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1.
J Drugs Dermatol ; 21(5): 529-530, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35533039

RESUMO

Nivolumab (anti PD-1 antibody) and ipilimumab (anti CTLA-4 antibody) are immune checkpoint inhibitors (ICI) that effectively stimulate the native T cell response and lead to an antitumor response. The medications have been approved for the treatment of metastatic melanoma. However, ICIs are associated with higher risk for cutaneous immune-related adverse events (irAEs). Although most of the adverse events present as maculopapular rash, some patients develop Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis which are dermatologic emergencies with high mortality. We report a fatal case of SJS associated with nivolumab and a non-fatal case of TEN with nivolumab/ipilimumab combination therapy in patients with metastatic melanoma. It is also not unusual to develop SJS or TEN after weeks or months on checkpoint inhibitor therapy. Given the high rate for mortality, dermatologists and other clinicians should closely follow any rash from these immunotherapies due to the risk for future development of SJS or TEN. J Drugs Dermatol. 2022;21(5):529-530. doi:10.36849/JDD.6559.


Assuntos
Exantema , Melanoma , Síndrome de Stevens-Johnson , Exantema/induzido quimicamente , Humanos , Ipilimumab/efeitos adversos , Melanoma/patologia , Nivolumabe/efeitos adversos , Síndrome de Stevens-Johnson/diagnóstico , Síndrome de Stevens-Johnson/etiologia
2.
Cancer Chemother Pharmacol ; 89(5): 629-641, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35366072

RESUMO

PURPOSE: Apalutamide plus androgen-deprivation therapy (ADT) has been approved for treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC) based on data from phase 3 TITAN study. This analysis was conducted to describe pharmacokinetics of apalutamide and N-desmethyl-apalutamide and explore relationships between apalutamide exposure and selected clinical efficacy and safety observations. METHODS: 1052 patients were randomized to apalutamide + ADT (n = 525) or placebo + ADT (n = 527). A previously developed population pharmacokinetic model was applied. Cox regression analysis investigated the relationships between apalutamide exposure and overall survival (OS; n = 1004) and radiographic progression-free survival (rPFS; n = 1003). Logistic regression analysis assessed the relationships between apalutamide exposure and selected clinically relevant adverse events (n = 1051). RESULTS: Apalutamide + ADT treatment was efficacious in extending rPFS and OS versus placebo + ADT. Within a relatively narrow apalutamide exposure range (coefficient of variation: 22%), no statistical association was detected between rPFS, OS and apalutamide exposure quartiles. Incidence of skin rash and pruritus increased significantly with increasing apalutamide exposure. CONCLUSIONS: Differences in apalutamide exposure were not associated with clinically relevant differences in rPFS or OS in patients with mCSPC. Patients with increased apalutamide exposure are more likely to develop skin rash and pruritus. Dose reductions may improve these adverse events, based on an individual risk-benefit approach.


Assuntos
Exantema , Neoplasias de Próstata Resistentes à Castração , Antagonistas de Androgênios/efeitos adversos , Castração , Exantema/induzido quimicamente , Humanos , Masculino , Prurido/induzido quimicamente , Tioidantoínas
3.
Zhonghua Zhong Liu Za Zhi ; 44(4): 297-307, 2022 Apr 23.
Artigo em Chinês | MEDLINE | ID: mdl-35448917

RESUMO

The mutation rate of anaplastic lymphoma kinase (ALK) in patients with non-small cell lung cancer is 3% to 7%. Due to its low mutation rate and better long-term survival compared with epidermal growth factor receptor-positive non-small cell lung cancer patients, therefore, it's called "diamond mutation". At present, there are three generations of ALK tyrosine kinase inhibitor (TKI) drugs in the world. The first-generation ALK-TKI drug approved in China is crizotinib, and the second-generation drugs are alectinib, ceritinib and ensartinib. Among them, ensartinib is an ALK-TKI domestically developed, and its efficacy is similar to that of alectinib. The main adverse event is transient rash, and compliance to ensartinib is better from the perspective of long-term survival of patients. The manifestation of rash caused by ensartinib is different from that of other ALK-TKI drugs. In order to facilitate clinical application and provide patients with more treatment options, under the guidance of the Committee of Cancer Rehabilitation and Palliative Care of China Anti-Cancer Association, this article collects and summarizes the common adverse reactions of ensartinib. Based on the clinical practice, a clear adverse classification and specific treatment plan are formulated, in order to provide a corresponding reference for clinicians to make more comprehensive clinical decisions.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Exantema , Neoplasias Pulmonares , Quinase do Linfoma Anaplásico , Carbazóis/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Consenso , Exantema/induzido quimicamente , Exantema/tratamento farmacológico , Humanos , Neoplasias Pulmonares/patologia , Piperazinas , Inibidores de Proteínas Quinases/efeitos adversos , Piridazinas
4.
J Postgrad Med ; 68(2): 102-105, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35466662

RESUMO

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe, idiosyncratic reaction to a drug which presents after a prolonged latency period. Although it most commonly occurs with aromatic anticonvulsants, antibiotics are also occasionally implicated. A 50-year-old male was admitted for left pyopneumothorax. He was started on intravenous piperacillin-tazobactam (Pip/Taz) and clindamycin. After 10 days of treatment, he developed high grade fever with maculopapular rashes with areas of scaling. He had elevated WBC counts with eosinophils of 21% and raised serum transaminases. After excluding other possible etiologies for febrile illness, a possibility of DRESS was considered. Naranjo scale, used for causality assessment, yielded a total score of 6, pointing toward probable adverse drug reaction. Also, the patient had 6 out of the 7 inclusion criteria for DRESS as per European Registry of Severe Cutaneous Adverse Reaction (RegiScar) scoring. Pip/Taz was found to be causative drug and was discontinued. He was conservatively managed with antipyretics and topical steroids. Fever subsided the day after stopping Pip/Taz and his rashes resolved gradually. In conclusion the possibility of antibiotics-induced DRESS should be considered and high index of vigilance is advised.


Assuntos
Síndrome de Hipersensibilidade a Medicamentos , Eosinofilia , Exantema , Antibacterianos/efeitos adversos , Síndrome de Hipersensibilidade a Medicamentos/diagnóstico , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Eosinofilia/induzido quimicamente , Exantema/induzido quimicamente , Febre/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Piperacilina/efeitos adversos , Tazobactam/efeitos adversos
5.
Lancet Glob Health ; 10(5): e705-e714, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35427527

RESUMO

BACKGROUND: Pellagra is caused by niacin (vitamin B3) deficiency and patients with pellagra present with a characteristic rash. Isoniazid disrupts intracellular niacin synthesis and might induce niacin deficiency. In 2017, Malawi scaled up continuous isoniazid preventive treatment (IPT) for tuberculosis prevention among people living with HIV. In addition, an under-diversified diet based on subsistence maize, as is commonly the case in Malawi, is a risk factor for pellagra. We aimed to investigate whether large-scale isoniazid exposure in Malawi contributed to the cumulative risk for pellagra in a nutritionally vulnerable population. METHODS: We did a matched case-control study to evaluate the association between daily, continuous isoniazid exposure and pellagra. We matched sequentially enrolled patients with pellagra each with four control participants by sex and age from referral dermatology centres in three IPT scale-up districts in Malawi (Lilongwe, Blantyre, and Zomba) to evaluate isoniazid as a risk for pellagra using multivariable conditional logistic regression. We established a community clinic referral system surrounding the dermatology clinic in each district to enhance case-finding and included all patients with pellagra, regardless of referral status. The primary outcome was dermatologist-diagnosed pellagra. We calculated the interval between isoniazid initiation and rash onset and assessed 30-day clinical outcomes after multi-B vitamin treatment containing 300 mg nicotinamide daily. FINDINGS: Between Feb 5 and Aug 9, 2019, we enrolled 197 patients with pellagra and 781 matched controls. Isoniazid exposure was associated with an increased risk of pellagra (adjusted odds ratio 42·6 [95% CI 13·3-136·6]). Significant covariates included HIV infection, referral status, food insecurity, underweight, excess alcohol consumption, and, among women, lactation. The median time from isoniazid initiation to rash onset was shorter during the season of food scarcity (5 months [IQR 3-7]) compared with the harvest season (9 months [8-11]; hazard ratio 7·2 [95% CI 3·2-16·2], log-rank p<0·0001). Those with isoniazid-associated pellagra who discontinued isoniazid and adhered to multi-B vitamin treatment showed 30-day clinical improvement. INTERPRETATION: Continuous IPT scale-up and the annual period of food scarcity both increased the risk of pellagra in Malawi. Use of shorter rifamycin-based regimens for tuberculosis prevention and food fortification in populations with undernutrition might reduce this risk. Niacin-containing multi-B vitamin co-administration with isoniazid as pellagra prevention is worth exploring further. FUNDING: This study was supported by the President's Emergency Plan for AIDS Relief through the US Centers for Disease Control and Prevention under project 7173.


Assuntos
Antituberculosos , Infecções por HIV , Isoniazida , Pelagra , Tuberculose , Antituberculosos/efeitos adversos , Estudos de Casos e Controles , Exantema/induzido quimicamente , Exantema/tratamento farmacológico , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Humanos , Isoniazida/efeitos adversos , Masculino , Niacina/uso terapêutico , Pelagra/induzido quimicamente , Pelagra/complicações , Pelagra/tratamento farmacológico , Tuberculose/complicações , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , Complexo Vitamínico B/uso terapêutico
6.
BMJ Case Rep ; 15(3)2022 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-35236685

RESUMO

We present a case of severe rash following induction of elexacaftor, tezacaftor and ivacaftor (ELX/TEZ/IVA) in a young adult male cystic fibrosis patient. While rash is a commonly reported side effect which resolves in 1-2 weeks with minimal intervention, our patient had presented with fever and widespread rash prompting medication cessation. After a washout period, reintroduction with 1/2 tablet of ELX/TEZ/IVA produced a similar systemic response within 24 hours. Repeat attempt, this time with 1/8 tablet and increasing in increments of an eighth daily, was successful and has allowed our patient to experience the transformative benefits of ELX/TEZ/IVA including improved pulmonary function and reduced episodes of infective exacerbation. This case illustrates one of the most common side effects of ELX/TEZ/IVA triple therapy, and our experience of desensitisation to ELX/TEZ/IVA in a challenging case of rash.


Assuntos
Agonistas dos Canais de Cloreto , Exantema , Aminofenóis , Benzodioxóis , Agonistas dos Canais de Cloreto/efeitos adversos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Combinação de Medicamentos , Exantema/induzido quimicamente , Humanos , Indóis , Masculino , Pirazóis , Piridinas , Pirrolidinas , Quinolonas , Adulto Jovem
7.
Pediatr Neurol ; 129: 19-23, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35151015

RESUMO

BACKGROUND: Following approval by the US Food and Drug Administration (FDA) in late 2019, cenobamate (Xcopri) has been utilized to treat adults with focal seizures. Based on its robust efficacy from the phase 2 trials, we began using cenobamate in our adolescent and young adult patients whose seizures were not controlled with previously available options. This study expanded its real-world application to this cohort with focal epilepsy and a history of drug-related rash. METHODS: We conducted a retrospective study of our patients exposed to cenobamate (n = 45). We evaluated dosage and serum levels, efficacy, drug interactions, and adverse effects. RESULTS: After gradually increasing cenobamate to clinical effect using the FDA-approved dosing protocol, 60% (n = 22) of patients were responders. Adolescents were treated with an average daily dose of 204.0 mg, and adults with 223.4 mg cenobamate, and had serum levels of 20.5 µg/mL and 26.7 µg/mL, respectively. The side effect profile observed was similar to that seen in the phase 2/3 registry trials. Importantly, patients with a prior history of rash to other medications or antiseizure medications (n = 5) experienced no rashes related to cenobamate. CONCLUSIONS: This real-world study supports the findings of prior controlled studies regarding the efficacy of cenobamate as a treatment for focal seizures in adolescents and suggests that patients with a history of rash may benefit from this medication.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Exantema , Adolescente , Anticonvulsivantes/efeitos adversos , Carbamatos , Clorofenóis , Método Duplo-Cego , Exantema/induzido quimicamente , Exantema/tratamento farmacológico , Humanos , Estudos Retrospectivos , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Tetrazóis , Resultado do Tratamento , Adulto Jovem
8.
Cancer Treat Rev ; 103: 102333, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35033866

RESUMO

Tyrosine kinase inhibitors have been successfully developed in combination with immune checkpoint inhibitors to treat advanced renal cell carcinoma (RCC), further advancing treatment. While safety profiles are generally manageable with combination regimens, overlapping adverse events (AEs) and immune-related AEs can make treatment more complex. The CheckMate 9ER study evaluated the tyrosine kinase inhibitor cabozantinib in combination with the anti-programmed cell death protein-1 antibody nivolumab in patients with previously untreated advanced RCC. Cabozantinib + nivolumab demonstrated superiority over sunitinib for progression-free survival, overall survival, and objective response rate. These outcomes supported the approval of cabozantinib + nivolumab as a first-line therapy for advanced RCC. The safety profile was manageable with prophylaxis, supportive care, dose holds and reductions for cabozantinib, and dose holds and immunosuppressive therapy for nivolumab. This review discusses the safety results of CheckMate 9ER and provides guidance on managing some of the more clinically relevant AEs with a focus on overlapping AEs, including diarrhea, elevated amylase/lipase, hepatotoxicity, dermatologic reactions, fatigue, endocrine disorders, and nephrotoxicity. We discuss AE management strategies (prophylaxis, supportive care, dose modification, and immunosuppressive therapy), and provide recommendations for identifying the causative agent of overlapping AEs and for consulting specialists about organ-specific immune-related AEs. Optimizing AE management can maintain tolerability and should be a priority with cabozantinib + nivolumab treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Anilidas/administração & dosagem , Anilidas/efeitos adversos , Ensaios Clínicos como Assunto , Diarreia/induzido quimicamente , Doenças do Sistema Endócrino/induzido quimicamente , Exantema/induzido quimicamente , Fadiga/induzido quimicamente , Gastroenteropatias/induzido quimicamente , Humanos , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos
9.
J Clin Exp Hematop ; 62(1): 18-24, 2022 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-34980789

RESUMO

Bendamustine is now recognized as a key drug for indolent B-cell lymphoma (iBCL), mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Skin toxicity associated with bendamustine is one of the characteristic adverse effects. We retrospectively examined the relationship between bendamustine-associated drug rashes and disease prognosis of iBCL and MCL at our institution. Between January 2011 and August 2019, 65 patients (39 men and 26 women, median age 68, range 41-84 years) were treated with bendamustine alone (n=11, 120 mg/m2 on days 1 and 2) or a combination of rituximab and bendamustine (n=54, 90 mg/m2 on days 1 and 2). Of these patients, 47 had follicular lymphoma (FL), 10 had MCL and 8 had other iBCLs. Drug rash occurred in 27 (41.5%). Eight cases (29.6%) were grade 1, 5 (18.5%) were grade 2 and 14 (51.9%) were grade 3. The onset was in the first course in 17 (63.0%), 2nd course in 5 (18.5%), 3rd course in 2 (7.4%), 4th course in 1 (3.7%) and 5th course in 2 (7.4%). No treatment was administered in 1 case (3.7%), topical steroid was applied in 10 (37.0%), antiallergic drug was administered in 2 (7.4%), topical steroid and antiallergic drug were administered in 5 (18.5%), and oral and topical steroid and antiallergic drug were administered in 9 (33.3%). The 3-year progression-free survival (PFS) and overall survival (OS) in patients with rash development were 80.0% and 85.5%, respectively, and those in patients without development were 36.4% and 54.0%, respectively (p=0.009 and 0.02, respectively). By multivariate analysis, the development of rash was associated with a better PFS and a diagnosis of iBCL was associated with a better OS. This study revealed that bendamustine-induced rash is associated with a favorable prognosis among patients with iBCL.


Assuntos
Exantema , Linfoma de Células B , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/efeitos adversos , Exantema/induzido quimicamente , Exantema/tratamento farmacológico , Feminino , Humanos , Linfoma de Células B/patologia , Prognóstico , Estudos Retrospectivos , Rituximab
11.
Biochem Pharmacol ; 197: 114914, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35041812

RESUMO

Tyrosine kinase inhibitors (TKIs) are molecular-targeted anticancer drugs. Their benefits are limited by dermal toxicities, including hand-foot skin reaction (HFSR), which is commonly found in skin areas subjected to friction. The present study aimed to explain the incidence of HFSR in patients treated with TKIs by focusing on keratinocyte toxicity and inhibition of vascular endothelial growth factor receptor (VEGFR), which plays an essential role in angiogenesis. Mice with gene knockout for the immunosuppressive cytokine interleukin-10 exhibited HFSR-like phenotypes, such as cytotoxicity in keratinocytes and increased number and size of blood vessels after repeated doses of regorafenib, sorafenib, and pazopanib, all of which cause high incidence of HFSR, in combination with tape-stripping mimicking skin damage at the friction site. Comprehensive examination of the direct cytotoxic effects of 21 TKIs on primary cultured human keratinocytes revealed that 18 of them reduced the cell viability dose-dependently. Importantly, the ratio of the trough concentration in patients (Ctrough) to the LC50 values of cell viability reduction was higher than unity for four HFSR-inducing TKIs, suggesting that these TKIs cause keratinocyte toxicity at clinically relevant concentrations. In addition, eight HFSR-inducing TKIs caused inhibition of VEGFR-2 kinase activity, which was validated by their ratios of Ctrough to the obtained IC50,VEGFR-2 of more than unity. All 12 TKIs with no reported incidence of HFSR exhibited less than unity values for both Ctrough/LC50,keratinocytes and Ctrough/IC50,VEGFR-2. These results suggested that a combination of keratinocyte toxicity and VEGFR-2 inhibition may explain the incidence of HFSR upon TKI usage in humans.


Assuntos
Exantema/induzido quimicamente , Queratinócitos/efeitos dos fármacos , Inibidores de Proteínas Quinases/toxicidade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Animais Recém-Nascidos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Exantema/metabolismo , Exantema/patologia , Pé/patologia , Mãos/patologia , Humanos , Queratinócitos/metabolismo , Queratinócitos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Knockout , Camundongos Transgênicos , Compostos de Fenilureia/toxicidade , Piridinas/toxicidade , Sorafenibe/toxicidade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
12.
J Urol ; 207(5): 1010-1019, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35020444

RESUMO

PURPOSE: Patients with prostate cancer (PCa) treated with apalutamide frequently develop rash. We aim to characterize apalutamide-related dermatological adverse events (dAEs) and management. MATERIALS AND METHODS: We assessed 303 patients with PCa treated with apalutamide. DAE frequency and time to onset were calculated and clinicopathological features and management described. Associations between dAE occurrence and clinical trial participation, as well as abiraterone/prednisone exposure were detected using logistic regression models. RESULTS: Seventy-one (23.4%) patients had all-grade dAE occurring at a median of 77 (IQR: 30-135) days post-exposure. Twenty (6.6%) dAE-related therapy interruptions included: 8 (2.6%) with dose maintained on rechallenge, 7 (2.3%) with dose reduction and 5 (1.7%) with discontinuation. Common dAEs were maculopapular rashes (33.8%) and xerosis (32.4%). Seven (77.8%) of 9 histological analyses of skin biopsies supported a drug reaction. No significant differences in laboratory hematological, hepatic and renal function were detected between dAE and no dAE cohorts. Most treated grade 1/2 dAEs (29, 40.8%) required topical steroids (14, 19.7%); few required oral steroids (3, 4.2%) ± oral antihistamines. Most grade 3 dAEs (8, 11.3%) required oral/topical steroids (5, 7.0%); few required topical steroids (3, 4.2%) ± oral antihistamines. Clinical trial patients (180, 59.4%) were more likely to report dAEs than those in the off-trial setting (OR=5.1 [95% CI 2.55-10.12]; p <0.001). Of clinical trial patients, concomitant abiraterone/prednisone recipients (109 of 180, 60.6%) were more likely to report dAEs (OR=3.1 [95% CI 1.53-6.17]; p=0.002). CONCLUSIONS: Apalutamide-related dAEs are frequent and can be managed with topical ± oral steroids. With expanded approval of apalutamide, dAE identification and management are essential.


Assuntos
Exantema , Neoplasias da Próstata , Antagonistas de Receptores de Andrógenos/efeitos adversos , Exantema/induzido quimicamente , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Tioidantoínas/efeitos adversos
13.
J Oncol Pharm Pract ; 28(4): 969-971, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35037787

RESUMO

INTRODUCTION: Chronic myeloid leukemia (CML) is a malignant clonal disorder of hematopoietic stem cells characterized by a translocation of genetic material between chromosomes 9 and 22 resulting in the BCR-ABL fusion oncogene expression. Nilotinib is a potent second-generation tyrosine kinase inhibitor available as first line treatment. Among side effects QTc interval prolongation, pancreatitis, metabolic disorders and skin reactions are the most commonly seen. CASE REPORT: Here we describe a rare case of lichen planopilaris eruption that developed during therapy with nilotinib. MANAGEMENT & OUTCOME: Nilotinib dosage was reduced together with introduction of hydroxychloroquine with progressive improvement of alopecia. DISCUSSION: Collaboration with dermatologist and nilotinib dose reduction allowed to continue the drug maintaining major molecular response and patient's quality of life.


Assuntos
Exantema , Leucemia Mielogênica Crônica BCR-ABL Positiva , Líquen Plano , Resistencia a Medicamentos Antineoplásicos , Exantema/induzido quimicamente , Proteínas de Fusão bcr-abl , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Líquen Plano/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas , Qualidade de Vida
14.
J Geriatr Oncol ; 13(3): 302-307, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34716122

RESUMO

OBJECTIVES: To assess the toxicity patterns and effectiveness of doublet chemotherapy when administered at reduced doses of 20% (FOLFOX or FOLFIRI) in combination with anti-EGFR antibodies (cetuximab or panitumumab) in old, vulnerable patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: We performed a retrospective observational study of RAS and BRAF wild-type, vulnerable patients aged ≥70 years with previously untreated mCRC. The primary endpoint was safety, and secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: One hundred and eighteen patients were collected from 14 selected Italian centres. The median age was 75 (range, 70-85). Geriatric screening by G8 tool gave a score ≤ 14 in all patients. In total, 75 and 43 patients received FOLFOX or FOLFIRI, respectively, in combination with panitumumab (53%) or cetuximab (47%). The overall incidence of grade (G) 3-4 neutropenia was 11.8%, and for skin rash 11%. The most frequent adverse events were G1-2 skin rash (49.1%), G1-2 diarrhea (21.1%) and G1-2 nausea (17.7%). The ORR was 57.3%. Stable disease was observed in 29.1% of patients, with a disease control rate of 86.4%. With a median follow-up of 18 months, the median PFS was 10.0 months (95% confidence interval [CI]: 8.5-11.4), while the median OS was 18.0 months (95% CI: 16.0-19.9). No statistically significant difference was observed between the regimens in terms of ORR, PFS (p = 0.908), and OS (p = 0.832). CONCLUSION: This study shows that with an appropriate design, including reduced doses, vulnerable older patients best tolerate chemotherapy when combined with anti-EGFR antibodies.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Exantema , Neoplasias Retais , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cetuximab/efeitos adversos , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Exantema/induzido quimicamente , Exantema/tratamento farmacológico , Fluoruracila , Humanos , Leucovorina/efeitos adversos , Panitumumabe/uso terapêutico
17.
J Clin Pharm Ther ; 47(4): 477-482, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34778985

RESUMO

WHAT IS KNOWN AND OBJECTIVE: It was previously reported that the incidence of lenalidomide (LEN)-induced skin rash is reduced by administration of bortezomib (BOR) prior to LEN administration in patients with multiple myeloma (MM). Therefore, we investigated whether LEN-induced skin rash is affected by the duration of BOR administration and the dosing interval between BOR and LEN administration. METHOD: A retrospective investigation was conducted among MM patients who received BOR treatment prior to LEN treatment in Eiju General Hospital from May 2010 to December 2020. We investigated whether the BOR administration duration and interval duration from the completion of BOR administration to the initial LEN administration affect the development of LEN-induced skin rash. RESULT AND DISCUSSION: Twenty-eight of the 81 patients exhibited LEN-induced skin rash (34.6%). The administered duration, but not the interval, was significantly longer in the group without skin rash. Cut-off values were set for the duration of administration and interval, which were 35 days and 30 days, respectively. Multivariate analysis was performed on patients which are administered duration of more than 35 days and intervals of less than 30 days, and those who are not applicable. A significant difference was observed in the incidence of skin rash for each factor. WHAT IS NEW AND CONCLUSION: The risk of reduced LEN-induced skin rash is affected not only by the presence of prior BOR administration, but also by the duration of BOR and the interval from the completion of BOR to the initial LEN administration.


Assuntos
Exantema , Mieloma Múltiplo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/efeitos adversos , Dexametasona/uso terapêutico , Exantema/induzido quimicamente , Exantema/epidemiologia , Exantema/prevenção & controle , Humanos , Lenalidomida/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Estudos Retrospectivos
18.
Clin Cancer Res ; 28(5): 882-892, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34844977

RESUMO

PURPOSE: TIGIT (T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain) is a co-inhibitory receptor of T-cell and natural killer cell activity. Targeting TIGIT with or without PD-1/PD-L1 checkpoint inhibition may enhance antitumor immunity. PATIENTS AND METHODS: This Phase 1a/b trial was a first-in-human, open-label, multicenter, dose-escalation and -expansion study in patients with locally advanced or metastatic solid tumors. Using 3 + 3 design, patients underwent 14-day treatment cycles with anti-TIGIT antibody etigilimab alone (Phase 1a; 0.3, 1.0, 3.0, 10.0, 20.0 mg/kg intravenously) or in combination with anti-PD-1 antibody nivolumab (Phase 1b; 3.0, 10.0, 20.0 mg/kg etigilimab and 240 mg nivolumab). Primary objective was safety and tolerability. RESULTS: Thirty-three patients were enrolled (Phase 1a, n = 23; Phase 1b, n = 10). There were no dose-limiting toxicities (DLT). MTD for single and combination therapy was not determined; maximum administered dose was 20 mg/kg. The most commonly reported adverse events (AE) were rash (43.5%), nausea (34.8%), and fatigue (30.4%) in Phase 1a and decreased appetite (50.0%), nausea (50.0%), and rash (40%) in Phase 1b. Six patients experienced Grade ≥3 treatment-related AEs. In Phase 1a, 7 patients (30.0%) had stable disease. In Phase 1b, 1 patient had a partial response; 1 patient had prolonged stable disease of nearly 8 months. Median progression-free survival was 56.0 days (Phase 1a) and 57.5 days (Phase 1b). Biomarker correlative analyses demonstrated evidence of clear dose-dependent target engagement by etigilimab. CONCLUSIONS: Etigilimab had an acceptable safety profile with preliminary evidence of clinical benefit alone and in combination with nivolumab and warrants further investigation in clinical trials.


Assuntos
Exantema , Segunda Neoplasia Primária , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Exantema/induzido quimicamente , Exantema/tratamento farmacológico , Humanos , Náusea/induzido quimicamente , Segunda Neoplasia Primária/tratamento farmacológico , Nivolumabe/uso terapêutico
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