TREATMENT OF OTHER GYNECOLOGIC CANCERS Bradley J. Monk,

TREATMENT OF OTHER GYNECOLOGIC CANCERS Bradley J. Monk,

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. Josephs 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) [email protected] 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)

[email protected] 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) [email protected] COMPLICATIONS OF HYDATIDIFORM MOLE Pulmonary complications ARDS trophoblast embolization Hemorrhage, uterine perforation Thyroid storm PIH Symptomatic theca lutein cysts Malignant sequelae [email protected] 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 [email protected] POST-MOLAR GTN Rising or plateauing hCG plateau: < 1 log drop over 14 days (at least 3 values) Obvious metastases Necessitates chemotherapy [email protected] 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. [email protected] 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. [email protected] 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 [email protected] EMA/CO [email protected] Newlands ES et al J Clin Oncol. 2000 Feb;18(4):854-9. 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. [email protected] 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 ++++) [email protected] 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 FPFP hCG LDH Dysgerminoma + Yolk sac tumor +

Immature teratoma Embryonal carcinoma + + Choriocarcinoma +

Mixed tumor Other markers: CA 125, CA 19-9, NSE, angiotensin, MCSF [email protected] 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 residue 3: 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. [email protected] Germ Cell Tumors: Standard Chemotherapy BEP Protocol J our 1 2 3 4 5 Cisplatine 20 mg/ m I V * *

* * * # # # # # Etoposide 100 mg/ m I V Blomycine 30 mg I V Early chemotherapy after surgery Dose intensity important Gershenson DM, et al. J Clin Oncol. 1990;8(4):715-720. [email protected]

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 [email protected] 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] Response rates in GOG phase II trials in advanced uterine LMScytotoxic 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%) [email protected] [email protected] [email protected] 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] [email protected] 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 [email protected] R A N D O M I Z E Gemcitabine 900 mg/m IV days 1 and 8 Docetaxel 75 mg/m IV day 8 Placebo (for Bevacizumab) Day 1 Every 3 weeks Regimen II:* Gemcitabine 900 mg/m IV days 1 and 8 Docetaxel 75 mg/m IV day 8

Bevacizumab 15 mg/kg IV day 1 Every 3 weeks Until disease progression or adverse effects prohibit further therapy L LMS [email protected] 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] Malignant Mixed Mullerian Tumor = Carcinosarcoma [email protected] MMMT: Biphasic Morphology [email protected] MMMT: Heterologous Components (Rhabdomyoblasts) [email protected] 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 [email protected] 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 0.8

Alive 13 16 Dead 78 72 Total 91 88 Proportion Surviving 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 Month s on Stu dy [email protected] Homesley et al J Clin Oncol 25:526-531, 2007 Activated 9/2009: Target accrual 424 patients over 5.5 years [email protected] Epithelial Uterine Corpus Cancer FIGO Stage IC [email protected]

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 [email protected] 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

[email protected] 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 p=.01 (95% CI, 0.52 to 0.89; P .01) favoring AP Randall et al. J Clin Oncol 24:36-44, 2006

[email protected] 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 [email protected] R A N D O M I Z

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 [email protected] 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 [email protected] 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 [email protected] Median PFS (months) 13.5 13.3 HR=1.03 [email protected]

Miller DS SGO 2012 Median PFS (months) 13.5 13.3 HR=1.03 [email protected] 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 [email protected] 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

Thresholds: 10%, 25% a No prior taxane allowed b 77% (20/26) prior paclitaxel c [email protected] Lincoln et al, 2003; Muggia et al, 2002; Miller et al, 2002; Fracasso et al, 2006; Garcia et al, 2008. 94% (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 [email protected] Age-Standardized Cervical Cancer Rates in 2008 [email protected] 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 [email protected] [email protected] 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) [email protected] 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, 177183 1999) [email protected] 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 [email protected] R A N D O M I Z E 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) [email protected] 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 [email protected] R A N D O M I

Z 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 [email protected] Standard Anterior and Lateral External-beam

Irradiation Ports Used to Treat Locally Advanced Cervical Carcinoma Limited to the Pelvis [email protected] Monk et al J Clin Oncol 25:2952-2965. 2007 Systemic Therapy for Advanced and recurrent Disease [email protected] 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. [email protected] 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 710 y1 10 y2 HPV Disappearance 1-2 y3,4,6 ~69 mo5,6 Colposcopy demonstrates demonstrates abnormal abnormal vasculature vasculature and and angiogenesis angiogenesis dependent dependent progression progression Colposcopy 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. Ostr AG. Int J Gynecol Pathol. 1993;12:186-192; [email protected] GOG 204

Primary Stage IVB or recurrent/persistent carcinoma of the cervix measurable disease GOG performance status 0-1 ANC 1500/ll platelets 100,000/ll serum creatinine 1.5 mg/dl no CNS disease no past or concomitant invasive cancer no prior chemotherapy (unless concurrent with radiation) [email protected] 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 [email protected] R A N D O M I Z

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 and randomly Trial Profile assigned 2/21/2006 127 assigned to TP 4 ineligible 11/20/2009

126 assigned to TC 5 ineligible 25Maximum 6 cycles of treatment until disease progression or unacceptable toxicity 123 efficacy analysis 125 safety analysis [email protected] 121 efficacy analysis 126 safety analysis Kitagawa R, et al. J Clin Oncol. 2012;30(Suppl): Abstract 5006. Overall Survival 1.0 Arm N Events 0.9

TP 123 106 TC 121 98 0.8 Proportion (www.jcog.jp/en/) 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 Cox regression with tumors outside prior irradiation field[yes/no] as strata [email protected] Kitagawa R, et al. J Clin Oncol. 2012;30(Suppl): Abstract 5006. 6 Beyond GOG 204 Novel Agents and Non-platinum Doublets [email protected] GOG 240 Primary Stage IVB or recurrent/persistent carcinoma of the cervix Measurable disease GOG performance status 0-1 ANC 1500/lL Platelets 100,000/lL

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: vs Winner of GOG 204 (Cisplatin + Paclitaxel) 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: vs Winner of GOG 204 (Cisplatin + Paclitaxel) 3 hrs q 21 days Futile April 2012 Paclitaxel 175 mg/m2 over 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: vs Winner of GOG 204 (Cisplatin + Paclitaxel) 3 hrs q 21 days Futile April 2012 Paclitaxel 175 mg/m2 over 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]

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