GYNAECOLOGY RADIOTHERAPY AND CHEMOTHERAPY IN GYNAECOLOGY د. اسراء المعيني

1. GYNAECOLOGYRADIOTHERAPY AND CHEMOTHERAPY IN GYNAECOLOGYد. اسراء المعيني

2. PRINCIPLES OF RADIATION THERAPY • Following the discovery of x-ray the biological effect of ionizing radiation (IR) has been used either alone or in conjunction with other modalities to treat variety of condition being or malignant • RT can be directed by external beam therapy ,internal placement of radio nucleotide sources, termed brachytherapy or by instillation of radio nucleotide

3. THE ROLE OF RADIATION THERAPY IN THE MANAGEMENT OF GYNECOLOGICAL CANCERS • Intent site • Curative cx,vulva,vagina • Adjunvctive to surgery cx ,vulva,vagina, uterus • Palliative metastasis causing symptoms ,bleeding ,pain obstruction ,spinal compression, brain metastasis • As adjuvant treatment in the post operative setting if there is a high probability of regional recurrence . • for uterus occasionally as primary modality for inoperable tumors • For epithelial ovarian tumor ,the indication for RT as minimal limited role for external beam therapy in germ cell tumor and gestation trophoblastic neoplasia

4. RADIOTHERAPY • EXTERNAL RADIATION THERAPY • Indicated when an area to be irradiated is large ,e.g cx cancer and the draining nodes • The basic tent of radiation therapy is to maximize the tumor dose while minimizing the the damage to the surrounding normal tissues ,the area determined by means of CT MRI

5. BRACHYTHERAPY • Radiation implants ,means treatment at a short distance during this therapy sealed or unsealed radioisotopes are inserted or instilled in to the cancer or its immediate vicinity • Indicated only when the cancer volume is small ,less than 3-4cm in greatest dimension . • BT is typically practiced after external radiation therapy has decreased the tumor size • Intra cavitory, interstitial, intra peritoneal brachytherapy: • During intra cavitory BT ,the applicators holding the sealed sources, such as cesium are inserted in to a body cavity such as the uterus, interstitial BT requires the placement of catheters or needles directly in to the cancer and surrounding tissues. • The typical sources used in interstitial brachytherapy is irridum unsealed sources, such as phosphorus and gold are available as solutions for instillation in to peritoneal cavities

6. NORMAL TISSUE RESPONSE TO IONIZING RADIAATION • In general radiation therapy is less well tolerated when: • 1-the volume of tissues irradiated is larger • 2-IR dose is high • 3- the dose per fraction is larger • 4-the patient age is advanced • 5-others can exacerbated the radiation damage to normal tissue these include previous surgery • 6-Concurrent chemotherapy • 7-Infection • 8-Diabetes mellitus • 9-HT • 10- inflamatory condition (crohn disease)

7. Tissue with rapid proliferation rate such as epithelium of the small intestine or oral cavity are irradiated the onset of acute clinical S/S with in few days or weeks • This in contrast with tissues such as muscular renal ,neural tissues, which have low proliferative rates and may not display signs of radiation damage for months to years after treatment • The concepts of tolerance doses for normal tissues was developed as guide to avoid serious complication in clinical radiation oncology practice

8. 1-epithelium and parenchyma • Atrophy is the most consistent sequel (include lining epithelium skin GIT……..) necrosis ,ulceration ,capillary the most sensitive vessels ,rupture wall ,large arteries (atheroma-like calcification) • 2-skin erythema dry desqumation, necrosis ,hyper and hypopigmentation can be seen ,the skin remains atrophied, thin and dry • 3-vagina commonly leads to acute vaginal mucositis mucosal ulceration is rare delayed reaction ,vaginal shortening ,atrophic vaginitis ,formation of synechiae or telangictasia ,these avoided ,by use the dilators vaginal intercourse resumed following treatment • Rectovaginal fistula can develop after IR sexual dysfunction

9. 4-ovary and pregnancy outcomes • It s effect depend on age and dose of IR above 40 years sterility • Among female childhood cancer survivors who received abd irradiation ,higher spontaous abortion ,lower first born weight • 5-bladder acute cystitis 2-3 weeks of start treatment frequency ,pain develop commonly hematuria is rare • Major chronic complications bladder contracture , haematuria • 6- small bowel vulnerable to IR acute early damage acute malabsorption syndrome (nusea ,vomiting,diarrhea,pain) later chronic nature of radiation induced enteritis

10. 7-kidney acute radiation nephropathy typically 6-12 month after IR expose ,chronic nephropathy • 8-Radiation induced carcinogenesis • In general ,those receiving higher IRdose and those expose at an earlier age have increased risks for 2nd malignancies, and susceptibility of specific to types to radiatin – induced carcinogenesis • High breast BM • Moderate ovary bladder • Low cx uterus rectum

11. PRINCIPLES OF CHEMOTHERAPY • INTRODUCTION • Each tumor type has its own characteristics ,which explains why the same chemotherapy regimen is not equally effective for the whole spectrum of gynaecology cancers • THE CELL CYCLE • G0 resting phase • G1 protein synthesis RNA synthesis ,DNA repair • S new DNA synthesis • G2premitotic phase phase twice DNA, contact as they prepare for division • M actual mitosis chromosomal division

12. CLINICAL SETTING • CLINICAL USE OF CHEMOTHERPY • Chemotherapy may be used in different ways • INDUCTION CHEMOTHERAPY is define as primary for patients with an advanced malignancy when no feasible alternative treatment exists • ADJUVANT CHEMOTHERAPY describes systemic treatment after a primary tumor has been controlled but risk of recurrence remains high • NEOADJUVANT CHEMOTHERAPY • Refers to drug treatment directed at an advanced cancer to decrease preoperatively the extent or morbidity of a subsequent surgical resection • SALVAGE CHEMOTHERAPY applied to recurrent disease or to a tumor that is refreactory to initial treatment

13. Combination therapy • In principle combination of chemotherapy provides maximum cell kill with minimal or tolerable adverse patient side effect • Drugs are selected based on their proven efficacy as single agents, different mechanisms of action ,and minimally over lapping toxicities • Multiple drugs with different mechanism of action tends to minimize the emergence of drug resistance • Drugs used in any combination should have clinical data indicating that their effects will be synergistic at least additive evaluating response to chemotherapy

14. CLINICAL END POINTS IN EVALUATING RESPONSE TO CHEMOTHERAPY • -Partial response a decrease of 50%or more in the product of all measurable lesion lasting for at least one month with out the development of new lesions • -Stable disease of less than 50% of an increase of 25%in the product of the diameters of all measurable disease • -Progression an increase of 25% or more of measurable lesion as described above or the identification of new lesions • -Complete complete resolution of all disease lasting for at least one month

15. CHEMOTHERAPUTIC DRUGS • In gynecological oncology diverse compounds that have demonstrated activity includes • Antimetabolites ,alkalating agents ,anti tumor antibiotic ,plant alkaloids ,hormonal agents ,biologic therapies • These drugs may be used as single agent or in combination regimens • ATIMETABOLITES • Analoge of naturaly occurring substances in the metabolic pathways leading to the synthesis of purines , pyrimidines ,and nuclic acids • In most case ,they are S phase specific agents that are most effective in rapidly growing tumors associated with short doubling times and large growth fractions • e.g methotrexate tightly binds to dihydrofolate reductas , blocking the reduction of dihydrofolate to active form of folic acid various steps in denovo purine syntheis are halted ,arrest DNA,RNA protein synthesis cause fatal bone marrow toxicity this can be prevented by early administration of folinic acid • renal toxicity ,acute cerebral dysfunction ,excreted through the kidney

16. ALKYLATING AGENTS • Bind to DNA breaks DNA synthesis work at any phase of active replication • Cyclophosphamide oral ,iv, toxicity chief role is as part of combination chemotherapy cyclophosphomide is the C of the EMA-CO in GTN treatment or use as s ingle agent salvage therapy for recurrent epithelial ov.cancer

17. ANTITUMOR ANTIBIOTICS • Derived from microorganism antitumor antibiotics exert their cytotoxic effects by DNA inter calation they cell cycl non specific • DACTINOMYCIN • This agent is used to treat GTN as a single agent or as a part of combination chemotherapy also known as adriamycinD is A of EMA-CO is a product of the genus ;streptomyces and because anchored in to purine –pyrimidne DNA base pairs resulting in inhibition of DNA synthesis ,excreted through billiary tree give i.v. rout toxicity Bone marrow depression ,nusea vomiting allopacia

18. PLANT—DERIVED AGENTS • Disturbance of normal assembly ,disassembly and stabilization of intracellular microtubules • Taxanes ,vinca alkaloids ,topiosomerase inhibitor • TAXANES • Paclitaxel cell cycl specific agents maximal activity during the M phase they act to poison ,the mitotic spindle by preventing depolymerization of the microtubules,and inhibition cellular replication • Given I.V for recurrent of epithelial tumor ,ca ovary, end ca, ca cx,GTN • S.E peripheral neuropathy,neurotoxicity BMD, alopecia ,bradycardia,hypersensitivity reaction

19. polymerization by binding to the tubulin ,at different side is of EMA-CO GTN • Neurotoxicity is the most common dose limiting toxicity • BIOLOGICAL THERAPY • Designed to more accurately target specific tumors while avoiding much of the toxicity seen in refered to as immunotherapy or biological response modifer therapy • May enhance the chemosensitivity of malignant cell to treatmrnt or may use the body immune system to attack the cancer • VACCINES • Therapeutic cancer vaccines are designed to induce cellular component of the immune system to recognize and attack tumors • Bone toxicity ,GTT toxicity