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Ovarian Cancer

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Eric Harris

on 16 April 2014

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Transcript of Ovarian Cancer

Borderline Ovarian Tumors
Ovarian Cancer
Key Facts from American Cancer Society:
About 21,980 women will be diagnosed with ovarian cancer in 2014.
About 14,270 women will die from ovarian cancer in 2014
Ovarian cancer ranks 5th in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system.
A woman's risk of getting ovarian cancer during her lifetime is about 1 in 72.
Her lifetime chance of dying from ovarian cancer is about 1 in 100.
About 1/2 of the women diagnosed with ovarian cancer are 63 years or older.
It is more common in white women than African-American women.

Pathology
Includes fallopian tubal and primary peritoneal cancers
Accounts for 90% of all malignant tumors of the ovaries
4 subtypes of Epithelial Ovarian Cancer
Papillary serous tumor (75%)
-most common type, may contain psammoma bodies
Mucinous (10%)
-pseudomyxoma peritonei associated
Endometrioid (10%)
–associated w/ endometriosis
Clear cell (rare)
- bad prognosis; chemoresistant.
Pathologic characteristics similar to malignancy, but tumors of low malignant potential
Most of these are serous; Often nuclear atypia, cellular proliferation without invasion
Can have visual appearance of peritoneal carcinomatosis without real invasion by nodules
5 year OS is >85% (over 95% if Stage I at diagnosis)
Found in younger women ages 40-60
Most are Stage 1 at diagnosis
1. Sex cord stromal tumors including granulosa cell tumor and Sertoli-Leydig tumor account for 8% ovarian cancers
2. Germ cell tumors: most are teratomas and most are benign; These tend to occur in young women/girls. Overall prognosis is favorable.
3. Can have mixed tumors with elements of more than one type.

Other Histologies
Epidemiology and Risk Factors
Case Presentation
65 y/o woman presents to outside hospital ER with 2 month history of abdominal pain, early satiety and bloating
CT shows ascites, omental caking and a right adnexal mass
She is transferred to UF Health where CBC and CMP are WNL. CA-125 is 2147
Screening
Ongoing trial looking at mortality benefit of multimodality screening (MMS) with CA-125 + TV-US.
200,000+ post-menopausal women aged 50-74 randomized 2:1:1 to no screening, annual TVUS, vs MMS respectively.
Prelim Data published in Lancet Oncol 2009 (Menon et al):
Sensitivity: 89% MMS vs 85% US
Specificity: 99.8% MMS vs 98.2% US
PPV: 43% vs 5%
UKCTOCS Trial
Randomized 78,000 women (55-74 y/o) to screening (annual CA-125 for 4-6 years and TV-US for 4 years) vs usual care
first published 13 year follow-up JAMA 2011 (Buys et al)
212 women diagnosed with OC in screening vs 176 in control.
118 deaths vs 100 deaths OC.
3285 false positives,1080 underwent surgery, 163 of those with serious complication
PLCO
Not recommended for general population
May play a role in high risk women (i.e. BRCA) but still not validated in clinical trials
Also not ready for primetime: ROCA, ROMA, OVA1, OvaSure, and odor detection (?)
Bottom Line
Decrease risk
: young age of first pregnancy, OCPs, breast feeding
Increase Risk
: nulliparity, older age at first pregnancy, late menopause, early menarche, HRT, PID
Age is the biggest risk, followed by +Fam Hx
RR 3.6 for OC in a first degree relative
BRCA and HNPCC increase risk
All ovarian cancers meet criteria for genetic counseling
Risk factors/Genetics
35-46% with BRCA1 will develop OC by age 70.
13-23% for BRCA2
Risk-reducing salpingo-oopherectomy shown to reduce OC risk, OC-related and even all-cause mortality
BRCA
Risk for OC varies for HNPCC syndrome
Appears to depend on the specific mismatch gene
MLH1 20% lifetime risk
MSH2 24%
MSH6 1% (protective?)
HNPCC (Lynch Syndrome)
Diagnosis/Staging
H&P, Family history
Abd/pelvic exam +/- GI eval if appropriate
US +/- abd/pelvic CT
Chest imaging
CA-125 (other tumor markers as clinically indicated)
CBC, CMP
If diagnosed by previous surgery/cytopath at OSH, NCCN recs institutional pathology review to confirm diagnosis

Initial Workup
FIGO + TNM
Stage I — limited to one or both ovaries
IA — involves one ovary; capsule intact; no tumor on ovarian surface; no malignant cells in ascites or peritoneal washings
IB — involves both ovaries; capsule intact; no tumor on ovarian surface; negative washings
IC — tumor limited to ovaries with any of the following: capsule ruptured, tumor on ovarian surface, positive washings
Stage II — pelvic extension or implants

IIA — extension or implants onto uterus or fallopian tube; negative washings
IIB — extension or implants onto other pelvic structures; negative washings
IIC — pelvic extension or implants with positive peritoneal washings
Stage III — peritoneal implants outside of the pelvis; or limited to the pelvis with extension to the small bowel or omentum

IIIA — microscopic peritoneal mets beyond pelvis
IIIB — macroscopic peritoneal mets beyond pelvis less than 2 cm in size
IIIC — peritoneal mets beyond pelvis > 2 cm or lymph node metastases
Stage IV — distant mets to the liver or outside the peritoneal cavity
Staging
Treatment
Early Stage Disease (Stage I and II)
Late Stage Disease (Stage III and IV)
Surgery
Response Assessment and Follow Up
H&P q 3-6 mos up to 5 years posttreatment, then annually.
CA-125 or other tumor markers (eg, HE4) every visit if initially elevated.
Other testing or imaging only as clinically indicated.
Post-Treatment Surveillance
Carbo/taxol
Carbo/weekly taxol
Carbo/gem
Carbo/gem/bev
Carbo/Doxil
Cis/gem
Platinum-Sensitive Recurrence
Pipeline
"So I had a hysterectomy, and they found a tumor that they said was the size of an orange. (See, for women they use the citrus-fruit comparison; for men it's sporting goods: "Oh, it's the size of a softball," or, in England, a cricket ball.) I languished in the hospital for ten days, on a floor where everybody had cancer, so the sympathy playing field was level. You can't say, "Hey, can you keep it down? I just had my operation." You might get, "So what? I'm on my fifth. “Poor thing” doesn’t really come into play much on this floor. My mother, who also had this disease (yeah, I inherited the cancer gene; my older brother got the blue eyes, but I’m not bitter) –"
No Screening
Genetic counselling for all
Good Gyn-Onc Surgeon
Early disease (high vs low risk)
Advanced disease: adjuvant platinum -based treatment (IV +/- IP)
Relapse: platinum sensitive or not
Summary
Managed/staged surgically with laparotomy, peritoneal washings, removal of implants, omentectomy, biopsies
Extraovarian disease is Stage II-IV
Outcomes for node-positive and node-negative disease are similar. Lymphadenectomy not routinely performed.
No role for adjuvant chemo if BOT without invasive implants. Most physicians would consider chemo only if invasive implants identified
FIGO recs further surgery for relapses

Grade 1 (low grade)
– the cancer cells are growing slowly, look quite similar to normal cells (are well differentiated) and are less likely to spread than high-grade cancers.
Grade 2 (moderate grade)
– the cells look more abnormal and are growing slightly more quickly.
Grade 3 (high grade)
– the cancer cells are growing more quickly, look very abnormal (are poorly differentiated) and are more likely to spread than low-grade cancers.
Grade
Adjuvant Chemotherapy

Low Risk (>90% 5 yr survival):
IA and IB and grade 1

High Risk (40-80% 5 yr survival):
Stage IC or II
Clear cell histology
Grade 3 histology
Grade 2?
Preplanned combined analysis of two parallel RCT’s (ICON/ACTION) in high risk, early stage disease
1990-2000: 925 pts (477 ICON and 448 ACTION) Median f/u was 4 years
Randomly assigned to adjuvant platinum-based chemo (n: 465)or obs (460)

OS chemo: 82%, OS obs:74% (p 0.008)
RFS chemo:76% vs. RFS obs: 65% (0.001)


Randomized 429 women with stage III ovarian or primary peritoneal cancer to
IP chemo:
IV paclitaxel 135 mg/m2 on day 1 (24h infusion)
IP cisplatin 100 mg/m2 on day 2
IP paclitaxel 60 mg/m2 on day 8
or...
IV chemo:
IV paclitaxel 135 mg/m2 on day 1 (24h infusion)
IV cisplatin 75 mg/m2 on day 2


Armstrong et al. NEJM 2006.

Stage III EOC
Great PS
Young without extensive comorbidities
Optimally debulked dx <one cm (This is a MUST)


Trial 1
Stages Ia-Ib randomized post-op to obs (n=38) vs. Melphalan IV D1-5, every 4-6 wks X 12 cycles (n=43)
Median f/u 6 years
5 yr DFS 91% vs 98% (p=0.41)
5 yr OS 94% to 98% (p=0.43)

Trial 2
Stage I-II randomized post-op to Melphalan (n=68) vs. single IP 32P (n=73)
Median f/u: 6 years
5 yr DFS 80% in both
5 yr OS 81% vs. 78% (p=0.48)

Low Risk (aka Favorable)
Young, et al. NEJM 1990; 322(15):1021-7.

IP/IV Chemotherapy
Armstrong DK NEJM 2006:354:34-43
ACTION/ICON1
Consider neoadjuvant chemotherapy if bulky disease
TAH-BSO
Pelvic and paraaortic LN sampling
Peritoneal cytology is collected after the incision is made.
Omentectomy and cytology of the diaphragm.
15-30% are upstaged during surgery
Surgeons should discuss IP chemotherapy and consent for IP port prior to surgery

Volume of residual disease correlates inversely with survival
optimal cytoreduction = residual tumor implants no larger than 1 cm
20 month improvement in median survival
Relapse
Platinum-Resistant
Overall likelihood of relapse for all stages: 62%
80-85% in Stage III-IV disease
Categorize relapses based on platinum-free interval (PFI)
PFI> 6 mos = "platinum sensitive"
PFI< 6 mos = "platinum-resistant"
patients w/o response or progresson first line platinum:= "platinum refractory"
GOG 252
Ongoing Phase III trial which recruited stage II-IV patients
randomized into 3 arms:
Arm 1:
IV carbo +weekly IV taxol + bev (cycles 2-6)
Arm 2
: IP carbo+weekly IV taxol + bev
Arm 3
: IP cis + IV taxol+ IP taxol (GOG 172)+ bev

Basic Principals
Cytoreduction
Rationale:
Chemo response improves in the setting of minimal disease burden.
Improves symptoms and quality of life.
May improve or restore host immune competence related to tumor-derived cytokines.
Involves resecting/debulking all sites in the pelvis, omentum in addition to splenectomy, bowel resection, partial hepatectomy, cystectomy and diaphragmatic resection as needed.
Systemic para-aortic and pelvic lymphadenectomy is controversial
placement of IP port.
GOG 172
IV Chemotherapy
High Risk (Non-Favorable)
GOG 111
410 women with stage III or IV ovarian cancer
Randomized after surgery to 6 cycles of cisplatin 75 mg/m2 + either:
Cyclophosphamide 750 mg/m2
or
Paclitaxel 135 mg/m2 (over 24h)

McGuire et al. NEJM 1996;334:1-6
ORR: 60% cis/cytoxan vs 73% cis/taxol
CR: 31% vs 51%
GOG 158
792 pts with Stage III-IV s/p optimal cytoreductive sx randomized to either:
cisplatin 75 mg/m2 plus a 24-hour infusion of paclitaxel 135 mg/m2
-or-
carboplatin AUC at 7.5 IV plus IV paclitaxel 175 mg/m2 over 3 hours

Median PFS: 19.4 mos vs 20.7 mos (cis vs carbo)
Median OS: 48.7 mos vs 57.4 nos (cis vs carbo_

most toxicites worse in cis arm except for low plts. neurotxicity equal
Ozols et al. J Clin Oncol 2003;21:3194-3200
Bevacizumab
GOG 218
3 arms:
Carb/taxol/bev+ bev X 15 mos
Carbo/taxol/bev + placebo X15mos
carbo/taxol/placebo + placebo X 15mos
Median PFS 14.1 vs 10.3 mos
No OS or QOL advantage
ICON7
included 30% with high risk early stage disease
Carbo/taxol/Bev + Bev maintenance x 12 mos
Carbo/taxol
Improved ORR 67 vs 48 %
Median PFS 24 vs 22 months
No difference in OS or QOL
More serious (grade 3/4) adverse events
HE4-Human Epididymis Protein 4
FDA-approved by the FDA in 2008 for monitoring for recurrence/progression.
It is also a component of the Risk of Malignancy Algorithm (ROMA).

AURELIA
361 patients with platinum-resistant randomized to chemo with or without bevacizumab (15 mg/kg every three weeks)
Chemo options, investigator’s choice of 1 of the following:

Paclitaxel 80 mg/m2 days 1, 8, 15, and 22 q 4 weeks (n=115)
Topotecan 4 mg/m2 days 1, 8, and 15 q 4weeks (or 1.25 mg/m2 on days 1 through 5 every three weeks) (n=120)
Doxil 40 mg/m2 day 1 q 4weeks (n=126)

Median PFS : 3.4 mos w/chemo vs 6.7 mos chemo+bev. (p= .001)
RECIST ORR was 11.8% versus 27.3%, (p=0.001)
Median OS, 13.3 v 16.6 mos (p= 0.176)
GI perforation occurred in 2.2% of bevacizumab-treated patients.
Davis A, et al, “Platinum resistant” ovarian cancer: What is it, who to treat and how tomeasure benefit?, Gynecol Oncol
(2014), http://dx.doi.org/10.1016/j.ygyno.2014.02.038
Platinum Resistant
Platinum Resistant
Platinum Resistant
Epithelial Ovarian Cancer
The End
PARP Inhibition
Phase II trial for Olaparib maintenance: 265 Patients with relapsed PSOC were randomized to olaparib, 400 mg PO bid, or placebo.
Median PFS favors olaparib: 8.4 mos vs 4.8 mos (p< 0.001)
Interim analysis of OS (38% maturity) showed no significant benefit
J Ledermann et al, NEJM, 2012 Apr 12;366(15):1382-92
Texas Woman Makes Emotional Plea For Compassion As Drug Company Refuses Cancer Treatment*
"Since BioMarin has refused her pleas for the potentially life-saving drug [BM-673], Sloan said she feels like she's now waging two wars –- one against the cancer eating away at her body, and one against the pharmaceutical company hiding behind red tape and corporate double talk."
*posted 9/11/2013. Huffington Post
Published online before print March 17, 2014, doi: 10.1200/JCO.2013.51.4489
JCO March 17, 2014 JCO.2013.51.4489
ChemoFx by PrecisionTherapeutics
ChemoFx by PrecisionTherapeutics
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