RESUMEN
Canakinumab is a human IgGκ monoclonal antibody, with high affinity and specificity for IL-1ß. The Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS) trial, evaluating canakinumab for cardiovascular disease, provided the first signal of the potential of IL-1ß inhibition on lung cancer incidence reduction. Here, we describe the rationale and design for CANOPY-N, a randomized Phase II trial evaluating IL-1ß inhibition with or without immune checkpoint inhibition as neoadjuvant treatment in patients with non-small-cell lung cancer. Patients with stage IB to IIIA non-small-cell lung cancer eligible for complete resection will receive canakinumab or pembrolizumab as monotherapy, or in combination. The primary end point is major pathological response by central review; secondary end points include overall response rate, major pathological response (local review), surgical feasibility rate and pharmacokinetics. Clinical trial registration: NCT03968419 (ClinicalTrials.gov).
Lay abstract A previous study showed that canakinumab reduced the risk of lung cancer in patients with heart disease. Canakinumab blocks an inflammatory protein called IL-1ß that is involved in cancer. Anti-cancer drugs used before surgery ('neo-adjuvant') can improve the success rate of surgery and may help prevent the cancer from returning. Neo-adjuvant trials help us understand how the drugs work and how they affect cancer. CANOPY-N (NCT03968419) is an ongoing randomized, exploratory, Phase II clinical trial testing canakinumab and pembrolizumab (a different cancer immunotherapy), alone or combined, for patients with early non-small-cell lung cancer. The study will test whether treatment can kill most cancer cells in the surgery sample ('major pathological response'). It will also investigate other effects on cancer biology, levels of molecules that measure possible clinical benefit ('biomarkers') and side effects.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , Adolescente , Adulto , Anticuerpos Monoclonales Humanizados/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Ensayos Clínicos Fase II como Asunto , Femenino , Humanos , Interleucina-1beta/antagonistas & inhibidores , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/cirugía , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/inmunología , Masculino , Terapia Neoadyuvante/métodos , Estadificación de Neoplasias , Neumonectomía , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto JovenRESUMEN
PURPOSE: The addition of checkpoint inhibitors to first-line treatment has prolonged survival of patients with non-small-cell lung cancer (NSCLC), but prognosis remains poor, with new treatment options needed. Canakinumab, a human, monoclonal anti-interleukin (IL)-1ß antibody, has potential to enhance the activity of PD-L1 inhibitors and chemotherapy (CT) by inhibiting protumor inflammation. METHODS: CANOPY-1 was a phase III, randomized, double-blind study comparing canakinumab (200 mg subcutaneously once every 3 weeks) versus placebo, both combined with pembrolizumab (200 mg intravenously once every 3 weeks) and platinum-based doublet CT, as first-line treatment for advanced/metastatic NSCLC without EGFR or ALK mutations. The primary end points were progression-free survival (PFS) and overall survival (OS). The secondary endpoints included overall response rate, safety, and patient-reported outcomes. RESULTS: Overall, 643 patients were randomly assigned to canakinumab (n = 320) or placebo (n = 323). With a median study follow-up of 6.5 months, the median PFS was 6.8 months with canakinumab versus 6.8 months with placebo (hazard ratio [HR], 0.85; 95% CI, 0.67 to 1.09; P = .102). With a median study follow-up of 21.2 months, the median OS was 20.8 months with canakinumab versus 20.2 months with placebo (HR, 0.87; 95% CI, 0.70 to 1.10; P = .123). No unexpected safety signals were observed for canakinumab combination. Infection rates were comparable between treatment and control arms. A higher frequency of neutropenia and ALT increase (grade ≤2) were reported in the treatment arm. Higher baseline C-reactive protein and IL-6 levels were associated with shorter PFS and OS. Patients treated with canakinumab had clinically meaningful delays in deterioration of lung cancer symptoms, including chest pain and coughing per LC13 and dyspnea per LC13 and C30. CONCLUSION: The addition of canakinumab to first-line pembrolizumab and CT did not prolong PFS or OS in patients with NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43), gastrointestinal stromal tumor (n = 1), adenocarcinoma of the small intestine (n = 3), low-grade glioma (n = 13), high-grade glioma (n = 45), hairy cell leukemia (n = 55) and multiple myeloma (n = 19). The primary endpoint of investigator-assessed overall response rate in these cohorts was 56%, 53%, 0%, 67%, 54%, 33%, 89% and 50%, respectively. Secondary endpoints were median duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Median DoR was 14.4 months, 8.9 months, not reached, 7.7 months, not reached, 31.2 months, not reached and 11.1 months, respectively. Median PFS was 6.7 months, 9.0 months, not reached, not evaluable, 9.5 months, 5.5 months, not evaluable and 6.3 months, respectively. Median OS was 14.5 months, 13.5 months, not reached, 21.8 months, not evaluable, 17.6 months, not evaluable and 33.9 months, respectively. The most frequent (≥20% of patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%) and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers. ClinicalTrials.gov registration: NCT02034110 .
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Adenocarcinoma , Glioma , Humanos , Imidazoles/efectos adversos , Piridonas/efectos adversos , Pirimidinonas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Proteínas Proto-Oncogénicas B-raf/genética , Mutación/genéticaRESUMEN
INTRODUCTION: The phase II, single-arm ASCEND-3 study assessed the efficacy and safety of ceritinib in anaplastic lymphoma kinase (ALK) inhibitor (ALKi)-naive patients with ALK-rearranged NSCLC who had received at least three previous lines of chemotherapy. Here, we report the final efficacy and safety results. METHODS: Eligible patients (including those with asymptomatic or neurologically stable brain metastases) received oral ceritinib (750 mg/day, fasted). The primary end point was investigator-assessed overall response rate (ORR). Secondary end points were Blinded Independent Review Committee-assessed ORR; investigator- and Blinded Independent Review Committee-assessed overall intracranial response rate, duration of response, time to response, disease control rate, and progression-free survival (PFS); overall survival (OS); and safety. Exploratory end points included patient-reported outcomes. RESULTS: Of the 124 patients enrolled, 122 (98.4%) had received previous antineoplastic medications (31 patients [25.0%] received at least three regimens), and 49 (39.5%) had baseline brain metastases. The median follow-up time (data cutoff: January 22, 2018) was 52.1 (range, 48.4-60.1) months. The investigator-assessed ORR was 67.7% (95% confidence interval [CI]: 58.8-75.9), and the median PFS was 16.6 months (95% CI: 11.0-23.2). The median OS was 51.3 months (95% CI: 42.7-55.3). Most common adverse events (all grades, ≥60% of patients, all-causality) were diarrhea (85.5%), nausea (78.2%), and vomiting (71.8%). Overall, 18 patients (14.5%) had an adverse event leading to treatment discontinuation. Health-related quality of life was maintained during ceritinib treatment. CONCLUSIONS: Ceritinib exhibited prolonged and clinically meaningful OS, PFS, and duration of response in chemotherapy-pretreated (at least three lines), ALKi-naive patients with ALK+ NSCLC. The safety profile was consistent with that reported in previous studies.
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Antineoplásicos , Neoplasias Pulmonares , Quinasa de Linfoma Anaplásico/genética , Antineoplásicos/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas , Calidad de Vida , Proteínas Tirosina Quinasas Receptoras , SulfonasRESUMEN
BACKGROUND: Patients with anaplastic lymphoma kinase-rearranged (ALK+) non-small cell lung cancer (NSCLC) treated with crizotinib inevitably relapse, with brain as common site of progression. PATIENTS AND METHODS: ASCEND-6, a phase 1/2, single-arm study, included adult Chinese patients with stage IIIB or IV ALK+ NSCLC pretreated with crizotinib as the last therapy (irrespective of prior chemotherapies [≤2]). Primary endpoints were pharmacokinetics (PK), safety, and tolerability. Key secondary endpoint was overall response rate (ORR; investigator assessed). RESULTS: Of the 103 enrolled patients, all received prior crizotinib, 70 % received ≥1 prior chemotherapy regimen, and 63.1 % had brain metastases at baseline. In the phase 1 component, 20 patients completed a 5-day PK run-in period. Median Tmax (n = 16) was â¼6 h; geometric means of AUC0-24 h (n = 16) and Cmax (n = 16) at steady state were 22,000 ng*h/mL and 1080 ng/mL, respectively. In the final analysis, median follow-up time was 34 months (range: 27.8-40.6). The ORR was 41.7 % (95 % confidence interval [CI]: 32.1-51.9), and median progression-free survival was 7.2 months (95 % CI: 4.1-7.5). Median overall survival was 17.5 months (95 % CI: 10.8-24.3). Most frequent adverse events, regardless of study drug relationship (mostly grade 1/2), were diarrhea (74.8 %), vomiting (62.1 %), alanine transaminase increased (59.2 %), aspartate transaminase increased (58.3 %), and nausea (58.3 %). CONCLUSIONS: Ceritinib PK in Chinese patients is consistent with those observed in the global ASCEND-1 study. Ceritinib was well tolerated and showed durable responses in Chinese patients with ALK+ NSCLC who progressed after crizotinib and ≤2 prior lines of chemotherapy.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Preparaciones Farmacéuticas , Adulto , Quinasa de Linfoma Anaplásico/genética , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , China , Crizotinib/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Recurrencia Local de Neoplasia , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/uso terapéutico , SulfonasRESUMEN
BACKGROUND/AIMS: Prolactin (PRL) secretion and its gene expression are inhibited by dopamine. Prolactinomas are the most common secreting pituitary adenomas, and dopamine agonists (DA) are the first choice for their treatment. However, a subset of patients is resistant to DA. As the mechanisms involved in DA resistance are not fully understood, the aim of this study was to obtain new insights regarding the molecular differences between the prolactinomas that are responsive to DA and those that are resistant. METHODS: Tumor tissue samples were collected from 17 patients who harbored prolactinomas, which were classified as responsive or resistant according to their clinical and laboratorial reaction to DA. The expression of 6 genes was evaluated by real-time polymerase chain reaction: dopamine receptor type 2 (DRD(2)), nerve growth factor-beta (NGFB) and its receptor (NGFR), estrogen receptor-alpha (ERA), estrogen receptor-beta (ERB) and the pituitary tumor transforming gene (PTTG). RESULTS: Median DRD(2) and NGFR expression in responsive patients was significantly higher than in resistant ones (p = 0.029 and p = 0.020, respectively). Moreover, the expressions of DRD(2) and NGFR were positively correlated with PRL decrease during treatment (r = 0.66, p = 0.005 and r = 0.57, p = 0.044, respectively). Furthermore, ERB expression was positively correlated to PTTG expression (r = 0.68, p = 0.032) and negatively correlated to NGFB expression (r = -0.75, p = 0.02). CONCLUSIONS: DRD(2) and NGFR expressions are related to the responsiveness of prolactinoma to DA. However, PTTG, ERB and ERA expressions are not. Also ERB, ERA and PTTG expressions did not present a clear correlation to tumor aggressiveness. Furthermore, the response of prolactinomas to DA should be viewed as a spectrum ranging from the most responsive to the most resistant ones.
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Agonistas de Dopamina/uso terapéutico , Neoplasias Hipofisarias/tratamiento farmacológico , Neoplasias Hipofisarias/metabolismo , Prolactinoma/tratamiento farmacológico , Prolactinoma/metabolismo , Adulto , Resistencia a Antineoplásicos/genética , Femenino , Expresión Génica , Humanos , Masculino , ARN Mensajero/metabolismoRESUMEN
INTRODUCTION: In an earlier report of the ASCEND-8 study (open-label, phase I, three-arm study, treatment-naive patients and pre-treated patients with advanced/metastatic NSCLC), it was shown that ceritinib 450 mg with food had comparable exposure and better gastrointestinal tolerability than 750-mg fasted. METHODS: Here, we report efficacy and updated safety data from primary efficacy analysis of the ASCEND-8 study. Key secondary endpoints were overall response rate and duration of response, assessed by blinded independent review committee (BIRC) using Response Evaluation Criteria in Solid Tumors 1.1. RESULTS: In total, 306 patients were randomized to ceritinib 450-mg fed (n = 108) or 600-mg fed (n = 87) or 750-mg fasted (n = 111), of which 304 patients were included in safety analysis and 198 treatment-naive patients (ALK receptor tyrosine kinase [ALK]-positive by immunohistochemistry) were included in the efficacy analysis (450-mg fed [n = 73], 600-mg fed [n = 51], and 750-mg fasted [n = 74]). The BIRC-assessed overall response rate was 78.1% (95% confidence interval [CI]: 66.9-86.9), 72.5% (95% CI: 58.3-84.1), and 75.7% (95% CI: 64.3-84.9), respectively; and the median duration of response (months) by BIRC was not estimable (NE) (95% CI: 11.2-NE), 20.7 (95% CI: 15.8-NE), and 15.4 (95% CI: 8.3-NE), respectively. Based on the safety analysis (n = 304), the 450-mg fed arm showed the highest median relative dose intensity (100% versus 78.5% versus 83.7%), lowest proportion of patients with dose reductions (24.1% versus 65.1% versus 60.9%), and lowest proportion of patients with gastrointestinal toxicities (75.9% versus 82.6% versus 91.8%). CONCLUSION: Ceritinib at a dose of 450 mg with food compared to 750-mg fasted showed consistent efficacy and less gastrointestinal toxicity.
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Quinasa de Linfoma Anaplásico/genética , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Ayuno , Alimentos , Neoplasias Pulmonares/tratamiento farmacológico , Pirimidinas/uso terapéutico , Sulfonas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/genética , Neoplasias Óseas/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Estudios de Seguimiento , Reordenamiento Génico , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Pronóstico , Criterios de Evaluación de Respuesta en Tumores Sólidos , Adulto JovenRESUMEN
BACKGROUND: Pituitary tumor transforming gene (pttg) is a novel oncogene that is expressed at higher level in most of the tumors analyzed to date compared to normal tissues. Nevertheless, its expression in prolactinomas and its relation with the pituitary dopamine receptor 2 (D2R) are not well defined. We sought to determine the pituitary level of pttg in three different experimental models of prolactinomas with altered dopaminergic control of the pituitary: the dopaminergic D2R knockout female mouse, the estrogen-treated rat, and the senescent female rat. These three models shared the characteristics of increased pituitary weight, hyperprolactinemia, lactotrope hyperplasia and reduced or absent dopaminergic action at the pituitary level. We also studied samples from human macroprolactinomas, which were characterized as responsive or resistant to dopamine agonist therapy. RESULTS: When compared to female wild-type mice, pituitaries from female D2R knockout mice had decreased PTTG concentration, while no difference in pttg mRNA level was found. In senescent rats no difference in pituitary PTTG protein expression was found when compared to young rats. But, in young female rats treated with a synthetic estrogen (Diethylstylbestrol, 20 mg) PTTG protein expression was enhanced (P = 0.029). Therefore, in the three experimental models of prolactinomas, pituitary size was increased and there was hyperprolactinemia, but PTTG levels followed different patterns.Patients with macroprolactinomas were divided in those in which dopaminergic therapy normalized or failed to normalize prolactin levels (responsive and resistant, respectively). When pituitary pttg mRNA level was analyzed in these macroprolactinomas, no differences were found. We next analyzed estrogen action at the pituitary by measuring pituitary estrogen receptor alpha levels. The D2R knockout female mice have low estrogen levels and in accordance, pituitary estrogen receptors were increased (P = 0.047). On the other hand, in senescent rats estrogen levels were slightly though not significantly higher, and estrogen receptors were similar between groups. The estrogen-treated rats had high pharmacological levels of the synthetic estrogen, and estrogen receptors were markedly lower than in controls (P < 0.0001). Finally, in patients with dopamine resistant or responsive prolactinomas no significant differences in estrogen receptor alpha levels were found. Therefore, pituitary PTTG was increased only if estrogen action was increased, which correlated with a decrease in pituitary estrogen receptor level. CONCLUSION: We conclude that PTTG does not correlate with prolactin levels or tumor size in animal models of prolactinoma, and its pituitary content is not related to a decrease in dopaminergic control of the lactotrope, but may be influenced by estrogen action at the pituitary level. Therefore it is increased only in prolactinomas generated by estrogen treatment, and not in prolactinomas arising from deficient dopamine control, or in dopamine resistant compared with dopamine responsive human prolactinomas. These results are important in the search for reliable prognostic indicators for patients with pituitary adenomas which will make tumor-specific therapy possible, and help to elucidate the poorly understood phenomenon of pituitary tumorigenesis.
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Dopamina/metabolismo , Lactotrofos/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Hipofisarias/metabolismo , Prolactinoma/metabolismo , Adulto , Animales , Antineoplásicos Hormonales/farmacología , Resistencia a Antineoplásicos , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias Hormono-Dependientes/metabolismo , Neoplasias Hormono-Dependientes/patología , Neoplasias Hipofisarias/patología , Prolactinoma/patología , Ratas , Ratas Sprague-Dawley , Receptores Dopaminérgicos/genética , SecurinaRESUMEN
Ceritinib is a second-generation selective and potent oral anaplastic lymphoma kinase (ALK) inhibitor approved for ALK-positive advanced non-small cell lung cancer previously treated with crizotinib. Population pharmacokinetic (PK) analysis was performed to describe the PK of ceritinib and was used to evaluate the covariate effects on systemic exposure at its label dose (750 mg orally once daily). Ceritinib concentration-time data from 4 clinical studies were described by a 1-compartment model with delayed first-order absorption and time-dependent elimination. The apparent clearance at steady state (CL/Fss ) was determined to increase with body weight and albumin but decrease with an increase in alanine aminotransferase. Japanese ethnicity appeared to significantly influence the apparent fractional turnover rate of the inhibited metabolic enzyme (kout ). No dose adjustment was necessary in patients with lower body weight or with preexisting mild hepatic impairment. The ceritinib steady-state exposure (AUCss ) at 750 mg increased by 8% (90% prediction interval [PI], 2-16) in non-Japanese Asians and 31% (90%PI, 17-44) in Japanese patients compared with that in white patients. Other covariates including sex, age, baseline Eastern Cooperative Oncology Group performance status, baseline total bilirubin, baseline estimated glomerular filtration rate, prior crizotinib treatment, and concomitant use of proton pump inhibitors had no statistically significant effect on ceritinib PK parameters. In conclusion, the nonlinear PK of ceritinib was described using a population-based approach in patients with ALK-positive tumors. None of the covariates assessed in this study were considered clinically relevant and therefore do not warrant dose adjustment.
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Pirimidinas/farmacocinética , Proteínas Tirosina Quinasas Receptoras/genética , Sulfonas/farmacocinética , Adulto , Quinasa de Linfoma Anaplásico , Antineoplásicos/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Masculino , Modelos Biológicos , Mutación , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidoresRESUMEN
INTRODUCTION: Ceritinib, 750 mg fasted, is approved for treatment of patients with ALK receptor tyrosine kinase gene (ALK)-rearranged (ALK-positive) NSCLC previously treated with crizotinib. Part 1 of the ASCEND-8 study determined whether administering ceritinib, 450 mg or 600 mg, with a low-fat meal may enhance gastrointestinal (GI) tolerability versus 750 mg fasted in patients with ALK-positive NSCLC while maintaining similar exposure. METHODS: ASCEND-8 is a multicenter, randomized, open-label, phase 1 study. Part 1 investigated the steady-state pharmacokinetics (PK) and safety of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg fasted in patients with advanced ALK-positive NSCLC who were either treatment naive or pretreated with chemotherapy and/or crizotinib. Part 2 will assess efficacy and safety of ceritinib in treatment-naive patients. RESULTS: As of June 16, 2016, 137 patients were randomized (450 mg fed [n = 44], 600 mg fed [n = 47], and 750 mg fasted [n = 46]); 135 patients received ceritinib. Median follow-up duration was 4.14 months. At steady state, relative to 750 mg fasted, 450 mg with food demonstrated comparable PK as assessed by maximum (peak) concentration of drug in plasma and area under the plasma concentration-time curve from time zero to 24 hours, whereas 600 mg with food demonstrated approximately 25% higher PK. Relative to 750 mg fasted, 450 mg with food was associated with a lower proportion of patients with GI toxicities, mostly grade 1 (diarrhea [43.2%], nausea [29.5%], and vomiting [18.2%]); there were no grade 3 or 4 events, study drug discontinuations, or serious AEs due to GI toxicities. CONCLUSION: Ceritinib, 450 mg with food, had similar exposure and a more favorable GI safety profile than ceritinib, 750 mg in fasted patients with ALK-positive NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Pirimidinas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/efectos de los fármacos , Sulfonas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Quinasa de Linfoma Anaplásico , Carcinoma de Pulmón de Células no Pequeñas/patología , Ayuno , Humanos , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Pirimidinas/administración & dosificación , Pirimidinas/farmacología , Sulfonas/administración & dosificación , Sulfonas/farmacologíaRESUMEN
Prolactinomas are the more prevalent functioning pituitary tumors, and dopamine agonist drugs (DA) are the main therapeutic option for patients harboring such tumors. Bromocriptine (BRC) resistance, defined as failure to normalize prolactin (PRL) and/or to shrink the tumor is reported in 5 to 18% of the patients treated with this drug, the first DA widely used. Cabergoline (CBG) can bring PRL to normalization and reduce tumor size in up to 86% and 92% of the patients, respectively. Even with this newer DA, a subset of patients does not respond to therapy and are truly resistant. The mechanisms for resistance are not yet fully clarified, so the treatment for the resistant prolactinoma is still a challenge. Transsphenoidal surgery associated or not to radiotherapy is an important tool, but PRL may not normalize, mainly in macroprolactinomas. Treatment with sex steroids or ovulation induction can solve the hypogonadism or infertility, when the tumor growth is under control. New drugs as anti-estrogens, new DA, specific analogs for somatostatin receptor subtypes, chimeric molecules associating dopamine and somatostatin effect, and PRL antagonists are under investigation and can be future alternatives for DA resistance.
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Agonistas de Dopamina/uso terapéutico , Neoplasias Hipofisarias/terapia , Prolactinoma/terapia , Resistencia a Antineoplásicos , Humanos , Neoplasias Hipofisarias/tratamiento farmacológico , Prolactinoma/tratamiento farmacológicoRESUMEN
Bromocriptine (BRC) and other dopamine agonist drugs are the first-choice treatment for prolactinomas. However, the major disadvantage is the need for prolonged therapy. We retrospectively studied 131 patients [62 microprolactinoma (MIC), 69 macroprolactinoma (MAC)], who achieved serum prolactin (PRL) normalization during BRC use. Twenty-seven percent of them (31% MIC and 69% MAC) underwent previous surgery. Twenty-seven patients (20.6%: 25.8% MIC and 15.9% MAC) persisted with normoprolactinemia after a median time of 44 months of BRC withdrawal. The median time of BRC use was 47 months. There were no statistically significant differences regarding age, gender, BRC initial dose, length of BRC use, tumor size, pregnancy during treatment, previous surgery, or radiotherapy among patients who persisted with normoprolactinemia and those who did not, using both univariate and multivariate analysis. BRC-induced prolactinoma cell alterations are highly controversial; and so, whether the mechanism of PRL normalization after BRC withdrawal is related to BRC use or whether it is attributable to natural history is a matter for debate. A periodic assessment of PRL levels during BRC (and other dopamine-agonist drugs) withdrawal is recommended to avoid the unnecessary maintenance of therapy in a subset of patients with prolactinomas.
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Bromocriptina/administración & dosificación , Antagonistas de Hormonas/administración & dosificación , Neoplasias Hipofisarias/tratamiento farmacológico , Prolactina/sangre , Prolactinoma/tratamiento farmacológico , Adolescente , Adulto , Anciano , Niño , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neoplasias Hipofisarias/patología , Embarazo , Prolactinoma/patología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
We evaluated the drug-drug interaction between pasireotide SC and verapamil, a known P-glycoprotein inhibitor. Subjects received pasireotide SC (single dose, 600 µg) on day 1, and samples for pharmacokinetics evaluation were collected from days 1 to 8. Subjects received an oral dose of verapamil 240 mg/d for 10 days (days 15-24). On day 18, subjects also received pasireotide SC 600 µg. Pharmacokinetic sampling for pasireotide SC and verapamil was done during days 18 to 25 and days 15 to 21, respectively. Safety evaluations were performed throughout the study period, including a 30-day post-treatment follow-up. Pharmacokinetic profiles of pasireotide SC alone and in combination with verapamil sustained-release (SR) were superimposable with the geometric mean ratios (90% confidence interval [CI]) of 0.98 (0.91-1.06) for C(max), 0.97 (0.90-1.04) for AUC(last), and 0.98 (0.92-1.05) for AUC(inf). Exploratory analyses showed a 17% (90% CI, 0.72-0.94) reduction in C(trough) and 31% (0.58-0.82) reduction in C(max) (8 hours post-dose) for verapamil SR with pasireotide SC versus verapamil alone. Pasireotide SC with or without verapamil was well tolerated. In conclusion, there was no change in the rate of pasireotide absorption and elimination or extent of exposure following concomitant administration with verapamil.
Asunto(s)
Antiarrítmicos/farmacocinética , Antineoplásicos Hormonales/farmacocinética , Somatostatina/análogos & derivados , Verapamilo/farmacocinética , Adulto , Antiarrítmicos/administración & dosificación , Antineoplásicos Hormonales/administración & dosificación , Interacciones Farmacológicas , Humanos , Masculino , Persona de Mediana Edad , Somatostatina/administración & dosificación , Somatostatina/efectos adversos , Somatostatina/farmacocinética , Verapamilo/administración & dosificación , Verapamilo/efectos adversosRESUMEN
PURPOSE: Chemotherapy-induced diarrhea (CID) is a relatively common adverse event in the treatment of patients with colorectal cancer. The LAR for Chemotherapy-Induced Diarrhea (LARCID) trial evaluated the efficacy and safety of long-acting release octreotide (octreotide LAR) for the prevention of CID in this population. PATIENTS AND METHODS: Patients with colorectal cancer starting adjuvant or first-line treatment with a chemotherapy combination containing fluorouracil, capecitabine, and/or irinotecan were randomly assigned to receive octreotide LAR 30 mg intramuscularly every 4 weeks (experimental arm) or the physician's treatment of choice in case of diarrhea (control arm). RESULTS: A total of 139 patients were randomly assigned, most of whom received fluorouracil- and oxaliplatin-containing chemotherapy regimens. The rate of diarrhea was 76.1% in the experimental group (n = 68) and 78.9% in the control group (n = 71). Treatment with octreotide LAR did not prevent or reduce the severity of CID. Treatment choices for diarrhea management included loperamide in the majority of patients. No benefit from octreotide LAR was identified in terms of need for diarrhea treatment, opioids, or intravenous hydration or in the rate of hospitalization or quality of life. CONCLUSION: This study could not prove the efficacy of octreotide LAR in the prevention of CID.
Asunto(s)
Antidiarreicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Diarrea/prevención & control , Octreótido/uso terapéutico , Adulto , Anciano , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Capecitabina , Preparaciones de Acción Retardada , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Diarrea/inducido químicamente , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Irinotecán , Loperamida/uso terapéutico , Masculino , Persona de Mediana Edad , Calidad de Vida , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
This study aims to compare economic and patient impacts of the treatment of acromegaly with two different somatostatin analogues (octreotide LAR and lanreotide SR) in Brazil. A cost-effectiveness analysis was carried out under the Brazilian Public Health Care System (SUS) perspective. A decision analytical model was developed based on the Brazilian Public Health Care System Clinical Guideline for Acromegaly. A hypothetical cohort of 276 patients was followed for two years. Data were extracted from literature and administrative databases. Based on the analytical model, treatment with octreotide LAR would avoid 12 and 17 cases of GH and IGF-I elevated serum levels, respectively. Octreotide LAR was a cost-saving strategy, with net savings of R$10,448,324 (US$4,465,096) to SUS. Annual net savings per patient were R$ 18,928 (US$8,089). Treatment of acromegaly with octreotide LAR is a dominant strategy when compared to the treatment with lanreotide SR in Brazil. Sensitivity analysis did not alter the cost-saving status.
Asunto(s)
Acromegalia/tratamiento farmacológico , Antineoplásicos Hormonales/economía , Atención a la Salud/economía , Octreótido/economía , Péptidos Cíclicos/economía , Somatostatina/análogos & derivados , Acromegalia/economía , Antineoplásicos Hormonales/uso terapéutico , Brasil , Análisis Costo-Beneficio , Humanos , Octreótido/uso terapéutico , Péptidos Cíclicos/uso terapéutico , Guías de Práctica Clínica como Asunto , Sensibilidad y Especificidad , Somatostatina/economía , Somatostatina/uso terapéuticoRESUMEN
OBJECTIVE: To determine the prevalence of systemic hypertension, diabetes mellitus, hypercholesterolemia, and hypertriglyceridemia in a Brazilian population in relation to body mass index. METHOD: Retrospective evaluation of 1213 adults (mean age: 45.2 +/- 12.8; 80.6% females) divided into groups according to body mass index [normal (18.5 - 24.4 kg/m2); overweight (25 - 29.9 kg/m2); grade 1 obesity (30 - 34.9 kg/m2); grade 2 obesity (35 - 39.9 kg/m2), and grade 3 obesity (> or = 40 kg/m2)]. The prevalence of hypertension, diabetes mellitus, hypercholesterolemia, and hypertriglyceridemia were analyzed in each group. The severity of cardiovascular risk was determined. High-risk patients were considered those reporting 2 or more of the following factors: systemic hypertension, HDL < or = 35 mg/dL, total cholesterol > or = 240 mg/dL, triglycerides > or = 200 mg/dL when HDL < or = 35 mg/dL, and glycemia > or = 126 mg/dL. Moderate-risk patients were those reporting 2 or more of the following factors: systemic hypertension, HDL < or = 45, triglycerides > or = 200 mg/dL, and total cholesterol > or = 200 mg/dL. RESULTS: The prevalence of systemic hypertension, diabetes mellitus, hypertriglyceridemia, and low HDL-cholesterol levels increased along with weight, but the prevalence of hypercholesterolemia did not. The odds ratio adjusted for gender and age, according to grade of obesity compared with patients with normal weight were respectively 5.9, 8.6, and 14.8 for systemic hypertension, 3.8, 5.8, and 9.2 for diabetes mellitus and 1.2, 1.3, and 2.6 for hypertriglyceridemia. We also verified that body mass index was positively related to cardiovascular high risk (P < .001) CONCLUSION: In our population, cardiovascular risk increased along with body mass index.
Asunto(s)
Diabetes Mellitus/etiología , Hiperlipidemias/etiología , Hipertensión/etiología , Hipertrigliceridemia/etiología , Obesidad/complicaciones , Adulto , Índice de Masa Corporal , Brasil/epidemiología , Enfermedades Cardiovasculares/etiología , Diabetes Mellitus/epidemiología , Femenino , Humanos , Hiperlipidemias/epidemiología , Hipertensión/epidemiología , Hipertrigliceridemia/epidemiología , Masculino , Prevalencia , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
This study aims to compare economic and patient impacts of the treatment of acromegaly with two different somatostatin analogues (octreotide LAR and lanreotide SR) in Brazil. A cost-effectiveness analysis was carried out under the Brazilian Public Health Care System (SUS) perspective. A decision analytical model was developed based on the Brazilian Public Health Care System Clinical Guideline for Acromegaly. A hypothetical cohort of 276 patients was followed for two years. Data were extracted from literature and administrative databases. Based on the analytical model, treatment with octreotide LAR would avoid 12 and 17 cases of GH and IGF-I elevated serum levels, respectively. Octreotide LAR was a cost-saving strategy, with net savings of R$10,448,324 (US$4,465,096) to SUS. Annual net savings per patient were R$ 18,928 (US$8,089). Treatment of acromegaly with octreotide LAR is a dominant strategy when compared to the treatment with lanreotide SR in Brazil. Sensitivity analysis did not alter the cost-saving status.
O objetivo deste estudo é comparar o impacto econômico e o impacto nos pacientes com acromegalia do tratamento com dois diferentes análogos de somatostatina (octreotida LAR e lanreotide SR) no Brasil. Um estudo de custoefetividade foi realizado a partir da perspectiva do Sistema Único de Saúde (SUS). Foi desenvolvido um modelo analítico de decisão baseado no Protocolo Clínico e Diretrizes Terapêuticas de Acromegalia do SUS. Uma coorte hipotética de 276 pacientes foi seguida por dois anos. Dados foram obtidos da literatura e bases de dados oficiais do SUS. Baseado no modelo analítico, o tratamento com octreotida LAR evitaria 12 e 17 casos com níveis elevados de GH e IGF-I, respectivamente. Octreotida LAR foi uma estratégia econômica, gerando economia de R$10.448.324 (US$4.465.096) para o SUS. A economia anual por paciente foi de R$18.928 (US$8.089). O tratamento de acromegalia com octreotida LAR é estratégia dominante quando comparado com o tratamento com lanreotida SR no Brasil. A análise de sensibilidade não alterou seu status de econômica.
Asunto(s)
Humanos , Acromegalia/tratamiento farmacológico , Antineoplásicos Hormonales/economía , Atención a la Salud/economía , Octreótido/economía , Péptidos Cíclicos/economía , Somatostatina/análogos & derivados , Acromegalia/economía , Antineoplásicos Hormonales/uso terapéutico , Brasil , Análisis Costo-Beneficio , Octreótido/uso terapéutico , Guías de Práctica Clínica como Asunto , Péptidos Cíclicos/uso terapéutico , Sensibilidad y Especificidad , Somatostatina/economía , Somatostatina/uso terapéuticoRESUMEN
Prolactinomas são os tumores hipofisários funcionantes mais freqüentes, sendo as drogas agonistas dopaminérgicas (AD) a principal opção para seu tratamento. Resistência à bromocriptina (BRC), primeiro AD a ser utilizado, definida como ausência de normalização da prolactina (PRL) ou de redução tumoral durante o tratamento, é relatada em 5 a 18 por cento dos pacientes tratados. Novos AD, como a cabergolina (CBG), são alternativa eficaz já que podem normalizar a PRL e reduzir tumores em até 86 por cento e 92 por cento dos casos, respectivamente. Mesmo assim, uma porcentagem dos pacientes pode ser chamada de resistente aos AD. Os mecanismos para a resistência ainda não são completamente elucidados e, embora pouco freqüentes, os prolactinomas resistentes aos AD representam um desafio para o tratamento. As alternativas como cirurgia e radioterapia podem não alcançar a normalização da PRL e, portanto, não resolver os sintomas ligados à hiperprolactinemia. Tratamento do hipogonadismo com reposição de esteróides sexuais, assim como estimulação ovulatória quando o desejo for a gravidez, podem ser alternativas para casos com crescimento tumoral controlado. Novas drogas como anti-estrógenos, novos AD, análogos específicos de subtipos do receptor da somatostatina, drogas quiméricas com ação no receptor da somatostatina e da dopamina e antagonistas da PRL estão sendo estudados e podem representar alternativas futuras ao tratamento deste grupo de pacientes.
Asunto(s)
Humanos , Agonistas de Dopamina/uso terapéutico , Neoplasias Hipofisarias/terapia , Prolactinoma/terapia , Resistencia a Antineoplásicos , Neoplasias Hipofisarias/tratamiento farmacológico , Prolactinoma/tratamiento farmacológicoRESUMEN
Esta apresentação tem o objetivo de discutir o tema "hiperaldosteronismo primário" (HAP). Inicialmente, serão apresentados os dados clínicos, laboratoriais, radiológicos e o resultado do estudo anátomo-patológico do tumor de uma paciente portadora de "aldosteronoma", seguindo-se uma discussão centrada em três pontos principais: 1) a investigação de HAP em pacientes com hipertensão arterial; 2) o diagnóstico etiológico do HAP; e 3) o tratamento das várias formas de apresentação do HAP.
Asunto(s)
Humanos , Femenino , Adulto , Hiperaldosteronismo/diagnóstico , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Adrenalectomía , Diagnóstico Diferencial , Hipertensión/diagnóstico , Hiperaldosteronismo/terapia , Hipopotasemia/diagnóstico , Sistema Renina-Angiotensina/fisiologíaRESUMEN
OBJETIVO: Determinar prevalência de hipertensão arterial, diabete melito, hipercolesterolemia e hipertrigliceridemia em uma população brasileira de acordo com grau de obesidade. MÉTODO: Estudo retrospectivo em 1213 adultos (média de idade: 45,2 ± 12,8 anos; 80,6 % sexo feminino) em grupos de acordo com índice de massa corpórea (normal:18,5-24,4 Kg/m2; sobrepeso 25-29,9 Kg/m2; obesidade classe1: 30-34,9 Kg/m2; classe 2: 35-39,9 Kg/m2 ; classe 3:³ 40 Kgm2). Analisamos presença de hipertensão arterial, diabete melito, hipercolesterolemia e hipertrigliceridemia em cada grupo. Determinamos severidade do risco cardiovascular, considerando risco alto pacientes com 2 ou mais dos seguintes fatores: hipertensão arterial, HDL < 35mg/dl, colesterol total >240mg/dl, triglicérides >200mg/dl quando HDL < 35mg/dl e glicemia >126mg/dl; risco moderado aqueles com 2 ou mais dos seguintes fatores: hipertensão arterial, HDL < 45, triglicérides >200mg/dl e colesterol total >200mg/dl. RESULTADOS: Houve aumento significativo da prevalência de hipertensão arterial, diabete melito, hipertrigliceridemia, HDL-colesterol baixo, porém não houve maior prevalência de hipercolesterolemia. O odds ratio, ajustado para idade e sexo, para obesidade em relação aos indivíduos de peso normal foi 5,9, 8,6 e 14,8 para hipertensão; 3,8, 5,8 e 9,2 para diabete melito e 1,2, 1,3 e 2,6 para hipertrigliceridemia. Após estabelecer severidade do risco cardiovascular, verificamos que o índice de massa corpórea se correlacionou de forma significativa com alto risco cardiovascular (p< 0.0001). CONCLUSÃO: Em nossa população, observamos aumento do risco cardiovascular com aumento do índice de massa corpórea.