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TREATMENT OF “OTHER”
GYNECOLOGIC CANCERS
Bradley J. Monk, M.D.
Professor and Director
Division of Gynecologic Oncology
Department of Obstetrics and Gynecology
Creighton University School of Medicine at St. Joseph’s Hospital and
Medical Center, a Dignity Health Member
University of Arizona Cancer Center-Phoenix
Arizona USA
[email protected]
THE SPECTRUM OF GESTATIONAL
TROPHOBLASTIC DISEASE
• Non-Malignant GTD
– Complete hydatidiform mole
– Partial hydatidiform mole
• Malignant GTD
– Persistent mole
– Invasive mole
– Gestational choriocarcinoma
– Placental site trophoblastic tumor (PSTT)
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COMPLETE MOLE
• Clinical
–
–
–
–
–
size > dates in > 50% cases
enlarged theca lutein cysts in 25-30%
medical complications more common
high hCG titers
malignant sequelae in 20%
• Pathology
–
–
–
–
trophoblastic proliferation
hydropic degeneration
absence of vasculature
fetal death before organogenesis
• Cytogenetics
– diploid, sperm derived chromosomes
• 92 - 96% 46 XX (reduplication), 4 - 8% 46 XY (dispermic)
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PARTIAL MOLE
• Clinical
–
–
–
–
–
often presents as missed abortion, size < dates
enlarged theca lutein cysts rare
medical complications uncommon
lower hCG titers
malignant sequelae in < 5 - 10%
• Pathology
–
–
–
–
focal trophoblast proliferation (syncitiotrophoblast)
focal hydropic change
placenta and fetus grossly identifiable
fetal death during 1st trimester (dysmorphic)
• Cytogenetics
– triploid (69 XXX, 69 XXY, 69 XYY)
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COMPLICATIONS OF
HYDATIDIFORM MOLE
• Pulmonary complications
– ARDS
– trophoblast embolization
•
•
•
•
•
Hemorrhage, uterine perforation
Thyroid storm
PIH
Symptomatic theca lutein cysts
Malignant sequelae
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FOLLOW-UP AFTER
MOLAR EVACUATION
• Clinical assessment
– q 2 weeks until remission, then q 3 months x 1 year
• Chest x-ray
• Contraception x 6-12 months
• hCG
– immediately following molar evacuation
– q 1-2 weeks until negative x 2
– then q month x 6-12 months
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POST-MOLAR GTN
• Rising or plateauing hCG
– plateau: < 1 log drop over 14 days (at least 3
values)
• Obvious metastases
• Necessitates chemotherapy
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WORK-UP FOR MALIGNANT GTN
• Clinical assessment
• Imaging
– chest x-ray
– CT if chest x-ray negative?
– head CT
– abdominal/pelvic ultrasound or CT
• Laboratory
 CBC, platelets, renal and liver function studies, blood
type and antibody screen.
 baseline hCG level.
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Scoring to Determine Therapy
FIGO 2000
Figo scoring
0
1
2
4
Age
<40
≥40
-
-
Antecedent pregnancy
Mole
Abortion
Term
-
<4
4 - <7
7 - <13
≥13
<103
103 - <104
104 - <105
≥105
<3
3 - <5
≥5
-
Lung
Spleen, kidney
Gastrointestinal
Liver, brain
Number of metastases
-
1-4
5-8
>8
Previous failed
chemotherapy
-
-
Single drug
2 or more drugs
Interval months from
index pregnancy
Pretreatment serum hCG
(IU/L)
Largest tumor size
(including uterus) cm
Site of metastases
Low Risk 0-6, High Risk >6
Kohorn EI, et al. Int J Gynecol Cancer. 2000;10(1):84-88.
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CHEMOTHERAPY FOR NONMETASTATIC
MALIGNANT GTN / LOW RISK
• Single agent chemotherapy
– Methotrexate (35 - 50 mg/m2 I.M. weekly)
– Dactinomycin
– Methotrexate/folinic Acid
• Remission
– 3 consecutive normal  hCG titers (q wk)
• Alternative drug used if:
– hCG rises or plateaus
– new metastases develop
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EMA/CO
Newlands ES et al J Clin Oncol. 2000 Feb;18(4):854-9.
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Patient requires treatment
n = 598
Low risk
outcome
Low risk
Methotrexate/folinic Acid
n = 485
67%
hCG normalized for
6 weeks
n = 324
MT X resistance
or toxicity
n = 161
hCG less than
100 IU/I
n = 67
33%
Hi risk
EMA/CO
hCG greater
than 100 IU/I
n = 94
Single agent actinomycin D
87% hCG normalized for
6 weeks
n = 58
~100% cure rate
Adapted from: McNeish IA, et al J Clin Oncol. 2002;20(7):1838-1844.
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13%
Actinomycin D
resistance or toxicity
n=9
hCG normalized for
6 weeks
Ovarian Germ Cell Tumors (GCT)
Clinical Presentation / Classification
• Stage (FIGO)
–
–
–
–
Stage I: vast majority
Stage II: exceptional
Stage III: 20 to 30 %
Stage IV: <10 % (lung, liver)
• Ascites: 20 %
• Pre surgical tumoral
ruptures: 20 % (tumor
volume ++++)
• Primitive GCTs
–
–
–
–
–
Dysgerminoma
Yolk sac tumor
Embryonal carcinoma
Other
Mixed GCTs
• Biphasic or tri teratoma
– Immature teratoma
– Mature teratoma
• Monodermal teratoma & somatic
tumors
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Germ Cell Tumors:
Tumor Markers
αFP
hCG
LDH
Dysgerminoma
–
±
+
Yolk sac tumor
+
–
±
Immature teratoma
±
–
–
Embryonal
carcinoma
+
+
±
Choriocarcinoma
–
+
±
Mixed tumor
±
±
±
Tumor Type
• Other markers: CA 125, CA 19-9, NSE, angiotensin, MCSF
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Ovarian Germ Cell Tumors:
Chemotherapy
• Platinum-based chemotherapy (Williams 1987)1 especially since 1987 3 or
4 cycles of BEP (Gershenson 1990)2
• Depending on the tumor stage/postoperative residue3:
– Stages II and III: 3 or 4 cycles BEP (residual tumor)
– Stage IV: 4 cycles BEP
– Stages I (70%): *pure dysgerminoma Ia
*immature teratoma Ia Ib grade 1
= no additional treatment after surgery
• Chemotherapy for all the other
• Adjuvant radiotherapy: no more indication (except some cases of
BEP = bleomycin, etoposide, platinum
dysgerminoma
1. Williams SD, et al. N Engl J Med. 1987;316(23):1435-1440. 2. Gershenson DM, et al. J Clin Oncol. 1990;8(4):715-720. 3. de La
Motte Rouge T, et al. Ann Oncol. 2008;19(8):1435-1441.
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Germ Cell Tumors:
Standard Chemotherapy
• BEP Protocol
Jour
1
2
3
4
5
Cisplatine 20 mg/m² IV
*
*
*
*
*
Etoposide 100 mg/m² IV
#
#
#
#
#
Bléomycine 30 mg IV
°
• Early chemotherapy after surgery
• Dose intensity important
Gershenson DM, et al. J Clin Oncol. 1990;8(4):715-720.
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8
15
°
°
Uterine Mesenchymal Tumors
• Smooth Muscle Tumors:
Leiomyoma
Cellular Leiomyoma
Highly Cellular Leiomyoma
Intravenous Leiomyomatosis
Leiomyosarcoma
• Stromal Tumors:
Endometrial Stromal Nodule
Endometrial Stromal Sarcoma
• Mixed Endometrial Stromal / Smooth Muscle Tumor
•Mixed Mullerian Tumors:
Adenosarcoma
Malignant Mixed Mullerian Tumor (Carcinosarcoma)
• Undifferentiated Uterine Sarcoma
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Uterine Mesenchymal Tumors
• Smooth Muscle Tumors:
Leiomyoma
Cellular Leiomyoma
Highly Cellular Leiomyoma
Intravenous Leiomyomatosis
Leiomyosarcoma
• Stromal Tumors:
Endometrial Stromal Nodule
Endometrial Stromal Sarcoma
• Mixed Endometrial Stromal / Smooth Muscle Tumor
•Mixed Mullerian Tumors:
Adenosarcoma
Malignant Mixed Mullerian Tumor (Carcinosarcoma)
• Undifferentiated Uterine Sarcoma
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Response rates in GOG phase II trials in
advanced uterine LMS—cytotoxic therapy
Drug
GOG phase II PI,
reference
# prior regimens
Response rate
Look
gemcitabine
0-1
9/42( 20%)
Sutton
liposomal doxorubicin
0
5/32 (16%)
Gallup
paclitaxel
0-1
4/48 ( 8%)
Sutton
paclitaxel
0
3/33 ( 9%)
Thigpen
cisplatin
0
1/33 ( 3%)
Sutton
doxorubicin
0
7/28 ( 25%)
Sutton
ifosfamide
0
6/35 ( 17%)
Thigpen
etoposide IV
0
0/28 ( 0%)
Rose
etoposide PO
1
2/29 ( 7%)
Miller
topotecan
0
4/36 ( 11%)
Smith
trimetrexate
0-1
1/23 ( 4%)
Hensley
gemcitabine + docetaxel
0
15/42 ( 36%)
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Prophylactic Chemotherapy After
Hysterectomy for Early Stage Disease
• Between 30% and 50% with high-grade uterine leiomyosarcoma
remain progression-free at 2 years
• Adjuvant pelvic radiation does not improve outcome
• 47 women treated on phase II study
gemcitabine 900 mg/m(2) over 90 min days 1 and 8
+ docetaxel 75 mg/m(2) day 8, every 3 weeks for 4 cycles
• 78% (95% confidence interval, 67%-91%) progression-free at 2 yrs
• 57% (95% confidence interval, 44%-74%) progression-free at 3 yrs
• Median PFS not reached and exceeded 36 months.
Hensley MLCancer. 2013 Jan 18. doi: 10.1002/cncr.27942. [Epub ahead of print]
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GOG 0250: phase III gem-docetaxel + placebo
v. bevacizumab
GOG 250
Regimen I:*
-Uterine LMS
-Measurable disease
-No prior cytotoxic therapy
S
T
R
A
T
I
F
Y
* All patients will receive GCSF
on day 9 of each cycle
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R
A
N
D
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M
I
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E
Gemcitabine
900 mg/m² IV days 1 and 8
Docetaxel
75 mg/m² IV day 8
Placebo (for Bevacizumab)
Day 1
Every 3 weeks
Regimen II:*
Gemcitabine
900 mg/m² IV days 1 and 8
Docetaxel
75 mg/m² IV day 8
Bevacizumab
15 mg/kg IV day 1
Every 3 weeks
Until disease
progression or
adverse effects
prohibit further
therapy
L
LMS
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Uterine Mesenchymal Tumors
• Smooth Muscle Tumors:
Leiomyoma
Cellular Leiomyoma
Highly Cellular Leiomyoma
Intravenous Leiomyomatosis
Leiomyosarcoma
• Stromal Tumors:
Endometrial Stromal Nodule
Endometrial Stromal Sarcoma
• Mixed Endometrial Stromal / Smooth Muscle Tumor
•Mixed Mullerian Tumors:
Adenosarcoma
Malignant Mixed Mullerian Tumor (Carcinosarcoma)
• Undifferentiated Uterine Sarcoma
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Malignant Mixed Mullerian Tumor = Carcinosarcoma
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MMMT: Biphasic Morphology
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MMMT: Heterologous Components (Rhabdomyoblasts)
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GOG Protocol 161
R
A
N
D
O
M
I
Z
E
Ifosfamide alone 2.0 g/m2 I.V. daily x 3 days
+ Mesna* q 21 days up to 8 cycles
Ifosfamide 1.6 g/m2 I.V. daily x 3 days
+ paclitaxel 135 mg/m2 3-hour day 1
+ Mesna* q 21 days up to 8 cycles
* IV or PO Mesna:
• IV = 2 g IV over 12 hours starting 15 minutes before ifos;
• PO =4 g in 3 doses of 1.33 g 1 hour before and 8 hours after ifos q day x 3 days
The starting ifos dose was 1.2 g/m2 if prior RT
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Homesley et al J Clin Oncol 25:526-531, 2007
GOG Protocol 161
By Randomized Treatment
1.0
0.9
Treatment Group
Ifosfamide
Ifosfamide + Paclitaxel
Proportion Surviving
0.8
Alive
13
16
Dead Total
78
91
72
88
0.7
HR = 0.69
(95% CI, 0.49 to 0.97; P = .03)
Stratifying by PS
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
12
24
36
48
60
Months on Study
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Homesley et al J Clin Oncol 25:526-531, 2007
Activated 9/2009: Target accrual 424 patients over 5.5 years
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Epithelial Uterine Corpus Cancer
FIGO Stage IC
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G-2 Endometrioid
Adenocarcinoma
Squamous Differentiation
Endometrial Tumorigenesis
Estrogen
Type I: Endometrioid
Simple
hyperplasia
Complex
hyperplasia
Complex
atypical
hyperplasia
Endometrioid
cancer
Normal
epithelium
Atrophy
Endometrial
intraepithelial
carcinoma
Serous cancer
Type II: Serous
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Niemen et al, 2009; Ellenson et al, 2004.
GOG122: Endometrial (Stage III/IV)
• Endometrial Cancer
• Stage III/IV
• No distant mets:
Aortic nodes negative
Aortic nodes unknown
Aortic nodes positive
with neg. scalene &
neg. CXR
Open:
Closed:
Accrual:
04-May-92
25-Feb-00
422 pts
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I
Whole Abdomen
Radiation Therapy
II
Cisplatin 50 mg/m2
Doxorubicin 60 mg/m2
x8
Conclusions: Released - Feb 2003
ASCO Abstract 2003
Chemotherapy = superior survival
Randall et al. J Clin Oncol 24:36-44, 2006
GOG 122
Stage-adjusted death HR = 0.68
(95% CI, 0.52 to 0.89; P .01)p=.01
favoring AP
Randall et al. J Clin Oncol 24:36-44, 2006
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GOG 258
Surgical stage III
or IVA endometrial
carcinoma
-All Cell types
-must have hysterectomy
and BSO
-Pelvic node sampling
and aortic node sampling
optional
Opened Jun 29, 2009
Accrual Goal = 804
Study Chair D Matei
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R
A
N
D
O
M
I
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E
REGIMEN I
Cisplatin 50 mg/m2 IV
Days 1 and 28
plus Volume-directed RT
followed by Carboplatin AUC 5*
plus Paclitaxel 175 mg/m2
q 21 days for 4 cycles
REGIMEN II
Carboplatin AUC 6 plus
Paclitaxel 175 mg/m2
q 21 days for 6 cycles
Secondary endpoints TR and QOL
Recurrent Disease
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Phase III Trial of Doxorubicin Plus Cisplatin With or
Without Paclitaxel Plus Filgrastim in Advanced
Endometrial Carcinoma: GOG Protocol 177
Fleming GF et al J Clin Oncol 2004;22:2159-66
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GOG-209: Schema
Advanced, Recurrent
Endometrial Cancer
Doxorubicin 45 mg/m2 day 1
Cisplatin 50 mg/m2 day 1
Paclitaxel 160 mg/m2 24 hour day 2
G-CSF 5 mcg/kg days 3-12
Q 21 days x 7
Carboplatin AUC 6
Paclitaxel 175 mg/m2 3 hr
Q 21 days x 7
Planned accrual: 900 patients/795 failures - 60 months
(now 1300 includes non-measurable disease)
Equivalency HR < 1.20 for Carbo/paclitaxel arm
Opened: 8-25-2003
Closed: 4-20-2009
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Median
PFS
(months)
13.5
13.3
HR=1.03
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Miller DS SGO 2012
Median
PFS
(months)
13.5
13.3
HR=1.03
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Miller DS SGO 2012
Endometrial Cancer: Single Agents With
No Prior Chemotherapy
Agent
RR (%)
Reference
Doxorubicin
37
Thigpen et al, 1979
Cisplatin
20
Thigpen et al, 1989
Carboplatin
28
30
Long et al, 1988
Green et al, 1990
Paclitaxel
36
Ball et al, 1996
Ifosfamide
24
Sutton et al, 1996
Topotecan
20
Wadler et al, 2003
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Phase II Studies
129 Series (1 prior)
Study
Agent
N
RR (%)
129-C
Paclitaxel
44
27.3a
129-H
Liposomal doxorubicin
42
9.5
129-J
Topotecan
22
9
129-K
Oxaliplatin
52
13.5
129-N
Docetaxel (weekly)
26
7.7b
129-P
Ixabepilone
50
12c
129-O
Pemetrexed
26
4
129-Q
Gemcitabine
23
4
aNo
Thresholds: 10%, 25%
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Lincoln et al, 2003; Muggia et al, 2002; Miller et al, 2002; Fracasso et al, 2006; Garcia et al, 2008.
prior taxane allowed
b77%
(20/26) prior paclitaxel
c94%
(47/50) prior paclitaxel
Pegylated Liposomal Doxorubicin
• GOG 86-M – 1st line
– PLD 40 mg/m2 IV q 4 weeks
– RR - 11.5% (6/52)
• Homesley, Gyn Onc 98: 2005
• GOG 129H – 2nd line
– PLD 50 mg/m2 IV q 4 weeks
– 32/42 received prior doxorubicin
– RR – 9.5% (4/42)
• Muggia, JCO 20: 2002
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Age-Standardized Cervical Cancer Rates in 2008
Jemal A et al CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90.
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Radical hysterectomy
• Used to treat cervical
cancers with invasion
> 3mm but confined
to the cervix and
vagina < 4 cm (Stage
IA2 –IB1)
• Removal of
parametrium and
upper vagina
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When is RT or Chemo/RT Indicated
After Radical Hysterectomy?
Radiation if two of the following:
• deep invasion, large tumor or vascular invasion
– GOG 92 (Sedlis A et. al Gyn Onc 73:177-183, 1999)
Chemo-RT if one of the following:
• Positive margin, parametrial extension, positive node
– GOG 109 (Peters WA et. al. J Clinic Oncol 18:1606-1613, 2000)
RT=Radiation therapy
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Early Stage Intermediate Risk Cervical Cancer
• Large, deeply invasive tumors with vascular invasion
limited to the cervix after radical hysterectomy
• GOG 92 established to role of postoperative pelvic
radiation (Sedlis et al Gyn Oncol 73, 177–183 1999)
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GOG/KGOG 263
(GOG 92 Replacement)
Stage IA2-IB2:
Large, deeply
invasive tumors with
vascular invasion
limited to the cervix
after radical
hysterectomy
PI = SANG YOUNG RYU
N = 480
Primary Endpoint = RFS
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R
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N
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Pelvic Radiation
Pelvic Radiation and
Weekly cisplatin (CCRT)
Early Stage High Risk Cervical Cancer
OS Probability
• Positive nodes, parametrial extension, positive margins
after radical hysterectomy
• GOG 109 established the role of postoperative cisplatin
and pelvic radiation (Peters WA et al J Clin Oncol. 2000
Apr;18(8):1606-13)
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RTOG 0724 (GOG 109 Replacement)
Stage IA2-IB2:
Positive nodes,
parametrial
extension,
positive margins
after radical
hysterectomy
PI = Anuja Jhingran
N = 400
Primary Endpoint = DFS
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R
A
N
D
O
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I
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E
Pelvic Radiation and
Weekly cisplatin (CCRT)
Pelvic Radiation and
Weekly cisplatin (CCRT)
followed by carboplatin +
Paclitaxel x 4 cycles
What is the Global Standard
Therapy for Stage IB2 - IVA?
• External beam pelvic radiation (40 to 60 Gy)
• Brachytherapy (8,000 to 8,500 cGy to Point A)
• I.V. Cisplatin chemotherapy
– Cisplatin 40mg/m2 (Max dose 70mg) IV q wk
during RT (6wks)
• GOG 120 (Rose PG et al. Concurrent cisplatin-based
radiotherapy and chemotherapy for locally advanced
cervical cancer. NEJM 340(15):1144, 1999
Monk et al J Clin Oncol 25:2952-2965. 2007
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Standard Anterior and Lateral External-beam
Irradiation Ports Used to Treat Locally
Advanced Cervical Carcinoma Limited to the Pelvis
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Monk et al J Clin Oncol 25:2952-2965. 2007
Systemic Therapy for Advanced
and recurrent Disease
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HPV Impacts Oxygenation and Angiogenesis
in Cervical Cancer
DNA Damage
X HPV E6 blocks induction
p53
Cell cycle
arrest
E6
p53 degradation
Apoptosis (cell
death)
DNA Repair
Monk BJ et al Gynecol Oncol. 2010 Feb;116(2):181-6.
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Increased
VEGF
Angiogenesis
Evolution of an HPV infection
Transient Infection
Persistent Infection
Normal  Precancerous, potential to regress or persist to severe disease
HPV Infection
CIN 1,2
 Invasive
CIN 2,31
Cervical Cancer2
7–10 y1
≥10 y2
HPV Disappearance
1-2 y3,4,6
~6–9 mo5,6
Colposcopy demonstrates abnormal vasculature and angiogenesis dependent progression
CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; HR, high risk.
1. Schiffman M, Kjaer SK. J Int Cancer Natl Monogr. 2003;31:14-19; 2. Ostör AG. Int J Gynecol Pathol. 1993;12:186-192;
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GOG 204
Primary Stage IVB or
recurrent/persistent
carcinoma of the cervix
measurable disease
GOG performance status 0-1
ANC  1500/µl
platelets 100,000/µl
serum creatinine  1.5 mg/dl
no CNS disease
no past or concomitant
invasive cancer
no prior chemotherapy
(unless concurrent with
radiation)
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R
A
N
D
O
M
I
Z
E
Regimen 1
Paclitaxel 135 mg/m2 over 24 hours and
CDDP 50 mg/m2 repeated q 3 wks for 6 cycles
Regimen 2
Vinorelbine 30 mg/m2 IV bolus day1 and 8 and
CDDP 50 mg/m2 IV day 1 repeated q 3 wks for 6 cycles
Regimen 3
Gemcitabine 1000mg/m2 IV day 1 and 8 and
CDDP 50 mg/m2 IV day 1 repeated q 3 wks for 6 cycles
Regimen 4
Topotecan 0.75 mg/m2 over 30 minutes days 1, 2, & 3
CDDP 50 mg/m2 IV day 1, q 3 wks for 6 cycles
ALL REGIMENS
Quality of life Assessment:
Baseline
Before cycle 2
Before cycle 5
9 mo. after study entry at follow-up visit
BJ Monk et al J Clin Oncol. 2009 Oct 1;27(28):4649-55.
(www.jcog.jp/en/)
Multicenter (30 Specialized Institutions), Randomized Phase III Trial
JCOG 0505
Trial Design
Stage IVB, persistent or
recurrent cervical
cancer; not amenable to
curative surgery /
radiotherapy
* Balancing factors:
• Tumors outside of the prior
irradiation field
(yes or no)
• PS 0-1 or 2
• SCC or non-SCC
• Institution
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R
A
N
D
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M
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E*
Standard arm: TP
Paclitaxel 135 mg/m2 24h d1
Cisplatin 50 mg/m2 2h d2
every 21 days for 6 cycles
Experimental arm: TC
Paclitaxel 175 mg/m2 3h d1
Carboplatin AUC 5 1h d1
ClinicalTrials.gov Identifier:NCT00295789
(www.jcog.jp/en/)
25253
patients
enrolled
Trial
Profileand randomly assigned
2/21/2006 ～ 11/20/2009
127 assigned to TP
126 assigned to TC
4 ineligible
5 ineligible
25Maximum 6 cycles of treatment
until disease progression or unacceptable toxicity
123 efficacy analysis
125 safety analysis
121 efficacy analysis
126 safety analysis
Kitagawa R, et al. J Clin Oncol. 2012;30(Suppl): Abstract 5006.
[email protected]
(www.jcog.jp/en/)
Overall Survival
1.0
Arm
N
Events
0.9
TP
123
106
TC
121
98
0.8
Proportion
0.7
0.6
Median(m)
[95% CI]
18.3 m
[16.1-22.9]
17.5 m
[14.2-20.3]
1-yr
OS
2-yr
OS
3-yr
OS
72.4%
38.8%
18.3%
67.6%
31.5%
21.3%
HR: 0.994 [90% CI: 0.789-1.253 (<1.29)]
noninferiority one-sided P = .032#
0.5
0.4
0.3
0.2
0.1
0.0
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
Years after randomization
#stratified
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Cox regression with “tumors outside prior irradiation field[yes/no]” as strata
Kitagawa R, et al. J Clin Oncol. 2012;30(Suppl): Abstract 5006.
6
Beyond GOG 204
Novel Agents and Non-platinum Doublets
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GOG 240
Primary Stage IVB or
recurrent/persistent carcinoma
of the cervix
Measurable disease
GOG performance status 0-1
ANC  1500/µL
Platelets 100,000/µL
Serum creatinine 1.5 mg/dL
No CNS disease
No past or concomitant
invasive cancer
No prior chemotherapy
(unless concurrent with
radiation)
Open to enrollment April 6, 2009
Closed to enrollment Jan 3, 2012
Sample size = 452
Study Chair = KS Tewari
[email protected]
Regimen 1**
Paclitaxel* + CDDP 50 mg/m2
R
A
N
D
O
M
I
Z
E
Regimen 2**
Paclitaxel* + CDDP 50 mg/m2 + Bevacizumab 15/mg/kg
Regimen 3**
Paclitaxel 175 mg/m2 over 3 hrs on day 1 +
Topotecan 0.75 mg/m2 over 30 mins days 1-3
Regimen 4**
Paclitaxel 175 mg/m2 over 3 hrs on day 1 +
Topotecan 0.75 mg/m2 over 30 mins days 1-3 +
Bevacizumab 15/mg/kg
* 135 mg/m2 over 24 or 175 mg/m2 over 3 hours
ALL REGIMENS
** Cycles repeated q21 days to progression/toxicity
Quality of life Assessment:
Baseline
Before cycle 2
Before cycle 5
9 mo. after study entry at follow-up visit
GOG 240 (GOG 204 Replacement)
• 2 x 2 Factorial Design
– First Randomization:
Winner of GOG 204 (Cisplatin + Paclitaxel)
vs
Paclitaxel 175 mg/m2 over 3 hrs q 21 days
Topotecan 0.75 mg/m2 days 1, 2, and 3 q 21 days
– Second Randomization: Bevacizumab 15 mg/kg q 21 days
vs
No Bevacizumab
• Primary Endpoint = survival, superiority trial (30% reduction in HR)
[email protected]
ClinicalTrials.gov Identifier:NCT00803062
GOG 240 (GOG 204 Replacement)
• 2 x 2 Factorial Design
– First Randomization:
Winner of GOG 204 (Cisplatin + Paclitaxel)
vs
2
Paclitaxel 175 mg/m over 3 hrs q 21 days
Futile April 2012
Topotecan 0.75 mg/m2 days 1, 2, and 3 q 21 days
SGO 2013 in Los Angeles
– Second Randomization: Bevacizumab 15 mg/kg q 21 days
vs
No Bevacizumab
• Primary Endpoint = survival, superiority trial (30% reduction in HR)
[email protected]
ClinicalTrials.gov Identifier:NCT00803062
GOG 240 (GOG 204 Replacement)
• 2 x 2 Factorial Design
– First Randomization:
Winner of GOG 204 (Cisplatin + Paclitaxel)
vs
2
Paclitaxel 175 mg/m over 3 hrs q 21 days
Futile April 2012
Topotecan 0.75 mg/m2 days 1, 2, and 3 q 21 days
SGO 2013 in Los Angeles
– Second Randomization: Bevacizumab 15 mg/kg q 21 days
Winner Feb 2013
vs
No Bevacizumab
ASCO 2013 in Chicago
• Primary Endpoint = survival, superiority trial (30% reduction in HR)
[email protected]
ClinicalTrials.gov Identifier:NCT00803062
Adding Bevacizumab to Chemotherapy
Improves Survival
Tumor Type
Regimen
First-line Metastatic
Colorectal Cancer
IFL + Placebo
(N=411)
15.6
IFL + Bev
(N=402)
20.3
PC
(N=444)
10.3
PC + Bev
(N=434)
12.3
TP or TT
(N=225)
13.3
TP or TT + Bev
(N=227)
17.0
Non-Squamous NSCLC
Recurrent or advanced
Cervical Cancer
Median Survival
(Months)
Hazard Ration
0.66
0.80
0.71
Bev = bevacizumab; NSCLC = non-small cell lung cancer; IFL = Irinotecan, 5-FU, leucovorin;
PC = paclitaxel and carboplatin; TP = paclitaxel and cisplatin; TT = topotecan and paclitaxel
[email protected]
http://www.gene.com/download/pdf/avastin_prescribing.pdf
Thank You
[email protected]