Chemotherapy of malignant tumors Ewa Chmielowska

Intraductory remarks Indication to carry out an anticancer CHT should only be made by a specialized oncologist And should only be realized under the supervision of and trained staff Qualification, monitoring , Safety/effective treatment

Chemotherapy - What is this ? Chemotherapeutic agent are focused on killing rapidly proliferating cancer cells Target – cellular metabolic process including DNA, RNA and protein biosynthesis Not specific for cancer cells New type of CHT is termed targeted therapy. These are biologic agents more specific for cancer cells ( signal transduction and cellular signalling stop)

The history Chemotherapy have been known since the 1950s Alkylating( CTX) ,antimetabolites:antifolates( MTX, Cytosar)fluoropirymidines( FU), microtubules agents( VCR) Topoisomerase interactive agents: TPT, Camto,Vp Antracyclines Cisplatin and analogues Taxanes

Biotherapeutics Interferons: recombinant alfa 2 Interleukin-2 Ipilimumab nivolumab

Old targeted anticancer drug= endocrine manipulation Breast cancer: selective estrogen receptor modulator – Tamoxifen,raloxifen, fulvestrant Medroksyprogesterone Aromatase inhibitors steroidal and nonsteroidal – blocked estrogen synthesis via conversion of the androgen and testosteron in post menopausal women LHRH analogs

Endocrine amnipulation Prostate cancer: LHRH analogs- Antiandrogens – flutamid( treatment combined with GnRH analog) Bicalutamid -nonsteroidal antiandrogen binding receptor 4 times more than flutamid Lastly: abiraterone, enzalutamid

New Targeted Anticancer Drug Histone Deacetylase Inhibitors( HDACs) – enzyme involved in epigenetic gene regulation Monoclonal antibody (Mabs) mouse, human: rituximab, trastuzumab, alemtuzumab, ibritumomab tiuxetan, bevacyzumab, cetuximab, panitumumab TKI inhibitors: gefitinib, erlotinib M-TOR inhibitors: everolimus, temsirolimus

Dose calculation and modification Dose is calculated on the basis of the individual body surface area, sometimes on the basis of the patient weight, or on renal function(AUC) Dose modifications are indicated in dependence of the toxicity- hematologic or others – reduction or delay – CTC criteria Maximal dose( individual or cumulative) should not to be exceeded: eg ADB, BLEO

Metronomic chemotherapy Chronic administration Low dose at close regular intervals No prolonged drug free interruptions Lower toxicity Reduced risk of drug resistant tumor cells Antiangiogenic activity

Special pre and co-medication -examples To redue risk of hypersensivity ( taxanes, pegylated doxorubicin) – dexamethasone Monitoring the blood level of drug ( MTX, FU) Folinic acid to rescue HD MTX Mesna- uroprotective agent ( HD CTX, Ifosfamid) To reduce risk of nephrotoxicity ( cispatinum) hydratation 0,9 % Saline minimum 1000 ml

Chemotherapy – steps in drug development Drug candidate selection via pharmacology Production and formulation Safety assesssment – toxicology Phase I clinical trials Phase II Phase III-IV Approval via FDA , EMA General Medical practice

What we should know Pharmacokinetics and pharmacodynamics of the drug– concentration-response relationships: bioavailability, volumes of distribution, protein binding free, drug concentration, clearance, elimination half time, dose proportionality Mechanism of resistance

Practice informations Treatment plan is based on: 1.pathomorphologic diagnosis ( includes IHC or genetic evaluation) 2.TNM staiging ( any necessairy lab, CT scans, endoscopy) 3. all informations about concomitant diseases 4. toxicity profile of agents 5. patients prefernce

Type of therapy Radical Palliative Best supportive care Remission induction Maintenance Consolidation

What we should done during treatment Control the efficacy ( CR, PR, SD, PD) Control the toxicity Differentiate between symptoms of progression and others comorbidities Remember about roules of combined modality treatment ( with surgery, radiotherapy)

Homework Group 1: breast cancer and ovarian cancer Group 2: lung cancer and colon cancer Questions : 1 .Clinical course of disease 2. Main rules of treatment