RESUMEN
BACKGROUND: Combinations of avelumab [anti-programmed death-ligand 1 (anti-PD-L1)] or talazoparib [poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor] with binimetinib (MEK inhibitor) were expected to result in additive or synergistic antitumor activity relative to each drug administered alone. Here, we report phase Ib results from JAVELIN PARP MEKi, which investigated avelumab or talazoparib combined with binimetinib in metastatic pancreatic ductal adenocarcinoma (mPDAC). PATIENTS AND METHODS: Patients with mPDAC that had progressed with prior treatment received avelumab 800 mg every 2 weeks plus binimetinib 45 mg or 30 mg two times daily (continuous), or talazoparib 0.75 mg daily plus binimetinib 45 mg or 30 mg two times daily (7 days on/7 days off). The primary endpoint was dose-limiting toxicity (DLT). RESULTS: A total of 22 patients received avelumab plus binimetinib 45 mg (n = 12) or 30 mg (n = 10). Among DLT-evaluable patients, DLT occurred in five of 11 patients (45.5%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in three of 10 patients (30.0%) at the 30-mg dose. Among patients treated at the 45-mg dose, one (8.3%) had a best overall response of partial response. Thirteen patients received talazoparib plus binimetinib 45 mg (n = 6) or 30 mg (n = 7). Among DLT-evaluable patients, DLT occurred in two of five patients (40.0%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in two of six patients (33.3%) at the 30-mg dose. No objective responses were observed. CONCLUSIONS: Combinations of avelumab or talazoparib plus binimetinib resulted in higher-than-expected DLT rates. However, most DLTs were single occurrences, and the overall safety profiles were generally consistent with those reported for the single agents. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT03637491; https://clinicaltrials.gov/ct2/show/NCT03637491.
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Adenocarcinoma , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Adenocarcinoma/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: Solid cancer is an independent prognostic factor for poor outcome with COVID-19. As guidelines for patient management in that setting depend on retrospective efforts, we here present the first analyses of a nationwide database of patients with cancer hospitalized with COVID-19 in Belgium, with a focus on changes in anticancer treatment plans at the time of SARS-CoV-2 infection. METHODS: Nineteen Belgian hospitals identified all patients with a history of solid cancer hospitalized with COVID-19 between March 2020 and February 2021. Demographic, cancer-specific and COVID-specific data were pseudonymously entered into a central Belgian Society of Medical Oncology (BSMO)-COVID database. The association between survival and primary cancer type was analyzed through multivariate multinomial logistic regression. Group comparisons for categorical variables were carried out through a Chi-square test. RESULTS: A total of 928 patients were registered in the database; most of them were aged ≥70 years (61.0%) and with poor performance scores [57.2% Eastern Cooperative Oncology Group (ECOG) ≥2]. Thirty-day COVID-related mortality was 19.8%. In multivariate analysis, a trend was seen for higher mortality in patients with lung cancer (27.6% versus 20.8%, P = 0.062) and lower mortality for patients with breast cancer (13.0% versus 23.3%, P = 0.052) compared with other tumour types. Non-curative treatment was associated with higher 30-day COVID-related mortality rates compared with curative or no active treatment (25.8% versus 14.3% versus 21.9%, respectively, P < 0.001). In 33% of patients under active treatment, the therapeutic plan was changed due to COVID-19 diagnosis, most frequently involving delays/interruptions in systemic treatments (18.6%). Thirty-day COVID-related mortality was not significantly different between patients with and without treatment modifications (21.4% versus 20.5%). CONCLUSION: Interruption in anticancer treatments at the time of SARS-CoV-2 infection was not associated with a reduction in COVID-related mortality in our cohort of patients with solid cancer, highlighting that treatment continuation should be strived for, especially in the curative setting.
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COVID-19 , Neoplasias Pulmonares , Humanos , Bélgica/epidemiología , SARS-CoV-2 , Estudios Retrospectivos , Prueba de COVID-19 , Neoplasias Pulmonares/tratamiento farmacológico , Oncología Médica , Sistema de RegistrosRESUMEN
PRECISION is an initiative from the Belgian Society of Medical Oncology (BSMO) in collaboration with several stakeholders, encompassing four programs that aim to boost genomic and clinical knowledge with the ultimate goal to offer patients with metastatic solid tumors molecularly guided treatments. The PRECISION 1 study has led to the creation of a clinico-genomic database. The Belgian Approach for Local Laboratory Extensive Tumor Testing (BALLETT) and GeNeo studies will increase the number of patients with advanced cancer that have comprehensive genotyping of their cancer. The PRECISION 2 project consists of investigator-initiated phase II studies aiming to provide access to a targeted drug for patients whose tumors harbor actionable mutations in case the matched drug is not available through reimbursement or clinical trials in Belgium.
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Neoplasias , Medicina de Precisión , Bélgica , Genómica , Humanos , Oncología MédicaRESUMEN
BACKGROUND: The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). RESULTS: Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. CONCLUSIONS: Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Antígeno B7-H1/metabolismo , Factores de Transcripción Forkhead , Microambiente TumoralRESUMEN
BACKGROUND: The aim of the RESGEX study was to compare the efficacy and safety of the anti-epidermal growth factor receptor (anti-EGFR) antibody tomuzotuximab against cetuximab both in combination with chemotherapy in patients with recurrent and/or metastatic squamous cell cancer of the head and neck in the first-line treatment. PATIENTS AND METHODS: In this phase II trial 240 patients were equally randomized for six cycles to receive either tomuzotuximab (initial dose 990 mg then 720 mg) weekly and cisplatin 100 mg/m2 and fluorouracil (5-FU; 1000 mg/m2/day, days 1-4) every 3 weeks or cetuximab (400 mg/m2 subsequent 250 mg/m2) weekly with the same chemotherapeutic backbone followed by antibody maintenance treatment. The primary endpoint was progression-free survival. RESULTS: Median progression-free survival was 6.5 months [95% confidence interval (CI) 5.9-7.9 months] in the tomuzotuximab group and 6.2 months (95% CI 5.8-7.3 months) in the cetuximab group (P = 0.86). The median overall survival (OS) estimate was 11.6 months (95% CI 9.5-17.2 months) in the tomuzotuximab group and 13.8 months (95% CI 12.3-16.4 months) in the cetuximab group (P = 0.96). In an exploratory analysis a small subgroup of p16-positive patients had a significantly longer OS compared with p16-negative patients (hazard ratio 1.860, 95% CI 1.09-3.16, P = 0.02). CONCLUSIONS: The glyco-engineered antibody tomuzotuximab failed to demonstrate improved efficacy with a chemotherapeutic backbone in the first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma. It remains a so far unanswered question whether such antibody would partner better with different drugs such as checkpoint inhibitors.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Escamosas/tratamiento farmacológico , Cetuximab/uso terapéutico , Células Epiteliales , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológicoAsunto(s)
Carcinoma de Células Transicionales/secundario , Deficiencia del Factor X/etiología , Neoplasias Pulmonares/secundario , Metástasis de la Neoplasia/fisiopatología , Neoplasias de la Vejiga Urinaria/complicaciones , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Pruebas de Coagulación Sanguínea , Carcinoma de Células Transicionales/complicaciones , Carcinoma de Células Transicionales/terapia , Terapia Combinada , Cistectomía , Deficiencia del Factor X/sangre , Humanos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/terapia , Masculino , Terapia Neoadyuvante , Radiocirugia , Neoplasias de la Vejiga Urinaria/terapiaRESUMEN
Over the last decades, advances in the knowledge of immunology have led to the identification of immune checkpoints, reinvigorating cancer immunotherapy. Although normally restricted to activated T and B cells, constitutive expression of CD70 in tumor cells has been described. Moreover, CD70 is implicated in tumor cell and regulatory T cell survival through interaction with its ligand, CD27. In this review, we summarize the targetable expression patterns of CD70 in a wide range of malignancies and the promising mechanism of anti-CD70 therapy in stimulating the anti-tumor immune response. In addition, we will discuss clinical data and future combination strategies.
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Ligando CD27/inmunología , Inmunoterapia , Neoplasias/terapia , Animales , Humanos , Neoplasias/inmunologíaRESUMEN
We report a 49-year-old patient with necrotizing myopathy and a right renal mass. After laparoscopic radical nephrectomy, a remission of myopathy was seen. Pathologic evaluation of the nephrectomy specimen revealed a clear cell renal cell carcinoma. Relapse of myopathy 6 months postoperatively coincided with the diagnosis of the appearance of liver metastatic disease. After initiation of treatment with an mTOR-inhibitor, myopathy became less active requiring smaller amounts of corticosteroids with a complete remission of myopathy after 3 months of systemic treatment for metastatic renal cell cancer.
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Carcinoma de Células Renales/complicaciones , Neoplasias Renales/complicaciones , Enfermedades Musculares/etiología , Síndromes Paraneoplásicos/etiología , Humanos , Masculino , Persona de Mediana Edad , Músculos/patología , Enfermedades Musculares/patología , NecrosisRESUMEN
OBJECTIVES: Renal cell carcinoma (RCC) accounts for 2·4% of all new cancers in Belgium. Over the past decade, the armamentarium for systemic therapy of metastatic RCC (mRCC) has undergone important changes with implementation of targeted therapies directed against pathways involved in the pathogenesis of RCC. We describe first-line treatment choice of a group of patients in 9 Belgian oncology centres between October 2009 and November 2012. METHODS: A clinical report form was established to assess patient characteristics, Karnofsky performance score, Memorial Sloan-Kettering Cancer Center risk criteria (MSKCC) and first-line therapy of mRCC patients. Choice of therapy and starting dose was analyzed before and after reimbursement of pazopanib in Belgium. RESULTS: Ninety-six patients were eligible for the study. Non-smokers accounted for 53% of the patients. Seventy-three per cent of the patients had 0 or 1 MSKCC criteria in the group of patients that started treatment more than 1 year after initial diagnosis. In the group of patients that started therapy less than 1 year after diagnosis, 85% had 2 or more MSKCC criteria. This difference was statistically significant (P<0·0001). Overall distribution of the first-line therapies consisted of 43% sunitinib, 33% pazopanib, 14% temsirolimus, 7% everolimus and 3% sorafenib. Seventeen (18%) out of 96 patients started at a reduced dose level. CONCLUSION: This report shows that the guidelines for the start of first-line treatment in mRCC in 9 centres in Belgium were applied most of the time: a tyrosine kinase inhibitor was the first treatment choice for most patients while temsirolimus was an option for poor prognosis patients. In the majority of patients standard dose levels were initiated, although in some patients adaptation of dosage/treatment schedule was recorded.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Bélgica , Conducta de Elección , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
AIM: To determine whether EMD 1201081, a TLR9 agonist, added to cetuximab had antitumor activity in second-line recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). METHODS: This was a phase 2, open-label, randomized trial of EMD 1201081 0.32 mg/kg subcutaneously weekly plus cetuximab (combination) vs cetuximab monotherapy (control) in cetuximab-naïve patients with R/M SCCHN who progressed on 1 cytotoxic regimen. Crossover to combination was permitted after progression. RESULTS: Objective response rate in both arms was 5.7% (95% CI 1.2-15.7%) by independent assessment. Disease control was 37.7% for patients on combination (24.8-52.1%) and 43.4% on control (29.8-57.7%). Neither independent nor investigator assessments showed significant differences between study arms. Median progression-free survival was 1.5 months (1.3-2.6) for patients on combination, and 1.9 months (1.5-2.9) on control. The most frequent adverse events in the combination arm were rash (29.6%), acneiform dermatitis (22.2%), and injection site reactions (20.4%). Grade 3/4 dyspnea and hypokalemia were more frequent with cetuximab monotherapy (7.5% and 5.7% vs 1.9% each, respectively), and grade 3/4 respiratory failure and disease progression were more frequent with combination (5.6% each vs 1.9% each). CONCLUSION: EMD 1201081 was well tolerated combined with cetuximab, but there was no incremental clinical efficacy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cetuximab , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oligonucleótidos/administración & dosificación , Oligonucleótidos/efectos adversos , Criterios de Evaluación de Respuesta en Tumores Sólidos , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
Head and neck (H&N) cancer is mainly a cancer of the elderly; however, the implementation of comprehensive geriatric assessment (CGA) to quantify functional age in these patients has not yet been studied. We evaluated the diagnostic performance of screening tools [Vulnerable Elders Survey-13 (VES-13), G8 and the Combined Screening Tool 'VES-13 + (17-G8)' or CST], the feasibility of serial CGA, and correlations with health-related quality of life evolution [HRQOL; European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ)-C30 and -HN35] during therapy in hundred patients, aged ≥65 years, with primary H&N cancer undergoing curative radio(chemo)therapy. Respectively 36.8%, 69.0%, 62.1% and 71.3% were defined vulnerable according to VES-13, G8, CST and CGA at week 0, mostly due to presence of severe grade co-morbidities, difficulties in community functioning and nutritional problems. At week 4, significantly more patients were identified vulnerable due to nutritional, functional and emotional deterioration. The CST did not achieve the predefined proportion necessary for validation. Vulnerable patients reported lower function and higher symptom HRQOL scores as compared with fit patients. A comparable deterioration in HRQOL was observed in both groups through therapy. In conclusion, G8 remains the screening tool of choice. Serial CGA identifies the evolution of multidimensional health problems and HRQOL conditions during therapy with potential to guide individualised supportive care.
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Carcinoma de Células Escamosas/terapia , Evaluación Geriátrica/métodos , Neoplasias de Cabeza y Cuello/terapia , Calidad de Vida , Actividades Cotidianas , Anciano , Anciano de 80 o más Años , Quimioradioterapia , Estudios de Factibilidad , Femenino , Humanos , Masculino , Tamizaje Masivo , Estudios Prospectivos , Radioterapia , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
WHAT IS KNOWN AND OBJECTIVE: Sunitinib, a CYP3A4 substrate, is standard of care treatment in metastatic renal cell carcinoma (mRCC) and is administered orally as a single dose of 50 mg, in a 4 weeks on/2 weeks off regimen. Frequently, dose reduction is necessary because of toxicity, as is the association of comedication to treat side effects. In addition, existing comorbidities in these patients necessitate the intake of various classes of chronic medication. Only limited data are available on the risk of drug-drug interactions (DDI). The objective of our paper was to evaluate prescribed dose, comedication, risk of drug-drug interactions and outcome among patients with mRCC treated with sunitinib. METHODS: A single-centre, retrospective analysis was performed for patients with mRCC treated with sunitinib. The drug interaction databases 'Clinical Pharmacology' and 'Lexicomp' were used to screen for possible interactions. RESULTS AND DISCUSSION: The hospital files of 36 patients with mRCC were evaluated. Twenty-two patients received sunitinib as first-line treatment. Progression-free survival (PFS) in this first-line group was longer for patients that started with full-dose sunitinib (21·1 months; n = 12) than for patients started on reduced dose (3·5 months; n = 10). In the whole group of 36 patients, an average of 6·8 comedications was taken. Possible pharmacodynamic drug-drug interactions were most frequently found (47%) and reported as major interactions (QT prolongation). Risk of pharmacokinetic interactions due to co-administration of CYP inhibitors, CYP inducers, CYP substrates and PgP substrates was reported for 8%, 11%, 53% and 19%, respectively. These interactions were reported as major or moderate. WHAT IS NEW AND CONCLUSION: Patients with mRCC under treatment with sunitinib at a reduced starting dose had a decreased PFS compared with patients started with full-dose sunitinib. Due to adverse drug reactions and comorbidity, patients under sunitinib, a CYP3A4 substrate, took an average of 6·8 comedications provoking an important risk of major-to-moderate drug-drug interactions. With the help of a multidisciplinary team, avoidance of drug-drug interactions could be obtained. Moreover, serial ECG monitoring is recommended for patients at high risk of QT prolongation.
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Antineoplásicos/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Pirroles/administración & dosificación , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/farmacología , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Inductores del Citocromo P-450 CYP3A/farmacología , Inhibidores del Citocromo P-450 CYP3A/farmacología , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Humanos , Indoles/farmacocinética , Indoles/uso terapéutico , Masculino , Persona de Mediana Edad , Pirroles/farmacocinética , Pirroles/uso terapéutico , Estudios Retrospectivos , Factores de Riesgo , SunitinibRESUMEN
BACKGROUND: In this phase Ib, dose-escalation study, the oral irreversible ErbB family blocker afatinib (BIBW 2992) was combined with cisplatin (Cadila Healthcare Ltd, Ahmedabad, India) 50 or 75 mg/m(2)/paclitaxel (Bristol-Myers Squibb Pharmaceuticals Ltd, New York, USA) (Taxol)175 mg/m(2) (regimen A) or cisplatin 75-100 mg/m(2)/5-fluorouracil 750-1000 mg/m(2) (regimen B) in patients with advanced solid tumors. PATIENTS AND METHODS: The primary objective was to assess dose-limiting toxicities (DLTs) during cycle 1 for each regimen, from which the maximum tolerated dose (MTD) was determined. Patients received once daily oral afatinib 20, 30, 40 or 50 mg in 21-day cycles (3 + 3 design). RESULTS: The MTD for afatinib in regimens A (n = 26) and B (n = 21) was determined as 20 mg and 30 mg following DLTs in five and four patients in cycle 1, respectively. Most frequent adverse events (AEs, any grade) were diarrhea and nausea. Disease control was observed in 54% and 29% of patients in regimens A and B, respectively. Plasma sampling suggested no relevant pharmacokinetic interaction between afatinib and the chemotherapeutic agents. CONCLUSIONS: The MTD of afatinib was 20 mg with cisplatin-paclitaxel and 30 mg with cisplatin-5-fluorouracil. Pre-emptive management of side-effects is important to maintain adequate safety and tolerability. Both combinations showed antitumor activity across tumor types and lines of prior treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Fluorouracilo/administración & dosificación , Neoplasias/tratamiento farmacológico , Paclitaxel/administración & dosificación , Quinazolinas/administración & dosificación , Adulto , Afatinib , Anciano , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Cisplatino/uso terapéutico , Esquema de Medicación , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Humanos , Dosis Máxima Tolerada , Persona de Mediana Edad , Paclitaxel/efectos adversos , Paclitaxel/uso terapéutico , Quinazolinas/efectos adversos , Quinazolinas/uso terapéuticoRESUMEN
BACKGROUND: This phase II study assessed the safety and efficacy of everolimus, an oral mammalian target of rapamycin inhibitor in advanced transitional carcinoma cell (TCC) after failure of platinum-based therapy. PATIENTS AND METHODS: Thirty-seven patients with advanced TCC received everolimus 10 mg/day until progressive disease (PD) or unacceptable toxicity. The primary end point was the disease control rate (DCR), defined as either stable disease (SD), partial response (PR), or complete response at 8 weeks. Angiogenesis-related proteins were detected in plasma and changes during everolimus treatment were analyzed. PTEN expression and PIK3CA mutations were correlated to disease control. RESULTS: Two confirmed PR and eight SD were observed, resulting in a DCR of 27% at 8 weeks. Everolimus was well tolerated. Compared with patients with noncontrolled disease, we observed in patients with controlled disease a significant higher baseline level of angiopoietin-1 and a significant early plasma decrease in angiopoietin-1, endoglin, and platelet-derived growth factor-AB. PTEN loss was observed only in patients with PD. CONCLUSIONS: Everolimus showed clinical activity in advanced TCC. The profile of the plasma angiogenesis-related proteins suggested a role of the everolimus antiangiogenic properties in disease control. PTEN loss might be associated with everolimus resistance.
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Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Transicionales/tratamiento farmacológico , Sirolimus/análogos & derivados , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/efectos adversos , Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/patología , Everolimus , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Sirolimus/efectos adversos , Sirolimus/uso terapéutico , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Nephrotoxicity is an inherent adverse effect of certain anticancer drugs and may result in a variety of functional consequences that include any combination of glomerular or tubular dysfunction, hypertension and disturbance of the renal endocrine function. The nephrotoxic potential of most anticancer agents dramatically increases in the presence of borderline or overt pre-existing chronic kidney disease and measurement of renal function is therefore of utmost importance in the cancer patient before any treatment is initiated. This review summarizes some clinical nephrotoxic side effects of a selection of the most frequently used anticancer drugs. The drugs discussed are cisplatin, methotrexate, ifosfamide, citumixab and panitumumab, mitocin C and gemcitabine and antiangiogenesis drugs.
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Lesión Renal Aguda/inducido químicamente , Antineoplásicos/efectos adversos , Glomérulos Renales/efectos de los fármacos , Insuficiencia Renal Crónica/inducido químicamente , Lesión Renal Aguda/fisiopatología , Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antineoplásicos/administración & dosificación , Cetuximab , Cisplatino/efectos adversos , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Humanos , Hipertensión/inducido químicamente , Ifosfamida/efectos adversos , Metotrexato/efectos adversos , Mitomicina/efectos adversos , Panitumumab , Insuficiencia Renal Crónica/fisiopatología , GemcitabinaRESUMEN
Drugs with potential cardiac toxicity are prominent in cancer treatment, not only the old chemotherapeutic agents, but also the newer targeted drugs and biologic agents. As the long-term survival of patients with malignancies has improved and cancer turned into a chronic disease, physicians must take into account the short-term as well as long-term consequences of cancer treatment, such as chemotherapy-induced cardiotoxicity. We summarize some general characteristics and subsequently review specific antineoplastic agents that are associated with cardiac toxicity.
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Sistema Cardiovascular/efectos de los fármacos , Corazón/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Antibióticos Antineoplásicos/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Humanos , Microtúbulos/efectos de los fármacos , Calidad de Vida , Inhibidores de Topoisomerasa/efectos adversos , Moduladores de Tubulina/efectos adversosRESUMEN
PURPOSE: To evaluate the long term results and the characteristics of patients treated with high dose chemotherapy (HDCT) for an advanced germ cell tumour at Ghent University Hospital from 1996 to 2010. MATERIALS AND METHODS: A retrospective analysis of patients treated with HDCT for germ cell tumours was performed. Data about stage at diagnosis, different prognostic scoring systems, timing of HDCT, response to HDCT and relapse-free period were collected. The following endpoints were evaluated: complete or incomplete response to HDCT, relapse free survival and overall survival time. RESULTS: Of the 148 patients treated with chemotherapy for an advanced germ cell tumour from 1996 to 2010, 10 (6.8%) needed salvage treatment by means of HDCT. Six patients achieved a complete response to one cycle of HDCT and 2 additional patients achieved a complete response to a second cycle of HDCT. A retrospective analysis showed 8 long-term survivors with a maximum follow-up time of 152 months. Two patients were recently transplanted and are not evaluable for survival yet. CONCLUSIONS: Our study suggests that long-term survival can be obtained by means of HDCT for metastatic germ cell tumours, even in patients with bad prognostic features at diagnosis. The question of whether to use 1 or 2 cycles of HDCT still remains unanswered.
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Antineoplásicos/administración & dosificación , Carboplatino/administración & dosificación , Ciclofosfamida/administración & dosificación , Etopósido/administración & dosificación , Neoplasias de Células Germinales y Embrionarias/terapia , Adulto , Antineoplásicos Alquilantes/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Humanos , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias de Células Germinales y Embrionarias/mortalidad , Neoplasias de Células Germinales y Embrionarias/patología , Pronóstico , Terapia Recuperativa , Trasplante de Células Madre , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: Evaluate the predictive and prognostic value of semi-quantitative FDG-PET variables derived from pretreatment FDG-PET images in patients suffering from locally advanced squamous cell carcinoma of the head and neck (SCCHN), treated by means of concomitant radiochemotherapy. PATIENTS, METHODS: 40 patients with newly diagnosed SCCHN that were treated with concomitant radiochemotherapy underwent FDG-PET/CT for treatment planning; 18 patients had neck dissection prior to their baseline scan and to receiving radiochemotherapy. FDG-PET images were used to calculate metabolic tumour volumes using region growing and a threshold of 50% (MTV50) of primary lesions and involved lymph nodes as well as the mean and maximum standard uptake value (SUVmean and SUVmax) of the primary tumours. RESULTS: Neither SUVmean nor SUVmax values of the primary tumour were significantly different between responders and non-responders whereas MTV50 values of the primary tumour proved significantly higher in non-responders. SUVmean, SUVmax and MTV50 of the primary tumour were not predictive for overall or disease free survival. Contrariwise, dichotomized summed MTV50 values (cut-off≥31 cm3) of the primary tumour and involved lymph nodes in patients that didn't have neck dissection prior to radiochemotherapy were predictive for disease free and overall survival in both univariate and multivariate analysis (p≤0.05). CONCLUSION: Summed MTV50 values of both the primary tumour and involved lymph nodes provided independent prognostic information on disease free and overall survival.
Asunto(s)
Fluorodesoxiglucosa F18 , Neoplasias de Cabeza y Cuello/diagnóstico , Imagenología Tridimensional/métodos , Tomografía de Emisión de Positrones/métodos , Técnica de Sustracción , Tomografía Computarizada por Rayos X/métodos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Radiofármacos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Damage to DNA has emerged as a major culprit in cancer. Mammalian cells are continuously exposed to DNA damage, caused by exogenous toxins as well as endogenous activities such as DNA replication and cellular free radical generation. It is therefore essential that cells have DNA repair mechanisms in place to preserve its genomic integrity. Interestingly, cancer cells frequently harbour defects in DNA repair pathways, leading to genomic instability. This can foster tumorigenesis, but also provides a weakness in the tumour that can be exploited therapeutically. In this context, it has been shown that homologous recombination (HR)-deficient tumour cells--including those with defects in BRCA1/2--are highly sensitive to blockade of the base excision repair (BER) pathway via inhibition of the poly (ADP-ribose) polymerase (PARP) enzyme. This provides the basis for a novel 'synthetic lethal' approach to cancer therapy. Recent clinical trials have shown an enhancement of the cytotoxic effect of chemotherapy by adding a PARP inhibitor to the standard treatment. Still, clinical outcome may be even further improved if these drugs would be used as first-line therapy. In conclusion, it can be stated that an exciting new class of drugs has entered the arena of cancer therapy. However, additional clinical studies are needed before PARP inhibitors can definitely enter daily clinical practice.
Asunto(s)
Daño del ADN/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Benzamidas/uso terapéutico , Bencimidazoles/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Ensayos Clínicos como Asunto , Reparación del ADN/efectos de los fármacos , Reparación del ADN/fisiología , Femenino , Genes BRCA1/fisiología , Genes BRCA2/fisiología , Mutación de Línea Germinal , Humanos , Neoplasias/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Ftalazinas/uso terapéutico , Piperazinas/uso terapéuticoRESUMEN
BACKGROUND: The phase III EXTREME study demonstrated that combining cetuximab with platinum/5-fluorouracil (5-FU) significantly improved overall survival in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) compared with platinum/5-FU alone. The aim of this investigation was to evaluate elevated tumor EGFR gene copy number as a predictive biomarker in EXTREME study patients. PATIENTS AND METHODS: Dual-color FISH was used to determine absolute and relative EGFR copy number. Models of differing stringencies were used to score and investigate whether increased copy number was predictive for the activity of cetuximab plus platinum/5-FU. RESULTS: Tumors from 312 of 442 patients (71%) were evaluable by FISH and met the criteria for statistical analysis. A moderate increase in EGFR copy number was common, with high-level amplification of the gene occurring in a small fraction of tumors (â¼11%). Considering each of the models tested, no association of EGFR copy number with overall survival, progression-free survival or best overall response was found for patients treated with cetuximab plus platinum/5-FU. CONCLUSION: Tumor EGFR copy number is not a predictive biomarker for the efficacy of cetuximab plus platinum/5-FU as first-line therapy for patients with R/M SCCHN.