Principles of chemo for gyn (revised)

Principles of chemo for gyn (revised)

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  Principles of Chemotherapy HALETEKA, M.D, OB/GYN RESIDENT, MEKELLE UNIVERSITY 7/26/2019 1 HALE TEKA, M.D., RESIDENT PHYSICIAN By Hale at 5:35 pm, Jul 26, 2019
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  Contents 1. Biology ofcancer growth 2. Clinical use of chemotherapy 3. Pharmacologic principles 4. Chemotherapeutic drugs 5. Biological and targeted therapy 6. Side effects 7. Growth factors 8. Chemosensitivity and resistance assays 9. Cancer drug development 10. Chemotherapy regimens in common Gyn Onco 11. References 7/26/2019 2 HALE TEKA, M.D., RESIDENT PHYSICIAN
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  Introduction • General principlesof cancer treatment – Surgery – Chemotherapy • Incoorperated in the last 50 years – Radiotherapy 3 7/26/2019 Hale Teka, M.D., Resident Physician
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  Biology of CancereGrowth 7/26/2019 HALE TEKA, M.D., RESIDENT PHYSICIAN 4
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  Biology of CancerGrowth • There are inherent differences in between normal and cancerous cells in growth pattern – Cancer cells have more cell mass at active phase of replication and normal cells have more cell mass at G • Thus, chemotherapeutic drugs are designed to kill cancer cells and spare normal cells • All cancer cells have also inherent differences in their growth pattern – Thus different chemo therapies for different cancers 5 7/26/2019 Hale Teka, M.D., Resident Physician
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  The Cell Cycle •All cells follow the same basic sequence for replication • There are 5 phases of cell cycle • The time required to compelete these phases is called ➔ Cell Generation Time 6 7/26/2019 Hale Teka, M.D., Resident Physician
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  • Tumors donot have faster generation times, they instead have – More cells in active replication (only few cells in Go Phase) – Dysfunctional appoptosis 7/26/2019 Hale Teka, M.D., Resident Physician 7
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  Cancer Cell Growth •Gompertzian growth pattern – Exponential growth phase • When the cancer is microscopic and nonpalpable in early phase • Sensitive to chemotherapy – Delayed growth phase • Limitations in blood supply and increased interestitial pressure 8 7/26/2019 Hale Teka, M.D., Resident Physician
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  • Clinical implicationsof Gompertzian growth pattern 1. Metastatic loci more sensitive than the primary tumor 2. Debulking surgery leads to microscopic residues sesitive to chemotherapy • More cells are propelled from Go ➔ G1 3. Shrinking tumor takes more cells into active phase leading to enhanced response 9 7/26/2019 Hale Teka, M.D., Resident Physician
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  The Gompertzian growthcurve 10 •Most tumors have completed their exponential growth phase at the time of clinical detection. •During early stages of tumor expansion, growth is exponential, but with enlargement, tumor growth slows. 7/26/2019 Hale Teka, M.D., Resident Physician
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  Doubling Time • CellCycle – Activity of a single tumor cell • Doubling time – Time needed for a tumor (entire mass) to double in size • Growth fraction – Number of cells that are actively dividing – GTN has high growth fraction thus very sensitive to chemotherapy 11 7/26/2019 Hale Teka, M.D., Resident Physician
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  Cell Kinetics • Drugsachieve cell kill at several phases of the cell cycle – Cell cycle specific Vs nonspecific – Combining drugs that work at different cell cycle might enhance overall cell kill • Chemotherapeutic agents typically work by first-order kinetics – They kill a constant fraction of cells rather than a constant number • A cancer’s curability is inversely proportional to the number of viable tumor cells at the beginning of chemotherapy 12 7/26/2019 Hale Teka, M.D., Resident Physician
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  Cell Cycle Specific •Antimetabolites – 5-Fluorouracil (5-FU) – Gemcitabine – Methotrexate • Antitumor antibiotic – Bleomycin • Epipodophyllotoxins – Etoposide • Taxanes • Vinca alkaloids – Vinblastine – Vincristine Cell Cycle–Nonspecific • Alkylating agents – Busulfan – Cyclophosphamide • Anthracyclines – Doxorubicin • Antitumor antibiotics – Dactinomycin • Camptothecins – Topotecan • Platinum analogs – Carboplatin – Cisplatin 7/26/2019 13 Hale Teka, M.D., Resident Physician
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  Clinical Use ofChemotherapy 7/26/2019 HALE TEKA, M.D., RESIDENT PHYSICIAN 14
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  Clinical Setting • Induction –Primary treatment for patients with an advanced malignancy when no feasible alternative treatment exists • Adjuvant – Given to destroy remaining microscopic cells that may be present after the primary tumor is removed by surgery • Neoadjuvant – Drug treatment directed at an advanced cancer to decrease preoperatively the extent or morbidity of a subsequent surgical resection 15 7/26/2019 Hale Teka, M.D., Resident Physician
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  • Consolidation (Maintenance) –Given after cancer has disappeared following the initial therapy to prolong the duration of clinical remission or to prevent ultimate relapse • Salvage (Palliative) – Therapy applied to recurrent disease or to a tumor that is refractory to initial treatment 16 7/26/2019 Hale Teka, M.D., Resident Physician
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  Different Clinical Settingsfor Delivering Chemotherapy Categories Gynecologic Oncology Examples Induction Metastatic gestational trophoblastic neoplasia Adjuvant Platinum-based chemotherapy for advanced ovarian cancer after surgical debulking Neoadjuvant Primary platinum-based chemotherapy for advanced ovarian cancer that is initially unresectable Consolidation Paclitaxel or bevacizumab for advanced ovarian cancer in remission Salvage Recurrent or persistent gynecologic cancer not amenable to curative surgery or radiation 17 7/26/2019 Hale Teka, M.D., Resident Physician
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  Combination chemotherapy • Thegoal of combination chemotherapy is to provide maximum cell kill with minimal or tolerable adverse patient side effects • Drugs used in combination should have clinical data indicating that their effects will be synergistic or at least additive • Drugs are selected based on their 1. Proven efficacy as single agents, 2. Different mechanisms of action, and 3. Toxicities that overlap minimally or not at all 18 7/26/2019 Hale Teka, M.D., Resident Physician
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  Multimodality treatment • Combiningchemotherapy with radion therapy or surgery – Enhances efficacy – Toxity may be higher • Exmaples – Cervical cancer • Weekly cisplatin with standard radiotherapy – Makes the cancer more sensitive for radiation – Treats micrometastasis – Endometrial cancer • Nodal metastasis during surgery ➔ radiotherapy + Chemo – Ovarian cancer • Secondary cytoreductive surgery ➔ followed with chemotherapy 19 7/26/2019 Hale Teka, M.D., Resident Physician
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  Goals of treatment •Palliative intent – Instead of a defined number of treatment courses, a clinician must frequently revisit the treatment effectiveness and alter the dosage and timing of chemotherapy administration accordingly • Curative intent – Courses are predefined 20 7/26/2019 Hale Teka, M.D., Resident Physician
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  Directing care ofthe patient • Before starting infusion of chemotherapy – Complete medical history – Comprehensive physical examination – Discuss on alternatives • Blood work, including – a complete blood count, – comprehensive metabolic panel, and – tumor markers (e.g., CA125) as indicated • Adress coexisting conditions • Consent • Contact number 21 7/26/2019 Hale Teka, M.D., Resident Physician
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  Pharmacologic Principles 7/26/2019 HALETEKA, M.D., RESIDENT PHYSICIAN 22
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  Drug Dosing • Chemotherapeuticdrugs have narrow therapeutic window • Calculations can be made based on – BSA • Most drugs – GFR • Platinium based – Body weight • Bevacizumab 23 7/26/2019 Hale Teka, M.D., Resident Physician
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  Dose intensity (Density) •The amount of drug administered over time • Its primary importance is in highly responsive tumors in which cure can be achieved with chemotherapy 24 7/26/2019 Hale Teka, M.D., Resident Physician
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  Route of Administration •Systematic – PO, IV, IM, SC • Regional – For example • Intraperitoneal (IP) route for ovarian tumor 25 7/26/2019 Hale Teka, M.D., Resident Physician
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  Chemotherapeutic Agents andTheir Association with Extravasation Injury 26 7/26/2019 Hale Teka, M.D., Resident Physician
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  Excretion • Primarily viathe liver or kidney • Dose adjustment needed in – Liver or renal impairment – Elderly – Catchexic patients • Creatine level may be falsely low leading to over dosing 27 7/26/2019 Hale Teka, M.D., Resident Physician
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  Drug Interactions • Mostdrug interactions are of little consequence • Often drugs that are metabolized in the liver are at risk for interactions • For example: – Using methotrexate in a woman taking warfarin (Coumadin) will usually enhance the anticoagulant effect and thus will require a Coumadin dose reduction 28 7/26/2019 Hale Teka, M.D., Resident Physician
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  Allergic reaction • Anaphylactic,allergic, or hypersensitivity reaction during or after administration of chemotherapy • Instruct women to report symptoms • Avail trained staff to manage such reactions 29 7/26/2019 Hale Teka, M.D., Resident Physician
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  Management of HypersensitivityReactions 30 7/26/2019 Hale Teka, M.D., Resident Physician
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  Drug Resistance • Commonin larger tumor masses • It can be – Acquired • tumors no longer respond to drugs to which they were initially sensitive – Intrinsic • tumors are first exposed to an agent and fail to respond • It can develop to – one drug • Example: Low risk GTN – multiple drugs • Ovarian tumor (Pleiotropic resistance) 31 7/26/2019 Hale Teka, M.D., Resident Physician
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  Evaluating response tochemotherapy Clinical Endpoints in Evaluating Response to Chemotherapy Endpoint Definition Complete response (CR) Disappearance of all measurable “target” lesions Partial response (PR) A decrease of ≥30% in the sum of diameters of all target lesions Progressive disease (PD) An increase of ≥20% in the sum of diameters of target lesions or the identification of one or more new lesions Stable disease (SD) Neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD 32 7/26/2019 Hale Teka, M.D., Resident Physician
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  Chemotherapeutic Drugs 7/26/2019 HALETEKA, M.D., RESIDENT PHYSICIAN 33
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  Antimetabolites 35 7/26/2019 Hale Teka,M.D., Resident Physician
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  Methotrexate • Methotrexate (MTX) –FDA approved for • GTN and Ectopic Pregnancy – Binds to DHFR, blocking the reduction of dihydrofolate to tetrahydrofolate – Thymidylate synthetase and various steps in de novo purine synthesis are halted – This leads to • arrest of DNA, RNA, and protein synthesis – Fatal bone marrow toxicity at higher doses – Leucoverin rescue can prevent bone marrow toxicity 36 7/26/2019 Hale Teka, M.D., Resident Physician
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  Gemcitabine • Gemcitabine – FDAapproved for • Recurrent ovarian cancer • Also used for uterine sarcoma – Synthetic nucleoside analog that undergoes multiple phosphorylations to form the active metabolite – The resulting triphosphate is subsequently incorporated into DNA as a fraudulent base pair – Insertion of this fraudulent base pair serves as a stop codon – Dose limiting side effects • Myelosupression 37 7/26/2019 Hale Teka, M.D., Resident Physician
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  5-Fluorouracil • “False” pyrimidineantimetabolite • Thymidine synthetase inhibitor • Used in (not FDA approved for Gyn Onco) – Cervical cancer (Systemic use in combination with cysplatine) – VAIN (Topical use) • Toxicities – Myelosuppression – Vaginal complications – Dose limiting toxicities • Mocsitis and diarrhea • Hand-foot-syndrome (Palmar-plantar erythrodysesthesia) 38 7/26/2019 Hale Teka, M.D., Resident Physician
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  Alkylating agents 39 • Thealkylating agents are characterized by positively charged alkyl groups that bind to negatively charged DNA to form adducts •Binding leads to DNA breaks or cross-links and a halt to DNA synthesis. •In general, these drugs are cell cycle nonspecific agents that work at any phase of active replication. 7/26/2019 Hale Teka, M.D., Resident Physician
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  Cyclophosphamide • FDA approvedfor – GTN as the C in EMACO regimen – Recurrent ovarian cancer • Side Effects – Myelosuppression • Dose limiting toxicity – Hemorrhagic cystitis • Classic complication – Severe alopecia and GI toxicities – Damaging effects to ovarian function – Secondary malignancies • AML and • Bladder cancer 40 7/26/2019 Hale Teka, M.D., Resident Physician
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  Ifosfamide • Not FDAapproved for Gyn Onco • Used for salvage therapy in – ovarian, cervical and uterine cancers • Similar toxicity profile to cyclophosphamide • Has two toxic biproducts – Acrolein ➔ Bladder mucosa irritant – chloracetaldehyde➔ Neurotoxin • Hydration , renal dose adjustmet and Mensa may negate hemorrhagic cystitis 41 7/26/2019 Hale Teka, M.D., Resident Physician
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  Antitumor Antibiotics • Derivedfrom microorganisims • Cell cycle specific • Work by DNA intercalation 43 7/26/2019 Hale Teka, M.D., Resident Physician
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  Antitumor Antibiotics 44 7/26/2019 HaleTeka, M.D., Resident Physician
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  Dactinomycin • FDA approvedfor GTN • Mxm of action – Becomes anchored into purine-pyrimidine DNA base pairs, resulting in DNA synthesis inhibition – It also produces toxic oxygen-free radicals that cause DNA breaks • Mainly excreted through the biliary system • Side effects – Myelosuppression • Dose limiting side effect – GI toxicity – Alopesia – Vesication 45 7/26/2019 Hale Teka, M.D., Resident Physician
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  Bleomycin • FDA approvedfor – Malignant pleural effusion – Palliative therapy of recurrent squamous cervical cancer, squamous vulvar cancer, and testicular cancer • Off-label use – BEP – salvage treatment of GTN • Mxm of action – When complexed with iron, creates activated oxygen-free radicals, which cause DNA-strand breaks and cell death – It is maximally effective during the G2 phase 46 7/26/2019 Hale Teka, M.D., Resident Physician
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  • Side effects –Restrictive lung diseases ➔ pulmonary fibrosis • Classic and dose limiting side effect – Skin reactions – Not a myelosuppressive drug 47 7/26/2019 Hale Teka, M.D., Resident Physician
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  Doxorubicin • FDA approvedfor – Epithelial ovarian cancer – TAP for endometrial cancer • Mxm of action – This agent intercalates into DNA to inhibit DNA synthesis, inhibits topoisomerase II, and forms cytotoxic oxygen-free radicals • The drug is metabolized extensively in the liver and eliminated through biliary excretion 48 7/26/2019 Hale Teka, M.D., Resident Physician
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  • Side effects –Myelosuppression • Dose limiting side effect – Cardiotoxicity • Classic complication – Alopecia – GI toxicities 49 7/26/2019 Hale Teka, M.D., Resident Physician
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  Doxorubicin Hydrochloride Liposome •FDA approved for – Salvage treatment of recurrent epithelial ovarian cancer • Side effects – Stomatitis and – Palmar-plantar erythrodysesthesia (PPE) 50 7/26/2019 Hale Teka, M.D., Resident Physician
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  Plant Derived Agents •Taxanes – Paclitaxel – Docetaxel • Vinka alkaloids – Vincristine – Vinblastine – Vinerolobine • Topoisomerase inhibitors – Topotecan – Etoposide 51 7/26/2019 Hale Teka, M.D., Resident Physician
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  Chemotherapeutic Plant AlkaloidsUsed for Gynecologic Cancer 52 7/26/2019 Hale Teka, M.D., Resident Physician
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  Paclitaxel • Side effects –Dose limiting • Myelosuppression • Neurotoxicity – Hypersensitivity reaction – Alopecia (total body hair loss) 54 7/26/2019 Hale Teka, M.D., Resident Physician
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  Docetaxel • Side effects –Myelosuppression – Fluid retention syndrome 55 7/26/2019 Hale Teka, M.D., Resident Physician
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  Vincristine • The Oof EMA-CO • Side effects – Neurotoxicity is the main dose limiting side effect – GI toxicity – Myelosuppression 56 7/26/2019 Hale Teka, M.D., Resident Physician
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  Vinblastine • FDA approvedfor salvage recurrent GTN • Side effects – Myelosuppression – GI toxicity – Hypertension – Neurotoxicity 57 7/26/2019 Hale Teka, M.D., Resident Physician
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  Vinerolobine • Not FDAapproved for Gyn Onco – Used in salvage treatment for recurrent epithelial ovarian cancer and for treatment of cervical cancer • Side effects – Myelosuppression – GI toxicity – Neurotoxicity 58 7/26/2019 Hale Teka, M.D., Resident Physician
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  Topotecan • FDA approvedfor – Recurrent epithelial ovarian cancer and recurrent cervical caner – Myelosuppression, most commonly neutropenia, is the main dose- limiting side effect – GI toxicity is also common and includes nausea, vomiting, diarrhea, and abdominal pain. – Systemic symptoms, such as headache, fever, malaise, arthralgias, and myalgias, are typical – Alopecia is often as complete as that seen with paclitaxel therapy 59 7/26/2019 Hale Teka, M.D., Resident Physician
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  Etoposide • Use as –EMA-CO – BEP • Side effects – Myelosuppression – Gastrointestinal symptom – Most patients will develop alopecia – With etoposide, particularly if the total dose exceeds 2000 mg/m2, there is a small but significant risk of secondary malignancies (approximately 1 in 1000) • AML 60 7/26/2019 Hale Teka, M.D., Resident Physician
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  Miscellaneous • Carboplatin – FDAapproved for • adjuvant or salvage treatment of epithelial ovarian cancer – Side effects • Myelosuppression • Hypersensitivity reaction 61 7/26/2019 Hale Teka, M.D., Resident Physician
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  • Cisplatin – FDAapproved for ovarian, cervical, and germ cell cancer – Regimens • Alone – IP therapy for epithelial ovarian Ca – Cervical Ca • BEP • TAP • Side effects – Nephrotoxicity, electrolyte abnormalities, neurotoxicity, ototoxicity, GI toxicity, hypersensitivity reactions 62 7/26/2019 Hale Teka, M.D., Resident Physician
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  • Hexamethylmelamine – FDAapproved for • Consolidation therapy of advanced epithelial ovarian cancer and • Salvage treatment of recurrent epithelial ovarian cancer – Side effects • GI toxicity • Myelosuppression • Neurotoxicity 63 7/26/2019 Hale Teka, M.D., Resident Physician
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  Hormonal Agents • Tamoxifen –Competes for estrogen receptor but does not activate it – Used in breast Ca, Endometrial Ca • Megestrol Acetate – Antagonizes the effect of estrogen – Used in • Endometrial hyperplasia, • Nonoperable endometrial cancer, and • Recurrent endometrial cancer (Grade I disease) 64 7/26/2019 Hale Teka, M.D., Resident Physician
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  • Side effects –Weight from • fl uid retention and • increased appetite. – Thromboembolic events – Exacervation of hyperglycemia in DM patients 65 7/26/2019 Hale Teka, M.D., Resident Physician
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  Biological and targetedtherapy • Antiangiogenesis Agents – Bevacizumab – VEGF Trap – Sunitinib • Mammalian Target of Rapamycin Inhibitors • Poly (ADP) Ribose Polymerase Inhibitors – Olaparib (AZD2281) – Iniparib and – veliparib • Vaccines – Cervical Ca – Ovarian Ca 66 7/26/2019 Hale Teka, M.D., Resident Physician
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  Side Effects • BoneMarrow Toxicity • Gastrointestinal Toxicity • Dermatologic Toxicity – Liposomal doxorubicin, docetaxel, bleomycine • Neurotoxicity – Cisplatin, Paclitaxel, Vinca alkaloids, hexamethylmelamine, • Alopecia – Paclitaxel 67 7/26/2019 Hale Teka, M.D., Resident Physician
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  Emetic Risk ofIntravenously Administered Antineoplastic Agents Used in Gynecologic Oncology 69 7/26/2019 Hale Teka, M.D., Resident Physician
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  Drug Regimens forthe Prevention of Chemotherapy-Induced Emesis by Emetic Risk Category 70 7/26/2019 Hale Teka, M.D., Resident Physician
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  Growth Factors • EpoetinAlfa • Darbepoetin Alfa • Filgrastim • Pegfilgrastim 71 7/26/2019 Hale Teka, M.D., Resident Physician
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  CHEMOSENSITIVITY AND RESISTANCEASSAYS • Only in trials 72 7/26/2019 Hale Teka, M.D., Resident Physician
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  Cancer Drug Development •Increase dose, new combination, new route of the existing drugs • Test in cancer cell lines or in animals innoculated with the cancer ➔ Preclinical toxicology screen in animals ➔ 4 phase trial in humans – Phase I ➔ To define MTD – Phase II ➔ To see response – Phase III➔ RCTs – Phase IV ➔ Postmarketing 73 7/26/2019 Hale Teka, M.D., Resident Physician
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  Common Chemotherapeutic Regimensin Gyn Onco 74 7/26/2019 Hale Teka, M.D., Resident Physician
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  Cervical Ca • Indication –Stage IIB and above, concurrently with radiation • Regimen – Cisplatin weekly for 5 weeks • Advanced cervical ca – Cisplatin + Paclitaxel • Recurrent Cervical Ca or Secondary disease 75 7/26/2019 Hale Teka, M.D., Resident Physician
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  Chemotherapy Regimens andResponse Rates of Cervical Cancer 76 7/26/2019 Hale Teka, M.D., Resident Physician
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  Vaginal and InvasiveCancer of Vulva • Chemotherapeutic management is extrapolation of that of cervical 77 7/26/2019 Hale Teka, M.D., Resident Physician
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  Endometrial Ca • Indication –Advanced endometrial cancer • Regimen 1. TAP ➔ 7 doses 2. Carboplatin + Paclitaxel ➔ Less toxic regimen 3. Hormonal 78 7/26/2019 Hale Teka, M.D., Resident Physician
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  Uterine Sarcoma • Indication –Stage I-IV diasease • Regimen – Ifosfamide + Cisplatin 79 7/26/2019 Hale Teka, M.D., Resident Physician
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  Ovarian tumor • Epithelial –IV regimen • 3 weekly 3-6 cycles of carboplatin (Paraplatin) and paclitaxel (Taxol) +/- Bevacizumab – IP Regimen 80 7/26/2019 Hale Teka, M.D., Resident Physician
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  • Germ Cell –5 day course, 4 Cycles of BEP given every 3 weeks – 1 day course, 3 cycles of Carboplatin and etoposide every 3 weeks • SCST – 5 day course, 4 Cycles of BEP given every 3 weeks 82 7/26/2019 Hale Teka, M.D., Resident Physician
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  Postoperative treatment ofsex cord-stromal tumors. 83 7/26/2019 Hale Teka, M.D., Resident Physician
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  GTN • Low risk –MTX or Actinomycin D • High risk – EMACO 84 7/26/2019 Hale Teka, M.D., Resident Physician
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  References 1. F. GaryCunningham, 2016. Williams Gynecology, 3rd edition, The McGraw-Hill Companies, Inc. 2. TM DC Dutta’s Text Book of Gynecology, 2014, 6th Edition. 3. Te Linde’s Operative Gynecology, 2010, 10th Edition 4. Berek and Novak’s Gynecology, 2015, 15th Edition 5. James R. Scott, 2008. Danforth’s Obstetrics and Gynecology, 10th edition 6. UpToDate 21.6 86 7/26/2019 Hale Teka, M.D., Resident Physician
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  Thank you forlistening! 87 7/26/2019 Hale Teka, M.D., Resident Physician