Ovarian Cancer Flashcards
What are the steps in staging Ovary Cancer?
1) Obtain any free fluid for cytology can examination
2) If no free fluid, obtain Washings by instilling and recovering 50-100mls of saline.
- The fluid should irrigate the cul de sac, parabolic gutters and area beneath each diaphragm
3) Systematically, explore all intra-abdominal organs and surfaces. They should be visualized and palpated
- bowel
- liver
- GB
- diaphragm
- mesentery
- momentum
- entire peritoneum
4) Suspicious areas/adhesions should be biopsied. If there are no suspicious areas, multiple biopsies should be obtained from the peritoneum of the cul-de-sac, paracolic gutters, bladder, and intestinal mesentery
5) Diaphragm should be biopsied/scraped for cytology.
6) Omentum should be resected from the transverse colon
7) Retroperitoneum should be explored to evaluate pelvic LN. Suspicious LN should be removed and sent for frozen section. An ipsilateral dissection may be performed only for unilateral tumor
8) Para-aortic LN should be exposed and enlarged LN removed. Nodes superior to the inferior mesenteric artery should also be resected
9) In the absence of suspicious LN, pelvic and para-aortic LN should be sampled to exclude the possibility of microscopic stage III disease
10) A TAHBSO is performed
What are the epithelial ovarian cancers?
= Adenocarcinomas.
They can be subclassified into:
- Serous
- Endometrioid
- Transitional cell (Brenner)
- Mucinous
- Clear Cell
- Mixed epithelial Tumors
- Undifferentiated
- Unclassified
What are the risk factors for ovarian CA?
Age (mean age 59yo, decreases after 80yo)
FHx
- single first degree-relative with ovarian CA puts one at 3.6x risk, with lifetime risk of 5%
- BRCA 1 or BRCA 2
- HNPCC (MSH2 24% risk, MLH1 20%, MSH6 1%)
White race
Diet with high animal fat
Nulliparity or 1st birth after 35yo
Involuntary infertility
Late menopause
Early menarche
Which subtype of ovarian cancer is strongly a/w endometriosis?
Clear cell
Which mutation does clear cell ovarian CA carry in a significant proportion?
ARID1A mutations
ARID1A mutations are found in which type of ovarian CA?
Clear Cell
Endometrioid
What is a mixed ovarian CA?
Tumor consists of >1 histo type and minor component forms >10%
What are the types of Ovarian CA?
Type 1:
- low grade, indolent
- low grade serous, Endometrioid, mucinous, cc, Malignant Brenner
- Mutations of KRAS, BRAF, ERBB2, PTEN, PIK3CA, ARID1A
- relatively genetically stable
Type 2:
- No clear precursor lesion
- High grade, aggressive
- high-grade serous, high-grade Endometrioid, malignant mixed mesodermal tumors (MMMT) and undifferentiated tumor
- freq a/w TP53 mutations
What are some of the suspicious morphology on transvaginal US?
L.I.M.A.S
Large lesion Multi-lobular cysts Solid papillary projections Irregular internal septa toons Ascites
What is considered optimal cytoreduction?
No residual tumor measuring >1cm at the end of the surgery
What does CRS entail for ovarian CA?
TAHBSO Pelvic and para-aortic LN sampling Infra colic omentectomy Pelvic and peritoneal biopsies Pelvic and peritoneal Washings Appendectomy in case of mucinous histology
Is this true? Why?
Neoadj –> surgery is better than CRS –> chemo?
Vergote NEJM 2010
N=632
Aim: to identify if neoadjuvant chemo –> interval debulking was inferior to primary debulking surgery–> chemo
Incl criteria:
- Stage IIIC/IV epithelial ovarian CA, fallopian-tube carcinoma, PPC
Largest residual tumor was 1cm or less in 40% of primary debulked patients, and in 80% with interval debulking
Postop adverse effects and mortality higher after primary debulking
Conclusion–> Neoadj chemo not inferior
Subset analysis:
- initial CRS better for Stage III, lower volume disease
- initial Neoadj chemo better with Stage IV disease
Describe the FIGO staging broadly.
I - Tumor confined to ovaries
II - Tumor involves 1 or both ovaries with pelvic extension
III - Tumor involves 1 or both ovaries with microscopically confirmed peritoneal mets outside the pelvis +/- regional LN Mets
IV- Distant mets beyond the peritoneal cavity
Describe FIGO stage I
I = Tumor confined to the ovaries
IA = tumor limited to 1 ovary, capsule intact
- no tumor on ovarian surface
- no malignant cells in Ascites/peritoneal Washings
IB = Tumor limited to both ovaries, capsules intact.
- no tumor on ovary surface
- no malignant cells in Ascites/peritoneal Washings
IC: Tumor limited to one or both ovaries, with any of the following:
- Capsule ruptured
- tumor on ovarian surface
- positive malignant cells in the Ascites or positive peritoneal Washings
Describe FIGO Stage II
Stage II - Tumor involves 1 or both ovaries with pelvic extension
IIA: extension +/- implants in uterus +/- tubes
- no malignant cells in Ascites or peritoneal Washings
IIB: Extension to other pelvic organ
- no malignant cells in the Ascites or peritoneal Washings
IIC: IIA/B with positive malignant cells in the Ascites or positive peritoneal Washings
Describe FIGO Stage III
III = Tumor involves 1 or both ovaries with microscopically confirmed peritoneal mets outside the pelvis +/- regional LN mets
IIIA: microscopic peritoneal mets beyond the pelvis
IIIB: Macroscopic peritoneal mets beyond the pelvis, 2cm or less in greatest dimension
IIIC: Peritoneal mets beyond the pelvis >2cm in greatest dimension +/- regional LN mets
What are the trials supporting intraperitoneal chemotherapy?
1) GOG 172 trial by Deborah Armstrong
- NEJM 2006
- RCT Phase 3; n=400
- 2 arms in Stage III Ovarian CA with 1cm or less residual mass:
(I) IV Pac + IV CDDP
(II) IP Pac + IP CDDP; IV Pac
- 40% in IP group completed therapy
- mPFS 18m (IV) vs 24m (IP)
- mOS 50m vs 66m (IP)
2) Meta-analysis by Hess in 2007
- 6 RCTs 1700 patients (ovarian Ca)
- pooled HR for PFS 0.8 and pooled HR for OS 0.8 (both p significant)
3) GOG 104
- IV CDDP/Cyclo vs IP CDDP/IV Cyclo
- 2nd look laparotomy
- pCR 36% vs 47%
- mOS 41m vs 49m
4) GOG 114
- initially 3 arms:
> IV CDDP/IV Cyclo
> IV CDDP/IV Pac
> IV Carbo AUC9/IP CDDP/IVPac
- IV CDDP/Cyclo taken off
- PFS 28m vs 23m (IP better)
- OS 60m vs 50m (IP better)
What is the rationale for IP chemotherapy?
1) Major route of spread is within the peritoneal cavity
2) Ability to reduce tumor volume with debulking
3) Residual peritoneal tumor exposed to increased concentration of drug for prolonged period of time
What are the limitations of IP chemo?
Poor tumor penetration of bulky disease
Less exposure of extra-peritoneal dz to drug
What are the possible complications of IP chemo?
1) Obstruction to flow or inadequate distribution
2) Infection:
- peritonitis
- abdominal wall or catheter
3) Intestinal perforation
What are the trials that support dose-dense scheduling in ovarian CA?
1) JGOG 3016
- 2 arms:
(A) IV Pac (180)/IV Carbo (AUC6) q21 days x 6#
(B) IV Pac (80) D1,D8,D15 + IV Carbo (AUC 6) D1 q21d x 6#
- 6yr update
- mOS 60m vs 100m
- mPFS 28m vs 17m
2) MITO 7
- 2 arms:
(A) IV Pac (175)/Carbo AUC6 q21d x 6#
(B) IV Pac (60) + IV Carbo AUC2 D1,8,15 q21d x6#
- 2 yr f/u
- mPFS 17m (A) and 18m (B)
- QOL scores better with dad
- G3/4 and FN rates lower in (B)
What is the role of adjuvant chemotherapy for early stage epithelial ovarian cancer?
Cochrane Database by Winter-Roach. 1st published in 2009. 2 updates, latest in 2015
6RCTs (including ICON 1); >1200 patients
>95% with Stage I Ovarian CA
10yr OS HR 0.72
10yr PFS HR 0.67
Effective in prolonging survival in early stage disease. But uncertain benefit in low, and intermediate-risk early stage disease
Tell me about ICON5/GOG 182
5-arm study, to evaluate if incorporation of an additional cytotoxic agent improves OS and PFS in advanced epithelial Ovarian Ca and PPC who received Pac/Carbo.
Stage III/IV, n>4000
80% competed 8#
5arms: A) Pac/Carbo B) Pac/Carbo/Gem C) Pac/Carbo/Liposomal Doxorubicin D) Carbo+Topotecan --> Carbo/Pac E) Carbo+Gem --> Pac/Carbo
No improvements in PFS/OS
What is the role of Docetaxel in the treatment of Ovarian CA?
JNCI 2004, Vasey et al.
2 arms, 6# each:
A) Docetaxel (75)/ Carbo (AUC5)
B) Paclitaxel (175)/ Carbo (AUC5)
Responding patients get 3# more mono therapy Carbo
F/u 2 years
Similar PFS 15m, and OS of 60+%
Docetaxel with less overall and G2 neurotoxicity 10% vs 30%
Docetaxel with greater G3/4 neutropenia 94% vs 84%
Possible alternative
What is the role of Liposomal Doxorubicin in ovarian CA?
MITO-2
Stage IC-IV ovarian CA
2 arms:
A) Pac (175)/Carbo AUC 5
B) PLD (30)/Carbo AUC 5
N=820 f/u 3 years Median PFS 19m vs 17m (PLD vs Pac) p0.6 Median OS 60m vs 50m (PLD vs Pac) p0.3 Similar RR
What predicts OS for surgery at 1st relapse?
Need to fulfill 2 out of 3.
1) Complete resection at 1st surgery
2) Good PS
3) Absence of Ascites
Tell me about DESKTOP III
Prospective RCT evaluating role of surgery at relapse.
2 arms:
A) Chemo –> Surgery
B) Chemo alone
Choice of chemo is physician -determined
What are the DESKTOP trials?
DESKTOP I =
- exploratory study based on retrospective analysis
- n=267
- complete resection was a/w prolonged survival in recurrent ovarian CA
- identified criteria panel: PS, FIGO stage at Dx, residual tumor after primary surgery, absence of Ascites.
> Able to predict complete resection in 80%
DESKTOP 2:
- to verify the DESKTOP I score.
DESKTOP 3: Not out yet Prospective RCT evaluating value of surgery at relapse 2 arms: - Chemo--> Surgery - chemo alone Choice of chemo is physician dependent
What are the trials using Bevacizumab?
Upfront:
- ICON 7
- GOG 218
Recurrent disease:
- OCEANS (platinum-sensitive)
- AURELIA (platinum-resistant)
Tell me about ICON 7
N=1500
All stages
2 arms:
- Pac(175)/Carbo (AUC 5 or 6)/Bev (7.5mg/kg) + Bev
- Pac(175)/Carbo (AUC5/6)
Entire population: no significant diff in PFS/OS
High risk:
- PFS 20m vs 16m
- OS 39m vs 34m
High risk: Stage 3c sub optimally debulked; Stage 4, no debulking surgery (total 1/3 of population)
Tell me about GOG 218
N=1800
Stage III/IV
3 arms:
(A): Pac(175)/Carbo(AUC6)
(B): Pac(175)/Carbo(AUC6)/Bev(15mg/kg) –> Placebo
(C): Pac (175)/Carbo(AUC6)/Bev (15mg/kg)–>Bev (15mg/kg)
Median PFS: 11m vs 12m vs 15m
Median OS: 41m vs 39m vs 44m
What are the other anti-angiogenics that you know about in the treatment of ovarian ca?
Oral TKI
- pazopanib
- cediranib
- Nintedanib
Angiopoeitin inhibitor
- Trebananib
VEGF “Trap”
Is there any benefit with Pazopanib?
AGO-OVAR 16 trial
Investigated as a form of maintenance therapy.
Advanced EOC
- 1st line surgery + Chemo, if no PD and tumor Oral Pazopanib 800 mg daily
> Placebo
Primary endpoint PFS favors Pazopanib
- 18m vs 12m HR 0.8
OS data not mature, but no early detrimental effect
Tell me about ICON 6
ICON 6 trial tests Cediranib in platinum-sensitive R-EOC
Platinum-sensitive relapsed EOC
TFI >6 months following 1st line
3arms:
- chemo + placebo–> Placebo
- Concurrent chemo+ Cediranib –> placebo
- Concurrent chemo+ Cediranib –> Cediranib
Chemo agents: Platinum/Taxol; Platinum/Gem; Carboplatin
Cediranib maintenance improves PFS by 3months 12.5vs 9.4
Improves O by 2.7m
- 20m vs 18m
What other conditions causes raised CA 125?
Ovarian cancer - 85% elevated in advanced disease - 50% elevated in early disease Breast cancer Lung cancer Colon cancer Pancreatic cancer
Non-malignant conditions:
- endometriosis
- pelvic inflammatory disease
- ovarian cysts
When do we consider a colonoscopy +/- OGD in the management of suspected ovarian CA?
Particularly when CA 125/CEA ratio is 25 or less
What to do with Stage I ovarian CA patients?
IA/IB Grade 1 = Observe
IA/IB Grade 2 = Observe or IV Taxane/Carbo 3#-6#
IA/IB Grade 3 or clear cell = IV Taxane/Carbo 3#-6#
IC = IV Taxane/Carbo 3#-6#
What are the toxicities of IP chemotherapy?
Increased myelosuppression Renal toxicities Abdominal pain Neuropathy GI toxicities Metabolic toxicities Hepatic toxicities
What is VEGF expression in ovarian Cancer like?
Often over expressed
A/w poorer prognosis
Explain about the following molecular genetics of ovarian cancer.
- TP53
- BAX
- VEGF
- PTEN
1) TP53:
- mutated in ~50% of pts with ovarian cancer
2) BAX:
- pro-apoptotic Gene and overexpression is a/w increased responsiveness to chemotherapy and better prognosis
3) VEGF
- often over expressed and is a/w poor prognosis
4) PTEN
- PTEN and KRAS mutations are more common in mucinous or Endometrioid tumors
Majority of inherited disease in the Jewish population is due to one of the 3 founder mutations in BRCA1 and BRCA2. What are they?
185delAG
5382insC
617delT
Oral contraceptive use for 5 or more years is a/w what percentage decrease in the incidence of ovarian cancer?
50%
Tell me about sex cord-stromal tumors
Granulosa cell tumors most common subtype
They comprise only ~5% of all ovarian neoplasms
Peak incidence >50yo
Granules a cell tumors may secrete estrogen and be a/w endometrial hyperplasia and endometrial ca
Majority Dx in stage I, with 10-yr survival rates of 75%-95%
Late relapses may occur
Patients with advanced-stage dz fare more poorly
Most such patients will be offered chemotherapy, traditionally with BEP or other regimens used in germ cell tumors
Explain about the following molecular genetics of ovarian cancer.
- TP53
- BAX
- VEGF
- PTEN
1) TP53:
- mutated in ~50% of pts with ovarian cancer
2) BAX:
- pro-apoptotic Gene and overexpression is a/w increased responsiveness to chemotherapy and better prognosis
3) VEGF
- often over expressed and is a/w poor prognosis
4) PTEN
- PTEN and KRAS mutations are more common in mucinous or Endometrioid tumors
What is the OCEANS trial about?
Aim: Tested the efficacy & safety of Bev+Gem/Carbo cf Gem/Carbo in platinum-sensitive recurrent ovarian, primary peritoneal, or Fallopian tube cancer
N=500 2 arms: A) Gem/Carbo/Bev-->Bev - 6-10cycles, then Bev maintenance till PD - Gem 1000 mg/m2 D1,8; AUC 4 D1 q21d - Bev 15mg/kg D1 B) Gem/Carbo/Placebo--> Placebo
Median PFS 12m vs 8m
Objective RR 80% vs 60%
Duration of response 10m vs 7m
Sig S/e with Bev:
G3 or higher HTN 17% vs 1%
Proteinuria 9%
Tell me about GOG 158
Done by Ozols et al, JCO 2003
Aim: to establish that Pac/Carbo is non-inferior to Pac/CDDP
N=800 Optimally debulked, advanced ovarian CA 2 arms: A) CDDP (75)+CI Pac (135) B) Carbo (AUC 7.5)+Pac (175) over 3 hours
A: more common GI, Renal, Metabolic tox, G4 leukopenia
B: More thrombocytopenia
Med PFS: 19m vs 21m
Med OS: 49m vs 57m
What is the evidence to suggest that primary chemotherapy is non-inferior to primary surgery?
1) Vergote NEJM 2010
- n= 670
- majority with Stage IIIC or IV
- >5cm in 75% met lesions; >10cm in 60%
- 2 arms:
A) CRS –> Chemo
B) Chemo –> CRS
2) CHORUS study Lancet 2015
- n=550, Stage III/IV ovarian CA
- 2arms:
(1) Primary surgery –> 6# of chemotherapy
(2) 3#chemo –> Surgery –> 3# chemo
Chemo options:
A) Pac (175) + Carbo (AUC 5/6) or
B) alternative Carboplatin combination regimen
C) Carboplatin mono therapy
Med OS 23m in primary surgery group vs 24m in primary chemo group.
HR 0.9 in favor of primary chemo
Conclusion: Survival with primary chemo on-inferior to primary surgery
Criticisms:
- poor surgery quality
» 27% did not receive Bilateral oophrectomy
» 24% did not receive hysterectomy
» more than 80% did not receive upper abdominal surgeries
» median time was 120min surgery time, and optimum cytoreduction achieved only in 40%
- ?pt population. Authors attributed poor surgical outcomes to poor PS/older age
How many cycles of chemo can we give before surgery ?
Can we give more than 3? Why.
Bristow et al Gynecologic Oncology 2006
Meta-analysis
Stage III/IV ovarian Ca patients
Mean median OS 24.5m
Each 10% increase in maximal Cytoreduction was a/w 2m increase in median survival time.
Each incremental increase in pre-op chemo cycles was a/w decrease in median survival Time of 4months.
What is Unresectable disease for ovarian cancer?
Diffuse and/or deep infiltration of small bowel mesentery
Diffuse carcinomatosis involving stomach and/or large parts of the small/large bowel
Infiltration of duodenum and/or parts of pancreas
Involvement of large vessels of the hepatoduodenal ligament, celiac trunk or behind the ports hepatis
Involvement of liver parenchyma
What are the molecular alterations a/w high grade serous and low grade serous ovarian CA?
High grade serous (70% of ovarian CA)
- Chromosomal instability
- p53
- BRCA 1/2
Low grade serous
- BRAF
- KRAS
What are the molecular alterations a/w endometrioid ovarian CA?
pTEN
Beta-Catenin
KRAS
ARID1A
What are the molecular alterations a/w cc ovarian CA?
ARID1A
HNF1beta
IL6-STAT-HIF
PI3K/AKT/mTOR
What are the molecular alterations a/w Mucinous ovarian CA?
KRAS
HER2
By how much is one’s risk of ovarian CA lowered by undergoing risk-reducing Salpingo-Oophrectomy, assuming the person is a carrier of BRCA1 or 2 mutations
~80%
- confirmed by meta-analysis of 10 studies
Why 6# and not 3# of adjuvant chemotherapy?
1) GOG 157
Chan et al 2010 Gynecol Oncol
N=400
70% with Stage I disease, 30% ccOvarian, 25% endometrioid, 20% serous, 7% Mucinous, 15% others
Results:
- THose with serous tumors had a significantly lower risk of recurrence after 6# cf to 3# HR 0.3 in contrast to non-serous.
==========
2) Jeffrey Bell et al. GOG study.
N=460
Stage IAG3, STage IBG3, cc, IC, completely resected stage II Epithelial ovarian CA
2 arms: 3# vs 6# of IV Pac/Carbo AUC7.5 Q21 days
70% stage I
RESULTS:
- G3/4 neurotoxicity in 2% vs 11% (6#)
- 6# caused more severe anemia and granulocytopenia.
- RR for 6# was 24% lower, HR 0.76,
- 5y RR 20% (6#) vs 25%(3#)
- overall death rate similar
Tell me about the GOG 182-ICON5 study
Copeland Gyneol Onco 2003
Bookman et al.
Aim: To improve on the efficacy of standard platinum/Taxanes therapy by incorporating newer cytotoxic agents in sequential doublet and triplet combinations.
Newer agents studied: Gemcitabine, Liposomal doxorubicin, Topotecan
5 groups:
1) Pac/Carbo
2) Pac/Carbo/Gem
3) Pac/Carbo/Doxorubicin Liposomal
4) Carbo/Topotecan –> Carbo/Pac
5) Carbo/Gem –> Pac/Carbo
N>4000
RESULTS:
- no improvements in PFS/OS a/w any experimental regimen
CONCLUSION:
Addition of a 3rd cytotoxic agent did not provide any PFS/OS benefit after optimal/suboptimal cytoreduction
What is the evidence for Docetaxel-Carbo = Pac-Carbo?
JNCI 2004 Vasey et al.
N>1000
Stage IC-IV epithelial ovarian/primary peritoneal CA
2 arms, Q21days x6#:
1) Docetaxel (75)/Carboplatin AUC 5
2) Paclitaxel (175)/Carboplatin AUC 5
* In responding patients, additional 3# of Carboplatin alone was permitted. *
RESULTS:
PFS ~15m
2y OS ~65%
RR similar
Docetaxel/Carbo a/w substantially less overall and G2/higher neurotoxicity cf to Pac/Carbo.
Docetaxel/Carbo gives more 3/4 neutopenia
What is the MITO-2 about?
Sandro Pignata JCO 2011
Aim: To test if Liposomal Doxorubicin/Carbo was more effective than standard chemotherapy.
Stage IC-IV
N=800
2 arms:
1) Carbo AUC 5/Pac (175)
2) Carbo AUC 5/PLD (30)
Q21days X 6#
RESULTS:
Med PFS 19m vs 17m (Pac/Carbo) (Trend)
Med OS 60m vs 50m (Pac/Carbo) (trend)
Conclusion: Superiority not proven.
Pac/Carbo still remains as first line
What is the Calypso trial about?
Wagner BJC 2012
Recurrence of cancer >6/12 after 1st or 2nd line therapy
N=1000
2 arms:
1) Carbo/Doxil
2) Pac/Carb
6 cycles each
RESULTS:
Med survival times 31m (Carbo/Doxil) vs 33m (Carbo/Pac)
How is maximal cytoreduction a/w Survival?
Each 10% increase in maximal cytoreduction was a/w 2m increase in median survival time.
Evidence comes from Robert Bristow et al, meta-analysis
Tell me about the CHORUS trial
Sean Kehoe et al.
Non-inferiority trial
Stage III/IV ovarian CA. N=550
2 arms:
1) primary surgery –>6#chemo
2) 3# chemo–> surgery–> 3#chemo
Chemo:
Pac (175) /Carbo AUC 5/6; or
Alternative Carboplatin combination; or
Carboplatin monotherapy.
RESULTS:
- med OS 22.5m (Sx first) vs 24m (chemo first)
- G3/4 post-op adverse events and deaths within 28days after surgery were more common in the primary-surgery group.
CONCLUSION:
Survival with primary chemo is non-inferior to primary surgery
What are the 3 criteria to predict OS in choosing a patient to op on recurrence.
2 out of 3
1) Complete resection at 1st surgery
2) Good PS
3) Absence of Ascites
