bradley j. monk, m.d. professor and director division of gynecologic oncology
DESCRIPTION
Cervical Cancer: Evolutions in the Standard of Care. 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 - PowerPoint PPT PresentationTRANSCRIPT
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
Cervical Cancer:Evolutions in the Standard of Care
The Global Burden of Cancer to Women WorldwideNew Cases Annually Deaths Annually
9% of all new cancer cases 8% of total cancer deaths 85% of deaths occur in
developing countries
Jemal A et al CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90.
Age-Standardized Cervical Cancer Rates in 2008
Jemal A et al CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90.
Papillomaviruses in Human Cancer
•1842: Rigoni-Stern – prostitutes higher incidence of cervical cancer than nuns
•1951: George Otto Gey - HeLa (Henrietta Lacks) cells
•1928: Georgious Papanicolaou - “Pap smear”
Harald zur Hausen
•1983: Harald zur Hausen - discovers HPV
•2008: Harald zur Hausen - wins Nobel Prize
Infection With Oncogenic HPV Is Necessary to Cause Cervical Cancer1
1. Walboomers J et al. J Pathol. 1999;189:12-19. 2. Trottier H, Franco E. Vaccine. 2006;24S1:S4-15. 3. Moscicki A et al. Vaccine. 2006;24S3:42-51.4. Einstein M. Cancer Immunol Immunother.2008;57:443-51. 5. Östör A. Int J Gynecol Pathol. 1993;12:186-92.
Precancerous Lesions
Mild Cervical Lesions
Oncogenic InfectionsCommonly caused by HPV types 16 & 18
Persistent Infection
Mild Cervical Lesions/
Genital Warts
Cervical Cancer
Non-oncogenic infections do not lead to precancerous lesions or cervical cancer2
Non-oncogenic Infections
Persistent Infection
Most HPV infections will clear, and most cervical lesions will not progress3-5
[email protected] at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS
HPV E6
HPV E7
p53 degradation TSP-1 VEGF angiogenesis
Displacement ofHDAC1, HDAC4, HDAC7
HIF1α
pRb inactivation p21-RB pathway dysregulation
Tumor Hypoxia and Viral OncogenesDrive Angiogenesis in Cervical Neoplasia
Anti-VEGF therapy
Tewari KS, et al. Gynecol Oncol 2000;77:137-48.Monk BJ, et al. J Clin Oncol. 2009;27(7):1069-74.http://www.microbiologybytes.com/virology/Papillomaviruses.html
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
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
Wertheim
Wertheim E: Zur frage der radikaloperation beim uteruskebs. Arch Gynecol 61:627, 1900Wertheim E: Discussion on the diagnosis and treatment of carcinoma of the uterus. BMJ 2:689, 1905Wertheim E: The extended abdominal operation for carcinoma uteri. Translated by Grad H Am J Obstet Dis Women Child 66:169, 1912
Acceptable Alternatives to Radical Abdominal Hysterectomy and
Lymphadenectomy forStage IA2 and IB1 Cervical Cancer
• Radical traechelectomy (or cone) and nodes (Fertility sparing)
• Intracavitary brachytherapy and pelvic RT +/- chemo• Laparoscopic radical hysterectomy and nodes• Robotic radical hysterectomy and nodes• Simple hysterectomy and nodes
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
Pro
babi
lity
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
THE OUTBACK TRIAL/GOG 0274A Phase III trial of adjuvant chemotherapy
following chemoradiation as primary treatment for locally advanced cervical
cancer compared to chemoradiation alone Linda Mileshkin on behalf of ANZGOGKathleen Moore on behalf of the GOG
ClinicalTrials.gov Identifier: NCT01414608
Design Stage IB2-IVaCervical cancer:Stratify for- FIGO stage- Pelvic nodal
involvement- Uterine +ve on
MRI
Standard chemoXRT
Standard chemoXRT
4 cyclesCarboplatin + Paclitaxel
ClinicalTrials.gov Identifier: NCT01414608
• Early stage cervical cancer usually cured with radical local excision
– Randomized trials have established role of adjuvant CCRT• CCRT used to treat locally advanced disease• Tumor stage, tumor grade, race, age and angiogenesis
independently prognostic• Anti-angiogenic agents rationale and underdevelopment
Summary of Primary Treatment
Chemotherapy for Recurrent Cervical Cancer - Lessons Learned in the 80’s and 90’s
• Platinum-based therapies most effective• Cisplatin more active than carboplatin• Two ways to increase response without prolongation in
Survival– Increase platinum dose– Add Ifosfomide to cisplatin
• Single agent cisplatin at 50 mg/m2 became standard
GOG 204
Primary 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.
By Treatment GroupP
ropo
rtion
Sur
vivi
ng
0.00.10.20.30.40.50.60.70.80.91.0
Months on Study0 12 24 36
Treatment Alive Dead Total CIS+PAC 29 74 103
Alive Dead Total
CIS+VIN 23 85 108
Alive Dead Total
CIS+GEM 20 92 112
Alive Dead Total
CIS+TOP 22 89 111
GOG 204: Overall Survival
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
RANDOMIZE*
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
Kitagawa R, et al. J Clin Oncol. 2012;30(Suppl): Abstract 5006.
Trial Profile
(www.jcog.jp/en/)
25253 patients enrolled and randomly assigned
127 assigned to TP126 assigned to
TC4 ineligible 5 ineligible25Maximum 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.
Best Response – RECIST v1.0Women With Target Lesions
(www.jcog.jp/en/)
Best Response TP (n = 102)
TC (n = 99)
P Value**
No. of patients (%)
Complete response (CR) 4 (3.9%) 7 (7.1%)
Partial response (PR) 56 (54.9%) 55 (55.6%)
Stable disease (SD) 23 (22.5%) 19 (19.2%)
Progressive disease (PD) 7 (6.9%) 9 (9.1%)
Not evaluable (NE)* 12 (11.8%) 9 (9.1%)
Objective Response 60 (58.8%) 62 (62.6%) .665** Fisher’s exact test * NE due to missing data
Kitagawa R, et al. J Clin Oncol. 2012;30(Suppl): Abstract 5006.
Overall Survival (www.jcog.jp/en/)
0.00.10.20.30.40.50.60.70.80.91.0
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6Years after randomization
Prop
ortio
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.
• Failed first-line cytotoxic drug treatment• 125 mg/m(2) IV over 30 minutes on days 1, 8, and 15 of
each 28 day cycle• Median PFS = 5.0 months• Median OS = 9.4 months• 10 (28.6%; CI 14.6%-46.3%) of 35 patients = PR• 15 patients (42.9%) had SD
Alberts DS, et al. Gynecol Oncol. 2012;127(3):451-455.
Agents Targeting the VEGF Pathway
VEGFR-2VEGFR-1PPP
PPPP
P
Endothelial cell Small-molecule inhibitors
Anti-VEGFR antibodies
VEGFAnti-VEGF antibodies
(bevacizumab)Soluble VEGFRs
(VEGF-TRAP)
Podar and Anderson. Blood. 2005;105:1383.
• Persistent or recurrent squamous cervical cancer
• 1-2 prior cytotoxic regimens (not including initial chemo-RT)
• Measurable disease• GOG PS ≤ 2
GOG 227-C
Bevacizumab 15 mg/kg IVq 21 days until diseaseprogression orprohibitive toxicity
Monk BJ, Sill MW, Burger RA, Gray HJ, Buekers TE, Roman LD.J Clin Oncol. 2009 Mar 1;27(7):1069-74.
GOG 227-CBy Treatment Group
Prop
ortio
n Pr
ogre
ssio
n-Fr
ee
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
PFS of Bev (Blue) versusGOG Historical Database(Failing one or two cytotoxicregimens, not includingchemo-RT)
Bevacizumab
GOG Historical Database(Failing one or two cytotoxicregimens, not includingchemo-RT)
Monk BJ et al J Clin Oncol. 2009 Mar 1;27(7):1069-74.
GOG 240 Primary 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 = 452OS HR reduction of 30%Study Chair = KS TewariClinicalTrials.gov Identifier: NCT00803062
Tewari KS et al N Engl J Med. 2014 Feb 20;370(8):734-43.
GOG 240 – Non-platinum ObjectivePrimary 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 = 452OS HR reduction of 30%Study Chair = KS TewariClinicalTrials.gov Identifier: NCT00803062
Tewari KS et al N Engl J Med. 2014 Feb 20;370(8):734-43.
GOG 240 – Bevacizumab ObjectivePrimary 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 = 452OS HR reduction of 30%Study Chair = KS TewariClinicalTrials.gov Identifier: NCT00803062
Tewari KS et al N Engl J Med. 2014 Feb 20;370(8):734-43.
HR 1.20 (98.74% CI 0.82-1.76; 1-sided p=0.880)Median OS: 15 m (CP) and 12.5 m (TP)RR: 38.4% (CP), 28.7% (TP) [2-sided p=0.0364]CR: n=26 (CP), n=16 (TP) p=NS
Cisplatin-Paclitaxel backbone
Topotecan-Paclitaxel backbone
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 12 24
Pro
porti
on S
urvi
ving
Months on Study
GOG 240 – Non-platinum Objective
Tewari KS et al. Presented at the 2013 SGO Annual Meeting on Women’s Cancer. Abstract #1.
Overall Survival - Prior Platinum Exposure
HR 1.18 (95% CI 0.84-1.65)RR: 34% (CP) vs 24% (TP)
HR 1.35 (95% CI 0.676-2.688)RR: 54% (CP) vs 42% (TP)
Prior Cisplatin No Prior Cisplatin
Cisplatin-Paclitaxel backbone
Cisplatin-Paclitaxel backbone
Topotecan-Paclitaxel backboneTopotecan-Paclitaxel backbone
GOG 240 – Non-platinum Objective
Tewari KS et al. Presented at the 2013 SGO Annual Meeting on Women’s Cancer. Abstract #1.
GOG 240 – Bevacizumab ObjectivePrimary 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 = 452OS HR reduction of 30%Study Chair = KS TewariClinicalTrials.gov Identifier: NCT00803062
Chemotherapy + Bev (n=227)
183 (81)
8.2
HR=0.67 (95% CI, 0.54-0.82)2-sided P=0.0002
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3612 24
Pro
porti
on P
rogr
essi
on-F
ree
Months on Study
Chemotherapy(n=225)
Events, n (%) 184 (82)
Median PFS, mos 5.9
RR, % 36 (CR, n=14) 48 (CR, n=28)2-sided P=0.00807
GOG 240 – Bevacizumab Objective
Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS Tewari KS et al N Engl J Med. 2014 Feb 20;370(8):734-43.
Cis + Pac + Bev(n=115)67 (58.3)
HR=0.68 (95% CI, 0.48-0.97)P=0.0348
Cis + Pac(n=114)
Events, n (%) 69 (60.5)
Median OS, mos 14.3 17.5
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 12 3624
Pro
porti
on S
urvi
ving
Months on Study
RR, % 45 (CR, n=9) 50 (CR, n=17)
2-sided P=0.5090
GOG 240 – Bevacizumab ObjectiveCisplatin + Paclitaxel Cohort N=229
Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS Tewari KS et al N Engl J Med. 2014 Feb 20;370(8):734-43.
Subgroup No. of Patients Hazard RatioAge Age ≤ 40 years 112
40 < Age ≤ 48 years 11148 < Age ≤ 56 years 10856 years < Age 121
Performance Status 0 2631 189
Prior Platinum RT No 115Yes 337
Disease Status Advanced 76Recurrent/Persistent 376
Topotecan Treatment No 229Yes 223
Race Not Black 392Black 60
Histology Adenocarcinoma 86Adenosquamous 44Other 12Squamous 310
Pelvic Disease No 210Yes 242
Overall 452
0.0 0.5 1.0 1.5 2.0 2.5Experimental Better Control Better
GOG 240: OS and Prognostic Factors
= HR does not cross 1.0
Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS Tewari KS et al N Engl J Med. 2014 Feb 20;370(8):734-43.
GOG 240: Treatment Exposure andSpecific Adverse Events
Adverse Event, n (%) Chemo Alone (n=219)
Chemo + Bev (n=220)
Treatment cycles, median (range) 6 (0-30) 7 (0-36)
Grade 5 AE(s) 4 (1.8) 4 (1.8)
GI events, non-fistula (grade ≥2) 96 (44) 114 (52)
GI fistula (grade ≥3)* 0 (0) 7 (3)
GI perforation (grade ≥3) 0 (0) 5 (2)
GU fistula (grade ≥3)* 1 (0) 6 (2)
Hypertension (grade ≥2)* 4 (2) 54 (25)
Proteinuria (grade ≥3) 0 (0) 4 (2)
Pain (grade ≥2) 62 (28) 71 (32)
Neutropenia (grade ≥4)* 57 (26) 78 (35)
Febrile neutropenia (grade >3) 12 (5) 12 (5)
Thromboembolism (grade ≥3)* 3 (1) 18 (8)
Bleeding CNS (any grade) 0 (0) 0 (0)
GI (grade ≥3) 1 (0) 4 (1)
GU (grade ≥3) 1 (0) 6 (3)*p<0.05
Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS Tewari KS et al N Engl J Med. 2014 Feb 20;370(8):734-43.
GOG 240: Health Related Quality of Life• FACT for Cervical Cancer – Trial Outcome Index
• Physical well-being (7 items)• Functional well-being (7 items)• Cervix Cancer subscale (15 items)• Score range: 0-116 points• Clinically meaningful change: 4-5 points
• Compliance with completion of HRQoL questionnaires ranged from 96% pre-cycle 1 to 63% 9 mos post-cycle 1 and was balanced across arms
Yost KJ, Eton DT. Eval Health Prof 2005;28:172-91.
FACT-Cx TOI Score Chemo Alone Chemo + Bev Difference 98.75% CIPre-cycle 1 77.9 75.8 -2.17 -6.43–2.09
Pre-cycle 2 77.4 76.9 -0.47 -3.59–2.64
Pre-cycle 5 77.6 74.7 -2.95 -6.81–0.90
6 mos post-cycle 1 74.0 71.2 -2.84 -7.40–1.73
9 mos post-cycle 1 74.5 72.7 -1.80 -7.10–3.50
GOG 240: Mean FACT-Cx TOIPatients receiving bevacizumab reported 1.2 points lower on average (not significant)
Assessment Time
Chem Alone
Chemo + Bev
Pre-cycle 1 Pre-cycle 2 Pre-cycle 5 5 mos post cycle 1
9 mos post cycle 1
120
110
100
90
80
70
60
50
40
30
10
0
20
Scor
e
98.75% CI -4.1 – 1.7P=0.3
Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS Tewari KS et al N Engl J Med. 2014 Feb 20;370(8):734-43.
Progress in Survival in Advanced and Recurrent Cervical Cancer
1989 1997 2002 2004 2005 2009 201302468
1012141618
GOG 110 Cisplatin + Ifosfamide
GOG 149 Cisplatin + Ifosfamide + Bleomycin
GOG 169 Cisplatin + Palitaxel
GOG 179 Cisplatin + Topotecn
Mon
ths
Year
GOG 64 Cisplatin
GOG 240 Cisplatin + Palcitaxel + Bevacizumab
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
• Only pelvic exenteration curative for central pelvic recurrences• Cisplatin doublets plus bevacizumab standard in treating
metastatic disease– Will bevacizumab gain regulatory approval?
Summary of Treatment forRecurrent Disease
