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BACKGROUND: Nivolumab is the first immune checkpoint inhibitor approved in Europe for the treatment of advanced renal cell carcinoma (aRCC) in patients resistant to prior antiangiogenic therapy. WITNESS is an ongoing, prospective, observational study designed to evaluate the effectiveness and safety of nivolumab in patients with aRCC treated in real life (or routine practice) in France (ClinicalTrials.gov identifier: NCT03455452). PATIENTS AND METHODS: This study includes adult patients with a confirmed diagnosis of aRCC who have initiated nivolumab after 1-2 prior lines of antiangiogenic therapy. Endpoints include overall survival (OS), progression-free survival (PFS), duration of treatment (DOT), duration of response (DOR), overall response rate (ORR), subgroup analyses, and treatment-related adverse events (TRAEs). Results after a median follow-up of 12.3 months are presented here. RESULTS: A total of 325 patients with aRCC were included, of whom 38.2% had a Karnofsky score <80, 77.8% received nivolumab as second-line therapy, and 69.5% had undergone a previous nephrectomy. In the overall population, median OS was 20.5 [95% confidence interval (CI) 17.6-25.0] months and median PFS was 5.2 (95% CI 4.5-5.9) months. ORR was 34.5%, median DOT was 3.8 months, and median DOR was 16.5 months. Nivolumab was effective in different subgroups including patients with bone or glandular metastases and those receiving baseline corticosteroids. Moreover, effectiveness was observed irrespective of prior nephrectomy and line of treatment. No new safety signals were identified; TRAEs of any grade were reported in 32.0% of patients, grade ≥3 and serious TRAEs in 11.1% each, and TRAEs leading to discontinuation in 8.9%. CONCLUSIONS: Preliminary results of the ongoing WITNESS study confirm the real-world effectiveness and safety of nivolumab monotherapy in previously treated patients with aRCC. Treatment benefits were similar to those observed in the pivotal phase III CheckMate 025 randomized clinical trial, despite a broader, real-life study population.
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Carcinoma de Células Renales , Neoplasias Renales , Nivolumab , Humanos , Nivolumab/uso terapéutico , Nivolumab/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/mortalidad , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/mortalidad , Femenino , Masculino , Francia , Anciano , Persona de Mediana Edad , Estudios Prospectivos , Adulto , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/farmacología , Supervivencia sin ProgresiónRESUMEN
INTRODUCTION: Immune checkpoint inhibitors (ICIs) are now standard of care in many cancers. They can generate immune-related adverse events (irAEs), but no biomarkers are available to identify patients who are more likely to develop irAEs. We assess the association between pre-existing autoantibodies and occurrence of irAEs. PATIENTS AND METHODS: We prospectively collected data from consecutive patients receiving ICIs for advanced cancers, in a single center between May 2015 and July 2021. Autoantibodies testing was performed before ICIs initiation including AntiNeutrophil Cytoplasmic Antibodies, Antinuclear Antibodies, Rheumatoid Factor anti-Thyroid Peroxidase and anti-Thyroglobulin. We analyzed the associations of pre-existing autoantibodies with onset, severity, time to irAEs and with survival outcomes. RESULTS: Of the 221 patients included, most had renal cell carcinoma (n = 99; 45%) or lung carcinoma (n = 90; 41%). Grade ≥2 irAEs were more frequent among patients with pre-existing autoantibodies: 64 (50%) vs. 20 (22%) patients (Odds-Ratio= 3.5 [95% CI=1.8-6.8]; p < 0.001) in the positive vs negative group, respectively. irAEs occurred earlier in the positive group with a median time interval between ICI initiation and irAE of 13 weeks (IQR = 8.8-21.6) vs. 28.5 weeks (IQR=10.6-55.1) in the negative group (p = 0.01). Twelve patients (9.4%) experienced multiple (≥2) irAEs in the positive group vs. 2 (2%) in the negative group (OR = 4.5 [95% CI: 0.98-36], p = 0.04). After a median follow-up of 25 months, median PFS and OS were significantly longer among patients experiencing irAE (p = 0.00034 and p = 0.016, respectively). CONCLUSION: The presence of pre-existing autoantibodies is significantly associated with the occurrence of grade ≥2 irAEs, with earlier and multiple irAEs in patients treated with ICIs.
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Antineoplásicos Inmunológicos , Neoplasias Renales , Neoplasias Pulmonares , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Estudios Retrospectivos , Neoplasias Pulmonares/tratamiento farmacológico , Autoanticuerpos/uso terapéuticoRESUMEN
BACKGROUND: An elevated pre-treatment neutrophil to lymphocytes ratio (NLR) is associated with poor prognosis in various malignancies. Optimal cut-off is highly variable across studies and could not be determined individually for a patient to inform his prognosis. We hypothesize that NLR variations could be more useful than baseline NLR to predict progression-free survival (PFS) and overall survival (OS) in patients (pts) receiving anti-PD1 treatment. PATIENTS AND METHODS: All pts with metastatic renal cell carcinoma (mRCC) and metastatic non-small cell lung cancer (mNSCLC) who received anti-PD1 nivolumab monotherapy in second-line setting or later were included in this French multicentric retrospective study. NLR values were prospectively collected prior to each nivolumab administration. Clinical characteristics were recorded. Associations between baseline NLR, NLR variations and survival outcomes were determined using Kaplan-Meier's method and multivariable Cox regression models. RESULTS: 161 pts (86 mRCC and 75 mNSCLC) were included with a median follow-up of 18 months. On the whole cohort, any NLR increase at week 6 was significantly associated with worse outcomes compared to NLR decrease, with a median PFS of 11 months vs 3.7 months (p < 0.0001), and a median OS of 28.5 months vs. 18 months (p = 0.013), respectively. In multivariate analysis, NLR increase was significantly associated with worse PFS (HR 2.2; p = 6.10-5) and OS (HR 2.1; p = 0.005). Consistent results were observed in each cohort when analyzed separately. CONCLUSION: Any NLR increase at week 6 was associated with worse PFS and OS outcomes. NLR variation is an inexpensive and dynamic marker easily obtained to monitor anti-PD1 efficacy.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Linfocitos/inmunología , Neutrófilos/inmunología , Nivolumab/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/secundario , Estudios de Factibilidad , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Renales/inmunología , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Recuento de Leucocitos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Estudios Prospectivos , Estudios Retrospectivos , Medición de Riesgo/métodos , Adulto JovenRESUMEN
BACKGROUND: Although sequential targeted therapy is standard in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC), the choice of drugs and optimal administration sequence have yet to be established. The objective of this study was to explore whether it is preferable to rechallenge a long-term responder to a first-line tyrosine kinase inhibitor (TKI) with a TKI or whether to switch to a mammalian target of rapamycin inhibitor (mTORi); to determine whether second-line treatment response depends on duration of first-line response (TD1). PATIENTS AND METHODS: Retrospective multicenter study (2004-2011) of 241 consecutive mRCC patients (clear-cell histology) who received a first-line TKI for ≥6 months followed by a second-line TKI (n = 118) or mTORi (n = 123). END POINTS: Progression-free survival (PFS) and time-to-treatment failure (TTF) on second-line therapy. Multivariable full-model: second-line drug, TD1, ECOG-PS before first- and second-line, best objective response (first-line), Fuhrman grade, number of metastatic sites, and presence of bone metastases. Adjustment covariable: International mRCC Database Consortium (IMDC) risk score. Multiple propensity score and missing data methods were used. Any correlation between first-line and second-line PFS was investigated using censored quantile regression models (CQRM). RESULTS: Sequence effect in the overall cohort was in favor of the TKI-TKI sequence over the TKI-mTORi sequence on using TD1 as continuous covariable (HR ≈ 0.75 for PFS and TTF). TKI-TKI superiority was attributed in large part to the 11-22 month (TD1) subgroup of patients which displayed significantly better outcomes [HR ≈ 0.5; median PFS (months): 9.4 (5.9-12.2) versus 3.9 (3.0-5.5), P = 0.003; TTF(months): 8.0 (5.5-11.0) versus 3.6 (3.0-4.6), P = 0.009]. Upon full CQRM, long-term second-line responders were more likely to have received a second TKI than an mTORi and to have been long-term responders to first-line TKI. CONCLUSIONS: m-ccRCC patients who remained on first-line TKI between 11 and 22 months benefited from a TKI rechallenge rather than from second-line mTORi.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Terapia Recuperativa/métodos , Anciano , Carcinoma de Células Renales/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Estudios Retrospectivos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Resultado del TratamientoRESUMEN
BACKGROUND: Randomized clinical trials showed the benefit of adjuvant trastuzumab-based chemotherapy (ATBC) for node-positive and/or >1 cm HER2+ breast carcinomas. No efficacy data have been published on ATBC in large series of pT1abN0 HER2+ tumors. PATIENTS AND METHODS: This retrospective study evaluated 276 cases of pT1abN0 HER2+ breast tumors in eight French cancer centers. Factors associated with prognosis and ATBC prescription were analyzed. RESULTS: A total of 129 cases (47%) were treated with ATBC (ATBC+), 19 with chemotherapy alone, 5 with trastuzumab alone, and 123 (45%) with neither trastuzumab nor chemotherapy (ATBC-). ATBC use was associated with the date of diagnosis (before or after June 2005) and with poor prognostic features. At a median follow-up of 44 months, there were 13 recurrences in the ATBC- group and 2 in the ATBC+ group. ATBC was associated with a significant survival benefit (99% 40-month disease-free survival for ATBC+ versus 93% for ATBC- cases; P = 0.018). Lack of hormone receptors (HRs) and the presence of lymphovascular invasion (LVI) were significantly associated with a poor prognosis and a greater benefit of ATBC. CONCLUSIONS: ATBC was associated with a significantly reduced risk of recurrence in pT1abN0 HER2+ tumors, and was more beneficial in HR- and/or LVI+ tumors.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma/tratamiento farmacológico , Quimioterapia Adyuvante , Anciano , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinoma/genética , Carcinoma/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Ganglios Linfáticos/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Receptores de Estrógenos , Estudios Retrospectivos , Factores de Riesgo , TrastuzumabRESUMEN
Treatment options for radioiodine resistant metastatic thyroid cancer patients are limited, and chemotherapy is considered an outdated therapeutic method for differentiated thyroid carcinoma. In this study, we evaluated the activity and safety of gemcitabine and oxaliplatin combination which is considered an out of label therapeutic method in patients with differentiated metastatic thyroid cancer refractory to 131-I treatment. Fourteen refractory patients (8 papillary, 6 follicular), six men/eight women with median age of 63 years and performance status (0-3) were included. Patients received gemcitabine (1,000 mg/m(2)) plus oxaliplatin (100 mg/m(2)) every 2 weeks until 12-cycles and each cycle correspond to 2 weeks treatment. This protocol was approved by the local Institutional Review Boards. Response rate was assessed every four cycles. Progression-free and overall survivals were calculated. Median treatment was 9.5 cycles (range 2-17) with 22 weeks duration. Overall response rate was 57%, with 7% achieving a complete response (1/14), 50% a partial response (7/14), and 28% with a stable disease. All patients with follicular subtype showed objective responses. Eleven patients progressed at a median time of 10.1 months; 10 of 14 patients still alive and the median survival was not reached (median follow-up of 19.8 months). The combination was generally well tolerated. No deaths occurred due to therapy and no grade IV toxicity was recorded. The most common treatment-related adverse events grade 1/3 includes asthenia, peripheral neuropathy, diarrhea, anemia, thrombocytopenia, and neutropenia. In conclusion, the GEMOX regimen is well tolerated and effective in advanced differentiated thyroid cancer. However, this retrospective data on a small sample size are considered preliminary and needs to be evaluated prospectively in a higher number of patients in a clinical trial.
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Adenocarcinoma Folicular/tratamiento farmacológico , Adenocarcinoma Papilar/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Uso Fuera de lo Indicado , Neoplasias de la Tiroides/tratamiento farmacológico , Adenocarcinoma Folicular/mortalidad , Adenocarcinoma Folicular/patología , Adenocarcinoma Papilar/mortalidad , Adenocarcinoma Papilar/patología , Adulto , Anciano , Anciano de 80 o más Años , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/uso terapéutico , Terapia Recuperativa/métodos , Neoplasias de la Tiroides/mortalidad , Neoplasias de la Tiroides/patologíaRESUMEN
One million people worldwide are affected by colorectal cancer (CRC) every year, resulting in 500,000 deaths. Incidence rate varies widely according to areas. It has been much more common in high-income countries. This trend begins to be reversed, with a stabilization of incidence rates in high-income countries and a dramatic increase in developing regions. CRC increase seems to overlap with the increasing level of urbanization in the latter. In the eighties, Doll and Peto already reported that 80% of cancer mortality was avoidable, particularly for CRC for which environmental influence is dominating. Observational studies have reported that migrants tended to reach similar CRC incidence levels that those of natives in the host country. An estimated 60% drop of all CRC cases could be obtained provided eating habits are modified, since these seem to be the main cause of incidence variations. Over the last ten years, many epidemiological studies and meta-analyses have been conducted. However, this abundant literature gave contradictory results. Therefore, in 1997, two groups of experts: the World Cancer Research Fund (WCRF) and the American Institute of Cancer Research (AICR), considered drafting a report on the correlation between diet and cancer a necessity. This systematic literature review, updated in 2007, established that red meat, processed meat and alcohol increase the risk of CRC. Conversely fibers, milk and calcium probably protect against CRC. Considering the most important prospective studies, randomised trials and the 2nd WCRF's report, our article aims at reviewing the evidences about diet and CRC.