Ovarian cancer with update from ASCO 2013

cases in Australia in 2010
Median age at diagnosis 63
Fourth commonest

cause of cancer death in women in developed countries
>60% of women diagnosed with Stage III/IV
symptoms of abdo pain, bloating, distension, constipation, back pain usually happen in advanced stage
To date, no mortality benefit demonstrated with CA125 and TVUS screening.

Ovary

20% 85%
IA Growth limited to one ovary, no ascites, capsule intact, no surface tumor extension
IB Same as IA but involves both ovaries
IC IA or IB but with positive washings or ruptured capsule
Stage II Extends to True Pelvis 5% 60%
IIA Involves fallopian tube or uterus
IIB Extension to other pelvic tissues
IIC Either IIA or IIB but with positive washings or ruptured capsule
Stage III Extends Beyond the True Pelvis 58% 26%
IIIA Tumor limited to true pelvis but microscopic positive biopsy outside the pelvis
IIIB Abdominal implants up to 2 cm
IIIC Positive lymph nodes or abdominal implants > 2 cm
Stage IV Distant Disease 17% 12%

Stage at diagnosis 5-yr OS

cell/Krukenberg

history of breast, ovarian, or colon cancer ?3x baseline risk
Personal

history of breast or colon cancer
Familial cancer syndrome (10%)
BRCA (breast cancer) gene mutation
Hereditary nonpolyposis colon cancer (HNPCC)

Other potential risk factors
Early menarche (younger than 12 years of age)
Late menopause (older than 52 years of age)
Hormone replacement therapy
First pregnancy at older than 30 years of age
Infertility, endometriosis
(fertility Rx does not increase risk)

risk of developing ovarian cancer :
Taking birth control pills for

more than 5 years
Breastfeeding
Pregnancy
A hysterectomy or a tubal ligation

= HNPCC.
Chen S, et al. J Clin Oncol. 2007:25:1329-1333. Aarnio

M, et al. Int J Cancer. 1999:81:214-218.

or breast cancer
Age of onset of breast cancer
Younger than

50 years of age (premenopausal)
Bilateral breast cancer
Both breast and ovarian cancer in same patient
Ashkenazi Jewish ancestry (2% chance of BRCA)
Male breast cancer

evidence for a premalignant lesion in ovarian cancer.
The entire

peritoneum is at risk because peritoneal carcinomatosis may develop after an oophorectomy

w/o prior hx of oophorectomy
annual Ca125 for 6 years and

TVUS for 4 years in intervention grp
Median f/u:12.4 years
Results:
Similar detection rate (5.7 v 4.7 per 10000 person-yrs), HR 1.21 CI:0.99-1.48
<60% of ovarian ca detected were high grade serous subtype.
No difference in ovarian ca mortality (3.1 v 2.6 per 10000 person-years) HR 1.18 CI:0.82-1.71.
Harm from false-positive screen: 3285 cases with 15% major complication rate from surgical intervention!

JAMA 2011:305 (22):2295-2303

Ca125 and TVUS
Sensitivity >80%, NPV 99%, PPV 25% (ie 4

operations for 1 case of ca)
Only 30% of screen detected ca were stage 1-2
89% of screen detected ca were in BRCA carriers.
Only 4/2960 cases of screen detected ca in women with +FH!
UKFOCCS Phase 2: 4mthly Ca125 and annual TVUS plus ROCA (change in algorithmic scale of Ca125)
Breast or ovarian ca family, BRCA?proportion, HNPCC or Ashkenazi
4531 women median age 45 (35-84), only 1/3 >50yo
sens: 75% (or lower!) spec 96% PPV 13%
12 cases of screen-detected cancer, with 42% of cases in stage 1/2
11/12 underwent optimal cytoreduction (does not translate to cure)
14.4% underwent RRSO, 3.3% underwent RRSO due to false+, 4/653 had incidental ca (? Even higher number if proper serial sectioning method)

JCO 2013;31:49-57
ASCO 2013 abstr 5502

understanding of natural history
Poor performance of current test in detecting

early stage disease
No survival benefit demonstrated even in ‘high risk grp”
Potential for harm
RRBSO remains the standard of care for BRCA carriers and reduces risk of OC by 75-96%
Current estimated uptake of RRBSO in BRCA carriers by countries:
Australia 38%
UK 40%
France 70%
Canada 57%

tissue diagnosis
Perform surgical staging
Optimal debulking of tumour: improves response to

chemo, decreases disease related symptoms and potentially improves immune response
Exception: poor ECOG, disease ‘too bulky’ or other primary not able to be excluded. Consider neoadjuvant chemotherapy
Engage experienced gynaeonc surgeon for optimal primary debulking (GOG: <1cm residual disease, but ?less is even better)
Minimal benefit in interval debulking after ‘suboptimal primary debulking’
Benefit mainly lies with pts who received poor surgery upfront. EORTC v GOG152 trial

year improvement in OS was shown from a metaanalyses of

13 trials in stage 1 disease. However 90% of pts did not receive proper surgical staging/lymph node sampling.
Another metaanalyses showed adjuvant chemo significantly improved PFS and OS
Subgrp analyses showed benefit only in early stage disease that was incompletely resected
One trial showed benefit only in high risk disease.
ACTION trial showed improvement in RFS but only trend towards OS benefit. In pts who had complete surgical staging, there was no RFS or OS benefit

chemo in stage 1C or stage II, clear cell OC

(any stage), and grade 3 OC
No consensus on optimal chemotherapy agent and duration of treatment:
?carboplatin and paclitaxel
3 cycles vs 6 cycles of adjuvant Rx: GOG 157 showed non-significant trend towards less relapse but similar OS and more toxicity with 6 cycles.

Cisp/Cyclo showed 11% ARR favouring taxane NEJM 1996;334(1):1-6, JNCI 2000;92(9):699-708.
Carboplatin

is at least as effective as Cisplatin Ann Oncol 1999;10 supp1:35-41
SCOTROC: Docetaxel is as effective as Paclitaxel but more myelosuppressive JNCI 2004;96(22):1682
No additional benefit of continuing chemo beyond 6 cycles.
2006 metaanalysis of 60 trials with 15609 women:
Platinum monotherapy v Platinum-based combi: HR 1.16 CI:0.86-1.58)
Platinum-non taxane v Platinum-taxane: HR 1.28 CI:1.07-1.53)

more than 50% achieving CR after optimal cytoreduction
However, up to

70% relapse within 1-3 years.

II to IV (65% SIII, 15% SIV)
Carbo AUC6 + Pacli180mg/m2

D1 q3/52 v Carbo AUC6 D1 + Pacli 80mg/m2 D1,8,15 q3/52
Improved PFS 17.2m v 28m HR 0.71 CI: 0.58-0.88
Improved 3-yr OS 65.1% v 72.1% HR 0.75 CI 0.57-0.98
Improved OS at 6.4-yr fu: 62m v not reached HR 0.79 CI 0.63-0.99 (ASCO 2012)
Greater toxicity with dose dense strategy:
Neutropenia 88% v 92%, G3 or 4 anaemia 44% v 69%, Less treatment completion 61% v 73%
Similar rate of neurotox and febrile neut (9%)

to IV (66% SIII, 18% SIV)
Carbo AUC2 +Pacli 80mg/m2 both

D1,8,15 q3/52 v C AUC6+P 180mg/m2 q3/52 v
20m f/u: Similar PFS (18.8m v 16.5m HR 0.88 CI 0.72-1.06). OS immature
Better tolerated with less neuropathy (6% v16%), neutropenia, renal dysfunction (0% v 2%). Better QOL
Upcoming trials: ICON-8

combi may improve OS
Multiple trials. Biggest is GOG182-ICON5: JCO 2009;27(9):1419-1425
5

arms study of adding either Gemcitabine, Topotecan or Caelyx to backbone of Carbo/pacli
Study closed after 4312 pts accrued due to no PFS and OS benefit over CP

pts who do not have progression after surgery and completion

of >4 cycles of platinum-taxane chemo (940pts, FIGO II-IV, 85% in CR at entry). Improved PFS from 12.3m to 17.9m. OS immature ASCO 2013. JCO 2013;31 sup:abstr LBA5503

12m maintenance only managed to show improved PFS from 10.3m

to 11.2m to 14.1m. 2.3% risk of GI perf. No OS benefit: 39m in both arms. Note: crossover to Bev allowed at progression.
ICON-7: carbo/pacli v carbo/pacli+BevBev 36 wks at 7.5mg/kg Bev. Include 9% high risk stage early stage. Improved PFS at 42m (22m v 24m) but no difference in OS. In pts at high risk of progression (stage IV or stage III or residual tumour >1cm) there is improved PFS 14m v 18m, and OS 29m v 37m (posthoc analysis). 2013 QOL update showed no benefit with addition of Bev. Final OS pending
BOOST will re-examine 15m v 30m of Bev (if we believe final OS data from ICON-7

cavity increase the dose intensity without increasing plasma drug levels

and potentially decrease systemic SEs. Only use in optimally debulked pts
GOG104:
IV Cyclo +IV or IP Cisp100mg/m2 q3/52.
Improved OS with IP group 49m v 41m but at the cost of abdominal pain
GOG114:
6 cycles IV Cisp 75mg/m2+Pacli135mg/m2 q3/52 v 2 cycles of IV Carbo AUC9 q4/52 followed by 6 cycles of IP Cisp 100mg/m2+IV Paclitaxel 135mg/m2 q3/52
Improved OS with IP 63m v 52m, but only 18% received >2 IP cycles
GOG172:
IV Cisp 75mg/m2 +Pacli 135mg/m2 q3/52 v IV Pacli 135mg/m2+ IP Cisp 100mg/m2 + IP pacli 60mg/m2 d8
Improved OS with IP 65.6m v 49.7m. More haem toxicities
?benefit from additional dose of paclitaxel
Poor uptake: concern re tox and logistics issues

consensus on who should receive NACT. ?all pts need preop

laporoscopy for diagnostic and staging
Advantage in responders: less extensive surgery and less morbidity from surgery
EORTC 55971 Gynecol Oncol 2010;119(1):1-3
670 pts w potentially operable stage III and IV ovarian ca
Primary debulking surgery, then 6 cycles of chemo or 3 cycles of neoadjuvant carbo/paclitaxel with interval debulking surgery, then more chemo.
Improved optimal debulking rate (residual <1cm) 41.6% v 80.6%. (cw 75% optimal primary debulking rate in experienced centres)
Less periop complications: death 0.7% v 2.5%, infection 2 v 8&, haemorrhage 4 v 7%
Similar PFS (12m) and (OS 29 v 30m). Pts who had primary surgery had improved OS if no residual disease (45 v 38m) or <1cm disease (32 v 27m)!
Nb: 3% did not have met ovarian ca at laparotomy! 25% did not receive standard C/P

centres in UK and 2 in NZ
Non-inferiority trial with similar

design to EORTC 55971
Exclude >6% decrease in 3-yr estimated OS of 50%
Results: non-inferior PFS and OS
PFS: 11.3m v 10.7m
OS: 24.5m v 22.8m
Less postop morbidity/mortality with NACT
G3 or 4 complications: 14% v 24%
D/c within 2/52: 92% v 74%
Death within 28 days: 5.6% v 0.5%
Criticism of ‘suboptimal surgery’:
av duration of debulking surgery of 2 hrs,
Rate of residual disease >1cm in primary surgery arm of 61% v 25%
High rate of mortality
Nonetheless, both EORTC and CHORUS showed similar results
Neoadjuvant chemo is an alternative esp in women who are deemed unlikely to have residual microscopic disease post primary debulking.

do you treat?
Symptoms
Imaged lesions
Chemical

permission from the author.
Delayed
Early
Patients at Risk, n
Mos Since Randomization
Proportion Surviving
6
12
18
24
30
36
42
48
54
60
HR:

1.00 (95% CI: 0.82-1.22; P = .98)

Abs diff at 2 yrs: -0.1%
(95% CI diff: -6.8, 6.3%)

Early
Delayed

0

0.25

0.50

0.75

1.00

0

Overall Survival

positives
No improvement in OS
Exhaust treatment options
Toxicity
Impaired QoL
Cost
No ideal agent available
May

be homeopathic only

Pros
Stay ahead of disease
Improve survival?
Prevent symptoms
Maximize QoL
“Active approach” to care
Intuitive to do something
Minimize patient anxiety
Avoids patient “relocating”
Shortens visit time

et al. ASCO 2002. Abstract 829.
1000
900
800
700
600
500
400
300
200
100
0
100
90
80
70
60
50
40
30
20
10
0

(with PLD)
FDA-Approved Drugs in Ovarian Cancer
1964
Melphalan
Doxorubicin
1974

doxorubicin (PLD)[3,4]
Platinum vs platinum + paclitaxel[5]
Carboplatin vs carboplatin + gemcitabine[6]
Carboplatin

+ PLD vs carboplatin + paclitaxel[7]
PLD vs PLD + trabectedin[8]

1. ten Bokkel Huinink WW, et al. J Clin Oncol. 1997;15:2183-2193. 2. ten Bokkel Huinink WW, et al. Ann Oncol. 2004;15:100-103. 3. Gordon AN, et al J Clin Oncol. 2001;19:3312-3322. 4. Gordon AN, et al. Gynecol Oncol. 2004;95:1-8. 5. Parmar MK, et al. Lancet. 2003;361:2099-2106. 6. Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. 7. Vasey P, et al. ECCO ESMO 2009. Abstract 18LBA. 8. Monk BJ, et al. ESMO 2008. Abstract LBA4

platinum sensitive OC, followed by Bev maintenance. Improved PFS 8.4m

v 12.4m, RR 57.4% v 78.5%. No OS benefit at second interim analysis! ?crossover 33.3m v 35.2m JCO 2012;17:2039-2045