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Description : oncologic treatments and secondary effects

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Published on : May 23, 2023 | Views : 885 | Downloads : 0

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Machine Translated by Google
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DIARY Generalities in cancer Signaling pathways and targeted therapies • Advancing Oncology • Treatment of advanced disease Types of oncospecific treatments and their toxicities • Review of adverse effects Conclusions General recommendations Machine Translated by Google
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CANCER Machine Translated by Google
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Before we thought... Machine Translated by Google
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Now we know... Machine Translated by Google
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MOLECULAR TARGETS FOR TARGETED THERAPIES Machine Translated by Google
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Those weird names... Adenocarcinoma of the stomach or gastroesophageal junction: Trastuzumab (Herceptin®), ramucirumab (Cyramza®) Brain cancer: Bevacizumab (Avastin®), Everolimus (Afinitor®) Colorectal cancer: Cetuximab (Erbitux®), panitumumab (Vectibix®), bevacizumab (Avastin®), ziv-aflibercept (Zaltrap®), regorafenib (Stivarga®), ramucirumab (Cyramza®), nivolumab (Opdivo®) Cervical Cancer: Bevacizumab (Avastin®) Liver cancer: Sorafenib (Nexavar®), regorafenib (Stivarga®) Pancreatic cancer: Erlotinib (Tarceva®), everolimus (Afinitor®), sunitinib (Sutent®) Skin cancer: Vismodegib (Erivedge®), sonidegib (Odomzo®), ipilimumab (Yervoy®), vemurafenib (Zelboraf®), trametinib (Mekinist®), dabrafenib (Tafinlar®), pembrolizumab (Keytruda®), nivolumab (Opdivo®), cobimetinib (Cotellic™), alitretinoin (Panretin®), avelumab (Bavencio®) Prostate cancer: Cabazitaxel (Jevtana®), enzalutamide (Xtandi®), abiraterone acetate (Zytiga®), radium 223 chloride (Xofigo®) Lung cancer: Bevacizumab (Avastin®), crizotinib (Xalkori®), erlotinib (Tarceva®), gefitinib (Iressa®), afatinib dimaleate (Gilotrif®), ceritinib (LDK378/Zykadia™), ramucirumab (Cyramza®), nivolumab (Opdivo®), pembrolizumab (Keytruda®), osimertinib (Tagrisso™), necitumumab (Portrazza™), alectinib (Alecensa®), atezolizumab (Tecentriq™), brigatinib (Alunbrig™), trametinib (Mekinist®), dabrafenib (Tafinlar®) Kidney cancer: Bevacizumab (Avastin®), sorafenib (Nexavar®), sunitinib (Sutent®), pazopanib (Votrient®), temsirolimus (Torisel®), everolimus (Afinitor®), axitinib (Inlyta®), nivolumab (Opdivo® ), cabozantinib (Cabometyx™), lenvatinib mesylate (Lenvima®) Breast cancer: Everolimus (Afinitor®), tamoxifen, toremifene (Fareston®), trastuzumab (Herceptin®), fulvestrant (Faslodex®), anastrozole (Arimidex®), exemestane (Aromasin®), lapatinib (Tykerb®), letrozole (Femara®), pertuzumab (Perjeta®), ado-trastuzumab emtansine (Kadcyla®), palbociclib (Ibrance®), ribociclib (Kisqali®), neratinib maleate (Nerlynx™) Thyroid cancer: Cabozantinib (Cometriq®), vandetanib (Caprelsa®), sorafenib (Nexavar®), lenvatinib mesylate (Lenvima®) Bladder cancer: Atezolizumab (Tecentriq™), nivolumab (Opdivo®), durvalumab (Imfinzi™), avelumab (Bavencio®), pembrolizumab (Keytruda®) Head and neck cancer: Cetuximab (Erbitux®), pembrolizumab (Keytruda®), nivolumab (Opdivo®) Ovarian epithelial cancer, fallopian tube cancer, primary peritoneal cancer: Bevacizumab (Avastin®), olaparib (Lynparza™), rucaparib camsylate (Rubraca™), niraparib tosylate monohydrate (Zejula™) Dermatofibroma protuberans: Imatinib mesylate (Gleevec®) Leukemia: Tretinoin (Vesanoid®), imatinib mesylate (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), rituximab (Rituxan®), alemtuzumab (Campath®), ofatumumab (Arzerra® ), obinutuzumab (Gazyva®), ibrutinib (Imbruvica®), idelalisib (Zydelig®), blinatumomab (Blincyto®), venetoclax (Venclexta™), ponatinib hydrochloride (Iclusig®), midostaurin (Rydapt®), enasidenib mesylate (Idhifa®), inotuzumab ozogamicin (Besponsa®), tisagenlecleucel (Kymriah®), gemtuzumab ozogamicin (Mylotarg™), rituximab and hyaluronidase human (Rituxan Hycela™) Lymphoma: Ibritumomab tiuxetan (Zevalin®), denileukin diftitox (Ontak®), brentuximab vedotin (Adcetris®), rituximab (Rituxan®), vorinostat (Zolinza®), romidepsin (Istodax®), bexarotene (Targretin®), bortezomib (Velcade ®), pralatrexate (Folotyn®), ibrutinib (Imbruvica®), siltuximab (Sylvant®), idelalisib (Zydelig®), belinostat (Beleodaq®), obinutuzumab (Gazyva®), nivolumab (Opdivo®), pembrolizumab (Keytruda®), rituximab and hyaluronidase human (Rituxan Hycela™) Systemic mastocytosis: Imatinib mesylate (Gleevec®), midostaurin (Rydapt®) Multiple Myeloma: Bortezomib (Velcade®), carfilzomib (Kyprolis®), panobinostat (Farydak®), daratumumab (Darzalex™), ixazomib citrate (Ninlaro®), elotuzumab (Emplicit™) Neuroblastoma: Dinutuximab (Unituxin™) Soft tissue sarcoma: Pazopanib (Votrient®), olaratumab (Lartruvo™), alitretinoin (Panretin®) Myelodysplastic and myeloproliferative disorders: Imatinib mesylate (Gleevec®), ruxolitinib phosphate (Jakafi®) Giant cell tumor of bone: Denosumab (Xgeva®) Gastrointestinal stromal tumor: Imatinib mesylate (Gleevec®), sunitinib (Sutent®), regorafenib (Stivarga®) Endocrine and neuroendocrine tumors: Lanreotide acetate (Somatuline® Depot), avelumab (Bavencio®) Solid microsatellite tumors with high instability or poor repair due to incompatibility: Pembrolizumab (Keytruda®) Machine Translated by Google
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Past and present Machine Translated by Google
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responder molecular targets Side effects personalized cancer therapy other therapies no treatment Selection High response rate Specific drugc no benefit no selection conventional chemotherapy towards personalized therapy Machine Translated by Google
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Other not insignificant toxicities Machine Translated by Google
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The advancement of Oncology is much… EVOLUTION OF MEDICINE NO CURE SCIENTIFIC BREAKTHROUGH + SURVIVAL CHRONICITY HEALING Machine Translated by Google
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Survivals of up to 20 m in EGFR mutants and 30 m in metastatic ALK translocations THE THREE BIG KILLERS Survivals up to 30 m in clinical trials Metastatic disease ÿ terminal (but always a candidate for palliative care) Metastatic patient ÿ terminal patient Mean survival according to M1 location Ipsilateral pleura: 44 months Bone: 36 months. Lung: 24 months. Survival in 1st line metastatic Her-2+: 56.8 m Machine Translated by Google
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For this reason, the treatment of advanced cancer… Machine Translated by Google
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Until when the oncospecific treatment? According to number of cycles or tumor progression • Limiting dose due to adverse effects No clinical benefit Unacceptable toxicity Patient decision Machine Translated by Google
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"In the middle ground is virtue" (Aristotle) Machine Translated by Google
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CHEMOTHERAPY: inhibits the proliferation RENTERS DRUG INHIBITORS of TOPOISOMERASES ANTIBIOTICS ANTIBIOTICS SYSTEMIC TREATMENTS for DISSEMINATED CANCER of tumor cells NON-PERSONALIZED TREATMENT Inhibition of Inhibition of DNA, RNA synthesis INHIBITORS of microtubules -Block cell proliferation in a NONSPECIFIC way -damages rapidly dividing cells - NON-SPECIFIC SIDE EFFECTS -Act in different phases of the cell cycle CLASSICAL CHEMOTHERAPY ANTIFOLATES AND ANTIMETABOLITES THERAPEUTIC GROUP ANTHRACYCLINES ANTHRACYCLINES (doxorubicin) CISPLATIN CARBOPLATIN OXALIPLATIN CAPECITABINE (XELODA) GEMCITABINE They cause breaks in the DNA strands IRINOTECAN TOPOTECAN ETOPOSIDE MECHANISM ACTION Inhibition of DNA synthesis formation inhibition of the mitotic spindle It interferes with the enzyme topoisomerase I that maintains the structure of the DNA TAXANES (taxol, taxotere) vinorelbine Machine Translated by Google
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QT Toxicities: General GENERAL TOXES Grade I 2000-1500 NEUROPATHY CISPLATIN Grade II 1499-1000 TAXOTERE Grade III 999-500 CISPLATIN CISPLATIN vinorelbine NO-> CARBOPLATIN TAXANES TAXANES (taxol) vinorelbine TAXANES NEUTROPENIA CISPLATIN Grade IV <500 TAXANES PLATINUMS NO-> VINORELBINE CHEMOTHERAPY TOXICITIES CHRONICLE ACUTE ANEMIA THROMBLETOPENIA NEUTROPENIA ASTHENIA Machine Translated by Google
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HORMONE THERAPY: first targeted therapy (hormone- dependent tumors) First target-directed therapy It is used in breast cancer, prostate and endometrial cancer. WATERFALL INTRACELLULAR DIANA Machine Translated by Google
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HT toxicities in breast cancer: silent effects TOXICITIES OF HORMONE THERAPY in BREAST CANCER Bone pain, joint stiffness, tendinitis AROMATASE INHIBITORS TAMOXIFEN endometrial hyperplasia ovarian cysts Endometrial cancer thrombosis and phlebitis COMMON SIDE EFFECTS Hot flushes Genitourinary tonos: vaginal dryness repeat cystitis decreased libido Asthenia Tnos of mood SPECIFIC SIDE EFFECTS Osteoporosis/ aggravation/ fractures Hypercholesterolemia Gastritis-> no ulcers cardiovascular alt ** It is known, for example, that some of the antidepressants used with can often decrease the effectiveness of tamoxifen (paroxetine) Machine Translated by Google
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Ttos toxicities (QT/HT) in prostate gland Water retention: 31% vs 22% Ra-223 Enzalutamide Diarrhea: 47% vs. 11% (G3: 6% vs <1%) No increase in secondary neoplasms Elective crises?* ALSYMPCA Docetaxel Others: asthenia, alopecia (65%), nail toxicity (30%), dysgeusia (18%), mucositis (20%), peripheral edema (19%) TROPICS Peripheral neuropathy: 14% vs 3% TAX-327 Diarrhea: 18% vs. 14% Neutropenia: 32% vs 22% Febrile neutropenia: 3% vs 2% Diarrhea: 25% vs 15% (G3: 2% vs. 2%) cabazitaxel Diarrhea: 21% vs. 18% Neutropenia: 1% vs 1% Anemia: 23% vs 26% Febrile neutropenia: 1% vs 1% Anemia: 31% vs 31% (G3-4: 13% vs. 13%) Thrombocytopenia: 12% vs 6% Diarrhea: 32% vs 10% Hypokalemia: 17% vs 8% Hypertransaminasemia: 10% vs 8% Abiraterone AFFIRM Cardiac events: 6% vs 8% Asthenia: 34% vs 29% Neutropenia: 82% vs 58% Febrile neutropenia: 8% vs 1% COU-301 Peripheral neuropathy: 32% vs 10% HTA, Cardiac events: 13% vs 11% The toxicity profile favors Hormonal Agents over QT Machine Translated by Google
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Soluble VEGF receptors VEGF Antibodies that inhibit bevacizumab) –P P– P– –P –P P– P– P– TED THERAPIES against molecular targets that activate the cancer cascade MECHANISM of ACTION of TARGETED TREATMENTS Migration, permeability, DNA synthesis, survival BEVACIZUMAB TRASTUZUMAB PERTUZUMAB ERLOTINIB GEFINITIB LAPATINIB MTachinAe TransRlated bGy GoogEle
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ALK TRANSLOCATION mild-moderate NEUTROPENIA QT prolongation bradycardia DRILLING INTESTINAL ERLOTINIB CRIZOTINIB GEFITINIB TOXICITIES OF TARGETED THERAPIES Anti-EGFR: TYROSINE KINASES INHIBITORS Targeted Therapies Toxicities: Specific (“Class”) Machine Translated by Google
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PANITUMUMAB CETUXIMAB Anti-VEGF-A Anti-EGFR: MONOCLONAL ANTIBODIES BEVACIZUMAB -HTA -PROTEINURIA -BLEEDING -SLOWING in the HEALING of WOUNDS -PERFORATION RISK HYPOMAGNESEMIA ALLERGIC REACTIONS mild-moderate Targeted Therapies Toxicities: Specific (“Class”) TOXICITIES OF TARGETED THERAPIES Machine Translated by Google
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IMMUNOTHERAPY: enhances the natural antitumor immune response Machine Translated by Google
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Immune-related toxicities: not so mild and caution with corticosteroids DIGESTIVE enterocolitis Diarrhea Abdominal pain Blood or mucus in the stool • Intestinal perforation Peritoneal signs • Ileus Fever In symptomatic patients, rule out infectious etiologies Consider endoscopic evaluation in case of persistent or severe symptoms LIVER Signs such as • Abnormal liver function tests (eg, AST, ALT) or total bilirubin Rule out infectious causes or malignancy Increase frequency of liver function test monitoring until resolution CUTANEOUS itching rash Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune mediated. NEUROLOGICAL Symptoms such as • Unilateral or bilateral weakness • Sensory disturbances • Paresthesia, headache, dizziness, change in mood Aseptic meningitis/encephalitis, Guillain-Barré ENDOCRINE Signs and symptoms such as Fatigue Headache • Altered mental status • Abdominal pain • Unusual bowel movements • Hypotension • Abnormal thyroid function tests and/or serum biochemistry (hypothyroidism) • Hypophysitis, hypogonadism • Adrenal insufficiency (including acute ) • Hyperthyroidism or hypothyroidism • Nonspecific symptoms that may resemble other causes (eg, brain metastases) PULMONARY, RENAL Pneumonitis ERA (creatinine elevation) OTHER ADVERSE REACTIONS, including ocular manifestations Machine Translated by Google
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symptomatic treatment (prednisone 0.5-1 mg/kg/day) (methylprednisolone 1-2 mg/kg/day) - Oral corticosteroids -High-dose IV corticosteroids resolution - We delay dose until - If symptoms do not remit 5-7 days consider other immunosuppressive treatments - Discontinue Nivolumab Definitively Management of IT AEs according to severity/persistence mild Persistent mild or moderate Serious, severe, or life- threatening Machine Translated by Google
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"It is worth it who takes it from you" (Anonymous) Machine Translated by Google
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- Any F can produce it (especially QT and Tki) ASTHENIA • Frequent 65.70% (up to 10% g.3) • Differential diagnosis: hypothyroidism, anemia, depression, insomnia, malnutrition, hypophosphatemia, hypoMg, dehydration, cancer, or comorbidities Treatment of the cause + non-pharmacological measures + psychotherapy Machine Translated by Google
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Osmotic and secretory diarrhea Impaired intestinal motility and GI perforation • Typhlitis (neutropenic enterocolitis) • Immune- mediated colitis (abdominal pain, alt.endoscopic and radiological of colonic inflammation) Hydration, Loperamide +/- Ocreotide (contraindicated in Immunotherapy) or Corticosteroids (for this) 5Fu, Capecitabine, Irinotecan, Cabazitaxel Suni/Sora/Pazopanib, Axitinib, Cabozantinib Lapatinib, Imatinib, Crizotinib Trametinib, Ibrutinib Ipilimumab, Pembrolizumab, Nivolumab Bevacizumab, Cetuximab, Panitumumab DIARRHEA (but also ILEUS/Constipation) Machine Translated by Google
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…. - -QT Cetuximab, Erlotinib Suni/Pazo/Sorafenib High sensitivity, dysgeusia, xerostomia, stomatitis • Sometimes without mucosal lesions (functional) Associated with candidiasis Relationship with oral hygiene Non-alcoholic rinses, bicarbonate water, thyme, topical anesthetics, nystatin + dietary measures MUCOSITIS Machine Translated by Google
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ARTERIAL HYPERTENSION (and proteinuria) …. - Effects on vascularity Frequency 30%-60% (g.3 in 10%), early onset • Surrogate response factor/SV • Important to monitor Non- serious and controllable with antiHTN (BP<140/90): angiotensin inhibitors, beta-blockers, diuretics, ACE inhibitors (do not use Verapamil/ Diltiazem x Sunitinib, Pazopanib Bevacizumab Abiraterone Machine Translated by Google
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CARDIAC TOXICITY FEVi decrease, arrhythmias, QT prolongation, ischemic heart disease Infrequent and generally reversible • Echocardiogram/basal ECG and controls Interruption/suspension required if g.3-4 ACE inhibitors, beta-blockers, furosemide - Anthracyclines (Adriamycin>Epirubicin; protected with liposomal Adriamycin) Fluorpyrimidines (5-Fu, Capecitabine) Taxanes -Tki: Suni/Pazopanib … Caution with other Fs that prolong QT Machine Translated by Google
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SKIN TOXICITY Liposomal Adriamycin, Fluorpyrimidine, Mtx Suni/Sora/Pazopanib (improves when taken in the evening), Cabozantinib, Imatinib Dabrafenib, Vemurafenib, Regorafenib Immunotherapy EGFR inhibitors: Gefitnib, Erlotinib, Lapatinib Hand-foot syndrome (palmar-plantar erythrodysesthesia): physical or functional (tingling and numbness), lichenoid reactions, acneiform eruption, photosensitivity, pigmentation • Forces interruptions and delays Prevention and treatment: emollients, keratolytics and salicylic agents, topical corticosteroids, pregabalin Machine Translated by Google
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EFFECTS ON HAIR AND NAILS Alopecia • Depigmentation of skin (yellow) and hair (“a stripes") Paronychia, onycholysis, pyogenic granuloma There is no treatment for the hair but the nails (AB, silver nitrate) Chemotherapy Tki: Suni/Sora/Pazopanib Machine Translated by Google
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METABOLIC TOXICITIES and others Hyperglycemia (Metformin) • Hypercholesterolemia, HyperTg (Atorvastatin, fibrate) • Hypophosphatemia, hypomagnesemia (phosphate, Mg) • Hepatotoxicity: GOT/GPT elevation, B • Neurological disorders: posterior reversible encephalopathy, aseptic meningitis, neuropathies, S.Guillain- Barré • Nephrotoxicity: nephritis, IR Asymptomatic pancreatitis m-TOR inhibitors: Temsiolimus, Everolims Immunotherapy -QT Machine Translated by Google
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INFECTIONS By direct toxicity Due to immunosuppression associated with cancer Due to Neutropenia • Opportunistic infections in patients with Immunotherapy (immunosuppression to treat adverse effects) Temsirolimus, Everolimus -QT Immunotherapy Machine Translated by Google
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PNEUMONITIS -QT Temsirolimus and Everolimus Immunotherapy Infrequent Important to exclude other causes: infection and lung disease (lymphangitis, PTE, M1 pulmonary) Corticosteroids and support measures Machine Translated by Google
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ENDOCRINE TOXICITY Hypothyroidism > hyperthyroidism • Hypophysitis (headache, fatigue and radiological alt.) Adrenal crisis Specific treatment, corticosteroids +/- Infliximab Suni/Pazo/Sorafenib Immunotherapy: Ipilimumab, Tremelimumab, nivolumab, pembrolizumab Machine Translated by Google
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HEMATOLOGICAL TOXICITY Anemia, Neutropenia and Thrombocytopenia • Hemorrhage/bleeding • Arterial and venous thromboembolism: D Transfusions, EPO, Filgrastim LMWH Especially the QT Bevacizumab The rest of the treatments Machine Translated by Google
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CYP3A4 and other interactions St. John's wort Grapefruit Alternative therapies Machine Translated by Google
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“Quality of Life is more important than life itself (Alexis Carrel) Machine Translated by Google
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Support Treatment Machine Translated by Google
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CONCLUSIONS Adverse effects can appear at any time . organ or system Its frequency and severity depends on the type of drug, disease situation, and patient • They are generally reversible and can be treated • Often associated with tumor response to treatment Sometimes, they force delays and dose reduction • They must always warn to act on them Machine Translated by Google
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In all patients receiving oncospecific treatment It is recommended… Call HDD to consult (for the patient to do so on the phone indicated for this) • Send to the hospital if fever (except in the 1st 24h of adm.) Symptomatic treatment in the first place • When suspected: do not remain in doubt • Do not forget that sometimes they are related to therapeutic benefit We work as a team: ESAD may be the one that realizes the adverse effect before Machine Translated by Google
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It is discouraged… In patients treated with Immunotherapy (“vaccines”): prescribe corticosteroids, Loperamide if diarrhea Drugs that interact with CYP3A4 • Neglect persistent symptoms Stay with the doubt without consulting Machine Translated by Google
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(Antonio Machado) Thank you all!! Machine Translated by Google