Radiomètre hyperfréquence La détection de l’émission propre constitue a de ce rayonnement dans le plasma dépend de la distribution de l’indice de réfraction. donné lieu à peu de recherches, ou du moins à peu de publications (Letarte. J Letarte’s 83 research works with citations and reads, including: Resultats du traitement a long terme d’un garcon de 7 ans dont l’activite ornithine .. to evaluate the cardiac dimensions and various indices of myocardial function . Suivre. Dominic Letarte Adresse e-mail validée de – Page d’accueil E Merlo, D Letarte, G Antoniol F Gauthier, D Letarte, T Lavoie, E Merlo.
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Anaplastic lymphoma kinase ALK rearrangements have been identified as key oncogenic drivers in a small subset of non-small-cell lung cancers nsclc s. Small-molecule Alk kinase inhibitors such as crizotinib have transformed the natural history of nsclc for this subgroup of patients. Because of the prevalence of nsclcALK -positive patients represent an important example of the paradigm for personalized medicine.
Although Alk inhibitors such as crizotinib are well tolerated, there is a potential for adverse events to occur. Proactive monitoring, treatment, and education concerning those adverse events will help to optimize the therapeutic index of the drugs. Indiec present review summarizes the management of treatment-related adverse events that can arise with Alk inhibitors such as crizotinib.
The use of targeted therapies for subsets of molecularly-defined cancers has been a paradigm shift in cancer treatment. In non-small-cell lung cancer nsclcthe shift was first seen with the discovery that mutations in the epidermal growth factor receptor predicted responsiveness indce epidermal growth factor receptor tyrosine kinase inhibitors.
Although those inhibitors are generally well tolerated, they have a unique side effect profile that differs from that of traditional cytotoxic therapy. Given the effectiveness of targeted therapies, patients will often be taking the agents for long periods of time. Inanaplastic lymphoma kinase ALK gene rearrangements were identified in nsclc 12.
Although ALK had previously been identified in subsets of anaplastic large-cell lymphomas 3 and inflammatory myofibroblastic tumours 4its identification in nsclc was what prompted the investigation of Alk inhibition as a therapeutic strategy. Given the letartf of nsclcestimates suggest that several hundred patients with advanced ALK -positive nsclc will be diagnosed annually in Canada 5. In bringing a new class of therapeutics into the clinic, it is essential that the multidisciplinary team be familiar with management of the ae s that can arise—especially in the case of a therapy that will be used in a very specific subgroup of patients and with which clinicians may have limited experience 6.
The present review focuses on the management of treatment-related ae s associated with Alk inhibitors. It focuses df nsclcgiven that most of the available data relate to that disease and that the other populations in which Alk inhibitors have shown benefit are relatively rare tumours.
Similarly, the focus of the discussion is crizotinib, because that agent is currently the only Alk inhibitor approved by the U.
Food and Drug Administration and Health Canada; however, we also highlight emerging data concerning second-generation Alk inhibitors. Preclinical studies have highlighted the importance of ALK as an oncogenic driver in nsclc and the associated sensitivity to Alk inhibition 17.
Patients with ALK rearrangements tend to be younger at diagnosis median age: In Canada, patients are currently screened for ALK by immunohistochemistry, with fluorescence in situ hybridization used for confirmation. Crizotinib is a small-molecule receptor tyrosine kinase inhibitor initially designed to target c-Met, but subsequently found to be active against Alk.
A phase i trial in advanced ALK -positive nsclc profile demonstrated an impressive A global phase ii study in a similar patient population profile confirmed that remarkable clinical activity 9. A phase iii study in advanced ALK -positive nsclc progressing on a first-line platinum-based doublet compared crizotinib with standard second-line chemotherapy using pemetrexed or docetaxel profile That study demonstrated significant improvements in response rate and progression-free survival in favour of crizotinib, but no overall survival benefit was observed, presumably because of crossover.
On the basis of the data from profile andcrizotinib received accelerated approval from the U. Food and Drug Administration and Health Canada. Despite the impressive activity of crizotinib, resistance is generally inevitable 11 One approach to overcoming resistance is the development of next-generation Alk inhibitors The newer agents are generally more potent than crizotinib and structurally distinct.
As such, they may be associated with different ae profiles. Data on the efficacy of second-generation Alk inhibitors is limited mainly to phase i and ii studies. Several excellent reviews on the current understanding of ALK -positive nsclc and approaches to overcoming resistance are available 13 Nonetheless, crizotinib can be taken with or without food.
The solubility of crizotinib is pH-dependent: Medications such as proton pump inhibitors, histamine H2 blockers, and antacids may therefore have an effect on bioavailability, although the clinical relevance of this interaction is unknown.
Patients in the clinical trials were allowed to take all the foregoing medications while on treatment with crizotinib. Crizotinib is metabolized predominantly by CYP3A, and so co-administration with strong inhibitors of CYP3A4 such as ketoconazole increases the area under the curve of crizotinib and should be avoided.
Moderate inhibitors of CYP3A4 should be used with caution, and crizotinib toxicity should be monitored. Patients taking crizotinib should avoid grapefruit juice, a strong CYP3A4 inhibitor.
Caution should be exercised with the concomitant use of CYP3A-metabolized drugs with narrow therapeutic indices, especially when associated with cardiac arrhythmias The recommended dose of crizotinib is mg taken orally twice daily.
If dose reduction is necessary, mg taken orally twice daily can be used.
If further reduction is required, the dose can be modified to mg taken orally once daily. Because crizotinib is metabolized in the liver, hepatic impairment can lead to higher drug concentrations. In studies, patients were excluded if their serum se aminotransferase ast or alanine aminotransferase ast was more than 2.
Managing treatment–related adverse events associated with Alk inhibitors
In patients with significant hepatic dysfunction, crizotinib should be used with caution. The central nervous system cns is a common site of progression in ALK -positive, crizotinib-treated nsclc patients.
A number of reports describe patients who continued to respond systemically, but who progressed in the cns 17 One possible explanation comes from a pharmacokinetic analysis in a single patient showing poor cerebrospinal fluid penetration Routine surveillance of the cns should therefore be considered in all crizotinib-treated patients.
Patients who develop cns metastases as an isolated site of progression can often undergo cns radiation and continue crizotinib to control systemic disease Second-generation Alk inhibitors have shown promising activity in the cnsand further data will be forthcoming Crizotinib is generally well tolerated, with most ae s being grade 1 or 2.
Those ae s include visual disorders, gastrointestinal effects nausea, diarrhea, vomiting, constipationedema, and fatigue. Visual disturbance is a unique side effect associated with changes in ambient lighting—for example, moving from a dark to a light room. Patients commonly describe trails or flashes of light in their peripheral vision that are typically mild and short-lived discussed in more detail later in this article.
Table i describes the ae s commonly seen across the key studies in which the safety profile of crizotinib is quite consistent.
Nausea, vomiting, and diarrhea tend to occur early in treatment median time to onset: Over time, the visual and gastrointestinal effects tend to improve. Patients on treatment for more than 6 months did not have any new ae s or issues related to prolonged exposure 8. The occurrence of grades 3 and 4 toxicities was relatively uncommon. In profilethe most frequently described grades 3 and 4 ae s were elevated alanine aminotransferase 3.
Other rare, but potentially serious, toxicities include pneumonitis. Although leatrte possibility of serious ae s from crizotinib is relatively low, proactive monitoring is important to mitigate the risk. Table ii describes the key toxicities and suggests parameters letartf monitor.
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Table iii describes the recommended dose modifications for crizotinib-related ae s. Recommended monitoring for patients on crizotinib Dose modifications for crizotinib related adverse events Several second-generation Alk inhibitors are currently in phase i and ii testing.
Visual disorders were rare Further studies will help to elucidate the differences in side-effect profile between crizotinib and the second-generation Alk inhibitors. The most common side effect of crizotinib is visual disturbance. Typically, this disturbance occurs early median time to onset of less than 2 weeks. The visual effects are predominantly grade 1, and in the profile and trials, no patients required dose interruptions or reductions because of them 8 Ophthalmologic assessment was carefully performed in the profile study, and no clinically meaningful changes were found.
In patients treated on profilea visual symptom assessment questionnaire was completed on day 1 of each cycle. Over time, the visual effects occurred less frequently. Patients typically reported visual events in the morning or evening. The most common symptoms included the appearance of shimmering, flashing, or trailing lights; appearance of streamers, strings, or floaters; and overlapping shadows or afterimages.
The events were short-lived, typically lasting less than 1 minute.
Most patients reported that the visual effects were not at all or only a little bothersome. Similarly, they indicated no or minimal impact letartte visual effects on activities of daily living In clinical practice, patients on crizotinib do not require baseline or routine ophthalmologic assessments. However, if visual changes worsen in severity, ophthalmologic evaluation should be considered. A practical question about ability to drive often comes up at crizotinib start.
No specific data address legarte question, but the product monograph recommends that caution should be exercised during driving or operating machinery by patients who experience vision disorders. We typically advise patients to observe how their vision is invice in low light conditions and, if they are significantly affected a minority of patientsto refrain from driving at those times of day until symptoms improve.
Abnormalities in liver enzymes are frequently observed with crizotinib, and in some cases, significant elevations can occur. A pooled analysis of profile and that included more than patients treated with crizotinib calculated the overall incidence of liver enzyme abnormalities Table iv Incidence of hepatic learte abnormalities among patients in profile and profile Most patients who experience liver enzyme elevation do so within the first 2 months of treatment.
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However, liver enzyme elevation can occur later on as well. Transaminase elevations are usually reversible, and patients kndice typically able to resume treatment at the same or a lower dose. Temporary discontinuation or dose reduction because of a hepatic adverse event occurred in 5. Permanent discontinuation because of a hepatic adverse event occurred in 1. Based on those findings, it is important to monitor liver enzymes while patients are on crizotinib, especially within the first 2 months.
Symptoms of liver dysfunction should prompt assessment for possible drug-induced liver injury.