Download Early stage ovarian cancer: To treat or not to treat?

Adjuvant chemotherapy
for early stage epithelial
ovarian cancer
Vanda Salutari
Fondazione Policlinico Universitario A
Gemelli
U.O. Ginecologia Oncologica
The risk of relapse is not negligible
30%
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
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
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
1545 pts
•Early stage ovarian cancer: To treat or not to treat?
LOW RISK FEATURES
-Grade 1 and 2
OS
90%
-Stage IA-IB
- comprehensively
surgical staging
HIGH RISK FEATURES
-Stage IC and II
OS
40-80%
- Grade 3
Chan JK, Gynecol Oncol 2010
Trope C, JCO 2007
- Clear cell hystology
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 2015 5 randomized RCTs, no new
studies met the inclusion criteria, 10-year follow up (ICON1): 1277
women
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 1.20 to
3.1; P = 0.71
NR
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%
Log rank test
DFS P = 0.41
OS P = 0.43
NR
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 0.66 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 IaIb grade 1-2-3
FIGO IcIIa 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
HRs
OS: HR 0.69;
to 1.08; P = 0.10
RFS: HR 0.63;
P = 0.02
OS 77% (adjuvant
arm) versus
70% (no
treatment)
Not reported
Subgroup analysis
Showed that nonoptimally staged patients
in observation arm
had significantly worse
survival
1/3 OF PTS WERE NOT
OPTIMALLY STAGED
* LOW/INTERMEDIATE RISK: IA G1/G2
I B G1
I C G1
HIGH RISK: IA G3
I B G2
I C G3
ANY CLEAR CELL
OS at 5 yrs
CT
OS at 10 yrs
NO CT
CT
NO CT
PFS
5 yrs
10 yrs
CT
NO CT
CT
NO CT
SUBGROUP ANALYSIS BY SURGICAL STAGING
OS
PFS
CT
NO CT
CT
NO CT
SUBGROUP ANALYSIS BY RISK FACTORS
OS
PFS
CT
NO CT
CT
NO CT
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)
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
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
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
73%
62%
57%
Median FU=38 months
54%
80%
70%
63%
29%
1.3.2 Adjuvant systemic chemotherapy for stage I disease
1.3.2.1 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).
1.3.2.2 Offer women with high-risk stage I disease (grade 3 or
stage Ic) adjuvant chemotherapy consisting of six cycles of
carboplatin.
1.3.2.3 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.
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
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
 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
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
 6 cycles vs 3
cycles may
decrease
recurrence in
high risk serous
OC
 OS was not
different
 Further sudies
are needed to
confirm
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
OC is not one disease
Outcome depends on histotype
FIVE HISTOTYPES
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……
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
THE FUTURE……
One
of
these
functional
signatures is based on 19 elements,
called
Barcode,
which
are
differentially expressed between
relapsing and not relapsing patients.
Stage I EOC
Barcode expression level can
be used in addition to clinical
parameters to improve stage I
tumor prognosis.
Why some stage I patients relapse?
Calura E., et al. Annals of Oncology 2016