1. Adjuvant chemotherapy for early stage epithelial ovarian cancer
Vanda Salutari
Fondazione Policlinico Universitario A Gemelli
U.O. Ginecologia Oncologica

2. The risk of relapse is not negligible
30%

3. The rationale of adjuvant CT after complete removal of disease ad adequate surgical staging is to eradicate any residual microscopic deposits of cancer cells responsible of potential recurrence of disease

4. ONE DISEASE MANY ISSUES
Early stage ovarian cancer: To treat or not to treat?
What type of chemotherapy?
How many cycles?
High grade serous ovarian cancer versus other histotypes

5. ONE DISEASE MANY ISSUES
Early stage ovarian cancer: To treat or not to treat?
What type of chemotherapy?
How many cycles?
High grade serous ovarian cancer versus other histotypes

6. 1545 pts

7. comprehensively surgical staging
Early stage ovarian cancer: To treat or not to treat?
LOW RISK FEATURES
Grade 1 and 2
Stage IA-IB
comprehensively surgical staging
OS 90%
HIGH RISK FEATURES
Stage IC and II
Grade 3
Clear cell hystology OS
40-80%
Chan JK, Gynecol Oncol 2010
Trope C, JCO 2007

8. Early stage ovarian cancer: To treat or not to treat?
3 Metanalyses:
1)Elit L Cancer 2004: 13 trials between 1965 and 2004
2) Winter Roach Cochrane Review 2012: 5 randomized trials between 1990 and 2003 involving 1277women, follow up of 46 to 121 months
3) Lawrie T: Cochrane Library, Dec randomized RCTs, no new studies met the inclusion criteria, 10-year follow up (ICON1): 1277 women

9. Trials of adjuvant chemotherapy versus no further treatment
Study ID
Participants
Intervention
5-year survival rates
5-year survival/ statistics
10-year survival rates
Adverse effects
Comments
Young 1990
48 treatment 44
observation
Melphalan
versus no further
treat
DFS 91% versus
98% OS 94%
versus 98%
Log rank test
DFS P = 0.41
OS P = 0.43 NR
16% hadsevere myelosuppression
26% had gastrointestinal
side effects.
One death: myelopr disorder
Trial under
powered to
show any real
differences
Bolis 1995
85 FIGO
(1976) I A-I B
Grade 2 and 3
Cisplatin
50 mg/m² × 6
Cycles versus no further
treatment
DFS 83% versus
64% OS 88%
versus 82%
DFS: HR 0.50; to 1. 19; P = 0.17
OS: HR to 3.1; P = 0.71
Nausea
and vomiting Leucopenia
thrombocytoP
Neuro tox renal
tox
There
were patients
with residual
disease in both
arms
Tropé 2000
162 high risk
stage I 36%pts
had low volume RT
Carboplatin 6
cycles AUC = 7 versus chemo at
progression
No difference
between arms
DFS 70% versus
71%,OS 86%
versus 85%
Dot reported
ICON1 2003
447 FIGO I-II
93%FIGO
stage 1
adjuvant
platinum-based chemotherapy
Versus treatment on PD (87% only platinum)
OS 79% (adjuvant
arm) versus 70% ( no treatment
HRs
OS: HR to
0.97; P = 0.03
OS 73% (adjuvant
arm) versus 64% (no treatment)
Not reported
Survival improvement
with adjuvant therapy
ACTION
2003
* 448 FIGO Ia-
Ib grade 1-2-3
FIGO Ic-
IIa FIGOI-IIa
clear cell
Adj platinumbased
CT versus
treatment on PD
Cisplatin OR Carboplatin
33%sigle platinum
OS 85% (adjuvant
arm) versus
78% (no treatment
OS: HR 0.69;
to 1.08; P = 0.10
RFS: HR 0.63;
P = 0.02
OS 77% (adjuvant
70% (no
treatment)
Subgroup analysis
Showed that non-optimally staged patients in observation arm
had significantly worse survival
1/3 OF PTS WERE NOT OPTIMALLY STAGED
HIGH RISK: IA G3
I B G2
I C G3
ANY CLEAR CELL
* LOW/INTERMEDIATE RISK: IA G1/G2
I B G1
I C G1

10. OS at 5 yrs CT
NO CT CT
NO CT
OS at 10 yrs

11. PFS
5 yrs
10 yrs CT
NO CT CT
NO CT

12. SUBGROUP ANALYSIS BY SURGICAL STAGINGOS
PFS CT
NO CT CT
NO CT

13. SUBGROUP ANALYSIS BY RISK FACTORSOS
PFS CT
NO CT CT
NO CT

14. LIMITS: Pts no prospectively stratified by surgical staging categories
In ACTION trial only 1/3 of pts were optimally staged
Evidence for pts with low and intermediate risk is incomplete (few pts in the trials)
None of the included studies assessed the impact of adjuvant CT on QoL
AE were poorly reported
Findings for the subgroup analysis were ambiguous and low quality (ICON1 posthoc analysis)

15. ONE DISEASE MANY ISSUES
Early stage ovarian cancer: To treat or not to treat?
What type of chemotherapy?
How many cycles?
High grade serous ovarian cancer versus other histotypes

16. What type of chemotherapy?
No evidences that a combination of carboplatin + paclitaxel for EOC is superior to carboplatin alone
Studies comparing these two regimens are lacking
Based on the results seen in advanced disease platinum based chemotherapy has been adopted for use in early stage disease but optimal adjuvant CT regimen is unknown
A well designed trial is needed to identify the optimal CT regimen in this population

17. In absence of clear recomandations, single agent carboplatin seems a reasonable option for intermediate and high risk early EOC pts
Which regimen can be regarded as standard comparator for future first line trials?
The recomended standard in early stages (FIGO I-IIA) ovarian cancer patients in whom adjuvant CT is indicated should contain at least Carboplatin 5-7,5 AUC

18. 73%
57%
Median FU=38 months
62%
54%
80%
70%
63%
29%

19. 1.3.2 Adjuvant systemic chemotherapy for stage I disease
Do not offer adjuvant chemotherapy to women who have had optimal surgical staging[11] and have low-risk stage I disease (grade 1 or 2, stage Ia or Ib).
Offer women with high-risk stage I disease (grade 3 or stage Ic) adjuvant chemotherapy consisting of six cycles of carboplatin.
Discuss the possible benefits and side effects of adjuvant chemotherapy with women who have had suboptimal surgical staging[11] and appear to have stage I disease.

20. EARLY OC WHAT TYPE OF CT IN SUMMARY
Low quality data available to inform an optimal regimen
Single agent carboplatin may be an acceptable alternative in I stages
Well designed trials are needed to identify the optimal chemotherapy regimen in this population

21. ONE DISEASE MANY ISSUES
Early stage ovarian cancer: To treat or not to treat?
What type of chemotherapy?
How many cycles?
High grade serous ovarian cancer versus other hystotypes

22. 24% reduction in recurrence rate in pts who underwent 6 cycles vs 3 cycles of CT
A subgroup analysis showed statistically significant benefit only in serous tumors
Non serous tumors was not influenced by the duration of CT

23. Relative risk of recurrence for OC pts receiving 6 vs 3 cycles of CT based on hystology
RFS and OS OC pts receiving 6 vs 3 cycles of CT based on hystology

24. 6 cycles vs 3 cycles may decrease recurrence in high risk serous OC
OS was not different
Further sudies are needed to confirm

25. ONE DISEASE MANY ISSUES
Early stage ovarian cancer: To treat or not to treat?
What type of chemotherapy?
How many cycles?
High grade serous ovarian cancer versus other histotypes

26. OC is not one disease Outcome depends on histotype

27. FIVE HISTOTYPES

30. CLEAR CELL OC: CURRENT STANDARD OF MANAGEMENT
Guidelines recomend adjuvant CT for CCOC independently of stage but…..
ACTION trial reported similar DFS for early stage treated or not with CT after surgery
In optimally staged FIGO IA-IB disease adjuvant platinum based CT might confer survival advantage?
Further studies are need……

32. MUCINOUS: CURRENT STANDARD OF MANAGEMENT
3-4 % of all OC
83% diagnosed at Stage I
Early stage , well differentiated 5 yrs OS=90%
Expansive growth pattern=good prognosis
Adjuvant CT is usually not given for stage I mucinous OC(RajaF, ann oncol 2012, Jain A, 2013, ICON 1:19.5% of cases were mucinous: no difference in outcome between CT and not CT)
Standard CT is less effective
Future systemic treatment for mucinous OC may be similar to treatment used in colon k including EGFR or HER2-based therapy

33. THE FUTURE……

34. In stage I EOC, defects in transcription regulation are associated with poor prognosis.
One of these functional signatures is based on 19 elements, called Barcode, which are differentially expressed between relapsing and not relapsing patients.

35. Stage I EOC
Why some stage I patients relapse?
Barcode expression level can be used in addition to clinical parameters to improve stage I tumor prognosis.
Calura E., et al. Annals of Oncology 2016