Ovarian Cancer

HE OVARIAN CANCER D R . L E I VA EPIDEMIOLOGY • Epithelial tumors represent the most common histology (90%) of ovarian tumors • Other histologies include the following: – Sex-cord stromal tumors – Germ cell tumors – Primary peritoneal carcinoma – Metastatic tumors of the ovary Jnf • 70% Sporadic • 10-15% Hereditary Random – BRCA1 and BRCA 2 – Lynch Syndrome Mutations • Risk Factors include – Nulliparity or older age at first pregnancy (>35 y/o) – No use of oral contraceptives – Smoking – Use of Postmenopausal HRT CLINICAL PRESENTATION • Often non-specific or detected incidentally • Suspicious/palpable pelvic mass on exam • Ascites or abdominal bloating • Pelvic or abdominal pain • Difficulty eating or getting full quickly • Urinary symptoms • Vaginal bleeding or discharge • Pain or bleeding during penetrative sex DIAGNOSTIC APPROACHES physiogemination • so PE • Transvaginal Ultrasound • CT Scan • PET Scan • Labs • CA-125 – Tumor antigen – Normal <46 U/mL – Generally >65 associated with malignancy in 90% of cases CA-125 (CANCER ANTIGEN 125) • CA 125 protein is a tumor marker • Present in greater number in ovarian CA cells than other cells • Grossly correlated with volume of disease • Prognosis and response to chemotherapy predicted by rate of decline (Normal value 0-35 u/mL) OVARIAN CANCER NATURAL HISTORY AND PATTERNS OF METASTASES • Ovaries shed malignant cells that disseminate throughout peritoneal cavity and retroperitoneal lymph nodes. • Metastasis is characterized by micrometastases throughout abdominal cavity • Disease is extensive (stage III-IV) in most patients before it is clinically detectable. 60-70% patient present with stage III-IV disease. • Malignant disruption of peritoneal lining results in accumulation of ascites in the peritoneal cavity • Ascites is a common finding on presentation for many patients INITIAL WORKUP AND DIAGNOSIS Concerangoto orlungs abdomen no SURGICAL OPTIONS • Should be performed by a Gynecologic Oncologist • Salpingo-oophorectomy (SO) • Removal of ovary and fallopian tube • Total Abdominal Hysterectomy (TAH) • Removal of uterus and cervix 4 8 • Debulking - reduction the bulk (volume) of tumor • When the intent is curative àknown as cytoreductive surgery (CRS); "cytoreduction“ • Interval debulking • Prior debulking surgery NOT optimal • Patient has a second surgery following 3-4 cycles of platinum-based therapy • In some instances; Interval debulking surgery is combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) – cisplatin 100 mg/m2 • Heats up body cavity to 105 -107.6 degrees F EN MALIGNANT PLEURAL EFFUSIONS FIRST-LINE MANAGEMENT OF OVARIAN CANCER: HISTORICAL EVOLUTION (1940-1990) • Platinum-based regimens are superior • Administering more than six cycles of no proven benefit • Cisplatin = carboplatin in activity, but carboplatin has fewer toxicities RECOMMENDATIONS FOR EARLY STAGE DISEASE • Early stage Disease: Stage 1A or 1B (Grade 1) – Comprehensive surgical staging – Followed by Observation • Early Stage Disease: Stage 1A, 1B (Grade ≥2) 1C (All Grades) – Comprehensive surgical staging followed by: – Stage I Disease: Taxane (paclitaxel or docetaxel) or liposomal doxorubicin plus carboplatin administered intravenously for 3-6 cycles. – Stage II Disease: Platinum based chemotherapy similar to that for Stage III or IV disease. INTRAPERITONEAL (IP) CHEMOTHERAPY • Stage III Patients who are optimally debulked (Possible for Stage II but no RCT and NOT recommended in Stage IV) • Stage III Patients – Survival increased by 16 months – Day 1: Paclitaxel 135 mg/m2 IV continuous infusion over 3 or 24 hours • 3 hours better tolerated than > 24 hours but not proven equivalent to 24 hour CIVI – Day 2: Cisplatin 75 -100 mg/m2 IP – Day 8: Paclitaxel 60 mg/m2 IP – Repeat every 3 weeks for 6 cycles IP CHEMOTHERAPY TOXICITIES • Only 42% of persons are able to complete 6 cycles due to toxicity • Leukopenia, infection, fatigue, rental toxicity, abdominal discomfort, and neurotoxicity wall ifPootot ptdoing • Patient selection is CRITICAL! – Optimally debulked Patients – Younger (<65 y/o) is healthy itmeansofCperson pretty sate 05 100g – Good-Excellent PS (High KPS, Low ECOG) Normal – Minimal to no comorbidities (renal, hepatic) à NO diabetes d/t increased neuro and nephrotoxicity – No significant bowel resection POST-PRIMARY TREATMENT Procida VEGF I G SURVEILLANCE AND FOLLOW-UP RECURRENCE – PLATINUM SENSITIVE ***PD or relapse appears >6 months from last platinum drug RECURRENCE - PLATINUM RESISTANCE ***PD or relapse appears <6 months from last platinum drug or while ON platinum atom mens do DONOT it GEMCITABINE (GEMZAR) • MOA: Cell cycle phase specific; Anti-pyrimidine • Administration: – Must infuse w/in 30-60 minutes or increased toxicity – Nadir: 10-14 Days; recovery 21 • Dose Modifications: – Numerous for ANC and PLT counts depending on therapy – Low Emetogenic risk (10-30%) • Monitoring: – CBC w/diff, LFTs – ADRs: BM suppression!!, fatigue, rash, rarely pulmonary fibrosis or interstitial pneumonitis BEVACIZUMAB (AVASTIN) • MOA: Anti-VEGF • Administration: – Held for 6 weeks prior to surgery and 28 days after surgery – BP >160/90 (Hold) T – Initial infusion 90 min – 2nd infusion 60 min – Remaining 30 min • Monitoring: – Urinalysis for proteinuria (do 24 hour collection for >2+), elevated BP, CBC w/diff • ADRs: Hypertension, proteinuria, severe bleeding, GI perforations,VTE, DVT, POOR WOUND HEALING IN ROLE OF BEVACIZUMAB IN OVARIAN CA • FDA approved June 13, 2018 for primary treatment of stage III-IV ovarian see cancer in combination with carboplatin + paclitaxel following initial surgical resection. • There is a well-established association between vascular endothelial growth I and the development and factor (VEGF) overexpression, increased angiogenesis progression of ovarian cancer. – Two phase III trials have been published regarding bevacizumab use in this setting – Both studies demonstrate a modest improvement in progression-free survival (PFS) with no change in overall survival (OS) and small but significant differences in patient-reported quality of life (worse in bevacizumab-treated patients). ROLE OF BEVACIZUMAB IN OVARIAN CA • Only patients randomized to receive bevacizumab maintenance therapy in these studies showed an improvement in PFS • Further analysis suggests that patients with ascites have a significantly improved PFS and OS with the addition of bevacizumab to carboplatin and paclitaxel BEVACIZUMAB CONTINUED • Data has shown that for patients with recurrent ovarian cancer who had been treated with bevacizumab first line and who relapsed ≥6 months after the last platinum-based therapy, rechallenge with bevacizumab in combination with platinumbased doublets was associated with significantly longer progression-free survival BEVACIZUMAB? • According to NCCN, patients should be counseled regarding efficacy, toxicity and cost prior to use in adjuvant setting. koku • Hypertension and gastrointestinal events were significantly higher in bevacizumab-treated patients. • Bevacizumab is FDA approved for adjuvant, recurrent and maintenance therapy. Latiner PAZOPANIB (VOTRIENT)mo • MOA: – TKI blocking VEGF and Platelet-Derived Growth Receptor • Administration: – Empty stomach (1 hr before or 2 hrs after a meal) – Do not crush tablets!!! – Dosing: • PO once daily treat until progression or unacceptable toxicity • Avoid with strong CYP3A4 inhibitors • Dosing Modifications: – Severe hepatic impairment don’t use • Monitoring: – CBC w/ diff, ECG, LFTs, electrolytes, Thyroid function tests • Drug Interactions: CYP3A4 substrate • ADRs: tumor pain, hepatotoxicity (fatal), cardiac events, QT prolongation, and severe/fatal bleeding TOPOTECAN (HYCAMTIN) • MOA: Cell cycle cell specific; Topoisomerase I inhibitor • Administration: IV or PO – Low emetic potential – Infused over 30 min – Oral take w/out regard to food I Wea – Irritant – Dosing: • Given Days 1- 5 Q 21 Days • Dose modifications: Renal Impairment; Caution in hepatic impairment • Monitoring: – CBC w/diff, SrCr, BUN, electrolytes, LFTs go • ADRS: bone marrow suppression (anemia/neutropenia/thrombocytopenia), rarely interstitial lung disease, N/V, diarrhea (severe) à Mg wasting! ALLERGIC RXNS • Can happen anytime – Taxanes (Paclitaxel and Docetaxel) • ~1-3 doses agents'PtmogeBta Alkylation – Platinum analogs (Carboplatin, Cisplatin, Oxaliplatin) • Between 6-8 dose • Desensitization protocols for patients who MUST have a platin – Inpatient – Controversial and no widely standardized protocol • Stop the infusion of – Run saline wide open I popepgdfirstittenBenadoyl – Administer H1 and H2 blockers as needed – Administer Steroids if rxn not subsiding (takes ~30-60 min to take full effect) – Can rechallenge if mild (grade 1 or 2) WRAP UP – OVARIAN CANCER • Ovarian Cancer is insidious and often silent killer • Patients mostly diagnosed with advanced disease • Different options depending on stage but always includes – Surgery – IP chemo +/- post-primary txt • Appropriate candidates – Chemotherapy with a platinum • Recurrence or persistent disease is common • Platinum sensitive vs. Platinum Resistant Disease • Allergic Rxns 56month toresistance CERVICAL CANCER • Cervical cancer is causally related to infection with oncogenic human papillomavirus (HPV) strains. • In sexually active adults it has been estimated that 75 to 80 percent will acquire genital tract HPV before the age of 50. Usually regresses and does not become pathogenic. • Oncogenic HPV strains infect epithelium of lower anogenital tract, including the cervical squamocolumnar junction. (SCJ) • More than 100 subtypes of HPV identified. HPV-16 and HPV-18 are responsible for more than 70% of invasive cervical cancers. CERVICAL CANCER HISTOLOGIES Histology Prevalence Comment Squamous cell 72.1% Highly associated with HPV Adenocarcinoma 19% Incidence is increasing over past 3 decades; traditional screening may be less effective; Screening using HPV testing may increase detection. HPV vaccination effective against this sub-type Adenosquamous < 5% Mixed glandular and squamous features; poor prognosis CERVICAL CANCER ETIOLOGY & PATHOGENESIS • Due to the causal relationship between HPV infection and cervical cancer, it is theoretically, a preventable disease. • HPV infection highly associated with cervical dysplasia • Cervical dysplasia is a precursor of cervical cancer CERVICAL CANCER ETIOLOGY & PATHOGENESIS • Cervical dysplasia is a precursor of cervical cancer • Risk of progression to invasive cancer increases with grade of dysplasia. • The majority of infections with HPV regress spontaneously. • Persistent HPV infection with an oncogenic subtype can result in progression to pre-cancerous lesions known as high-grade cervical dysplasia. • The time lag from infection with oncogenic HPV to the development of invasive cervical cancer is usually measured in years (often 10 or more). SCJ=Squamous Columnar Junction. Preferred site of initial HPV infection. PERSON IN THEIR 30’S CERVICAL CANCER • HPV can lay dormant within cervical cells for years as persistent HPV infection. • The presence of concurrent immunosuppression (e.g. transplantation, HIV) and/or carcinogenic cofactors such as nicotine accelerates the progression from persistent infection to invasive carcinoma. • HPV-6 and HPV-11 are associated with the development of genital warts. • HPV-16 and HPV-18 are responsible for more than 70% of invasive cervical cancers. • Infection with HPV is associated with the development of other cancers including oropharyngeal, anal, vaginal, vulvar, penile and non-melanoma skin cancers. CERVICAL CANCER SCREENING AND PREVENTION • In 2018, cervical cancer remained a major public health problem, ranking as the fourth most common cause of cancer incidence and mortality in women worldwide. • Substantial decline in mortality in developed countries due to effective screening programs. • Mass population screening using the Papanicolaou (PAP) test is effective at reducing the mortality from cervical cancer worldwide. • The long pre-invasive phase between infection with HPV and development of invasive disease make cervical cancer an ideal cancer for effective screening. • Early detection and appropriate treatment of cervical dysplasia can stop progression to cervical cancer. SCREENING TESTS FOR CERVICAL CA • The Papanicolaou (PAP) test is an effective screening tool at reducing the incidence and mortality from cervical cancer. • There are two types of PAP tests available: – The traditional PAP test scrapes the cervix for cells that are smeared on a slide and viewed under a microscope. Many sampling errors can occur with this test. – The liquid-based PAP tests obtain cervical cells with a brush and suspend them into a liquid that is then viewed under a microscope. The liquid method is most widely used because it reduces errors in sampling and HPV DNA testing can be performed on one sample. SCREENING TESTS FOR CERVICAL CA • HPV DNA testing: There are multiple approved tests for detecting HPV DNA. – Some assays test for the presence of high-risk (oncogenic) HPV strains, but do not detail specific strains. – Other tests specifically test for the presence of HPV-16 and HPV-18. CERVICAL SCREENING IN TRANSMASCULINE PERSONS • Avoidance of screening – Dysphoria – Negative experiences with Health Care Providers (HCPs) – Sexual trauma – Pain • Inadequate results (8.3X higher than cisgender women) • Testosterone use thins vaginal lining and decreases natural lubrication – Can pretreat with 2 weeks of vaginal estrogen – Use lots of lubrication and consider topical lidocaine • In one study, self-collected vaginal swab for high risk HPV DNA was 71.4% as effective as the HCP performed swab AMERICAN CANCER SOCIET Y CERVICAL CANCER SCREENING RECOMMENDATIONS (NCCN ENDORSED) Population (Age in years) Screening Method < 21 No screening 21-29 PAP q 3yrs Comments HPV testing should not be used for screening in this age group * Most HPV positivity in this group spontaneously regresses to normal. I 30-65 HPV and PAP “cotesting” q 5 yrs Screening by HPV testing alone is not recommended for most clinical settings >65 No screening following adequate negative prior screening HPV VACCINES AS CERVICAL CA PREVENTION Characteristic Brand name VLPs Manufacturer Volume per dose Administration VLPs = virus-like particles. Bivalent (2vHPV) Quadrivalent (4vHPV) 9-valent (9vHPV) Cervarix Gardasil Gardasil 9 16, 18 6, 11, 16, 18 6, 11, 16, 18, 31, 33, 45, 52, 58 GlaxoSmithKline Merck and Co., Inc. Merck and Co., Inc. 0.5 ml 0.5 ml 0.5 ml Intramuscular Intramuscular Intramuscular of HPV VACCINES • Gardasil 9® only HPV vaccine distributed in the U.S. Indicated in cisfemales ≥9 y/o and ≤ 45 y/o for prevention of: – Cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers caused by HPV infection – Genital warts – Precancerous or dysplastic lesions – Indicated in males 9-45 y/o for prevention of: – Anal, oropharyngeal and other head and neck cancers caused by HPV infection • • Genital warts • Precancerous or dysplastic lesions HPV vaccines are preventative and not therapeutic (i.e., are not effective in treating patients with HPV). DOSAGE AND ADMINISTRATION FOR GARDASIL 9® Age 9 through 14 years 15 through 45 years Regimen Schedule 2-dose 0, 6 to 12 monthsa 3-dose 0, 2, 6 months 3-dose 0, 2, 6 months a If the second dose is administered earlier than 5 months after the first dose, administer a third dose at least 4 months after the second dose. As in the clinical trial If using the 2-dose schedule, the first dose must be administered before the child's 15th birthday. HPV VACCINES • CDC/ACIP recommends routine vaccination at 11-12 years of age. (May start as early as 9 years old.) – 2 dose schedule: 0 and 6 months – Adolescents ≥ 15 years old, immunocompromised patients: • 3 dose schedule: 0,1,and 6 months CDC=Centers for Disease Control. ACIP=Advisory Committee on Immunization Practices VACCINE EFFICACY IN OLDER WOMEN (24-45 YEARS OLD) • Most trials conducted in ciswomen <26 years due to peak exposure to HPV occurs in this population • Second peak is now occurring due to higher incidence of divorce in 4th & 5th decade of life • Trial conducted in 3819 women aged 24-45 – 33% were positive for HPV 6,11,16,18 at baseline – Median follow up 2.2 years – 97-99% of ciswomen seroconverted to all strains by 7 months. There was a trend towards decreased immune response with increased age