ABSTRACT
The cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib is administered orally and cyclically, causing medication adherence challenges. We evaluated components of adherence to palbociclib, its relationship with pharmacokinetics (PK), and drug-induced neutropenia. Patients with metastatic breast cancer (MBC) receiving palbociclib, delivered in electronic monitors (EM), were randomized 1:1 to an intervention and a control group. The intervention was a 12-month interprofessional medication adherence program (IMAP) along with monthly motivational interviews by a pharmacist. Implementation adherence was compared between groups using generalized estimating equation models, in which covariates were included. Model-based palbociclib PK and neutrophil profiles were simulated under real-life implementation scenarios: (1) optimal, (2) 2 doses omitted and caught up at cycle end. At 6 months, implementation was slightly higher and more stable in the intervention (n = 19) than in the control (n = 19) group, 99.2% and 97.3% (Δ1.95%, 95% CI 1.1−2.9%), respectively. The impact of the intervention was larger in patients diagnosed with MBC for >2 years (Δ3.6%, 95% CI 2.1−5.4%), patients who received >4 cycles before inclusion (Δ3.1%, 95% CI 1.7−4.8%) and patients >65 (Δ2.3%, 95% CI 0.8−3.6%). Simulations showed that 25% of patients had neutropenia grade ≥3 during the next cycle in scenario 1 versus 30% in scenario 2. Education and monitoring of patient CDK4/6i cycle management and adherence along with therapeutic drug monitoring can help clinicians improve prescription and decrease toxicity.
ABSTRACT
Neutropenia is the most frequent dose-limiting toxicity reported in patients with metastatic breast cancer receiving palbociclib. The objective of this study was to investigate the pharmacokinetic-pharmacodynamic (PK/PD) relationships for toxicity (i.e., absolute neutrophil count, ANC) and efficacy (i.e., progression-free survival, PFS). A semi-mechanistic PK/PD model was used to predict neutrophils' time course using a population approach (NONMEM). Influence of demographic and clinical characteristics was evaluated. Cox proportional hazards models were developed to evaluate the influence of palbociclib PK on PFS. A two-compartment model with first-order absorption and a lag time adequately described the 255 palbociclib concentrations provided by 44 patients. The effect of the co-administration of proton-pump inhibitors in fasting conditions increased palbociclib clearance by 56%. None of the tested covariates affected the PD parameters. Model-based simulations confirmed the concentration-dependent and non-cumulative properties of palbociclib-induced neutropenia, reversible after treatment withdrawal. The ANC nadir occurred approximately at day 24 of each cycle. Cox analyses revealed a trend for better PFS with increasing palbociclib exposure in older patients. By characterizing palbociclib-induced neutropenia, this model offers support to clinicians to rationally optimize treatment management through patient-individualized strategies.
ABSTRACT
In last years, the therapeutic arsenal against breast cancer increased considerably with the arrival of signaling pathway inhibitors, immunotherapy, PARP inhibitors, tyrosine kinase inhibitors and antibody-drug conjugates. Consequently, the range of potential adverse events has also widened and differs from the usual chemotherapies and endocrine therapies. Depending on the administered therapy, the same symptoms can be harmless and treated symptomatically or the warning sign of a potential serious complication requiring a rapid action. We therefore discuss in this article the therapeutic role and some typical adverse events of these new therapies.
Ces dernières années, l'arsenal thérapeutique contre le cancer du sein s'est passablement enrichi avec les inhibiteurs des voies de signalisation, l'immunothérapie, les inhibiteurs de PARP (polyADP-ribose polymérase), les inhibiteurs de tyrosine kinase et les chimiothérapies immunoconjuguées. De ce fait, la gamme d'effets indésirables potentiels s'est également élargie et diffère des habituelles chimiothérapies et hormonothérapies. En fonction de la substance administrée, les mêmes symptômes peuvent être anodins et traités symptomatiquement, ou alors être le signe d'alerte d'une potentielle complication sévère et nécessiter une réaction rapide. Nous discutons dans cet article du rôle thérapeutique et des quelques effets indésirables typiques de ces nouvelles thérapies.
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Drug-Related Side Effects and Adverse Reactions , Antineoplastic Agents/adverse effects , Breast Neoplasms/chemically induced , Breast Neoplasms/drug therapy , Female , Humans , Immunotherapy , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic useABSTRACT
BACKGROUND: The prevalence of esophageal stenosis caused by immune checkpoint inhibitors in the context of induced immune mucositis and esophagitis is extremely rare. CASE PRESENTATION: We report the case of a patient with stage IV pulmonary adenocarcinoma treated for 6 months with nivolumab who developed bilateral sterile conjunctivitis followed by oropharyngeal mucositis and esophagitis complicated by a severe esophageal stenosis. The laryngeal margin and hypopharyngeal mucosa appeared highly inflammatory with fibrinous deposits. Esophagogastroduodenoscopy revealed mucositis with a scar-like structure immediately below the upper esophageal sphincter with nonulcerative mucosa and an inflammatory aspect of the entire esophagus. No involvement of the stomach was observed. Oropharynx biopsies displayed marked lymphocytic T cell-infiltration with several foci of monocellular necrosis in the squamous epithelium. No morphologic evidence of adenocarcinoma and no signs of mycotic, bacterial or viral infection were noted. A blood sample revealed a discrete increase in the erythrocyte sedimentation rate (ESR) with no eosinophilia or leukocytosis. Liver and kidney function panel tests were normal. A thoracoabdominal CT scan reported no evidence of disease recurrence. Despite multiple boluses of methylprednisolone and high doses of prednisone continued for several months, the patient experienced very rapid symptomatological reappearance during three steroid tapering attempts and aggravation of his esophageal stenosis to an aphagic stage, requiring a nasogastric tube. This long course of high-dose corticosteroid treatment was complicated with osteoporosis-induced fractures with several spontaneous compressions of thoracolumbar vertebrae requiring an enlarged T10 to L5 cementoplasty. Anti-IL-6 blockade therapy with tocilizumab resulted in excellent clinical response, allowing the total resolution of the immune-related adverse events (irAEs) and leading to successful steroid tapering. CONCLUSIONS: Herein, we describe the first case of a patient who developed autoimmune mucositis and esophagitis complicated by a severe refractory esophageal stenosis induced during treatment by nivolumab, which completely resolved after personalized treatment with tocilizumab, suggesting a role of IL-6 blockade in the management of severe steroid refractory esophageal stenosis and more broadly in refractory immune-related adverse events.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/adverse effects , Esophageal Stenosis/chemically induced , Esophageal Stenosis/drug therapy , Nivolumab/adverse effects , Adenocarcinoma/drug therapy , Aged , Conjunctivitis/drug therapy , Humans , Lung Neoplasms/drug therapy , Male , Programmed Cell Death 1 Receptor/antagonists & inhibitorsABSTRACT
Invasive breast cancer is the most common malignancy in women in industrialized countries. Three-quarters of breast cancers express estrogen and/or progesterone receptors and are considered endocrine-sensitive. Endocrine therapy reduces the risk of loco-regional, contralateral and distant recurrence. The management has become more complex with estrogen receptor inhibitors, aromatase inhibitors and ovarian function suppression. The choice of the regimen and its duration depend on the age, the menopausal status of the patient, her co-morbidities, the risk of cancer relapse and the tolerance. We summarize here the recent modifications of the endocrine therapy in early and advanced stage breast cancer.
Le cancer du sein est le cancer invasif le plus fréquent chez la femme dans les pays industrialisés. Trois quarts des cancers du sein expriment des récepteurs aux oestrogènes et/ou à la progestérone et sont susceptibles de répondre à un traitement antihormonal. En postopératoire, ce dernier permet de réduire le risque de rechute locorégionale, controlatérale et à distance. Entre inhibiteurs du récepteur, inhibiteurs de l'aromatase et suppression de la fonction ovarienne, la prise en charge s'est complexifiée et doit être dorénavant individualisée. Le choix du schéma thérapeutique ainsi que la durée du traitement dépendent de l'âge, du status hormonal de la patiente, de ses comorbidités, du risque de rechute et de la tolérance. Cet article résume les changements intervenus ces dernières années dans le traitement antihormonal en adjuvant et en situation métastatique.
