Chemo-, hormonal-, and targeted therapy Dr. Judit Toth Department of Oncology Medical University of Debrecen

Chemotherapy is used for a variety of purposes: To cure a specific cancer; To control tumor growth when cure is not possible; To relieve symptoms (such as pain) To shrink tumors before surgery or radiation therapy; To destroy microscopic cancer cells that may be present after the known tumor is removed by surgery (called adjuvant therapy). Adjuvant therapy is given to prevent a possible cancer micro-metastases

Chemotherapy Terms Adjuvant chemotherapy Neoadjuvant chemotherapy Palliative chemotherapy

Neoadjuvant Therapy : Definition Neoadjuvant therapy, also named primary therapy or preoperative therapy, is a systemic treatment delivered before the local treatment, such as surgery and/or radiotherapy

Neoadjuvant Therapy Rationale – Decrease in the tumor size leading to a more conservative surgery, and facilitating surgical procedures – To eradicate micrometastases

Neoadjuvant Therapy Rationale and Indication – Patients with locally advanced disease – Decrease in the tumor size leading to a more conservative surgery, and facilitating surgical procedures – To eradicate micrometastases Treatment – Chemotherapy – Hormonotherapy – Targeted therapy

8 Cancer and Treatment Strategies Two different approaches – Local disease – Local disease  curative treatment To treat the primary tumor (  local lymph nodes) To eradicate micrometastases = adjuvant therapy – Advanced or metastatic disease Very occasionally to cure!

9 Cancer and Treatment Strategies – Local disease – Advanced or metastatic disease – Advanced or metastatic disease  palliative treatment Advanced disease = unresectable tumor or large regional lymph node involvement Metastases To controll signs and symptoms of disease Improve quality of life Prolong life Very occasionally to cure!

10 Chemotherapy Classification (I) FamilyMoleculesTargets Anthracyclines- Anthracenediones Doxorubicin Epirubicin Idarubicin Mitoxantrone Topoisomerase II DNA Topo-I InhibitorsIrinotecan Topotecan Topoisomerase I DNA AntimetabolitesFluorouracil Methotrexate Mercaptopurine Fludarabine Cytarabine Gemcitabine Capecitabine Puric and pyrimidic bases

Chemotherapy Classification (II) FamilyMoleculesTargets Alkylating agentsCyclophosphamide Melphalan Ifosfamide Busulfan DNA Spindle inhibitorsVinorelbine Vincristine Vindesine Vinblastine Tubuline Docetaxel Paclitaxel Platinum saltsCarboplatine Cisplatine Oxaliplatine DNA

„saturation bombing” =chemotherapy?

Side effects of chemotherapy 14

Hair loss: why does it occur? Chemotherapy drugs are powerful medications that attack rapidly growing cancer cells. Unfortunately, these drugs also attack other rapidly growing cells in body. – including those in hair roots, eyelash, eyebrow, armpit and other body hair also falls out. Hair usually begins falling out one to three weeks after starting treatment and re-grows three to 10 months after treatment ends.

Side effects of chemotherapy Hair loss Myelo-suppression

Myelosuppression Bone marrow suppression is a common side effect of chemotherapy that is characterized by a decrease in blood cell production. Myelosuppression can result in the decrease in one, two or all three types of blood cells. – Anemia – Thrombocytopenia – Neutropenia Different kinds of growth factors can be used to target the reproduction of red blood cells, white blood cells or platelets.

Side effects of chemotherapy Hair loss Myelo-suppression Nausea, Vomiting – Prevention is best defense! 18

The vomiting centre (VC) in the medulla oblongata, the chemoreceptor trigger zone (CTZ) in the area postrema (AP) on the caudal margin of the IVth ventricle, aprepitant (Emend®) dolasetron (Anzemet®) granisetron (Kytril®) ondansetron (Zofran®) palonosetron (Aloxi®) proclorperazine (Compazine®) p romethazine (Anergan®),(Phenergan®) lorazepam (Ativan®) metoclopramide (Reglan®) dexamethasone (Decadron®) famotidine (Pepcid®) ranitidine (Zantac®) 19

Vomiting and nausea Certain chemotherapy drugs are more likely than are others to cause nausea and vomiting: Cisplatin Carboplatin Oxaliplatin Cyclophosphamide (Cytoxan) Doxorubicin or epirubicin Dacarbazine Anti-nausea medications are typically given before treatment !!! 20

Side effects of chemotherapy Cardiotoxicity and cardiomyopathy – Fortunately, heart disease associated with chemotherapy is relatively rare. (Not all chemotherapy drugs carry the potential side effect of heart damage and often temporary :Doxorubicin, 5-FU) – some newer anti-cancer treatments — such as trastuzumab (Herceptin) for breast cancer — may cause heart damage.

Peripheral neuropathy Peripheral neuropathy is caused by damage to nerves, most commonly the sensory nerves (nerves that sense touch, heat or pain). – Pain, burning or tingling in fingers, toes, hands and feet – Loss of sensation to touch – Muscle weakness and balance problems – Decreased reflexes 22

Skin side effects Allergy Hand foot syndrome (HFS) 23

Nephrotoxicity Strong nephrotoxic anticancer agents are: cisplatin and ifosfamide: – cause necrosis of the proximal tubules methotrexate: – deposits and blocks the tubule Sufficient renal function is important before administration of the anticancer drug ! 27

Sharp shooter = targeted therapy? 28

Examples of targets being investigated in cancer treatment Examples of targeted anticancer therapies approved or in development General targetSpecific targetAgent or approach Signal transductionGrowth factor receptors ErbB1 (EGFR) ErbB2 (HER2) ErbB1 and ErbB2 Bcr-Abl Ras Raf Erlotinib, gefitinib Trastuzumab Tyverb Imatinib Farnesyl transferase inhibitors Antisense oligonucleotides Angiogenesis and metastasis VEGFR2 VEGF Matrix metalloproteinases Integrins Sunitinib Bevacizumab Pazopanib AE-941 Humanised LM609 mAb Tumour suppressor gene p53 p16Gene therapy Cell-cycle controlCyclin-dependent kinases mTOR Flavopiridol Temsirolimus (CCI779) Everolimus 29

Endocrine Therapy

 Less toxic effective method of disease control  Hormone responsive disease:  70% of breast cancer patients (ER/PR+)  90% of prostatic cancer patients  Endometrium carcinoma  ~1% of other malignancies (Lung, renal cancer)

Hormonal therapy The signals from the hormonal receptors "turn on" growth in cells. Inhibitors of hormone synthesis: – Analogs of gonadotropin-releasing hormone (GnRH) can be used to induce a chemical castration – Aromataze inhibitors(letrozol, anastrazol,examestane) Hormone receptors antagonists: – Selective Estrogen Receptor Modulators(tamoxifen) – Antiandrogens(nilutamid, flutamide)

Thank you if you are still awake