1. No category

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
University of Arizona Cancer Center-Phoenix
Arizona USA
[email protected]
The Global Burden of Cancer to Women Worldwide
New 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.
[email protected]
Age-Standardized Cervical Cancer Rates in 2008
Jemal A et al CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90.
[email protected]
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”
•1983: Harald zur Hausen - discovers HPV
•2008: Harald zur Hausen - wins Nobel Prize
Harald zur Hausen
[email protected]
Infection With Oncogenic HPV Is
Necessary to Cause Cervical Cancer1
Oncogenic Infections
Commonly caused by HPV types 16 & 18
Non-oncogenic Infections
Persistent Infection
Persistent Infection
Mild Cervical Lesions
Mild Cervical
Lesions/
Genital Warts
Precancerous Lesions
Non-oncogenic infections do not lead to
precancerous lesions or cervical cancer2
Cervical
Cancer
Most HPV infections will clear, and most cervical lesions will not progress3-5
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.
[email protected]
Tumor Hypoxia and Viral Oncogenes
Drive Angiogenesis in Cervical Neoplasia
HPV E6
p53 degradation
 TSP-1
 VEGF
 angiogenesis
Anti-VEGF therapy
HPV E7
Displacement of
HDAC1, HDAC4,
HDAC7
pRb inactivation
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
[email protected]
 HIF1α
p21-RB pathway dysregulation
Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS
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;
[email protected]
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]
Wertheim
[email protected]
Wertheim E: Zur frage der radikaloperation beim uteruskebs. Arch Gynecol 61:627, 1900
Wertheim E: Discussion on the diagnosis and treatment of carcinoma of the uterus. BMJ 2:689, 1905
Wertheim 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 for
Stage 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
[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)
RT=Radiation therapy
[email protected]
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)
[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
THE OUTBACK TRIAL/GOG 0274
A 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 ANZGOG
Kathleen Moore on behalf of the GOG
ClinicalTrials.gov Identifier: NCT01414608
[email protected]
Design
Stage IB2-IVa
Cervical cancer:
Stratify for
- FIGO stage
- Pelvic nodal
involvement
- Uterine +ve on
MRI
[email protected]
Standard
chemoXRT
Standard
chemoXRT
ClinicalTrials.gov Identifier: NCT01414608
4 cycles
Carboplatin
+ Paclitaxel
Summary of Primary Treatment
•
•
•
•
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
[email protected]
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
[email protected]
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)
[email protected]
Regimen 1
Paclitaxel 135 mg/m2 over 24 hours and
CDDP 50 mg/m2 repeated q 3 wks for 6 cycles
R
A
N
D
O
M
I
Z
E
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.
GOG 204: Overall Survival
By Treatment Group
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Proportion Surviving
Treatment
CIS+PAC
CIS+VIN
CIS+GEM
CIS+TOP
0
[email protected]
12
24
Months on Study
Alive Dead Total
29
74 103
23
85 108
20
92 112
22
89 111
36
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
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
Kitagawa R, et al. J Clin Oncol. 2012;30(Suppl): Abstract 5006.
[email protected]
(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/)
Best Response – RECIST v1.0
Women With Target Lesions
TP
(n = 102)
Best Response
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%)
60
(58.8%)
62
(62.6%)
Objective Response
* NE due to missing data
.665
** Fisher’s exact test
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
[email protected]
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
[email protected]
• 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
[email protected]
Alberts DS, et al. Gynecol Oncol. 2012;127(3):451-455.
Anti-VEGF
antibodies
VEGF
Soluble
VEGFRs
(bevacizumab)
(VEGF-TRAP)
Agents Targeting
the VEGF Pathway
P
P
Anti-VEGFR
antibodies
P
P
VEGFR-1
P
P
VEGFR-2
Endothelial cell
Podar and Anderson. Blood. 2005;105:1383.
[email protected]
P
P
Small-molecule inhibitors
GOG 227-C
• Persistent or recurrent
squamous cervical cancer
• 1-2 prior cytotoxic
regimens (not including
initial chemo-RT)
• Measurable disease
• GOG PS ≤ 2
Monk BJ, Sill MW, Burger RA, Gray HJ, Buekers TE, Roman LD.
J Clin Oncol. 2009 Mar 1;27(7):1069-74.
[email protected]
Bevacizumab 15 mg/kg IV
q 21 days until disease
progression or
prohibitive toxicity
GOG 227-C
By Treatment Group
1.0
Bevacizumab
PFS of Bev (Blue) versus
GOG Historical Database
(Failing one or two cytotoxic
regimens, not including
chemo-RT)
Proportion Progression-Free
0.9
0.8
0.7
GOG Historical Database
(Failing one or two cytotoxic
regimens, not including
chemo-RT)
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
12
Months on Study
[email protected]
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 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
OS HR reduction of 30%
Study Chair = KS Tewari
ClinicalTrials.gov Identifier: NCT00803062
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
Tewari KS et al N Engl J Med. 2014 Feb 20;370(8):734-43.
[email protected]
GOG 240 – Non-platinum Objective
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
OS HR reduction of 30%
Study Chair = KS Tewari
ClinicalTrials.gov Identifier: NCT00803062
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
Tewari KS et al N Engl J Med. 2014 Feb 20;370(8):734-43.
[email protected]
GOG 240 – Bevacizumab Objective
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
OS HR reduction of 30%
Study Chair = KS Tewari
ClinicalTrials.gov Identifier: NCT00803062
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
Tewari KS et al N Engl J Med. 2014 Feb 20;370(8):734-43.
[email protected]
GOG 240 – Non-platinum Objective
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
1.0
Proportion Surviving
0.9
0.8
Cisplatin-Paclitaxel backbone
0.7
0.6
0.5
Topotecan-Paclitaxel backbone
0.4
0.3
0.2
0.1
0.0
0
12
Months on Study
Tewari KS et al. Presented at the 2013 SGO Annual Meeting on Women’s Cancer. Abstract #1.
[email protected]
24
GOG 240 – Non-platinum Objective
Overall Survival - Prior Platinum Exposure
Cisplatin-Paclitaxel backbone
Cisplatin-Paclitaxel backbone
Topotecan-Paclitaxel backbone
Topotecan-Paclitaxel backbone
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
Tewari KS et al. Presented at the 2013 SGO Annual Meeting on Women’s Cancer. Abstract #1.
[email protected]
No Prior Cisplatin
GOG 240 – Bevacizumab Objective
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
OS HR reduction of 30%
Study Chair = KS Tewari
ClinicalTrials.gov Identifier: NCT00803062
[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 – Bevacizumab Objective
Proportion Progression-Free
1.0
Events, n (%)
0.9
Median PFS, mos
0.8
Chemotherapy
(n=225)
Chemotherapy +
Bev (n=227)
184 (82)
183 (81)
5.9
8.2
HR=0.67 (95% CI, 0.54-0.82)
2-sided P=0.0002
0.7
RR, %
0.6
36 (CR, n=14)
48 (CR, n=28)
2-sided P=0.00807
0.5
0.4
0.3
0.2
0.1
0.0
0
12
24
36
Months on Study
Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS
[email protected]
Tewari KS et al N Engl J Med. 2014 Feb 20;370(8):734-43.
GOG 240 – Bevacizumab Objective
Cisplatin + Paclitaxel Cohort N=229
1.0
Events, n (%)
0.9
Median OS, mos
Proportion Surviving
0.8
Cis + Pac
(n=114)
Cis + Pac + Bev
(n=115)
69 (60.5)
67 (58.3)
17.5
14.3
HR=0.68 (95% CI, 0.48-0.97)
P=0.0348
0.7
RR, %
0.6
45 (CR, n=9)
50 (CR, n=17)
2-sided P=0.5090
0.5
0.4
0.3
0.2
0.1
0.0
0
12
24
36
Months on Study
Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS
[email protected]
Tewari KS et al N Engl J Med. 2014 Feb 20;370(8):734-43.
GOG 240: OS and Prognostic Factors
Subgroup
Age
Performance Status
Prior Platinum RT
Disease Status
Topotecan Treatment
Race
Histology
Pelvic Disease
Age ≤ 40 years
40 < Age ≤ 48 years
48 < Age ≤ 56 years
56 years < Age
0
1
No
Yes
Advanced
Recurrent/Persistent
No
Yes
Not Black
Black
Adenocarcinoma
Adenosquamous
Other
Squamous
No
Yes
Overall
No. of Patients
112
111
108
121
263
189
115
337
76
376
229
223
392
60
86
44
12
310
210
242
452
Hazard Ratio
0.0
0.5
1.0
Experimental Better
1.5
Control Better
2.0
2.5
= HR does not cross 1.0
Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS
[email protected]
Tewari KS et al N Engl J Med. 2014 Feb 20;370(8):734-43.
GOG 240: Treatment Exposure and
Specific Adverse Events
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)
Adverse Event, n (%)
*p<0.05
Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS
[email protected]
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% precycle 1 to 63% 9 mos post-cycle 1 and was balanced across arms
FACT-Cx TOI Score
Chemo Alone
Chemo + Bev
Difference
98.75% CI
Pre-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
Yost KJ, Eton DT. Eval Health Prof 2005;28:172-91.
[email protected]
GOG 240: Mean FACT-Cx TOI
Patients receiving bevacizumab reported 1.2 points lower on average (not significant)
120
Chem
Alone
110
Chemo +
Bev
100
90
80
Score
70
60
98.75% CI -4.1 – 1.7
P=0.3
50
40
30
20
10
0
Pre-cycle 1
Pre-cycle 2
Pre-cycle 5
5 mos post
cycle 1
9 mos post
cycle 1
Assessment Time
Presented at ASCO 2013 by: Krishnansu S. Tewari, MD, FACOG, FACS
[email protected]
Tewari KS et al N Engl J Med. 2014 Feb 20;370(8):734-43.
Progress in Survival in Advanced
and Recurrent Cervical Cancer
Months
GOG 240 Cisplatin + Palcitaxel + Bevacizumab
18
16
14
12
10
8
6
4
2
0

GOG 179 Cisplatin + Topotecn
GOG 110 Cisplatin + Ifosfamide





GOG 169 Cisplatin + Palitaxel
GOG 149 Cisplatin + Ifosfamide + Bleomycin
GOG 64 Cisplatin
1989
1997
2002
2004
Year
[email protected]
2005
2009
2013
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
Summary of Treatment for
Recurrent Disease
•
•
Only pelvic exenteration curative for central pelvic recurrences
Cisplatin doublets plus bevacizumab standard in treating
metastatic disease
– Will bevacizumab gain regulatory approval?
[email protected]
Thank You
[email protected]