Download Current state of upfront treatment for newly diagnosed advanced

Current state of upfront
treatment for newly diagnosed
advanced ovarian cancer
Ursula Matulonis, M.D.
Associate Professor of Medicine, HMS
Program Leader, Medical Gyn Oncology
Dana-Farber Cancer Institute
Boston, MA
Email: [email protected]
Phone: 617 632-2625
Agenda
„ Review
trials for upfront management of
newly diagnosed advanced ovarian cancer
„ Review ongoing studies
„ Review new therapies being tested
Ovarian cancer 2010
„ 22,500
cases diagnosed per year in the
United States and 16,500 deaths per
year1.
„ Most patients are diagnosed in late
stages; no screening test exists.
„ Pathology: 4 different types (serous,
endometrioid, clear cell and mucinous)
1Jemal
A, Siegel R, Ward E, et al: Cancer statistics, 2009. CA: Cancer J Clin 59(4):225-49, 2009
Unique aspects of newly diagnosed
advanced ovarian cancer
„
„
„
„
Upfront surgical management is standard of
care: allows access to tissue
OC is very chemotherapy sensitive at diagnosis;
>80% of cancers will respond to platinum- and
taxane-based chemotherapy upfront at dx.
Cancer becomes more treatment-refractory
following recurrence.
Few but some CTC’s.
Outcomes for newly diagnosed ovarian cancer
have reached a plateau with platinum/taxane
combinations.
Ovarian cancer staging
„
„
„
„
Stage I: confined to ovary(ies)
Stage II: local spread to pelvis
Stage III:
Stage IIIA: microscopic upper abdominal spread
Stage IIIB: upper abd implants <2 cm
Stage IIIC: ≥ 2cm implants and/or +nodal
involvement
Stage IV: spread outside the abdominal cavity.
Definition of “extent of debulking” is what is
residual post surgical debulking:
optimal cytoreduction/debulking: ≤ 1cm residual
suboptimal debulking: > 1cm residual cancer
Advanced ovarian cancer
PFS and OS for newly diagnosed advanced ovarian cancer
Study
Median PFS
Median OS
Comments
GOG 111
18 mos
38 mos
Suboptimally and stage IV
GOG 158
21 mos
57.4 mos
Optimally cytoreduced only
GOG 172
24 mos
65 mos
Optimally cytoreduced only.
Longest survival observed in
advanced ovarian cancer
GOG 182
16 mos
44 mos
Both optimal and suboptimal.
Study compared 5 arms of
treatment
Weekly pac vs q21 d 28 mos (vs.
Lancet 09
17 mos)
Not
reached
Both optimal and suboptimal
EORTC neoadjuvant
IGCS 2008
29/30 mos
Neoadjuvant vs. upfront
debulking
NEJM 1996
JCO 2003
NEJM 2006
JCO 2009
GOG 218: ASCO
2010
Both 12 mos
GOG111: Survival By Treatment
Pac + cis (38 mos)
Cy + cis
(24 mos)
Alive
(N)
Died
(N)
Cisplatin/
cyclophosphamide
28
174
13.0
Cisplatin/paclitaxel
45
138
18
Treatment
McGuire WP, et al. N Engl J Med. 1996;334:1-6.
Median PFS Relative
Survival (mo)
Risk
–
0.69
RANDOMIZE
GOG0182-ICON5: Schema
I
Carboplatin AUC 6 (d1)
Paclitaxel 175 mg/m2 (d1)
x8
II
Carboplatin AUC 5 (d1)
Paclitaxel 175 mg/m2 (d1)
Gemcitabine 800 mg/m2 (d1,8)
x8
III
Carboplatin AUC 5 (d1)
Paclitaxel 175 mg/m2 (d1)
Doxil 30 mg/m2 (d1, every other cycle)
x8
IV
Carboplatin AUC 5 (d3)
x4
Topotecan 1.25 mg/m2 (d1-3)
V
Carboplatin AUC 6 (d8)
Gemcitabine 1 g/m2 (d1,8)
Carboplatin AUC 6 (d1)
x4
Paclitaxel 175 mg/m2 (d1)
x4
JCO 2008
GOG0182-ICON5: Progression-Free
Survival
GOG0182-ICON5: Overall Survival
Primary Therapy—IP
Median PFS,
months
IV
GOG
1041
GOG
1142
GOG
1723
—
22
18.3
Hazard
ratio
IP
—
28
23.8
Median OS,
months
IV
—
0.78
(P = .01)
0.80
(P = .05)
41
52
50
Hazard
ratio
IP
49
63
66
PFS = Progression-free survival; OS = Overall survival; IV = Intravenous; IP = Intraperitoneal.
1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955.
2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007.
3. Armstrong DK, et al. N Engl J Med. 2006;354:34-43.
0.76
(P = .02)
0.81
(P = .05)
0.75
(P = .03)
GOG #172
Armstrong et.al. N Engl J Med 2006;354:34-43
BRCA Analysis
DNA Banking
Ovarian cancer
Optimal (<1cm)
Stage III
Stratify:
Gross residual
Planned 2nd look
R
A
N
D
O
M
I
Z
E
Second look
Laparotomy
(if chosen)
Paclitaxel 135 mg/m2/24h
Cisplatin 75 mg/m2
q 21 days x 6
Paclitaxel 135 mg/m2/24h
Cisplatin 100 mg/m2 IP D2
Paclitaxel 60 mg/m2 IP D8
q 21 days x 6
GOG #172: outcomes
Regimen 1
Intravenous
Regimen 2
Intraperitoneal
Progression-free
18.3 mos
23.8 mos
Overall Survival
49.5 mos
66.9 mos
(GOG 172)
Figure 1
By Treatment Group
1.0
Rx Group
IV
IP
Proportion Progression-Free
0.9
0.8
PF Failed Total
50
160 210
63
142 205
0.7
23.8 months for IP group
0.6
0.5
(Δ = 6 months)
0.4
0.3
18.3 months for IV
0.2
0.1
0.0
0
12
24
36
Months on Study
48
60
GOG Protocol 172
By Treatment Group
1.0
IP median overall survival = 66 months
0.9
(Δ = 16 months)
Proportion Surviving
0.8
0.7
0.6
0.5
IV median overall survival = 49.5 months
0.4
0.3
0.2
Rx Group
0.1
Rx
IV Group
IV
IP
IP
0.0
0
12
Lost to
Follow-up
Alive
5
93
11
117
24
Alive
Dead
Total
Dead
Total
78
117 210
93 88 205
127
101
210
205
36
48
Months on Study
Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03
N Engl J Med. 2006;354:34-43.
60
GOG Protocol 172 Toxicity
G3/4
G3/4
G3/4
G3/4
G3/4
G3/4
G3/4
G3/4
G3/4
*P ≤ 0.05
Leukopenia*
Platelet
GI*
Renal*
Neurologic Event*
Fatigue*
Infection*
Metabolic*
Pain*
IV, %
(N = 210)
64
4
24
2
9
4
6
7
1
IP, %
(N = 201)
76
12
46
7
19
18
16
27
11
Modulating Toxicity of
IP Therapy
„
New approaches to improve toxicity profile
– Timing of catheter placement
– Timing of chemotherapy
ƒ relative to surgery
ƒ relative to catheter placement
– Agents used
– Supportive care (anti-emetics, IV fluids, myeloid
growth factor)
„
Successful use of IP therapy requires:
–
–
–
–
Training
Skill
Experience
Dedication
GOG 252: Newest upfront IP study
IGCS Bangkok
October 25th 2008
Ovarian, tubal or peritonal cancer
FIGO stage IIIc-IV (n = 718)
Randomisation
Primary Debulking Surgery
3 x Platinum based CT
Interval debulking
(not obligatory)
> 3 x Platinum based CT
Neoadjuvant chemotherapy
3 x Platinum based CT
Interval debulking if no PD
> 3 x Platinum based CT
Primary Endpoint: Overall survival
Secondary endpoints: Progression Free Survival, Quality of Life, Complications
Randomised EORTC-GCG/NCIC-CTG trial
on NACT + IDS versus PDS
Statistical considerations
„ 704 patients were required in order to show
noninferiority with respect to survival
between PDS and NACT, with a one-sided
type I error of 0.05 and a power of 80%.
Randomised EORTC-GCG/NCIC-CTG trial on NACT +
IDS versus PDS
Baseline Characteristics (ITT)
FIGO Stage
IIIc
IV
Serous
Age
CA125 > 30 KU/L
Largest metastasis
(mm)
PDS
NACT -> IDS
77%
23%
64%
62 (25-86)
98%
80 (0-400)
77%
23%
58%
62 (33-81)
99%
80 (0-389)
Randomised EORTC-GCG/NCIC-CTG
trial on NACT + IDS versus PDS
Surgical findings and results (PP1)
Metastases before > 2 cm
Metastases before > 10 cm
No residual after surgery
≤ 1 cm after surgery
PDS
(n = 329)
95%
62%
NACT -> IDS
(n = 339)*
68%
27%
21%
46%
53%
82%
* % calculated on the 306 patients who underwent IDS.
Randomised EORTC-GCG/NCIC-CTG
trial on NACT + IDS versus PDS
Surgical characteristics (PP1)
PDS
(n = 329)
NACT -> IDS
(n = 339)*
2.7%
0.6%
8%
2%
1.2% / 0.3%
0,3% / 0.6%
Operative time (minutes)
180
180
Red blood cell transfusion
51%
53%
Hemorhage Grade 3/4
7%
1%
2.4%
0.3%
Postoperative mortality
(< 28 days)
Postoperative fever Gr 3-4
Fistula (bowel/GU)
Venous Gr 3/4
NACT + IDS versus PDS: ITT
Median PFS
Progression-free survival
PDS: 12 months
100
IDS: 12 months
90
HR for IDS:0.99
(0.87, 1.13)
80
70
60
50
40
30
20
10
0
(years)
0
O N
320 360
320 357
1
2
3
4
Number of patients at risk :
168
60
39
26
177
60
36
20
5
17
13
6
7
3
7
8
2
1
Treatment
Upfront debu
Neoadjuvant
NACT + IDS versus PDS: ITT
Overall survival
100
90
Median survial
80
70
PDS: 29 months
60
IDS: 30 months
HR for IDS:0.98 (0.85, 1.14)
50
40
30
20
10
0
(years)
0
2
4
6
8
10
O N
259 361
Number of patients at risk :
183
68
16
2
Treatment
Upfront debulking s
251 357
191
11
1
Neoadjuvant chemo
56
NACT + IDS versus PDS: ITT
Survival time: Figo stage
Events / Patients
Statistics
EORTC 55971 Upfront debulking
Neo-adj. Chemo (O-E)
Var.
III
190 / 276
191 / 273
IV
68 / 81
59 / 83
258/ 357
(72.3 %)
250/ 356
(70.2 %)
Total
Test for heterogeneity
Chi-square=0.5, df=1: p>0.1
*90% CI everywhere
-1.8
94.7
4
31.4
HR & CI*
(Upfront debulking :
Neo-adj. Chemo)
2.2 126.1
|1-HR|
% ± SD
2% ±9
increase
0.25
0.5
1.0
2.0
4.0
Upfront debulking Neo-adj. Chemo
better
better
Treatment effect: p>0.1
NACT + IDS versus PDS: ITT
Survival time: Age
Events / Patients
Statistics
EORTC 55971 Upfront debulkingNeo-adj. Chemo (O-E)
Var.
<50
50-70
>70
Total
34 / 46
31 / 56
172 / 244
161 / 221
53 / 71
259/ 361
(71.7 %)
Test for heterogeneity
Chi-square=2.59, df=2: p>0.1
*90% CI everywhere
6.1
15.5
0
82.7
59 / 80
-2.6
26.9
251/ 357
(70.3 %)
3.5
125.1
HR & CI*
(Upfront debulking :
Neo-adj. Chemo)
|1-HR|
% ± SD
3% ±9
increase
0.25
0.5 0.8 1.0
2.0
4.0
Upfront debulking Neo-adj. Chemo
better
better
Treatment effect: p>0.1
Multivariate analysis for OS(PP1)
P values
Optimal debulking
Histological type (9 categories)
Largest tumor size at
randomisation
Figo Stage (IIIc vs IV)
Country (14 categories)
0.0001
0.0003
0.0008
Age
WHO PS
Differentiation Grade
Treatment arm
0.0020
NS
NS
NS
0.0008
0.0014
Conclusions
In Stage IIIc-IV OVCA, NACT followed IDS produces similar OS and
PFS outcomes compared to standard primary debulking followed by
chemotherapy in FIGO Stage IIIc-IV ovarian carcinoma.
2.
There does not seem to be a subgroup based on
1. Stage IIIc or IV
2. Age
3. WHO performance
4. Histological type ovarian cancer
5. Countries with high or low optimal debulking rate
for which PDS or NACT -> IDS result in better survival.
1.
Because of the overall poorer PFS and OS compared to other
studies, the use of neoadjuvant chemotherapy is not considered
the standard of care in the United States, but is reserved for
patients who are too ill to undergo initial surgery or those patients
who have clearly non-debulkable cancer.
PFS and OS for newly diagnosed advanced ovarian cancer
Study
Median PFS
Median OS
Comments
GOG 111
18 mos
38 mos
Suboptimally and stage IV
GOG 158
21 mos
57.4 mos
Optimally cytoreduced only
GOG 172
24 mos
65 mos
Optimally cytoreduced only.
Longest survival observed in
advanced ovarian cancer
GOG 182
16 mos
44 mos
Both optimal and suboptimal.
Study compared 5 arms of
treatment
Weekly pac vs q21 d 28 mos (vs.
Lancet 09
17 mos)
Not
reached
Both optimal and suboptimal
EORTC neoadjuvant
IGCS 2008
29/30 mos
Neoadjuvant vs. upfront
debulking
NEJM 1996
JCO 2003
NEJM 2006
JCO 2009
GOG 218: ASCO
2010
Both 12 mos
Dose dense paclitaxel versus q 3 week paclitaxel
for newly diagnosed ovarian cancer
„
„
„
„
„
1
631 eligible patients were enrolled
Eligibility: stage II to IV epithelial ovarian cancer
Pts could have upfront or interval debulking
surgery
Primary endpoint was PFS
Treatment1:
Paclitaxel 180 mg/m2 + carboplatin AUC 6 day
both day 1
or
Paclitaxel 80 mg/m2 days 1, 8, 15 + carboplatin
AUC 6 day 1 (dose dense group)
Creatinine clearance calculated by Jelliffe and treatment given for 6 cycles
Katsumata et al, Lancet 2009
Progression-free survival
PFS for:
DD Pac: 28 months
q3 week: 17.2 mos
HR 0.75 (95% CI:
0.58-0.88)
p=0.015
Katsumata et al, Lancet 2009
Overall survival
3 year OS for:
DD Pac 72%
q3 week: 65%
HR 0.75 (95% CI:
0.57-0.98)
p=0.03
Katsumata et al, Lancet 2009
Progression-free survival according to baseline characteristics
Lancet,
2009
Grade 3/4 anemia was higher in the dose dense group
From: Katsumata et al, Lancet 2009
GOG—Frontline Trials
GOG
-218
GOG-218
Optimal or Suboptimal
EOC, PPC, FT cancer
Paclitaxel
Paclitaxel
Paclitaxel
Carboplatin Carboplatin Carboplatin
Placebo Bevacizumab Bevacizumab
Placebo
Placebo Bevacizumab
×15 months ×15 months ×15 months
Survival, PFS primary endpoints
Biologic & QOL endpoints
EOC = Epithelial ovarian cancer; PPC = Primary peritoneal cancer; FT = Fallopian tube; PFS = Progression-free survival;
QOL = Quality of life.
GOG 218 results
„
„
„
„
„
To be presented at ASCO 2010
Preliminary results were released via press
release in March 2010 (www.gene.com).
Patients receiving carboplatin/taxol/bevacizumab
+ bevacizumab maintenance did better than
carbo/taxol alone.
Patients receiving carboplatin/taxol/bevacizumab
(no maintenance) did equally well as patients
receiving carboplatin/taxol alone.
At this point, our group is not using
bevacizumab off study.
www.gene.com
Newer biologics being added to upfront
treatment
„ PARP
inhibitors
„ Src inhibitors
„ Other anti-angiogenics besides
bevacizumab
„ Notch inhibitors
Protocol 10-065
„ Pilot
study screening for druggable
mutations in both recurrent and newly
diagnosed advanced ovarian cancer.
„ Opened March 2010; 28 pts enrolled thus
far.
„ CLIA-approved PIK3CA, KRAS, and BRAF
testing at LMM (for clinical decision
making).
„ OncoMap platform used thereafter to test
for 1100 mutations in 100 oncogenes (for
research).
Standard of Care for pts with advanced
epithelial ovarian cancer: 2010
„
„
„
„
Upfront debulking surgery by a gynecologic oncologist.
If optimally cytoreduced (i.e. ≤ 1cm tumor remaining),
options are: Placement of an IP port and IP/IV tx1, IV
carboplatin/paclitaxel, or clinical trial.
If suboptimally cytoreduced, options are: IV
carboplatin/paclitaxel (q3 week or weekly paclitaxel)3 or
clinical trial
Neoadjuvant chemotherapy2 has demonstrated equivalent
results to upfront cytoreduction → chemotherapy, but this
appears more popular in Europe than the U.S. with lower
OS and PFS overall compared to other studies.
Armstrong DK, et al, N Engl J Med 354(1):34-43, 2006.
2 Vergote I et al. IGCS 2008 Meeting: Abstract #2008_1767.
Available at: http://www.igcs.org/Abstract/meeting_2008_1767.html.
1
3
Following completion of upfront
chemotherapy
„ CA125
monitoring every 3 months;
although off study, controversy exists
whether or not this is of benefit1
„ Several drugs are being tested in the first
maintenance setting.
„ There is no standard of care for use of
maintenance therapy2
GJ et al, J Clin Oncol 27(18s):Abstr 1, 2009.
2Foster et al, Gyn Onc 115:290-301, 2009
1Rustin
Conclusions
„ Standard
of care for newly diagnosed
advanced ovarian, tubal or peritoneal
cancer remains a platinum and taxane
combination
„ New options for patients include dose
dense administration of paclitaxel
„ Results of GOG 218 asking question of
role of bevacizumab in newly diagnosed
patients to be presented at ASCO 2010