Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Ovarian Cancer
Document related concepts
no text concepts found
Transcript
Ovarian Cancer A LITTLE HISTORY, A LITTLE SURGERY, A LITTLE GENETICS Jerry Perez, M.D. United States Statistics In 2015 22,280 new cases 14,240 deaths Lifetime risk 1 in 75 women will develop Ovarian Cancer 1 in 100 women will die of ovarian cancer 8th most common cause of Cancer among women 5th most common cause of cancer death SEER Cancer Statistics Factsheets: Ovary Cancer. National Cancer Institute. Bethesda, MD Ovarian Development Three main cell types of ovary: Coelomic epithelium, Germ Cells, Sex Cords Types of Ovarian Cancer Germ Cell Tumors Cells that will become the eggs of the ovary When fertilized become embryos Think stem cells Sex Cord Stromal Cell Tumors Derived from the mesoderm Produce hormones that support the eggs Epithelial Cell Tumors Outer coating of the ovary Gets injured every month with ovulation Each can be benign or malignant Germ Cell Tumors Benign and malignant account for 20% of all ovarian neoplasms, only 3-5% are malignant. Benign version is the Mature Teratoma Little monster Contains all germ cell layers Hair, teeth, sebum, bone, neural tissue most common, eyes not uncommon Thyroid Tissue Stoma Ovarii Teratoma Imaging Malignant Germ Cell Tumors Rare tumor accounting for 5% of ovarian Cancers Usually girls and young women peak incidence is 13 to 20 years of age. Good prognosis with overall survival of 93% Most retain normal menstrual cycles and fertility rates. Think pregnancy Rapidly growing Tumor markers: BHCG, AFP, LDH, Treatment: Fertility sparing cyto-reductive surgery Chemotherapy; Bleomycin, Etoposide, Cisplatin Lance Armstrong Tumor Malignant Germ Cell Tumors 13 y/o with a Bhcg of 1359, LDH 4682, Final path: 32 cm missed germ cell tumor 80% dysgerminoma And 20 % Yolk Sac tumor Sex Cord Stromal Cell Tumors Comprised of granulosa cel, theca cells, sertoli cells and Leydig cells, pure or in any combination. Benign or malignant Granulosa Cell Tumors Adult (peak 50 -55 Y/O) or Juvenelle Secrete estrogen so precocious puberty in prepubetal girls and hyperestrogen symptoms in menopausal women. Menstrual irregularities and breast enlargement 25% have AIN and 5% have endometrial cancer Sertoli-Leydig Cells AKA androblastomas Testosterone Virilzation Virilization Epithelial Cell Tumors Most Common Arise from the outer layer of the ovary or the epithelium Malignant or benign Benign mostly cystic with a normal or low CA-125 Malignant mostly complex often with an elevated CA-125 Benign Malignant Epithelial Ovarian Cancer Represent 90% of ovarian cancers 50% occur in women over the age of 65 Ethnically Diverse Dramatic rise in incidence at age 55 Most common cancer after breast cancer in women over 40 years of age particularly in developed countries Ovarian Cancer by Age Median age of diagnosis is 63. Median age of death is 70 SEER 2009-2013, http://seer.cancer.gov/statfacts/ html/ovary.html Epithelial Ovarian Cancer Survival by Stage Stage Relative 5-Year Survival Rate I 90% IA 94% IB 92% IC 85% II 70% IIA 78% IIB 73% III 39% IIIA 59% IIIB 52% IIIC 39% IV 17% Catch it early get a cure Seer Data Base Jan. 2014 Ovarian Cancer Stage and Screening 51% of ovarian cancer patients present with stage 3. and 15 % present with stage 4. Therefore 66% of patients present with a horrible prognosis. Screening: affordable, reproducible, reliable way to detect pathology (in an asymptomatic patient) at a stage in which treatment will affect the outcome. (eg: Pap, Mammogram, colonoscopy) For ovarian cancer there is no reliable way of screening. Silent Killer Metastasis in Ovarian Cancer Seeding vs. 3D Growth (Direct extension) Early spread via peritoneal fluid delivery and implantation Ovarian Cancer Metastasis Omentum Normal Omentum with Tumor CA-125 Glycoprotein that is measured from a blood test. Tumor marker Only 50% of stage I ovarian cancers will have an elevated CA-125 Non-specific: coelomic epithelium irritation increases CA-125 Endometriosis, diverticulitis, pregnancy, fibroid uterus, peritonitis, Ascities Does not correlate with volume of disease Study of 78,216 women randomized to either yearly CA-125 and pelvic ultrasound versus routine exam showed no survival benefit. History Ovarian Cancer Treatment Prior to the 1955 diagnosis to death was 6 months Chemotherapy discovered Combination chemotherapy in 1978 Cisplatin approved Oral Contraceptives found to cut Ovarian Ca risk 1981 Mid 1980s CA-125 discovered 1989 Carboplatin Approved 1992 Taxanes Emerge Mid-1990s BRCA 1 and BRCA 2 2005 Decoding the Ovarian Cancer Genome 2006 Ovarian Cancer begins in the fallopian tubes 2006 IP Chemotherapy begins 2010 Neo-adjuvant chemotherapy 2010 Bevacizumab approved Cancerprogress.net History of Ovarian Cancer Treatment World War I : Mustard gas invented by Germans . Used in Bari Italy raid with over 1,000 exposed. Sr. Francis Alexander performed autopsies showed profound lymphoid and myeloid suppression. Fast growing cells simply stopped growing. Too volatile for experimentation so change a nitrogen molecule for sulfur and get Alkeran (Melphalan) the first chemotherapy. First used for lymphoma Multiple side effects. Combination Chemotherapy Single agent chemotherapy : short lived responses less than 2 years TB treatment expanded to multidrug therapy Alkaran and Cytoxan 1978 Cisplatin approved Interferes with DNA replication Causes intrastrand crosslinking with purine bases Side effects Renal insufficiency and failure Hair loss Hearing Loss Nausea and Vomiting (one of the most emetogenic agents known) Hypocalcemia and hypomagnesaemia History of ovarian Cancer Treatment Mid 1980s Oral contraceptive pills found to decrease the risk of ovarian cancer Repetitive injury theory Women, especially young women, who use birth control pills for 5 or more years have a 50% reduction in ovarian cancer when compared to women who have never used birth control Works in BRCA Carriers, but debate regarding increase breast cancer risk Stop ovulation decreases risk Multiparity (up to 5 children) regardless of age of first conception breastfeeding Carboplatin approved Another platinum based chemotherapy Discovered at Michigan State University Similar efficacy to Cisplatin but much less side effects Eliminated nephrotoxicity Minimal nausea and vomiting Increase myelosuppression. Very stable 90% excreted in urine unmetabolized. Need 4X as much as cisplatin Sparty Paclitaxel (Taxol) Most significant chemotherapeutic agent for ovarian and Breast Cancer Discovered in 1962 Derived from the bark of the Pacific Nortwest Yew Tree (Taxus Brevifolia thus “Taxol”) Debarking kills tree. 1990 Robert Holton form Florida State University discovers how to synthesize it from the needles. Docetaxel from European Yew tree ( more common) Highly insoluble so use Cremaphor Severe anaphylaxis Abraxane- nanoparticle-albumin-bound paclitaxel Orphan drug for pancreatic cancer Ovarian Cancer Resistance Ovarian cancer is one of the most sensitive solid tumors with responses of up to 80% Ultimately develop resistance and die Minimal survival improvement in 20 years. Multiple mechanisms Decreased drug accumulation inside cell Increased cellular detoxification Increased DNA repair Multidrug resistance-associated protein (MRP) gene functions as an ATP-dependent pump for cytotoxic drugs and MRP plays the significant role for platinum resistance in ovarian cancer. Multi Drug Resistance Mechanisms of MDR towards cancer chemotherapeutic drugs. Cancer cells can develop resistance to multiple drugs by various mechanisms as depicted. Mechanisms include (a) decreased uptake of drug, (b) reduced intracellular drug concentration by efflux pumps, (c) altered cell cycle checkpoints, (d) altered drug targets, (e) increased metabolism of drug and (f) induced emergency response genes to impair apoptotic pathway. Cytoreductive Surgery If we know that cancer cells exposed to chemotherapy develop resistance, then does it follow that the fewer cells that see chemotherapy the lower the resistance to chemotherapy and the better the prognosis? Complete cytoreductive surgery Often includes splenectomy, diaphragm stripping, partial hepatic resection, partial bladder or ureteral resection, or bowel resection. Problem: High morbidity and mortality Mortality rate quoted at 2%l Morbidity: transfusion, prolonged hospital stays. DVT’s and embolisms. Survival advantage of cytoreductive surgery 1994 Dr. Hodkins publishes GOG study 97. Patients who are reduced down to1.5 cm have a survival advantage 2001 Dr. Chi cytoreduction down to <1cm 282 patients multivariate analysis (18 factors: age ascities, CA-125 56 month survival vs. 31 months (about 2 years) No difference in survival if over 2 cm of residual disease Dr. Robert Bristow meta-analysis showed that for every 10% increase in maximal cytoreduction you get a 5.5% increase in median survival Issue: Does the risk of surgery make sense if the morbidity is high and you might not be able to cytoreduce the patient. Pre-operative CA-125, and CT scans do not reliably predict which patients can be optimally cytoreduced. Neoadjuvant Chemotherapy European Organization of researchand Treatment of Cancer (EORTC) 718 patients randomized to either upfront surgery of 3 cycles of upfront chemotherapy followed by surgery Survival was 30 months in both groups. Morbidity was dramatically lower in the Neoadjuvant group CHORUS Trial (Lancet: Vol 386, July 2015) 87 women in UK and New Zealand essentially same design as EORTC trial No difference in survival at 22.6 months Problem: in US optimal cytoreductive surgery followed by IP chemotherapy has a median survival of 66months. Personal approach to treatment of Ovarian Cancer Young health patient’s I will almost always operate and be as aggressive as possible. Includes coon resection, pelvic and aortic lymph node dissection, hysterectomy, Bilateral salpingooophorectomy, often splenectomy with distal pancreatectomy, diaphragm stripping or resection and repair Older than 75 (moving target) clear evidence that mordity of surgery outweighs the benefits so neoadjuvant Not sure: Start with laparoscopy if it appears that I can resect everything will convert to laparotomy. If I can’t place a power port and disposition the patient to neoadjuvant Often interval cytoreductive surgery can be done robotically. Intraperitoneal chemotherapy Theory: ovarian cancer spreads by putting little seeds throughout the abdomen. It makes sense that putting chemotherapy (depth of penetration about 3mm) directly on the tumor should be more effective. Published August 3 in the Journal of Clinical Oncology, the prospective cohort study found that, compared with IV chemotherapy alone, treatment with both IP and IV chemotherapy was associated with improved 3-year overall survival in women with stage III ovarian cancer who, after surgery, had only very small tumor deposits remaining (1 cm or less in size). IP and IV chemotherapy extended median overall survival for patients with ovarian cancer by more than a year, compared with women treated with IV chemotherapy alone. IP Chemotherapy Not sure if the mechanism of action is due to direct application of chemotherapy or to extended pharmacokinetics More abdominal pain, nausea and vomiting , neutropenia and catheter complications than IV Chemo Only 40% of IP chemo patients can tolerate all 6 doses, but survival advantage begins after 2 doses. Risk factors for ovarian cancer Age: Rare if younger than 40. Obesity : 5 point increase in BMI increases ovarian cancer risk by 6% Responsible for 40% of cancers. Colon, Uterine, esophagus, gallbladder, thyroid and pancrease. 120,000 cancer cases/year in US Reproductive History: Term pregnancy prior oto age 26, multiple pregnancies decrease rik Nulliparous or first baby after age 35 increase risk Birth control :decreases risk Fertility Drug: Clomid increase risk for LMP tumors after 6 cycles Estrogen Replacement:1 additional cancer case per 1,000 users who have been on estrogen > 5 years Genetics: BRCA 1 and 2 American Inst for Cancer Research iand the World Cancer research fund March 2014 BRCA 1 and 2 & Mary-Claire King Degree in Math form Carleton College UC Berkley convinced to go into genetics Proved chimpanzees and humans ore 99% genetically the same After 17 years discovered a single gene on Chromosome 17 responsible for upto 10% of all breast cancers and upto 19% of all ovarian cancers Used LDS genealogy to find families with clusters of breast cancer Worked with Abuelas de Plaza de Mayo (Grandmothers of Plaza de Mayo) in Argentina. She used dental genetics to identify missing persons, ultimately identifying 59 children and helping return them to their biological families. BRCA 1 and 2 BRCA1 is a human tumor suppressor gene (to be specific, a caretaker gene), found in all humans; its protein, also called by the synonym breast cancer type 1 susceptibility protein, is responsible for repairing DNA. BRCA 2 is found on Chromosome 13. Tumor suppressor genes help repair DNA before it becomes cancer Not every BRCA carrier will develop cancer, but the likely hood of developing Breast and ovarian cancer is much higher Risks of BRCA Carriers Myriad Genetics BRCA Testing Consider When Breast cancer diagnosed before age 50 years Cancer in both breasts in the same woman Both breast and ovarian cancers in either the same woman or the same family Multiple breast cancers Two or more primary types of BRCA1- or BRCA2-related cancers in a single family member Cases of male breast cancer Ashkenazi Jewish ethnicity Ovarian Cancer begins in the Fallopian tubes—WHAT? 10% to 15% of fallopian tubes removed from women with BRCA1/2 mutations have precursor lesions, whereas the ovaries do not. Fifty percent to 60% of women without a genetic predisposition who developed sporadic ovarian cancer also have early tubal lesions and carcinomas. Genetic mutations and characteristics of early fallopian tube lesions lend further support to the fallopian tube origin of ovarian cancer. Moreover, studies have "consistently" found that tubal ligation reduces ovarian cancer risk by 50%, Jan. 20105 ACOG Committee opinion: he use of salpingectomy for ovarian cancer prevention in women with population risk already undergoing routine pelvic surgery for benign disease. If every patient that has completed childbearing and is undergoing a gynecologic procedure also has a bilateral salpingectomy,, the incidence of ovarian cancer should decrease between 20-30% Cancer Prevention Research, April 2015 Conclusion Not all Ovarian cancer are the same, but the most common, Epithelial Cell Cancers are the most lethal No way to screen for ovarian cancer Surgery and chemotherapy are the main therapeutic options for ovarian cancer. Debate rages on which should come first Genetic testing of all high rick patients should be performed Prophylactic salpingectomies at the time of a benign operative procedure is reasonable Lifestyle modifications including weight loss is always a good idea CRISPR and Gene Drive Technology https://www.ted.com/talks/jennifer_kahn_gene_editing_can_now_c hange_an_entire_species_forever?language=en Jennifer Kahn: Gene editing can now change an entire species -forever
