Understanding, recognizing, and managing toxicities of targeted anticancer therapies - Dy - 2. CA: A Cancer Journal for Clinicians. Introduction. The development of a large number of targeted therapies for cancer in the past decade has led to new mechanism- based adverse effects of new drug classes that affect virtually every organ system in the body. Early termination of the clinical development of some of these drugs was prompted by unanticipated toxicities. Moreover, the majority of these agents are administered in a continuous fashion, thus making cumulative toxicities a common event. A recent meta- analysis of randomized clinical trials with targeted agents showed what many individual studies have reported: that alongside the improvement in survival outcomes, treatment discontinuation due to toxicity and toxic deaths was greater for these new agents compared with control groups. This article aims to provide a succinct overview of toxicities, associated with novel agents (excluding radiopharmaceuticals and antibody–drug conjugates), and relevant implications for the management of patients. The targets and associated toxicities discussed in the following sections are graphically depicted in Figures 1 (signal transduction targets) and 2 (immunologic targets). Toxicities Associated With Signal Transduction Inhibitors.*Associated predominantly with monoclonal antibodies. ATE indicates arterial thromboembolism; CSR, central serous retinopathy; HZV, herpes zoster virus; LV, left ventricular; PAH, pulmonary arterial hypertension; PAOD, progressive arterial occlusive disease; RVO, retinal vein occlusion; SCC, squamous cell cancer; VTE, venous thromboembolism. ![]() Toxicities Associated With Drugs Modulating the Immunologic Response. CTLA4 indicates cytotoxic T- lymphocyte antigen 4; IMi. Ds, thalidomide and its analogues; MHC, major histocompatibility complex; PD- 1, programmed death 1; PD- L1, programmed death ligand. The Altmetric score indicates the internet activity relating to a specific article and includes news, blogs and social media. Ambassador David Gross, chair of Wiley Rein’s International & Internet Practice, recently moderated a panel, The Future of Digital Policy in the Global Economy, at. Mechanism- Based Toxicities. On- target toxicities, such as rash associated with inhibitors of the epidermal growth factor receptor (EGFR) signaling pathway or hypertension with inhibitors of the vascular endothelial growth factor receptor (VEGFR) signaling pathway are “class effects” and therefore difficult to prevent by designing different active molecules and thus need to be managed proactively. On 4 April 2013, Wiley revealed that he was leaving his record label Warner following a dispute about his new album The Ascent. Admitting he was unhappy with their. To apply for permission please send your request to [email protected] with specific details of your requirements. This should include, the Wiley title(s), and the. Want to watch this again later? Sign in to add this video to a playlist. BUY THIS TRACK ON iTUNES: http:// TAKEN FROM WILEY'S NEW ALBUM. Feedback for Exercises. 1: Introduction to Instructional Design 2. Using the case of Brad Wiley at the beginning of this chapter. What a pain in the rump to peel the eggs. Half the time the eggs just get ruined and you would be ashamed to serve the tray to your. In the News; Media Mentions; Press Releases; Publications; Alerts; Articles; Blogs; Newsletters; Events; Careers. Overview; Why Wiley Rein. Download 'Lights On' feat Angel & Tinchy Stryder now: http:// 'The Ascent' album out now: http:// Follow Wiley. This is the discography of UK grime artist Wiley. Wiley has released 10 studio albums, including 12 singles. Umusic blog Share our views on music and the biggest stories about the music business. A2A/Shockwave - 3D Lights Redux for FSX - FSPilotShop. Flight Simulator X Utilities. FSX Addons & hardware, yokes, pedals, scenery, aircraft. By definition, these mechanism- based toxicities are shared by all agents that reliably inhibit a specific target. Off- target toxicities are generally observed when therapeutic agents inhibit other unintended targets. Typically, these “off- targets” share structures or residues with the intended targets. ![]() Although these toxicities can be minimized by structural drug design to increase selectivity towards the main target, it is likely that in many instances, complete selectivity is either not feasible or even desired (eg, eliminating platelet- derived growth factor receptor (PDGFR) from a c- KIT inhibitor narrows the spectrum of clinical activity in gastrointestinal tumors). Due to cross- interaction of multiple pathways, toxicities can overlap, whether arising from on- or off- target mechanisms. Moreover, these toxicities can manifest in a wide variety of tissues and organs. Table 1 provides a summary of the frequency and suggested management of adverse effects, both on- and off- target, arising from various classes of targeted therapies discussed below. Table 1. Summary of Selected Adverse Effects Reported in Registrational Studies of FDA- Approved Agents (and in Select Agents Pending FDA Review) and Their Corresponding Management. Dermatologic. Rash. EGFR inhibitors. 49%- 9. Vandetanib < Erlotinibb, Panitumumab < Cetuximab. Prophylactic treatment with oral minocycline or doxycline should be considered, in particular for EGFR/B- raf/MEK inhibitors. Apply broad- spectrum sunscreen. Avoid alcohol- containing skin products. Emollients and mild topical steroids (eg, 1% hydrocortisone cream) can be applied on dry skin 2x- 3x daily. Topical antibiotics can be applied on papulopustular eruptions. For skin rash with moderate pruritus or tenderness, use 0. Withhold treatment for CTC . Continue prophylactic treatment. Avoid lansoprazole use with imatinib due to potential increased risk of dermatologic toxicity. HER2 inhibitors. 4%- 4. Trastuzumab, Pertuzumab < Lapatinib. B- raf inhibitors. Vemurafenib, Dabrafenib. B- raf/MEK inhibitor combination. Dabrafenib+Trametinib. MEK inhibitor. 84%- 8. Trametinib. Multikinase angiogenesis inhibitors. Axitinib, Cabozantinib, Pazopanib, Sunitinib < Regorafenib, Sorafenib,< Ponatinibm. TOR inhibitors. 22%- 5. Everolimus, Temsirolimus. ALK/c- met inhibitors. Crizotinib. Multikinase Abl inhibitors. Dasatinib < Imatinib < Nilotinib, Ponatinib, Bosutinib. BTK inhibitors. 16%- 2. Ibrutinib. HDAC inhibitors. Romidepsin. Proteasome inhibitors. Bortezomib. RXR agonist. Bexarotene (dose- dependent risk)Withhold treatment for CTC > 2 grade or higher rash. Reduce dose by 1. CTC . Permanently discontinue for severe exfoliative/bullous rash or if Stevens- Johnson syndrome is suspected. Immunomodulatory agents. Thalidomide, Lenalidomide, Pomalidomide. Withhold treatment for CTC . May resume at 5. 0% dose reduction upon resolution to baseline or less than grade 1 toxicity. Permanently discontinue for severe exfoliative/bullous rash or if Stevens- Johnson syndrome is suspected. Anti- CTLA4 antibody. Ipilimumab. For moderate rash, withhold therapy and resume once dermatitis improves or becomes localized. Administer topical (eg, 2. May resume therapy once prednisone dose is . If symptoms worsen or if presenting with severe reaction (eg, Stevens Johnson syndrome, toxic epidermal necrolysis), permanently discontinue ipilimumab. Initiate prednisone 1- 2 mg/kg/day or its equivalent. Steroid taper over a month maybe started once rash is improved. Hand–foot skin reaction. Multikinase angiogenesis inhibitors. Pazopanib < Axitinib . Application 2x- 3x a day of moisturizers containing salicylic acid, urea or ammonium lactate recommended upon initiation of treatment. For painful blisters, topical corticosteroids should be considered. Interrupt treatment for painful or intolerable CTC grade 2 or higher toxicities. Dose reduction to be considered as clinically indicated upon resumption of treatment when toxicity improves to CTC grade < 2. Ligand- binding angiogenesis inhibitors. Aflibercept+FOLFIRI (higher incidence compared to chemotherapy only arm)EGFR inhibitors. Cetuximab+FOLFIRI (higher incidence compared to chemotherapy only arm)Cutaneous squamous cell cancer/keratoacanthoma. B- raf inhibitors. Vemurafenib, Dabrafenib. Baseline skin examination and regular dermatologic evaluation. Local excision treatment as indicated. B- raf/MEK inhibitor combination. Dabrafenib+Trametinib. Ocular. EGFR inhibitors. Corneal abnormalities, eg, keratoconjunctivitis: Panitumumab < Erlotiniba, Cetuximab, Vandetanib. Continue treatment. Consider the use of supportive measures (artificial tears, antibacterial ointment if superimposed infection is suspected). Ophthalmologic evaluation is recommended for patients with vision changes, persistent eye pain, photosensitivity or presence of other drug- induced ocular anomalies such as trichiasis. Withhold treatment for CTC grade 3 symptoms. B- raf inhibitors< 1%- 1. NRUveitis, Retinal vein occlusion (RVO): Vemurafenib. Baseline and periodic ophthalmologic examination to be considered during MEK inhibitor therapy. Withhold treatment and coordinate ophthalmologic evaluation for CTC grade 2 or 3 visual changes. If no RVO or chorioretinopathy, may restart treatment at lower dose if symptoms promptly improve to . For prolonged recovery or grade 4 visual changes, permanently discontinue treatment. Chorioretinopathy is generally reversible upon drug discontinuation. B- raf/MEK inhibitor combination. Chorioretinopathy: Dabrafenib+Trametinib. MEK inhibitors< 1- 1. NRRetinal vein occlusion, Chorioretinopathy: Trametinib. ALK/c- met inhibitors. Vision disorders/light- dark adaptation: Crizotinib. Self- limiting. No dose interruption or reduction required. Anti- CTLA4 antibody< 1%NRUveitis, iritis, episcleritis: ipilimumab. Administer corticosteroid or immunosuppressive eye drops. Ophthalmologic examination recommended. Permanently discontinue for severe symptoms or if unresponsive to local therapies aforementioned. Initiated prednisone 1- 2 mg/kg/day or its equivalent. May taper over a month once symptoms improved. Cardiovascular. Decreased left ventricular ejection fraction. Close collaboration with cardiologist is recommended especially in high- risk patients. Baseline and periodic evaluation (eg, every 3 months) of LVEF is recommended for patients with known risk factors. If symptomatic, LVEF decline to < 5. May retreat if LVEF improves to 5. Discontinue treatment for CTC . A representative management algorithm can be found at jco. F2. large. jpg. HER2 inhibitors. NRLapatinib< Trastuzumab, Pertuzumab. Braf/MEK inhibitor combination. Dabrafenib + Trametinib. MEK inhibitor. 8%- 1. Trametinib. Multikinase Abl inhibitors. Imatinib, Nilotinib, Bosutinib < Dasatinib, Ponatinib. Hypertension. Angiogenesis inhibitors (ligand- binding or multikinase inhibitors)9%- 6. Sorafenib, Bevacizumab < Axitinib . BP should be monitored early within the first week of treatment standard anti- hypertensive therapy should be initiated promptly, preferably with ACEi if there are no contraindications. Target BP is < 1. Hg. Treatment should be interrupted for severe hypertension (. Dose reduction should be implemented upon improvement in BP control. Treatment should be permanently discontinued in patients with life- threatening symptoms (eg, reversible posterior leukoencephalopathy syndrome) or with persistently uncontrolled hypertension despite antihypertensive medications. QT prolongation. Multikinase angiogenesis inhibitors. NR- 1. 4%< 1%- 8%Cabozantinib, Ponatinib < < Pazopanib, Sunitinib < < Vandetanib (6. QT prolongation > 4. QT prolongation > 5.
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