Первый слайд презентации: CHEMOTHERAPY IN FEMALE GENITAL MALIGNANCIES
CRIMEAN FEDERAL UNIVERSITY DEPARTMENT OF OBSTERITICS AND GYNECOLOGY BY RAMANI SABARI SANTHOSH 153 A LA 1
Слайд 2: HISTORY
1 st effort to control cancer with the help of drugs is attributed to Li et al.(1956) He demonstrated permanent remission in trophoblastic disease. So, the key is that to understand the mode of action of the drugs at DNA level which has brought out newer effective drugs with less toxicity and improved and prolonged the survival of women with genital cancer
Слайд 3: TUMOUR CELL KINETICS (ca cells=cancer cells)
The fundamental key of ca cells is rapid proliferation,which keep repeating a cycle of biochemical events continously which culminate in cell division. Why rapidly? Because they expand geometrically,2 daughter cells proliferating and give rise to 4 cells
Слайд 4: 4 TYPES OF TUMOUR CELLS
Dividing tumour cell- is the compartment that ads to cell population, the cells in thos phase are most sensitive to cytotoxic agents. Resting cells- these are non dividing cells resting temporarilyG0 phase. they are refractory to chemotherapeutic agents. Differentiated cells- these cells have lost their dividing potential are waiting for natural death, they have little concern to chemotherapist Dying cells- they are terminal cells
Слайд 9: CHEMOTHERAPY RESPONSE
Sensitive to cycle Insensitive to Of no concern dependent agent cycle dependent agents to chemotherapy DIVIDING CA CELLS RESTING CELLS G0 DIFFERENTIATED CELLS DYING CELLS
Слайд 10: CHEMOTHERAPY
ARE CYTOTOXIC DRUGS. Chemotherapy has advanced tremendously in recent years, and is being increasingly used in the management of gynaecological malignancies. The drugs by virtue of prolongation of life and prolonged remission period allow a woman to live a ‘tolerable’ life.
Слайд 11: Characterictis of ca cells
Small rapidly growing tumours have many more rapidly dividing and growing cells; hence, the doubling time is short. However, these are the same tumours which have a high number of cells sensitive to cell cycle-specific cytotoxic drugs. As the tumour mass enlarges, the growth rate progressively slows down, doubling time becomes longer, the cell input may equal loss, hence a stationary size may be reached, and the sensitivity to cell-specific drugs diminishes.
Слайд 12: Continuation…
Another factor to be considered during cancer chemotherapy is the tumour load present at the commencement of therapy. Reduction in the burden of tumour cell load will bring an apparent remission, but during the interval between successive courses of cancer chemotherapy, the tumour growth recurs. This results in stepwise decrease in tumour cell mass.
Слайд 13: In order to attain maximum tumour cell kill, the following principles must be considered:
The chemotherapist must be well aware of the ‘total tumour cell kill concept’. Tumour cell kill by cytotoxic drugs follows the pattern demonstrated by Skipper and Perry (1970) that the killing of tumour cells by cytotoxic agents occurs in an exponential fashion, so that a given dose kills a constant fraction of the population, irrespective of its initial size. There is a clear dose–response relationship.
Слайд 14: Classification of Drugs
Alkylating drugs — Cyclophosphamide, ifosfamide, chlorambucil, melphalan, thiotepa (nonspecific drugs prevent DNA synthesis or its division), 6-mercatopurine Antimetabolites — Methotrexate and 5-fluorouracil interfere with enzymes required for DNA synthesis Antibiotics — Actinomycin -D, bleomycin, adriamycin, mitomycin (nonspecific), Doxorubicin. These inhibit RNA and DNA synthesis. They arrest mitosis.
Слайд 15: Continuation…
Plant alkaloids — Vincristine, vinblastine, taxol, docetaxel, etoposide (cell specific)— antimitotic. Hormones — Progesterone preparations, tamoxifen ( antioestrogen ). HRT if both ovaries are removed. Miscellaneous — Cisplatin, carboplatin, hydroxyurea, topotecan. Biological — Interferon. Improves host immune defence and maintains remission.
Слайд 20: Continuation…
Chemotherapy must aim at different cell kill. The dose must be so adjusted that maximum destruction of tumour cell is achieved with minimal damage to normal cells. Many cytotoxic drugs in present use show some degree of tissue selectivity. n Combination drug regimes and/or sequential drug regimes achieve superior tumour cell control with lowered side effects. Drugs with different actions yield better response and reduce drug resistance.
Слайд 21: Investigations required prior to chemotherapy are
Hb %, WCC and platelet count Serum electrolytes Kidney function tests Cardiac function with doxorubicin Pulmonary function with bleomycin Liver with methotrexate
Слайд 22: Contraindications
Hb % less than 10 g %, WCC less than 3000/mm3 platelet count less than 100,000/mm3. Liver and renal dysfunction.
Слайд 23: Route OF introduction:
Drugs can be given- orally ( alkylating agents ), intravenously or intraperitoneally at the end of surgery (but are not very effective).
Слайд 25: Therapy types: - ACCORDING to the time of introduction
NEOADJUVANT THERAPY: - Its given to shrink the tumor down before the surgical removal of the tumor. It is now recognized that some chemotherapy drugs act also as radiosensitizers and lead to superadded cell kill prior to or preferably along with radiotherapy and prior to surgery. M/C drug-. Cisplatin 40 mg2 weekly is given 1 h before radiotherapy. The renal functions should be normal before instituting this regime.
Other chemoradiation drugs in use are 5-FU, gemcitabine, cisplatin combined with gemcitabine 40 mg2 in 200 mL saline 2 h before radiation—it takes 1 h to administer. POST RADITION DRUGS: is not effective and poor response occurs on account of poor tissue oxygenation and poor vascularity not allowing the drugs to reach and penetrate the tumour. ADJUVANT THERAPY: -Its administrated after surgery to lesson the risk of melanoma recurring.
Слайд 27: Newer Anticancer Drugs- The development of new chemotherapy improves the disease free interval and prolongs survival
1. Vascular targeting agents (VTA) a. Angiogenesis inhibitors VEGF ligand bevacizumab ( avastin, genetech ) b. Receptor targeting VEGF Receptor tyrosine kinase inhibitor, cediranib, intedanib, anti-VEGF antibody inclone
The former primarily prevent development of new vessels in the tumour. The latter damage the established vessels in the tumour with cediranib 30 mg daily orally, 30% benefit is reported in recurrent epithelial ovarian tumours and fallopian tube cancer. Complication – Hypertension. Bowel perforation in intra-peritoneal tumours involving the bowel.
Vascular disrupting agents (VDA) fosbretabulin, olaparib (oral 100–600 mg daily). 2. Alpha folate receptor targeting – farletuzumab EC145 3. Novel cytotoxic agents (a) Trabectedin (b) Epothilone analogues (c) Topoisomerase 1 inhibitors (d) Pemetrexed (e) Aurora kinase inhibitors
Слайд 30: Gynecological diseases- with regime of chemotherapy:
Radiation with chemosensitization radiotherapy concurrently with weekly intravenous Cis-platinum chemotherapy (40 mg/m2) Vaginal cancer-stage 2,3,4
Слайд 31: Chemotherapy regimens SCCA Vulvar
First-Line Combination Therapy REGIMEN DOSING Paclitaxel (Taxol) + cisplatin (Platinol; CDDP) Day 1: Paclitaxel 135mg/m 2 IV, admi over 24 hr plus Day 2: Cisplatin 50mg/m 2 IV at a rate of 1mg/min. Repeat cycle every 3 weeks for 6 cycles. Carboplatin (Paraplatin) + paclitaxel Day 1: Carboplatin AUC=5mg/mL/min administered over 1 hr, followed by paclitaxel 175mg/m 2 administered over 3 hrs. Repeat cycle every 3 weeks for 6–9 cycles or until disease progression or unacceptable toxicity Chemotherapy regimens in SCCA Vulvar
First-Line Combination Therapy cont’d REGIMEN DOSING Cisplatin + topotecan (Hycamtin) Days 1–3: Topotecan 0.75mg/m 2 IV administered over 30 min plus Day 1: Cisplatin 50mg/m 2 IV. Repeat cycle every 3 weeks. Cisplatin + gemcitabine (Gemzar) Days 1 and 8: Cisplatin 30mg/m 2 + gemcitabine 800mg/m 2. Repeat cycle every 4 weeks.
First-Line Monotherapy REGIMEN DOSING Cisplatin (preferred as a single agent) Day 1: Cisplatin 50mg/m 2. Repeat cycle every 3 weeks for a total of 6 cycles.
Second-Line Therapy REGIMEN DOSING Bevacizumab ( Avastin ) Day 1: Bevacizumab 15mg/kg IV. Repeat cycle every 3 weeks. Docetaxel ( Taxotere ) Day 1: Docetaxel 100mg/m 2 IV, administered over 1 hr. Repeat cycle every 3 weeks Second-Line Therapy REGIMEN DOSING Bevacizumab (Avastin) Day 1: Bevacizumab 15mg/kg IV. Repeat cycle every 3 weeks. Docetaxel (Taxotere) Day 1: Docetaxel 100mg/m 2 IV, administered over 1 hr. Repeat cycle every 3 weeks
Слайд 35: Advanced Staging in cervical cancer
Chemoradiation is the mainstay of treatment 4-5 weeks of external radiation treats the primary tumor and adjacent tissues and lymph nodes Chemotherapy acts as a radiation sensitizer and may also control distant disease
First-Line Therapy with Radiotherapy REGIMEN DOSING Cisplatin 40mg/m2 IV on days 1, 8, 15, 22, 29, and 36 (total dose not to exceed 70mg per week). Cisplatin + 5-FU Days 1 and 29 : 4 hrs prior to external- beam radiotherapy: Cisplatin 50mgDinfusion /m2 IV at 1mg/min with standard hydration, plus Days 2–5, and 30–33: 5-FU 1000mg/m2 IV continuous infusion over 24 hrs (total dose 4000mg/m2 each course).
First-Line Therapy with Radiotherapy REGIMEN DOSING Cisplatin + 5-FU Days 1–5 of radiotherapy: Cisplatin 75mg/m2 IV over 4 hrs followed by 5-FU 4000mg/m2 IV over 96 hrs. Repeat cycle every 3 weeks for 2 additional cycles. Cisplatin + 5- FU +hydroxyurea Days 1 and 29: Cisplatin 50mg/m2 IV followed by 4000mg/m2 5- FU over 96 hrs; hydroxyurea 2g orally twice weekly for 6 weeks.
First-Line Therapy with Radiotherapy REGIMEN DOSING Induction therapy Days 1, 8, 15, 22, 29 and 36: Cisplatin 40mg/m2 + gemcitabine 125mg/m2 + concurrent external- beam radiotherapy 50.4Gy in 28 Cisplatin + gemcitabine + fractions, followed by brachytherapy radiotherapy +brachytherapy 30–35Gy in 96 hrs. Adjuvant therapy Day 1: Cisplatin 50mg/m2, plus Days 1 and 8: Gemcitabine 1,000mg/m2. Repeat every 3 weeks for 2 cycles.
Chemotherapy Regimens and other Treatment Regimens REGIMEN DOSING Day 1: Doxorubicin Cisplatin (Platinol; 45mg/m 2 IV + cisplatin 50mg/m 2 IV, followed by CDDP) +doxorubicin (Adria Days 2–11: Optional filgrastim mycin) (for adjuvant use) 5mcg/kg/day. Repeat cycle every 3 weeks; maximum 6 cycles. Day 1: Doxorubicin 45mg/m 2 IV + cisplatin 50mg/m 2 IV followed by Cisplatin + doxorubicin +p Day 2: Paclitaxel 160mg/m 2 3-hr IV infusion, followed by aclitaxel (Taxol) Days 3–12: Filgrastim 5mcg/kg SC. Repeat cycle every 3 weeks for max 7 cycles. Maximum BSA of 2.0 was used for calculations.
Chemotherapy REGIMEN DOSING Doxorubicin (Adriamycin) Day 1: 75mg/m 2 IV bolus. Repeat cycle every 31 days OR 60mg/m 2 –70mg/m 2 IV typically dosed every 3 weeks. Gemcitabine (Gemzar) +do cetaxel (Taxotere) +granulo cyte-colony-stimulating factor (G-CSF) Days 1 and 8: Gemcitabine 900mg/m 2 IV over 90 min, followed by Day 8: Docetaxel 100mg/m 2 IV over 60 min, followed by Days 9–15: G-CSF 150mcg/m 2 SC OR on Day 9 or 10: Pegfilgrastim 6mg SC. Repeat cycle every 3 weeks until disease progression or toxicity occurs. Gemcitabine Days 1, 8 and 15: Gemcitabine 1,000mg/m 2 IV. Repeat cycle every 4 weeks. Uterine Sarcoma Chemotherapy regimens
Chemotherapy in fallopian tube cancer Platinum based combination chemotherapy
Intravenous First-Line Primary Chemotherapy/Primary Adjuvant Therapy (Stage II–IV) REGIMEN DOSING Paclitaxel (Taxol) + carboplatin (Pa raplatin) Day 1: Paclitaxel 175mg/m 2 IV administered over 3 hrs + carboplatin AUC=5–7.5mg/mL/min IV administered over 1 hr. Repeat every 3 weeks for 6 cycles. Docetaxel (Taxotere) +carboplatin Day 1: Docetaxel 60–75mg/m 2 IV followed by carboplatin AUC=5–6mg/mL/min IV. Repeat every 3 weeks for 6 cycles. Dose-dense paclitaxel +carboplatin Day 1: Carboplatin AUC=6mg/mL/min IV administered over 1 hr, plus Days 1, 8, and 15: Paclitaxel 80mg/m 2 IV administered over 1 hr. Repeat every 3 weeks for 6 cycles. Ovarian cancer chemotherapy regimens
Intraperitoneal First-Line Therapy for Advanced Disease REGIMEN DOSING Paclitaxel + cisplatin (Platinol; CDDP) Day 1: Paclitaxel 135mg/m 2 continuous IV infusion over 24 hrs, followed by Day 2: Cisplatin 75– 100mg/m 2 IP, followed by Day 8: Paclitaxel 60mg/m 2 IP (maximum body surface area 2m 2 ). Repeat every 3 weeks for 6 cycles.