Lecture 16 - Ovarian Cancer Flashcards
Epidemiology
leading cause of death in US from gynecologic malignancies
minimal improvement over the past 7 decades
Etiology and pathogenesis
exact cause is unknown
“incessant ovulation” theory - women’s risk of developing ovarian cancer is related to # of ovulatory cycles, ovulation results in disruption and repair of epithelial lining of ovaries, repair of lining proposed as one origin of sporadic ovarian cancer
Etiology
germ line mutations responsible for ~5-10% of all ovarian cancers: BRCA1 and 2
5-10% of pts have hereditary non-polyposis colorectal cancer (HNPCC) or other rare genetic syndromes
Risk factors: increased risk
early menarche, late menopause (increased # and/or duration of ovulatory cycles)
increased age, nulliparity, in-vitro fertilization, 2 or more 1st degree relatives with ovarian cancer
genetic factors: BRCA-1, BRCA-2, p53 have increased risk for development of ovarian cancer
lynch II syndrome (HNPCC) - familial predisposition
Risk factors: decreased risk
multiple pregnancies, prolonged use of oral contraceptives, prophylactic oophorectomy (especially if BRCA mutation)
Clinical presentation: “silent killer”
most pts with stage I and II are asymptomatic
advanced disease: ascites, pleural effusion, constipation, small bowel obstruction, N/V - if experienced these sx for 12 or more days out of a month for 2 consecutive months, seek medical attention
Disease progression
disease dissemination invades through the ovarian capsule and throughout the peritoneal cavity
common presenting symptoms is ascites
Initial treatment
goal is cure
surgery + adjuvant chemo is standard approach first line
with relapse any therapy is palliative
Homologous recombination deficiency
50% high-grade serous ovarian carcinomas are homologous recombination deficient
defect in one or more genes involved in homologous repair pathway - includes germline and somatic BRCA pathogenic variants
Treatment overview
+/- neoadjuvant platinum-based chemo –> surgical staging and debulking –> adjuvant platinum-based chemo –> frontline maintenance therapy –> relapse –> recurrence therapy –> maintenance therapy of recurrence
Surgery
debulking surgery generally entails: total abdominal hysterectomy, bilateral salpingo-oophrectomy, omentectomy (fat layer over abdominal organs), pelvic and para-aortic lymph node sampling, paritoneal biopsies, paritoneal washings
Surgical outcomes
after surgery, pts divided into 2 groups: optimally debulked < 1 cm of disease (goal) or sub-optimally debulked > 1 cm of disease remaining (poorer prognosis)
second surgery following chemo is called a second look (not standard of care)
Adjuvant chemotherapy
stage IA or IB grade 1 disease: observation and follow up every 3 mo
all other stages: receive adjuvant chemo
current standard of therapy: paclitaxel and carboplatin given IV every 3 weeks; most pts receive 6 cycles of chemo
cyto-reductive surgery (tumor debulking) followed by adjuvant chemo
Hypersensitivity reactions
GYN/ONC pop is susceptible to these rxns due to chemotherapeutic agents utilized as well as # of cycles of chemo they receive
agents commonly used: paclitaxel, docetaxel, carboplatin, cisplatin all of which cause hypersensitivty rxns
exposures to multiple cycles of chemo increases risk of carboplatin hypersentivity rxns
Type I hypersensitivity
initial contact with agent
MOA: cross linking to mast cells and basophils which trigger release of histamine/other inflammatory mediators
sx: anaphylaxis, itching, rash, chest tightness
Type IV hypersensitivity
with repeated exposure to agent
MOA: T-cells recognize antigens - MHC and APC
sx: erythema, induration
Common chemo culprits
allergic to drug itself: carboplatin, cisplatin, docetaxel, paclitaxel, etoposide, toptecan -
NEED desensitization
infusion related reactions: paclitaxel - cremophor EL, doxil - liposome - decreasing infusion rate helps resolve sx
S/S of drug allergic reactions
hives, abrupt rash, itching, projectile vomiting, swelling, SOB
sx persist after stopping infusion
S/S infusion related reactions
flushing, redness, tingling, HA, SOB, pain
sx resolve quickly after stopping infusion
Paclitaxel
hypersensitivity rxns common, usually type I rxn
non-IgE mediated because most occur with 1st dose, due to the cremophor EL diluent
Taxane infusion reactions
result of direct effects on immune cells; usually occurs during 1st or 2nd exposure
mos common rxns to paclitaxel: facial flushing, back pain, chest or throat tightness
risk of having recurrent rxn decreases with repeated exposures
Paclitaxel: ways to avoid problems
standard pre-meds: dexamethasone, diphenhydramine, famotidine
Taxane reactions - paclitaxel
solubilizer: cremophor
pre-meds: diphenhydramine, famotidine, dexamethasone
Taxane reactions - docetaxel
solubilizer: polysorbate 80
pre-med: dexamethasone
Taxane reactions - albumin bound paclitaxel
solubilizer: human serum albumin
pre-med: non
Carboplatin hypersensitivity
more of type IV; hypersensitivity to platinum agents generally develops after multiple cycles of treatment
sx: cutaneous sx, vomiting, hypotension
Carboplatin mechanism could be 2-fold: Type I
drug/antigen specific IgE’s that have high binding affinity to receptors on mast cells and basophils - cross linking of these receptors trigger release of histamine and other inflammatory mediators
carboplatin in this situation described as a hapten
Carboplatin mechanism could be 2-fold: Type IV
delayed hypersensitivity rxn occurring when antigen sensitized cells release cytokines after subsequent contact - T cells recognize antigens through receptors at MHC at surface of APC –> stimulation of various T cells and cytokine production –> erythema and induration
repeated exposures (>/=8 cycles) increased risk of hypersensitivty reactions
Maintenance bevacizumab
recommended in those that received bevacizumab with chemo upfront prior to surgery to continue as monotherapy
NOT recommended with BRCA mutations
PARP inhibitors
MOA: poly-ADP-ribose polymerase inhibitor prevents PARP protein from repairing damaged DNA in cancer cells
olaparib, rucaparib, niraparib
all have approval in maintenance setting
check CBC!
biggest AE = anemia; rare AE: MDS or AML, pneumonitis
Prevention of Adverse effects
patient education, med review, antiemetics, nutrition: protein intake, hydration, multi-vitamine with iron
monitor: CBC, albumin, SCr, live enzymes, cholesterol
Metastatic diseae
goal is no longer cure
no standard therapy for recurrent disease
Recurrence
it pts relapses > 6mo following completion of initial platinum containing regimen, pt is platinum sensitive - treat with initial chemo regimen again
if pt relapses < 6mo after receiving platinum containing regimen, pt is considered platinum resistant and a salvage regimen is chosen
Platinum progressive
platinum refractory
no response or progression of disease during primary therapy with paclitxel/carboplatin
Treament regimen if pt is resistant or has primary refractory disease
chemo: combo if platinum sensitive - paclitaxel and carboplatin
non-platinum based if platinum resistant - liposomal doxorubicin
Ovarian cancer screening
NO effective screening tool
low-risk: annual physical and pelvic
high-risk (hereditary ovarian cancer and BRCA1/2): pelvic exam, transvaginal ultrasound, CA-125 (tumor marker blood test) every 6-12 mo starting at age 25-35
Ovarian cancer prevention
oral contraceptives: use for >5yrs decreases risk by ~50%
prophylactic oophorectomy decreased risk of ovarian cancer in high-risk pts
multiparity
