Ovarian Cancer Presentation

Ovarian Cancer Gauri Sabnis, PhD concorrelated Ifor deaths Reading: Katzung et al, Basic and Clinical Pharmacology, Chapter 54 Goodman and Gilman’s Pharmacological Basis of Therapeutics, Chapter 37 Dipiro et al, Pharmacotherapy: A pathophysiologic Approach, Chapter 110 1 Types of ovarian cancer r ✥Epithelial ovarian cancer ❊ Starts from the epithelial outer surface of the ovaries ⇥ 80-90% of all ovarian cancers ⇥ Subtypes – mucinous, endometrioid, clear cell, and serous 2Germ cell tumors ✥ nomoreaggressive ❊ Start from the follicular cells ❊ Teratoma and choriocarcinoma ⇥ Less than 2% of ovarian cancers ⇥ Good prognosis 5-year survival >90% 3 Stromal tumors ✥ ❊ Structures that hold the ovaries and cells that produce estrogen, progesterone (granulosa cells) ⇥ ~1% of ovarian cancers n✥Primary peritoneal carcinoma and fallopian tube cancer 5 Age Ear oneoftlebiggest riskftor Risk factors ✥FH - 1st degree relative (more number – greater risk) ❊ BRCA1 mutation pot ⇥ Prophylactic oophorectomy in women over 35 if childbearing is complete – RR 0.04 with avg. follow up of 9 years ✥Environmental factors: HPV infection, smoking, talc ✥Reproductive factors : conditions that increase total # of ovulations in a woman’s life less ofovulation period late menopause ❊ Early menarche, ⇧ crabeseofegg legoveronager ❊ Nulliparity noneverhawingkids ❊ First pregnancy after the age of 35 Same as breast cancer ❊ First pregnancy before the age of 20 ⇩ ❊ Tubal ligation WN ⇧ ❊ Hormone use - oral contraceptives Does NOT apply to breast cancer ovulation paraGodanomerefreeID1NOimport6 Capresenting lol oumbation garcon Sl Hormonal Contraceptives ✥Hormonal contraceptives reduce risk of ovarian cancer ❊Reducing number of ovulations ⇥ Every cycle, ovulation causes a small assault on the ovarian epithelium ⇥ Damage needs to be repaired ⇥ By inhibiting ovulation, contraceptives protect ovarian e epithelium ❊50% RR w/ 5-year use and >90% RR w/ 10-year use ❊Contraindicated in BRCAm 7 ✥Bloating, pelvic or abdominal pain ✥Trouble eating or feeling full quickly 1 no sa i ga ❊ Nausea, dyspepsia, flatulence ✥Urinary symptoms such as urgency or frequency Symptoms ✥Other symptoms ❊ Fatigue ❊ Upset stomach ❊ Back pain ❊ Pain during sex ❊ Constipation ❊ Menstrual changes ❊ Abdominal swelling with weight loss ✥Patient may present with ascites Fa'danumulationin wGi's shifting ❊ Abdominal distention, and stoned W dullness to percussion – pregnant-like abdomen 8 Development of ascites overenconcer startshedding that'sthestarting point 9 Screening ✥Physical pelvic exam ✥Ultrasound ✥Genetic screening – BRCA good congatfatso ✥Blood test – CA-125 t II very ❊Non-specific inflammatory antigen ❊Increased in numerous inflammatory conditions of the abdomen ⇥ Other gynecologic conditions – endometriosis; GI – diverticulitis, peptic ulcers etc. ❊Risk vs. benefit ✥Other sub-type - Germ cell tumors ❊Choriocarcinoma - hCG 10 Diagnosis B ✥Surgical excisional biopsy ❊Oophorectomy ❊Laparoscopic aspirational biopsy (rarely diagnostic) ❊Paracentesis (in presence of ascites) patneedyintostomachtoremove theflub Removeutures and surrounding tissue Omentectomy 11 Stages of ovarian cancer ✥Ovarian cancer cells spread via local shedding in the peritoneal cavity ❊Followed by implantation on the peritoneum and ❊Local invasion of bowel and bladder 12 A It Prognosis someonehasagates meansconcerhasalready spread ✥Prognosis is better for patients who have ❊Younger age ❊Good performance status ❊Cell type other than mucinous and clear cell ❊Lower stage ❊Well-differentiated tumor ❊Smaller disease volume prior to any surgical debulking ❊Absence of ascites robot tumor following primary ❊Smaller residual cytoreductive surgery 15 Treatment in ✥Radiation only palliative ✥Chemo after debulking surgery is standard Atd Paclitaxel and platinum regimen ❊ ⇥ Cisplatin and carboplatin are equally efficacious with carboplatin being better platinol a 1111 tolerated Gpahapiontin ❊ IV vs. IP chemotherapy textremlytoxic ⇥ 5.5 month increase in PFS and 15.9 month increase in OS with IP therapy ⇥ Significantly increased toxicities – abdominal pain, myelosuppression, neurotoxicity – only 42% pts could complete all 6 cycles ⇥ NCCN recommends IP Rx as first line to patients who can tolerate it - Younger patients with good ECOG score, minimal co-morbidities, adequate renal and liver function, and optimally debulked disease without significant bowel resection ✥Monitor CA-125 ✥Dry weight (ABW) for dose calculation when ascites are present 16 no Abraxane Paclitaxel ✥Taxane – inhibit depolymerization of microtubules – M-phase specific ❊ Hypersensitivity (anaphylaxis), due to polyethoxylated castor oil BBW (Kolliphor) – Pre℞ with GC, H1RA and H2RA Is e as ⇥ Requires non-PVC tubing (Taxol tubing) ❊ DLT: Neutropenia - <1500cells/mm3 – do not give o III ❊ Neuropathy ❊ Irritant with vesicant-like properties – extravasation - skin discoloration, tenderness, erythema, swelling, recall skin reactions ✥All toxicities higher with IP administration ✥Abraxane (nab-paclitaxel) – reduced hypersensitivity, increased peripheral neuropathy – off label (ovarian) ❊ Do not substitute ❊ Polysorbate 80 (hypersensitivity possible but no tubing restriction) 18 Agent soAllkaytion Cisplatin ✥Hydrated platinum ion reacts with N7 of guanine to cause DNA crosslinking ❊ Cell cycle non-specific ⇥ Ability to induce secondary malignancy ❊ Highly reactive ⇥ Vesicant (high) irritant (low) ⇥ Chloride leaving groups: Must be compounded, administered in NS (NO D5W) ⇥ Al3+ needles should NOT be used ✥ADRs: ❊ BBW: myelosuppression, NV, nephrotoxicity, neuropathy ❊ Hypersensitivity (delayed), secondary malignancy, TLS g ❊ Ototoxicity (cochlear – hearing; vestibular – delayed NV) ✥Px for ADRs – Balance ❊ Nephrotoxicity  Aggressive hydration, K+ and Mg2+, mannitol diuresis ❊ CINV  (4 drug cocktail) – delayed NV – NK1 ❊ Extravasation  Sod. thiosulfate 19 PARP inhibitors ✥BRCA 1 and 2 are critical for DNA damage repair of DSB with the homologous recombination pathway —strand invasion step ✥In cancers with mutated BRCA ❊ No DSB repair with Homologous recombination process ❊ SSB repair pathway is utilized which utilizes PARP enzyme ❊ Inhibition of PARP in BRCA mutated cells leads to DSB not getting repaired - leading to apoptosis ⇥ PARP inhibitors are approved for gremlin or somatic BRCA mutant breast and ovarian cancers ✥Since prevents DNA repair - chance for secondary malignancy ✥Myelosuppression, GI tox, CYP3A4 interactions 20 PARP inhibitors comet PARP inhibitor Indication BRCA consideration Other Niraparib Ovarian (maintenance) • Mutation not required NV (moderate) Rucaparib Ovarian (maintenance) • Mutation not required Advanced Ovarian • BRCA mutated Metastatic Breast (Her-2 negative) • gBRCAm Advanced Ovarian • gBRCAm or sBRCAm first line – maintenance • Recurrent maintenance Metastatic Pancreatic Prostate mCRPC Talazoparib Advanced Breast (Her-2 negative) • gBRCAm – maintenance • HR repair mutated • gBRCAm Olaparib CYP3A4 metabolism 21