[email protected] Bradley J. Monk, M.D. Professor and Director Division of Gynecologic Oncology...
68
[email protected] 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 TREATMENT OF “OTHER” GYNECOLOGIC CANCERS
-
Upload
todd-willis -
Category
Documents
-
view
212 -
download
0
Transcript of [email protected] Bradley J. Monk, M.D. Professor and Director Division of Gynecologic Oncology...
Bradley J. Monk, M.D.Professor and Director
Division of Gynecologic OncologyDepartment 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-PhoenixArizona USA
TREATMENT OF “OTHER” GYNECOLOGIC CANCERS
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)
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)
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)
COMPLICATIONS OFHYDATIDIFORM MOLE
• Pulmonary complications– ARDS– trophoblast embolization
• Hemorrhage, uterine perforation• Thyroid storm• PIH• Symptomatic theca lutein cysts• Malignant sequelae
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
POST-MOLAR GTN
• Rising or plateauing hCG– plateau: < 1 log drop over 14 days (at least 3
values)• Obvious metastases• Necessitates chemotherapy
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.
Scoring to Determine Therapy
FIGO 2000
Low Risk 0-6, High Risk >6Kohorn EI, et al. Int J Gynecol Cancer. 2000;10(1):84-88.
Figo scoring 0 1 2 4
Age <40 ≥40 - -
Antecedent pregnancy Mole Abortion Term -
Interval months from index pregnancy
<4 4 - <7 7 - <13 ≥13
Pretreatment serum hCG (IU/L)
<103 103 - <104 104 - <105 ≥105
Largest tumor size (including uterus) cm
<3 3 - <5 ≥5 -
Site of metastases Lung Spleen, kidney Gastrointestinal Liver, brain
Number of metastases - 1 - 4 5 - 8 >8
Previous failed chemotherapy
- - Single drug 2 or more drugs
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
Hi risk EMA/CO67% 33%
87%
~100% cure rateAdapted from: McNeish IA, et al J Clin Oncol. 2002;20(7):1838-1844.
13%
Patient requires treatmentn = 598
Low riskMethotrexate/folinic Acid
n = 485
MT X resistance or toxicity
n = 161
hCG normalized for 6 weeksn = 324
hCG greater than 100 IU/I
n = 94
hCG less than 100 IU/In = 67
Single agent actinomycin D
hCG normalized for 6 weeksn = 58
Actinomycin D resistance or toxicity
n = 9
hCG normalized for 6 weeks
Low risk outcome
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
Germ Cell Tumors: Tumor Markers
Tumor Type αFP hCG LDH
Dysgerminoma – ± +
Yolk sac tumor + – ±
Immature teratoma ± – –
Embryonal carcinoma
+ + ±
Choriocarcinoma – + ±
Mixed tumor ± ± ±
• Other markers: CA 125, CA 19-9, NSE, angiotensin, MCSF
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 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.
BEP = bleomycin, etoposide, platinum
Germ Cell Tumors: Standard Chemotherapy
• BEP Protocol
• Early chemotherapy after surgery • Dose intensity important
J our 1 2 3 4 5 8 15
Cisplatine 20 mg/m² IV * * * * * Etoposide 100 mg/m² IV # # # # #
Bléomycine 30 mg IV ° ° °
Gershenson DM, et al. J Clin Oncol. 1990;8(4):715-720.
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
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
Response rates in GOG phase II trials inadvanced uterine LMS—cytotoxic therapy
GOG phase II PI, reference
Drug # 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%)
Prophylactic Chemotherapy AfterHysterectomy 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]
GOG 0250: phase III gem-docetaxel + placebov. bevacizumab
Regimen I:*Gemcitabine 900 mg/m² IV days 1 and 8Docetaxel75 mg/m² IV day 8Placebo (for Bevacizumab)Day 1
Every 3 weeks
GOG 250
RANDOMIZE
STRATIFY
-Uterine LMS-Measurable disease-No prior cytotoxic therapy
Regimen II:*Gemcitabine 900 mg/m² IV days 1 and 8Docetaxel 75 mg/m² IV day 8Bevacizumab 15 mg/kg IV day 1
Every 3 weeks
Until disease progression or adverse effects prohibit further therapy
* All patients will receive GCSF on day 9 of each cycle
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
[email protected] Homesley et al J Clin Oncol 25:526-531, 2007
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
The starting ifos dose was 1.2 g/m2 if prior RT
* 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
GOG Protocol 161
GOG Protocol 161
By Randomized TreatmentP
ropo
rtio
n S
urvi
ving
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months on Study0 12 24 36 48 60
Treatment Group Alive Dead Total Ifosfamide 13 78 91
Alive Dead Total
Ifosfamide + Paclitaxel 16 72 88
Homesley et al J Clin Oncol 25:526-531, 2007
HR = 0.69(95% CI, 0.49 to 0.97; P = .03)Stratifying by PS
[email protected] 9/2009: Target accrual 424 patients over 5.5 years
Epithelial Uterine Corpus CancerG-2 EndometrioidAdenocarcinoma
Squamous DifferentiationFIGO Stage IC
Endometrial Tumorigenesis
Normal epithelium
Simple hyperplasia
Complex hyperplasia
Complex atypical
hyperplasia
Endometrial intraepithelial
carcinomaSerous cancer
Endometrioid cancer
Atrophy
Type I: Endometrioid
Type II: Serous
Estrogen
Niemen et al, 2009; Ellenson et al, 2004.
• Endometrial Cancer• Stage III/IV• No distant mets: Aortic nodes negative Aortic nodes unknown Aortic nodes positive with neg. scalene & neg. CXR
Open: 04-May-92Closed: 25-Feb-00Accrual: 422 pts
x 8Cisplatin 50 mg/m2
Doxorubicin 60 mg/m2II
Whole AbdomenRadiation Therapy
I
Conclusions: Released - Feb 2003ASCO Abstract 2003Chemotherapy = superior survival
GOG122: Endometrial (Stage III/IV)
Randall et al. J Clin Oncol 24:36-44, 2006
GOG 122
p=.01
Randall et al. J Clin Oncol 24:36-44, 2006
Stage-adjusted death HR = 0.68(95% CI, 0.52 to 0.89; P .01) favoring AP
GOG 258
Opened Jun 29, 2009Accrual Goal = 804Study Chair D Matei
Surgical stage III or IVA endometrial carcinoma-All Cell types-must have hysterectomy and BSO-Pelvic node sampling and aortic node sampling optional
RANDOMIZE
REGIMEN ICisplatin 50 mg/m2 IVDays 1 and 28plus Volume-directed RTfollowed by Carboplatin AUC 5*plus Paclitaxel 175 mg/m2q 21 days for 4 cycles
REGIMEN IICarboplatin AUC 6 plus Paclitaxel 175 mg/m2q 21 days for 6 cycles
Secondary endpoints TR and QOL
Phase III Trial of Doxorubicin Plus Cisplatin With orWithout Paclitaxel Plus Filgrastim in Advanced
Endometrial Carcinoma: GOG Protocol 177
Fleming GF et al J Clin Oncol 2004;22:2159-66
GOG-209: Schema
Advanced, Recurrent Endometrial Cancer
Doxorubicin 45 mg/m2 day 1Cisplatin 50 mg/m2 day 1
Paclitaxel 160 mg/m2 24 hour day 2G-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 armOpened: 8-25-2003 Closed: 4-20-2009
Endometrial Cancer: Single Agents With No Prior Chemotherapy
Agent RR (%) Reference
Doxorubicin 37 Thigpen et al, 1979
Cisplatin 20 Thigpen et al, 1989
Carboplatin 2830
Long et al, 1988Green et al, 1990
Paclitaxel 36 Ball et al, 1996
Ifosfamide 24 Sutton et al, 1996
Topotecan 20 Wadler et al, 2003
Phase II Studies129 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 prior taxane allowed
b77% (20/26) prior paclitaxel
c94% (47/50) prior paclitaxel
Lincoln et al, 2003; Muggia et al, 2002; Miller et al, 2002; Fracasso et al, 2006; Garcia et al, 2008.
Thresholds: 10%, 25%
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
Age-Standardized Cervical Cancer Rates in 2008
Jemal A et al CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90.
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
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
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)
Stage IA2-IB2: Large, deeply invasive tumors with vascular invasion limited to the cervix after radical hysterectomy
RANDOMIZE
Pelvic Radiation
Pelvic Radiation andWeekly cisplatin (CCRT)
GOG/KGOG 263(GOG 92 Replacement)
PI = SANG YOUNG RYUN = 480Primary Endpoint = RFS
Early Stage High Risk Cervical Cancer
• 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)
OS
P
rob
ab
ilit
y
Stage IA2-IB2: Positive nodes, parametrial extension, positive margins after radical hysterectomy
RTOG 0724 (GOG 109 Replacement)
RANDOMIZE
Pelvic Radiation andWeekly cisplatin (CCRT)
Pelvic Radiation andWeekly cisplatin (CCRT)followed by carboplatin +Paclitaxel x 4 cycles
PI = Anuja JhingranN = 400Primary Endpoint = DFS
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
Standard Anterior and Lateral External-beam Irradiation Ports Used to Treat Locally
Advanced Cervical Carcinoma Limited to the Pelvis
Monk et al J Clin Oncol 25:2952-2965. 2007
HPV Impacts Oxygenation and Angiogenesisin Cervical Cancer
DNA Damage
p53
Cell cycle arrest
Apoptosis (cell death)
DNA Repair
p53 degradationE6
HPV E6 blocks inductionXIncreased
VEGF
Angiogenesis
Monk BJ et al Gynecol Oncol. 2010 Feb;116(2):181-6.
Evolution of an HPV infection
HPV Disappearance1-2 y3,4,6
~6–9 mo5,6
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;
Colposcopy demonstrates abnormal vasculature and angiogenesis dependent progression
Transient Infection Persistent Infection
Normal Precancerous, potential to regress or persist to severe disease Invasive
HPV Infection CIN 1,2 CIN 2,31 Cervical Cancer2
7–10 y1 ≥10 y2
GOG 204Primary Stage IVB or recurrent/persistent carcinoma of the cervix
measurable diseaseGOG performance status 0-1ANC 1500/µlplatelets 100,000/µlserum creatinine 1.5 mg/dlno CNS diseaseno past or concomitant invasive cancer no prior chemotherapy (unless concurrent with radiation)
Regimen 1Paclitaxel 135 mg/m2 over 24 hours and CDDP 50 mg/m2 repeated q 3 wks for 6 cycles
Regimen 2Vinorelbine 30 mg/m2 IV bolus day1 and 8 and CDDP 50 mg/m2 IV day 1 repeated q 3 wks for 6 cycles
ALL REGIMENSQuality of life Assessment:BaselineBefore cycle 2Before cycle 59 mo. after study entry at follow-up visit
Regimen 3Gemcitabine 1000mg/m2 IV day 1 and 8 and CDDP 50 mg/m2 IV day 1 repeated q 3 wks for 6 cycles
Regimen 4Topotecan 0.75 mg/m2 over 30 minutes days 1, 2, & 3 CDDP 50 mg/m2 IV day 1, q 3 wks for 6 cycles
RANDOMIZE
BJ Monk et al J Clin Oncol. 2009 Oct 1;27(28):4649-55.
Trial Design
(www.jcog.jp/en/)
Multicenter (30 Specialized Institutions), Randomized Phase III Trial
Stage IVB, persistent or recurrent cervical cancer; not amenable to curative surgery / radiotherapy
R
A
N
D
O
M
I
Z
E*
Standard arm: TPPaclitaxel 135 mg/m2 24h d1Cisplatin 50 mg/m2 2h d2
every 21 days for 6 cycles
Experimental arm: TCPaclitaxel 175 mg/m2 3h d1Carboplatin AUC 5 1h d1
* Balancing factors: • Tumors outside of the prior
irradiation field(yes or no)
• PS 0-1 or 2• SCC or non-SCC• Institution
ClinicalTrials.gov Identifier:NCT00295789
JCOG 0505
Trial Profile
(www.jcog.jp/en/)
25253 patients enrolled and randomly
assigned
127 assigned to TP126 assigned to
TC4 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
2/21/2006 ～ 11/20/2009
Kitagawa R, et al. J Clin Oncol. 2012;30(Suppl): Abstract 5006.
Overall Survival (www.jcog.jp/en/)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6
Years after randomization
Pro
portio
n
Arm N Events Median(m)[95% CI]
1-yrOS
2-yrOS
3-yrOS
TP 123 106 18.3 m[16.1-22.9] 72.4% 38.8% 18.3%
TC 121 98 17.5 m[14.2-20.3] 67.6% 31.5% 21.3%
#stratified Cox regression with “tumors outside prior irradiation field[yes/no]” as strata
HR: 0.994 [90% CI: 0.789-1.253 (<1.29)]noninferiority one-sided P = .032#
Kitagawa R, et al. J Clin Oncol. 2012;30(Suppl): Abstract 5006.
GOG 240Primary Stage IVB or recurrent/persistent carcinoma of the cervix
Measurable diseaseGOG performance status 0-1ANC 1500/µLPlatelets 100,000/µLSerum creatinine 1.5 mg/dLNo CNS diseaseNo past or concomitant invasive cancer No prior chemotherapy (unless concurrent with radiation)
Regimen 1**Paclitaxel* + CDDP 50 mg/m2
Regimen 2**Paclitaxel* + CDDP 50 mg/m2 + Bevacizumab 15/mg/kg
ALL REGIMENSQuality of life Assessment:BaselineBefore cycle 2Before cycle 59 mo. after study entry at follow-up visit
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
RANDOMIZE
* 135 mg/m2 over 24 or 175 mg/m2 over 3 hours** Cycles repeated q21 days to progression/toxicity
Open to enrollment April 6, 2009Closed to enrollment Jan 3, 2012Sample size = 452Study Chair = KS Tewari
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 daysvs
No Bevacizumab
• Primary Endpoint = survival, superiority trial (30% reduction in HR)
ClinicalTrials.gov Identifier:NCT00803062
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 daysvs
No Bevacizumab
• Primary Endpoint = survival, superiority trial (30% reduction in HR)
ClinicalTrials.gov Identifier:NCT00803062
Futile April 2012SGO 2013 in Los Angeles
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 daysvs
No Bevacizumab
• Primary Endpoint = survival, superiority trial (30% reduction in HR)
ClinicalTrials.gov Identifier:NCT00803062
Futile April 2012SGO 2013 in Los Angeles
Winner Feb 2013ASCO 2013 in Chicago
Adding Bevacizumab to Chemotherapy Improves Survival
Tumor Type Regimen Median Survival (Months)
Hazard Ration
First-line Metastatic Colorectal Cancer
IFL + Placebo(N=411)
15.6 0.66
IFL + Bev(N=402)
20.3
Non-Squamous NSCLC PC(N=444)
10.3 0.80
PC + Bev(N=434)
12.3
Recurrent or advanced Cervical Cancer
TP or TT(N=225)
13.3 0.71
TP or TT + Bev(N=227)
17.0
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
http://www.gene.com/download/pdf/avastin_prescribing.pdf
