 33.3%. Disease control rate was 68% with one durable partial response. The MTD has not been reached and dose of 350 mg/m2, 5 days on, 2 days off has been declared as RP2D. Alofanib showed acceptable tolerability and preliminary signs of clinical activity in the late-line treatment of metastatic gastric cancer. (ClinicalTrials.gov identifier: NCT04071184).
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Neoplasias Gástricas , Humanos , Masculino , Femenino , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Benzoatos/farmacología , Benzoatos/uso terapéutico , Sulfonamidas/uso terapéutico , Receptor Tipo 2 de Factor de Crecimiento de FibroblastosRESUMEN
PURPOSE: It is known that 30% of clear cell renal cell carcinomas (ccRCC) will develop progressive disease after surgical treatment. These patients with high-risk ccRCC require adjuvant therapy after nephrectomy or resection of metastases. The article presents an overview of the results of recent studies in adjuvant therapy. METHODS: We analyzed the results of randomized trials of targeted therapy and checkpoint inhibitors in high-risk ccRCC patients. RESULTS: Targeted therapy did not significantly reduce this risk or/and did not affect overall survival. Three randomized studies investigating nivolumab, ipilimumab, and atezolizumab in the adjuvant setting also failed without improving disease-free survival. Pembrolizumab had a significant impact on the disease-free survival in the entire population, with the greatest effect in patients after metastasectomy, but mature overall survival data are not yet available. CONCLUSIONS: In conclusion, it must be noted that, at present, it has not been possible to achieve magnificent success in adjuvant therapy of RCC in patients at high risk of relapse after surgical treatment. There remains hope for adjuvant pembrolizumab, which has been used for high-risk population including patients with removed metastases who may benefit more from therapy.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Terapia Combinada , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Recurrencia Local de Neoplasia , Nivolumab/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Definitive concurrent chemoradiation (cCRT) is offered to only 3% of Russian patients with stage III NSCLC. To determine the patterns of care and barriers to cCRT utilization in Russia, we conducted a survey of practicing radiation oncologists (ROs). METHODS: Electronic IRB-approved survey containing 15 questions was distributed to Russian ROs. Fisher's exact test or Cochran-Armitage test of trend was used to assess the associations between clinical experience, practice type, and patterns of care. RESULTS: We analyzed 58 questionnaires completed by ROs-16 respondents from tertiary referral hospitals, and 42 from community or private centers. A total of 88% of respondents formulate treatment recommendations in multi-disciplinary tumor boards. For unresectable stage III NSCLC, the most common recommendation is sequential CRT (50%), followed by concurrent CRT (40%), with an observed higher utilization of cCRT in tertiary centers (9/16, 56% vs 14/42, 33%). Of the respondents, 31% do not offer cCRT to their pts. Among reasons for avoiding cCRT are (1) poor performance of pts (76%); (2) high toxicity of therapy (55%); (3) lack of consensus among tumor board members (33%); and (4) preference for sequential CRT (31%). Only 3% do not irradiate elective LNs. Eighty-six percent of respondents counsel their NSCLC pts regarding smoking cessation. CONCLUSIONS: Despite level 1 evidence, cCRT is rarely used in Russia for pts with locally advanced NSCLC, and preference for sequential therapy and concerns over high toxicity are the most common barriers. Education of Russian ROs may increase cCRT utilization, leading to improved survival, notably in the era of maintenance immunotherapy.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Quimioradioterapia , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Estadificación de Neoplasias , Especies Reactivas de Oxígeno/uso terapéuticoRESUMEN
Trimodality bladder preservation (BP) is an accepted alternative to radical cystectomy for patients with muscle invasive bladder cancer (MIBC). The global utilization of BP is variable, and practice patterns have not been previously studied in Russia. We sought to elucidate the contemporary BP practice patterns in Russia and determine the impact of the BP workshop on attitudes of Russian radiation oncologists (ROs) towards BP. The workshop was focused on patient workup, selection for BP, chemotherapy choices, radiation therapy (RT) contouring and planning, patient counseling. A total of 77 pre- and 32 matched post-workshop IRB-approved surveys, based on the workshop content, were analyzed using descriptive statistics to determine baseline clinical experience and patterns of care. The impact was judged by changes in participants' responses. A total of 56% of respondents had experience with delivering bladder-directed RT, and 60% of those treated both operable and inoperable MIBC patients. Only 10% felt uncomfortable offering an operable patient BP modality. Prior to the workshop, almost half of respondents estimated universal poor bladder (44%) and erectile functions (47%) after BP. The workshop resulted in dramatic change in participants' attitudes towards long-term urinary (Stuart-Maxwell test, p < 0.01) and sexual (exact McNemar test, p < 0.01) side effects. Prior to the workshop, only 47% of respondents routinely discussed smoking cessation (SC) with their patients, whereas after workshop, 88% agreed that SC discussion is mandatory (exact McNemar test, p = 0.04). BP for MIBC is commonly used in Russia. Our workshop resulted in dramatically improved understanding of long-term BP toxicities and inspired Russian ROs to incorporate SC counseling into routine clinical management.
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Neoplasias de la Vejiga Urinaria , Humanos , Masculino , Músculos , Federación de Rusia , Encuestas y Cuestionarios , Neoplasias de la Vejiga Urinaria/terapiaRESUMEN
BACKGROUND: Hepatitis C virus (HCV) interferes with activation of innate and adaptive immune responses. Theoretically, the efficacy and toxicity of immune checkpoint inhibitors in cancer patients infected with HCV may differ. Nevertheless, HCV was an exclusion criterion in most checkpoint inhibitor trials. We evaluated the efficacy and safety of nivolumab in metastatic renal cell carcinoma (mRCC) patients with or without chronic HCV infection. METHODS: In a matched cohort study, data were collected from 174 patients, retrospectively. All patients had clear-cell mRCC, chronic HCV infection (case study group), no evidence of other malignancy or cirrhosis, and had received nivolumab (3 mg/kg every 2 weeks) until disease progression or unacceptable toxicity. Quantitation of HCV RNA in plasma samples was performed before and during treatment with nivolumab with the automated HCV test (Hoffmann-La Roche, Switzerland). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and rate of grade 3-4 adverse events in study and control cohorts. RESULTS: A total of 44 matched patients were included. Groups were well balanced. HCV-infected patients had significantly longer OS and PFS. Median OS was 27.5 (95% CI 25.3-29.7) and 21.7 (20.3-23.1) in study and control groups, respectively (P = 0.005). Median PFS was 7.5 (5.7-9.3) and 4.9 (4-5.8) (P = 0.013). Despite no differences in ORR between groups (27% vs. 23%, P = 0.7), patients with HCV had significantly more durable responses (P = 0.01). Nivolumab was well tolerated in all HCV-positive patients. No unexpected toxicity was observed. Assessment of viral load during nivolumab therapy was available in 14 of 22 (64%) patients with HCV. Nivolumab did not significantly impact HCV concentration (mean change 210 IU/ml, P = 0.82) in the absence of antiviral therapy. CONCLUSIONS: The efficacy and safety profiles observed in this study support the administration of nivolumab in mRCC patients infected with HCV and warrant further investigation.
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Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Nivolumab/uso terapéutico , Antineoplásicos Inmunológicos/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nivolumab/farmacología , Estudios RetrospectivosRESUMEN
BACKGROUND: Very little is known about receptor tyrosine kinase (RTK) expression on peripheral blood mononuclear cells (PBMC) in humans including renal cell carcinoma (RCC) patients. OBJECTIVES: The primary objective of this study was to evaluate expression levels of major RTKs on PBMC and tumor-infiltrating lymphocytes (TIL) isolated from RCC patients. The secondary aim was to compare levels of RTK expression in RCC patients before surgery and on the 180th day after surgery (lymphocyte lifetime) and to compare them with the expression in healthy donors. In addition, we compared RTK and PD-L1 expression in TIL. METHODS: Tumor and blood samples were obtained from 20 patients with primary RCC immediately after surgical resection. Blood samples were collected from 20 healthy donors. Tumors were harvested into RPMI 1640 medium (Gibco) and processed within 4 h. TIL isolation was performed using a modified protocol [Baldan et al. Br J Cancer. 2015;112:1510-18]. Expression of RTKs was evaluated with NovoExpress Software. Twenty tumors from the same patients were stained with PD-L1 IHC assay (clone SP142; Ventana). RESULTS: PBMC and TIL express RTKs in humans. The RTK expression level was significantly lower on peripheral blood cells in patients with RCC (mean 41%, range 27.1-62.6%) as compared with healthy donor PBMC (mean 77.1%, range 72.1-80.1%, all p < 0.05). Furthermore, RTK expression was significantly downregulated on intratumoral cells (mean 40%, range 23.2-52.3%) in comparison with healthy donor PBMC. There was no significant recovery of RTK expression on the 180th day except for VEGFR2. Five of 20 (25%) patients were PD-L1 positive. PD-L1 expression on TIL was strongly associated with downregulated expression of PDGFRα (p = 0.017) and PDGFRß (p = 0.024). CONCLUSIONS: PBMC and TIL had similar low RTK expression levels in RCC patients. PBMC of healthy humans had a significantly higher expression of RTK. PD-L1 and PDGFRα-ß expression could correlate. Comprehensive basic and clinical studies will be needed to define a biological role of RTKs on different lymphocyte subsets and correlations between clinical outcomes and expression levels.
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Donantes de Sangre , Carcinoma de Células Renales/enzimología , Neoplasias Renales/enzimología , Leucocitos Mononucleares/enzimología , Linfocitos Infiltrantes de Tumor/enzimología , Proteínas Tirosina Quinasas Receptoras/sangre , Adulto , Anciano , Antígeno B7-H1/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Receptores del Factor de Crecimiento Derivado de Plaquetas/sangreRESUMEN
Radiation therapy (RT) is an effective treatment modality for hepatocellular carcinoma (HCC), but globally, it is underutilized. In Russia, practice patterns with regard to liver-directed radiation are unknown. Under the auspices of Russian Society of Clinical Oncology (RUSSCO), our team conducted an IRB-approved contouring workshop for Russian radiation oncologists. Pre- and post-workshop surveys were analyzed to determine baseline clinical experience and patterns of care for liver-directed RT among Russian providers. The effect of the contouring workshop on participants' knowledge was tested using mixed effects model. Forty pre-workshop and 24 post-workshop questionnaires were analyzable with a 100% response rate. Sixty percent of respondents had never evaluated a patient with HCC and only 8% (3 out of 40) reported treating an HCC patient with liver-directed RT. Nonetheless, 73% of respondents were comfortable offering liver-directed RT prior to the workshop. After the workshop, 85% of respondents felt comfortable treating a patient with HCC with liver-directed RT and 50% were comfortable recommending stereotactic body radiation therapy (SBRT). Measures of knowledge pertaining to evaluation of HCC patients and selection for appropriate liver-directed therapies were dramatically improved after the workshop. Liver-directed RT is not commonly used in Russia in the management of patients with HCC, and few centers are equipped for motion management. Our contouring workshop resulted in dramatically improved understanding of the evaluation and management of HCC patients. We recommend starting with a more protracted fractionated RT and building experience through attendance of additional educational activities, participation in multidisciplinary liver tumor boards, and prospective analysis of treatment toxicity and outcomes.
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Carcinoma Hepatocelular/radioterapia , Competencia Clínica , Neoplasias Hepáticas/radioterapia , Guías de Práctica Clínica como Asunto/normas , Pautas de la Práctica en Medicina/normas , Oncología por Radiación/educación , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/patología , Manejo de la Enfermedad , Humanos , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/patología , Oncólogos de Radiación , Radiocirugia/métodos , Federación de Rusia/epidemiología , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
Radiation oncologists in Russia face a number of unique professional difficulties including lack of standardized training and continuing medical education. To combat this, under the auspices of the Russian Society of Clinical Oncology (RUSSCO), our group has developed a series of ongoing in-person interactive contouring workshops that are held during the major Russian oncology conferences in Moscow, Russia. Since November 2016 during each workshop, we utilized a web-based open-access interactive three-dimensional contouring atlas as part of our didactics. We sought to determine the impact of this resource on radiation oncology practice in Russia. We distributed an IRB-approved web-based survey to 172 practicing radiation oncologists in Russia. We inquired about practice demographics, RUSSCO contouring workshop attendance, and the clinical use of open-access English language interactive contouring atlas (eContour). The survey remained open for 2 months until November 2017. Eighty radiation oncologists completed the survey with a 46.5% response rate. Mean number of years in practice was 13.7. Sixty respondents (75%) attended at least one RUSSCO contouring workshop. Of those who were aware of eContour, 76% were introduced during a RUSSCO contouring workshop, and 81% continue to use it in their daily practice. The greatest obstacles to using the program were language barrier (51%) and internet access (38%). Nearly 90% reported their contouring practices changed since they started using the program, particularly for delineation of clinical target volumes (57%) and/or organs at risk (46%). More than 97% found the clinical pearls/links to cooperative group protocols in the software helpful in their daily practice. The majority used the contouring program several times per month (43%) or several times per week (41%). Face-to-face contouring instruction in combination with open-access web-based interactive contouring resource had a meaningful impact on perceived quality of radiation oncology contours among Russian practitioners and has the potential to have applications worldwide.
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Anatomía/educación , Internet/estadística & datos numéricos , Neoplasias/radioterapia , Órganos en Riesgo/anatomía & histología , Guías de Práctica Clínica como Asunto/normas , Oncólogos de Radiación/educación , Oncología por Radiación/educación , Competencia Clínica , Humanos , Neoplasias/diagnóstico por imagen , Neoplasias/patología , Órganos en Riesgo/diagnóstico por imagen , Pautas de la Práctica en Medicina/normas , Federación de Rusia , Encuestas y CuestionariosRESUMEN
SUMMAY: Purpose Early data suggest that combining FGFR2 inhibitors with platinum-containing cytotoxic agents for the treatment of epithelial ovarian cancer may yield increased antitumor activity. We investigated antitumor activity of alofanib (RPT835), a novel allosteric FGFR2 inhibitor, in ovarian cancer in vitro and in vivo. Methods Equal amounts of ovarian cancer cell (SKOV3) lysates were analyzed for FGFR1-3 protein expression using Wes. To assess the efficacy of alofanib on FGF-mediated cell proliferation, SKOV3 cells were incubated and were treated with serially diluted alofanib. Basic FGF was added at a concentration of 25 ng/ml. Control wells were left untreated. Cell growth inhibition was determined using Promega's Cell Titer-Glo® assay. Immunocompromised mice were used for xenotransplantation of SKOV3 cancer cells. Seventy animals with measurable tumors were selected on day 10 and randomized into control groups (no treatment or chemotherapy alone (paclitaxel + carboplatin) and treatment groups (alofanib orally or intravenously (different dose levels) in combination with chemotherapy). Measurements of tumor volume (mm3) were performed by digital calipers every 3 days during 31 days after tumor inoculation. Number of tumor vessels and Ki-67 index were calculated. Results SKOV3 cells express FGFR1 and FGFR2 but not FGFR3. Basic FGF increased proliferation of the ovarian cancer cells in untreated control group (P = 0.001). Alofanib inhibited growth of FGFR2-expressing SKOV3 cells with GI50 value of 0.37 µmol/L. Treatment with alofanib in combination with paclitaxel/carboplatin resulted in tumor growth delay phenotype in all treatment groups compared to control non-treatment groups. Compound exhibited a dose-dependent effect on tumor growth. Daily intravenous regimen of alofanib (total maximum dose per week was 350 mg/kg) demonstrated significant effect (inhibiting growth by 80 % and by 53 % in comparison with vehicle and chemotherapy group alone, respectively (P < 0.001). Alofanib decreased number of vessels in tumor (-49 %; P < 0.0001) and number of Ki-67-positive SKOV3 cells (-42 %, P < 0.05). There were tumor necrosis and cell degeneration in alofanib group. Conclusions We suggest that FGFR2 inhibition has potent effects on ovarian cancer growth in preclinical studies.
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Antineoplásicos/uso terapéutico , Benzoatos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Sulfonamidas/uso terapéutico , Animales , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzoatos/farmacología , Carboplatino/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Ratones Desnudos , Neovascularización Patológica/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Paclitaxel/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/metabolismo , Sulfonamidas/farmacología , Carga Tumoral/efectos de los fármacosRESUMEN
Dysregulation of fibroblast growth factor (FGF) signaling in renal cell carcinoma is now well understood, and it is becoming increasingly likely that certain tumors become dependent on an activation of this pathway for their growth and survival. Dissecting the FGF/FGF receptor (FGFR) pathway offers the hope of developing new therapeutic approaches that selectively target the FGF/FGFR axis in patients whose tumors are known to harbor FGF/FGFR dysregulation. In this review, we summarize the existing data on the role of FGFR1 in the pathogenesis of renal cell carcinoma and discuss methodological issues for drug investigation in this setting.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Ensayos Clínicos como Asunto , Inhibidores Enzimáticos/uso terapéutico , Humanos , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Terapia Molecular Dirigida , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Cancer is one of the major non-communicable diseases posing a threat to world health. Unfortunately, improvements in socioeconomic conditions are usually associated with increased cancer incidence. In this Commission, we focus on China, India, and Russia, which share rapidly rising cancer incidence and have cancer mortality rates that are nearly twice as high as in the UK or the USA, vast geographies, growing economies, ageing populations, increasingly westernised lifestyles, relatively disenfranchised subpopulations, serious contamination of the environment, and uncontrolled cancer-causing communicable infections. We describe the overall state of health and cancer control in each country and additional specific issues for consideration: for China, access to care, contamination of the environment, and cancer fatalism and traditional medicine; for India, affordability of care, provision of adequate health personnel, and sociocultural barriers to cancer control; and for Russia, monitoring of the burden of cancer, societal attitudes towards cancer prevention, effects of inequitable treatment and access to medicine, and a need for improved international engagement.
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Neoplasias/terapia , Anciano , Anciano de 80 o más Años , Alcoholismo/epidemiología , Neoplasias de la Mama/diagnóstico , China , Neoplasias Colorrectales/diagnóstico , Características Culturales , Detección Precoz del Cáncer/tendencias , Desarrollo Económico/tendencias , Contaminación Ambiental/efectos adversos , Etnicidad , Femenino , Servicios de Salud/economía , Accesibilidad a los Servicios de Salud/tendencias , Fuerza Laboral en Salud/tendencias , Disparidades en Atención de Salud/tendencias , Humanos , India , Masculino , Medicina Tradicional China , Persona de Mediana Edad , Neoplasias/prevención & control , Servicios de Salud Rural/tendencias , Federación de Rusia/epidemiología , Sexismo , Fumar , Estigma Social , Servicios Urbanos de Salud/tendenciasAsunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Carcinoma de Células Transicionales/tratamiento farmacológico , Neoplasias Urológicas/tratamiento farmacológico , Carcinoma de Células Transicionales/patología , Humanos , Invasividad Neoplásica , Resultado del Tratamiento , Neoplasias Urológicas/patologíaRESUMEN
ABSTRACT: We assessed the preliminary efficacy and toxicity of intrapleural instillation of nivolumab in patients with large pleural effusion. Patients with metastatic cancers who have a large volume of pleural effusion and required evacuation were eligible. Thoracentesis followed by nivolumab (40 mg, single intrapleural instillation) was performed. The primary endpoint was 3-month recurrence-free survival. A total of 13 patients were enrolled. The study was terminated after stage 1 as no efficacy was observed; 7 patients (54%) had a recurrence of pleural effusion at 3 months. Thirteen (100%) patients had no recurrence, dyspnea, or cough within 1 month, and the median time to recurrence was 1.9 months (95% confidence interval [CI], 1.35-2.5). No adverse events were identified. We concluded that a single intrapleural instillation of the nivolumab at 40 mg was ineffective and well-tolerated in cancer patients with pleural effusion.
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Nivolumab , Derrame Pleural Maligno , Humanos , Nivolumab/administración & dosificación , Nivolumab/efectos adversos , Nivolumab/uso terapéutico , Femenino , Masculino , Anciano , Persona de Mediana Edad , Derrame Pleural Maligno/tratamiento farmacológico , Derrame Pleural Maligno/patología , Neoplasias/tratamiento farmacológico , Neoplasias/complicaciones , Neoplasias/patología , Toracocentesis/métodos , Anciano de 80 o más Años , Derrame Pleural/etiología , Derrame Pleural/tratamiento farmacológico , Derrame Pleural/patología , Adulto , Resultado del Tratamiento , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificaciónRESUMEN
Fibroblast growth factor (FGF) receptor 1 (FGFR1) is a potential therapeutic target for treatment of metastatic renal cell carcinoma (RCC). We investigated the preclinical activity of OM-RCA-01, a novel therapeutic humanized anti-FGFR1 antibody in RCC. OM-RCA-01 has been shown to inhibit in vitro kinase activity of FGFR1 and has high affinity (Kd of 1.59 nM). In human renal carcinoma Caki-1 FGFR1-expressing cells, OM-RCA-01 potently inhibited FGF-mediated signaling and proliferation. In vivo, the tumors in untreated mice or mice treated with non-specific IgG continued their aggressive growth to reach the size of 2,000 cm3, at which point the mice were killed. In contrast, treatment with OM-RCA-01 not only significant arrested further growth of the tumors (P < 0.01) but also demonstrated differences in tumor volume compared with vehicle already on Day 13. A similar anti-tumor activity of OM-RCA-01 was observed when the antibody was given in low (1 mg/kg) or high (10 mg/kg) doses (P = 0.917). In Matrigel assay, OM-RCA-01 significantly inhibited FGF-induced endothelial cell migration, capillary-like tubular structure and mature vessels formation. Administration of 10 mg/kg antibody for up to 35 days resulted in minimal body weight loss and no observations of gross toxicity were made. Collectively, the data obtained with OM-RCA-01 are consistent with potent inhibition of FGFR1-signaling, angiogenesis, and tumor growth. OM-RCA-01 is being developed clinically as an intravenous therapy for the treatment of clear cell RCC.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/inmunología , Animales , Carcinoma de Células Renales/inmunología , Línea Celular , Línea Celular Tumoral , Femenino , Humanos , Inmunoglobulina G/inmunología , Neoplasias Renales/inmunología , Ratones , Ratones Desnudos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVES: To evaluate the role of cytoreductive radiofrequency ablation (cRFA) in patients with metastatic renal cell carcinoma (RCC) with small primary tumours treated with immuno- or targeted therapy. To assess the efficacy of sunitinib in patients with metastatic RCC with unresected small primary tumours. PATIENTS AND METHODS: Three parallel single-arm prospective studies were conducted. Eligibility criteria were nearly identical for all trials and included: histopathologically confirmed RCC; metastatic measurable disease; size of primary tumour <5 cm; good or intermediate prognosis according to the Memorial Sloan-Kettering Cancer Center model; and no previous therapy. Study 1: Patients were treated with percutaneous cRFA under computed tomography guidance followed by interferon (IFN)-α, 9 MIU, s.c., three times per week. Study 2: Patients received cRFA followed by sunitinib in repeated 6-week cycles of 50 mg/day orally for 4 weeks, then 2 weeks off treatment. Study 3: Patients with unresected primary RCC received sunitinib alone. The primary endpoint was progression-free survival (PFS). RESULTS: Baseline patient characteristics (age, gender, histology, Eastern Cooperative Oncology Group performance status, metastatic sites, primary tumour size) were similar in all three studies. Efficacy data for 114 evaluable patients showed an objective response rate of 8% (95% confidence interval [CI] 4.5, 10.5) for study 1, 28.9% (95% CI 15.2, 34) for study 2, and 31.6% (95% CI 20.3, 38.9) for study 3. The median (95% CI) PFS times were 9.1 (6.9, 10.2), 13.4 (9.8, 14.4) and 12.7 (11.3, 13.5) months for studies 1, 2 and 3, respectively. Objective response rate was significantly higher and PFS significantly longer in the sunitinib trials than in study 1 (P < 0.01 all differences); no differences were found between studies 2 and 3 (objective response rate, P = 0.1; PFS, P = 0.6). Study 1 met its primary endpoint, showing that PFS was significantly longer than the expected 5 months (P = 0.02). The median (95% CI) objective survival (OS) times were greater in study 2 (cRFA/sunitinib) and study 3 (sunitinib-alone) than in study 1 (IFN-α) at 27.2 (22.6, 31.8) and 22.5 (20.7, 24.3) vs 19.5 (16.3, 22.7) months, respectively. Differences were significant (study 1 vs 2, hazard ratio [HR] = 0.55; P = 0.003; study 1 vs study 3 HR = 0.6, P = 0.01). OS was significantly longer in the cRFA/sunitinib group compared with the sunitinib-alone group (HR = 0.71; P = 0.04). There were no unexpected toxicities of medical treatment or complications of cRFA. CONCLUSIONS: cRFA is a safe and effective approach for select patients with metastatic RCC treated with immunotherapy. The cRFA technique did not improve PFS in patients treated with sunitinib; cRFA probably has impact on OS in these patients. This needs to be tested in a larger trial. Sunitinib was effective in patients with metastatic RCC with unresected small primary tumours.
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Carcinoma de Células Renales/terapia , Ablación por Catéter/métodos , Indoles/uso terapéutico , Interferón-alfa/uso terapéutico , Neoplasias Renales/terapia , Estadificación de Neoplasias , Pirroles/uso terapéutico , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/secundario , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Factores Inmunológicos/uso terapéutico , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sunitinib , Resultado del TratamientoRESUMEN
Disease management in challenging patient population with cancer and concomitant serious conditions presents an unmet clinical need. The major gap is the lack of data from properly designed trials that could support clinical decisions. Despite many advances in the fields of oncology, immunology, and infectious diseases, chronic viral infections in cancer patients remain to some extent terra incognita. Therefore, many patients lose the opportunity to receive the most advanced therapy, and physicians are compelled to make treatment decisions without sufficient evidence. In this review, we discuss the utility of immunotherapy in patients with chronic hepatitis C viral infection. Limited data from several studies and case reports support the hypothesis that immune checkpoint inhibitors can be used safely and effectively in this patient population. Available results warrant further investigation of immunotherapy in infected patients. Taking into account the current state of our knowledge, expanding clinical trial eligibility should be considered by investigators and sponsors to allow patient access to novel therapies and better matching of clinical research to the real-world population.
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Hepatitis C Crónica , Hepatitis C , Neoplasias , Humanos , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Oncología Médica , Inmunoterapia/métodos , Hepatitis C/complicacionesRESUMEN
About 40% of patients with non-small cell lung cancer (NSCLC) developed pleural effusions at some time during the course of their disease. Preliminary results from our Phase 2 multicentre clinical trial (Cohort 1) demonstrated the safety of intrapleural nivolumab in cancer patients. In Cohort 2 we assessed the preliminary efficacy and toxicity of intrapleural instillation of the nivolumab in patients with metastatic NSCLC and large pleural effusion requiring evacuation. Thoracentesis followed by nivolumab (40 mg, single intrapleural instillation) was performed. The primary endpoint was 3-month recurrence-free survival. Simon's two-stage design was used, with 13 patients planned for stage 1. If 11 or more patients did not have a pleural effusion after 3 months, an additional 35 patients were planned to be accrued for a total of 48. A total of 13 patients were enrolled. This study did not meet its primary endpoint and was terminated. Eight patients (61.5%) had a recurrence of pleural effusion at 3 months. The median time to recurrence was 1.84 months (95% CI 1.19-2.49). No adverse events were identified. We concluded that a single intrapleural instillation of the nivolumab at 40 mg was ineffective and well-tolerated in patients with metastatic NSCLC and pleural effusion.
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BACKGROUND: The goals of the OSURK registry study were to assess 5-year overall survival (OS) in patients with metastatic urothelial cancer diagnosed in 2017 in Kazakhstan and collect data on the use of various treatment options in routine clinical practice. METHODS: Patients with newly diagnosed metastatic bladder cancer (BC) were retrospectively identified in the national register of Kazakhstan (ERCP) between January 2017 and January 2018. ERCP is the biggest register in the country and includes patient data from 17 regions. Investigators collected patient information and processed records online on the following anonymised data: demographical characteristics, received treatment and outcomes. Patients were included in the study if mBC was confirmed histologically and they had at least one visit to the cancer center during the follow-up period. The outcomes of interest were overall survival (OS), patient characteristics and treatment patterns. RESULTS: Totally 480 adult patients with metastatic BC were included. Mean number of patients in one region per year was 28.2. Median age at diagnosis of mBC was 70.0 years (range, 30-100). Patients were predominantly male (81.3%), histological subtype of BC (urothelial carcinoma, etc.) was determined in 41%. Overall, 187 (39%) patients received systemic therapy for metastatic disease. Platinum-based chemotherapy was prescribed in 147 (76.8%) patients who received systemic treatment. The majority of treatment was with cisplatin (N=132, 70.6%). Sixty-four (13.3%) patients received ≥2 treatment lines. After median 60.5 months of follow-up the 5-year OS in patients with metastatic BC was 2.7%. The 1-, and 3-year OS rates were 31.0% and 9.8%, respectively. Median OS from the start of treatment was 7.3 months (95% CI 6.5-8.1). CONCLUSIONS: The results of the OSURK study indicate the need for further implementation of innovative drugs in real practice in order to significantly increase the OS of patients with metastatic BC.
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OBJECTIVE: Fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) has recently emerged as a critical event in the transformation and tumorigenicity of several murine and human tumors. This pathway could be a mechanism driving angiogenesis in patients with metastatic renal cell carcinoma (RCC). Membrane antigens such as FGFR expressed in RCC are attractive targets for new therapeutic and diagnostic applications. This study evaluated the expression of FGFR1 and FGFR2 in RCC. MATERIAL AND METHODS: Formalin-fixed, paraffin-embedded specimens of 100 primary tumors and 40 metastatic lymph nodes removed from 140 untreated RCC patients were evaluated by immunohistochemistry with FGFR1 and FGFR2 antibodies. The extent of FGFR expression was compared with 40 specimens of normal human kidney tissue (selected from the surgical diagnostic files). Significant differences in the immunoexpression of FGFR among these groups were assessed bychi-squared and Fisher's exact tests using a semi-quantitative scoring system on the extent of stained cells and intensity of corresponding immunostained cells (0 to 3+). RESULTS: Expression of FGFR1 was observed in 98% (98/100) of primary renal tumors and in 82.5% (33/40) of lymph-node metastases. Intensity was 3+ in allcases. Nuclear expression of FGFR1 was found in 68% (95/140). FGFR2 staining was seen in 4% (4/100) of primary tumors and in 5% (2/40) of lymph-node metastases. FGFR2 was expressed in RCC of non-clear cell histology. FGFR1 expression was significantly lower in the normal kidney tissue(p = 0.001) and was detected in 2.5% of cases (1/40); no FGFR2 expression was found. CONCLUSION: This study has shown for the first time that FGFR1 is highly expressed in RCC patients.
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Carcinoma de Células Renales/metabolismo , Neoplasias Renales/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/epidemiología , Carcinoma de Células Renales/patología , Femenino , Humanos , Neoplasias Renales/epidemiología , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Neovascularización Patológica/metabolismoRESUMEN
BACKGROUND: Cholangiocarcinoma has been traditionally considered a tumor with poor prognosis. Until now, surgical treatment has been the only more or less effective approach. SUMMARY: Over 10 years, chemotherapy with a combination of gemcitabine and cisplatin remains the standard first-line therapy for patients with locally advanced or metastatic cholangiocarcinoma, which leads to a median overall survival of 11.7 months. Several inhibitors of HER (ERBB), HGF/c-MET, Hedgehog, KRAS-BRAF-MEK-ERK, and PI3K/AKT/mTOR signaling pathways did not show their superiority to standard chemotherapy. The rise of hope is associated with the emergence of novel fibroblast growth factor receptors and isocitrate dehydrogenase inhibitors as well as immune checkpoint inhibitors.