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Gynecologic Cancers
Bradley J. Monk, M.D.Associate Professor
Division of Gynecologic Oncology
Chao Family Comprehensive Cancer Center
University of California Irvine Medical Center
Orange CA USA 92868
2
on behalf of MRC and EORTC collaborators; Mount Vernon Cancer Centre, Middlesex,
United Kingdom; Erasmus MC University Medical Center, Rotterdam, Netherlands
A randomized trial in ovarian cancer (OC) of
early treatment of relapse based on CA125
level alone versus delayed treatment based
on conventional clinical indicators
(MRC OV05/EORTC 55955 trials)
G. J. Rustin, M. E. van der Burg
J Clin Oncol 27:15s, 2009 (suppl; abstr 1)
Ovarian Carcinoma: CA-125
• Serum glycoprotein (OC-
125)
• Discovered during a
search to boost an
immunotherapy
(Corynebacterium
parvum)[1]
• Blood test introduced in
1981
– Elevated in 82% of
ovarian cancers; 1% in
controls[2]
• CA-125 cloned in 2001[3]
– Mapped to
chromosome 19
(p13.3)
– Gene: MUC16
– Very large molecule
1. Bast RC, et al. J Clin Invest. 1981;68:1331-1337. 2. Bast RC, et al. N Engl J Med. 1983;309:883-887.
3. Yin BW, et al. J Biol Chem. 2001;276:27371-27375.
Trial Profile
Registered patients
N=1442
Randomised
N=529 (37%)
Delayed treatmentN=264
N=233 (88%) started second-line
chemotherapy
Early treatmentN=265
N=254 (96%) started second-line
chemotherapy
Non randomised patientsN (%)
421 (29) CA125<2ULN and no relapse
at trial closure
61 (4) Simultaneous relapse and
CA125>2ULN
213 (15) Relapsed without CA125>2ULN
56 (4) Died
133 (9) Patient withdrawal
29 (2) Other/unknown reasons
Baseline characteristics:
All randomised patients (N=529)Early Delayed
Age Median (range) 60 (35-86) 61 (37-93)
FIGO
stage
I
II
III
IV
9%
11%
68%
12%
8%
10%
69%
13%
WHO PS 0
1
2 & 3
69%
29%
2%
75%
25%
<1%
Histology Serous
Endometroid
Mucinous
Clear cell
Undifferentiated
Adenocarcinoma not otherwise specified
Other
66%
12%
3%
4%
8%
6%
1%
59%
12%
3%
4%
6%
15%
1%
Second-line
chemotherapy
Regimen administered Early
N (%)
Delayed
N (%)
Single agent platinum
Combination platinum (no taxane)
Platinum + taxane based
Taxane without platinum
Other
Unknown treatment
No treatment given
Not yet given (no clinical relapse)
78 (29)
40 (15)
91 (34)
15 (6)
28 (11)
2 (1)
11 (4)
0
67 (25)
33 (13)
101 (38)
9 (3)
15 (6)
8 (3)
24 (9)
7 (3)
Total 265 264
0.0
00
.25
0.5
00
.75
1.0
0
Pro
po
rtio
n a
live
no
t s
tart
ed
se
co
nd
-lin
e c
he
mo
the
rap
y
264 177 116 91 69 56 49 42 33Delayed
265 23 16 14 11 11 10 10 9Early
Number at risk
0 3 6 9 12 15 18 21 24
Months since randomisation
Time from randomisation to
second-line chemotherapy
Median (months)
Early 0.8
Delayed 5.6
HR=0.29 (95% CI 0.24, 0.35) p<0.00001
0.0
00.2
50
.50
0.7
51
.00
Pro
po
rtio
n s
urv
ivin
g
264 236 203 167 129 103 69 53 38 31 19Delayed
265 247 211 165 131 94 72 51 38 31 22EarlyNumber at risk
0 6 12 18 24 30 36 42 48 54 60
Months since randomisation
Overall Survival
HR=1.00 (95%CI 0.82-1.22) p=0.98
Early
Delayed
Abs diff at 2 years= -0.1% (95% CI diff= -6.8, 6.3%)
Time from randomisation to first
deterioration in Global Health Score (or death)
0.0
00
.25
0.5
00
.75
1.0
0
Pro
po
rtio
n a
live
wit
ho
ut
de
teri
ora
tio
n in
GH
S
194 93 55 38 25Delayed190 68 44 23 12Early
Number at risk
0 6 12 18 24
Months since randomisation
Median (months)
Early 3.1
Delayed 5.8
HR=0.71 (95% CI 0.57, 0.87) p=0.001
• In early treatment arm based on rise of CA125
– Second-line chemotherapy started a median of 4.8
months earlier
– Third-line chemotherapy started a median of 4.6 months
earlier
• This early treatment did not improve overall survival
• HR=1.00, 95% CI 0.82-1.22, p=0.98
• Absolute difference at 2 years -0.1% (95%CI -6.8,
6.3%)
• Early chemotherapy does not improve Qol
Conclusions
June, 2009: SGO Statement on Use of
CA125 for Monitoring Ovarian Cancer
• Role of secondary cytoreduction not addressed
• Not stratified for residual disease after cytoreduction
• Remission not confirmed by imaging
• Treatment at relapse not standardized
• “Patients and their physicians should still have the
opportunity to choose [CA125 monitoring] as a
philosophy of active management that includes
participation in trials of novel therapies”
12
The David Geffen School of Medicine at UCLA, Los Angeles, CA; Santa Clara Valley
Medical Center, San Jose, CA; Cedars-Sinai Medical Center, Los Angeles, CA
Influence of residual disease and
extreme drug resistance assays on
outcome in patients with epithelial
ovarian cancer
A. Karam, J. Wang Chiang, E. Fung, V. Nossov, B. Y. Karlan
J Clin Oncol 27:15s, 2009 (suppl; abstr 5504)
Kern and Weisenthal, JNCI 1990
Kern and Weisenthal, JNCI 1990
Aims and Methods
• Aims:– Effects of EDR assay-guided therapy in epithelial
Ovarian Cancer (EOC)
– Outcomes in the primary and recurrent setting
• Retrospective review– 377 EOC patients at Cedars Sinai Medical Center,
Los Angeles
– EDR assays between 1995 and 2005
• End points– Time to first recurrence (TTP)
– Overall survival (OS)
– Survival after recurrence (RS)
Demographic and Clinical CharacteristicsVariable Frequency Percent
Age, years
Median (Range) 59.0 (24.4-89.1)
Race
White 315 87.7
Non-white 44 12.3
Residual Disease at 1° CRS
Microscopic 76 29.9
0.1-1 cm 145 57.1
≥1 cm 33 13.0
FIGO Stage
I/II 34 10.2
III/IV 300 89.8
Tumor Grade
1 11 3.9
2 14 4.9
3 260 91.2
Histology
Papillary Serous 265 77.9
Other 75 22.1
Variable Frequency Percent
Primary Chemotherapy
Platinum and taxane 231 88.8
Platinum based 25 10.7
Other 4 1.5
2° CRS
No 93 36.0
Yes 165 64.0
Recurrence type
Platinum resistant 75 29.4
Platinum sensitive 180 70.6
Residual Disease at 2° CRS
Microscopic 63 42.6
0.1-1 cm 55 37.2
≥1 cm 30 20.3
Status
NED 85 22.8
AWD 28 7.5
DOD 251 67.3
DOC 9 2.4
Adjuvant Therapy and Recurrence
EDR assay results Frequency Percent
EDR Assay at 1° CRS
No 125 36.5
Yes 217 63.5
N EDR Assays
1 292 85.4
≥2 50 14.6
EDR assay results
Carboplatin EDR 57 18.2
Cisplatin EDR 52 15.8
Cyclophosphamide EDR 85 26.1
Taxol EDR 51 15.7
Platinum EDR 81 23.1
Taxane EDR 58 17.2
Platinum + taxane EDR 15 4.5
EDR Assay Results
Multivariate Analysis
Multivariate Disease progression Death
Characteristic HR 95% CI p HR 95% CI p
Age decades 1.12 0.98 1.28 0.1 1.33 1.13 1.56 0.001
Stage
Stage <III 1.0 1.0
Stage ≥III 3.61 0.86 6.4 0.09 2.78 0.68 11.3 0.15
Tumor grade
Grade 1 1.0 1.0
Grade 2 or 3 1.87 0.68 5.14 0.23 5.41 0.73 40.1 0.10
1° CRS residual
Microscopic 1.00 1.00
0.1 to 1.0 cm 1.94 1.33 2.84 0.001 1.59 1.03 2.45 0.04
>1.0 cm 3.61 2.07 6.29 <0.001 2.14 1.09 4.20 0.03
Adjuvant chemotherapy
Platinum and taxane 1.00
Other 0.94 0.23 3.86 0.93
EDR assay
None 1.0
At primary surgery 1.13 0.75 1.72 0.55
CRS=Cytoreductive Surgery
Multivariate Analysis
Multivariate Death after recurrence
Characteristic HR 95% CI p
2° CRS residual disease
Microscopic 1.0
0.1 to 1.0 cm 1.14 0.74 1.77 0.55
>1.0 cm 2.84 1.71 4.71 <0.001
No 2° CRS 2.13 1.28 3.54 0.004
Initial PFS
<6 months 1.00
6 to 12 months 1.15 0.75 1.76 0.52
12 to 24 months 1.32 0.83 2.08 0.24
>24 months 1.25 0.84 1.86 0.28
EDR assay
None 1.0
At recurrence 0.83 0.55 1.27 0.40
CRS=Cytoreductive Surgery
Conclusion
• EDR did not predict outcomes in EOC
patients
• Age and disease residual important for
outcome
• Rationale for assays remains strong
– Continued research
– Gene-expression/microarray profiles
Limitations and Strengths
• Limitations:
– Retrospective nature
– Selection and ascertainment bias
– Incomplete information on salvage chemotherapy
• Strengths:
– Size of patient population
– Treated with platinum and taxane chemotherapy
– Long follow-up (median ~5 years)
Odense University Hospital, Odense, Denmark; University of Tuebingen, Tuebingen,
Germany; Centre Hospitalier , La Roche sur Yon, France; Philipps University, Marburg,
Germany; The Norwegian Radium Hospital, Oslo, Norway; University Hospital Ulm, Ulm,
Germany; Ubbo-Emmius-Klinik gGmbH, Aurich, Germany; St. Vincentius-Krankenhäuser,
Karlsruhe, Germany; Centre Léon Bérard, Lyon, France; HSK, Dr. Horst Schmidt Klinik
GmbH, Wiesbaden, Germany
A randomized, phase III study
(AGO-OVAR-9, GINECO-TCG, NSGO-OC-
0102): Gemcitabine-paclitaxel-carboplatin
(TCG) versus paclitaxel-carboplatin (TC) as
first-line treatment of ovarian cancer (OC):
Survival of FIGO stage I-IIA patients
J. Herrstedt, J. Huober, F. Priou, H. Müller, M.
Baekelandt, C. Kurzeder, J. Pfisterer, A. Stähle,
I. Ray-Coquard, A. du Bois
J Clin Oncol 27:15s, 2009 (suppl; abstr LBA5510)
GOG 182—Primary Therapy
FIGO III-IV
All residuum
EOC or PPC
International
Paclitaxel 175 mg/m2 3 hours
Carboplatin AUC 5 mg/mL•min
Paclitaxel 175 mg/m2 3 hours
Carboplatin AUC 5 mg/mL•min
Gemcitabine 800 mg/m2 days 1, 8 Paclitaxel 175 mg/m2 3 hours
Carboplatin AUC 5
mg/mL•min
PLD 30 mg/m2ALTERNATING
COURSES
Paclitaxel 175 mg/m2 3 hours
Carboplatin AUC 6
mg/mL•min,
x4 cycles
Topotecan 1.5 mg/m2 days 1 - 3
Carboplatin AUC 5 mg/mL•min,
x4 cycles
Paclitaxel 175 mg/m2 3 hours
Carboplatin AUC 6
mg/mL•min, x4 cycles
Gemcitabine 1,000 mg/m2 days 1, 8
Carboplatin AUC 6 mg/mL•min,
x4 cyclesTHEN
THEN
Paclitaxel 175 mg/m2 3 hours
Carboplatin AUC 6 mg/mL•min
All regimens = 8 cycles
Interval cytoreduction allowed
No second-look surgery
Endpoints: PFI, survival, response
N > 4,000 patients
PFI = Progression-free interval; FIGO =International Federation of Gynecologic Oncologists; EOC = Epithelial ovarian
cancer; PPC = Primary peritoneal cancer; AUC = Area under the concentration-time curve.
GOG0182-ICON5:
Progression-Free
Median PFS and HR (95% CI)
16.1 1.00016.4 0.990 (0.838-1.141)16.4 0.998 (0.832-1.136)15.3 1.094 (0.918-1.244)15.4 1.052 (0.888-1.206)
Bookman ASCO Abstract # 5002 2006; J Clin Oncol. 2009 Mar 20;27(9):1419-25.
GOG0182-ICON5:
Overall Survival
Median OS and HR (95% CI)
40.0 1.00040.4 0.978 (0.838-1.141)42.8 0.972 (0.832-1.136)39.1 1.068 (0.918-1.244)40.2 1.035 (0.888-1.206)
Bookman ASCO Abstract # 5002 2006; J Clin Oncol. 2009 Mar 20;27(9):1419-25.
R
A
N
D
O
M
I
S
A
T
I
O
N
q 21 x 6
Paclitaxel 175 mg/m² d1
Carboplatin AUC 5 d1
q 21 x 6
Gemcitabine 800 mg/m² d1+8
Paclitaxel 175 mg/m² d1
Carboplatin AUC 5 d1
STUDY DESIGN
0
0,25
0,5
0,75
1
0 6 12 18 24 30 36 42 48 54 60 66 72
PROGRESSION-FREE SURVIVAL (RECIST & CA125)
BY THERAPY: STRATUM 2+3 (FIGO IIB-IV)
[months]793 699 511 351 270 225 191 152 95 43 14 2
774 685 483 307 228 185 155 116 72 36 12 2
Patients
at risk
HR = 1.17 [95% CI: 1.05-1.31]
Logrank test: p = 0.0065
TC 793 pts. / 588 evts.
median 16.0 [14.9-17.4] mos.
TCG 774 pts. / 629 evts.
median 14.7 [14.0-15.9] mos.
OVERALL SURVIVAL BY THERAPY
STRATUM 2+3 (FIGO IIB-IV)
0
0,5
1
0 6 12 18 24 30 36 42 48 54 60 66 72 78
TC 793 pts. / 401 evts.
median 48.9 [43.1-51.2] mos.
TCG 774 pts. / 404 evts.
median 45.8 [40.0-49.5] mos.
HR = 1.03 [95% CI: 0.90-1.18]
p = 0.6955
793 750 705 638 557 489 420 338 226 89 31 5
774 740 693 628 554 484 411 322 208 87 28 5
31
Istituto Nazionale Tumori , Napoli, Italy; Università Cattolica del Sacro Cuore, Roma, Italy;
Istituto Regina Elena, Roma, Italy; CRO, Aviano, Italy; Ospedale Fatebenefratelli, Isola
Tiberina, Roma, Italy; Casa di Cura La Maddalena, Università di Palermo, Palermo, Italy;
Ospedale Oncologico M.Ascoli A.R.N.A.S., Palermo, Italy; Seconda Università di Napoli,
Napoli, Italy; Istituto Nazionale Tumori di Napoli, Napoli, Italy
Carboplatin plus paclitaxel (CP) versus
carboplatin plus stealth liposomal
doxorubicin (CLD) in patients with
advanced ovarian cancer (AOC): Activity
and safety results of the MITO-2
randomized multicenter trial
Pignata, G. Scambia, A. Savarese, R. Sorio, E. Breda, G.
Ferrandina, V. Gebbia, P. Musso, C. Gallo, F. Perrone
J Clin Oncol 27:15s, 2009 (suppl; abstr LBA5508)
Study population
Inclusion criteria
• Cyto/histological diagnosis of ovarian cancer
• FIGO Stage IC – II – III – IV
• Age 75
• ECOG Performance Status 0-2
• No previous chemotherapy
Main exclusion criteria
• ANC 2000/L, platelets 100000/L
• Creatinine 1.25 x UNL, SGOT and SGPT 1.25 x UNL
• Life expectancy of less than 3 months
R
a
n
d
o
m
Strata:
•Center
•PS (0-1, 2)
•Stage (IC, II, III, IV)
•Residual disease after surgery
(absent, 1 cm, 1 cm, no surgery)
Control arm
Carboplatin AUC 5, day 1
Paclitaxel 175 mg/m2, day 1
Treatment repeated every 21 days, for 6 cycles
Experimental arm
1:1
Study design
Carboplatin AUC 5, day 1
PLD 30 mg/m2, day 1
Treatment repeated every 21 days, for 6 cycles
Activity analysis: flow of patients
Analysis performed according to “intention to treat” principle
Pending information
Eligible for RECIST
Not eligible for RECIST
Non-target lesions only
Elevated CA-125 only
No lesions, normal CA-125
Carbo + Paclitaxel
(n=410)
10 pts
83 pts
88 pts
73 pts
156 (38%)
18 pts
99 pts
80 pts
79 pts
134 (33%)
Carbo + PLD
(n=410)
Objective response – RECIST
Women with target lesions
Carbo
+ Paclitaxel
(n=156)
Carbo
+ PLD
(n=134)
p (2)*
Objective response 92 (59%) 76 (57%) 0.70
Complete response 24 (15%) 22 (16%)
Partial response 68 (44%) 54 (40%)
No response 64 (41%) 58 (43%)
Stable disease 45 (29%) 41 (31%)
Progressive disease 9 (6%) 7 (5%)
Not evaluated 10 (6%) 10 (7%)
*Objective response vs no response
Toxicity (1)
Any grade Severe (G3)
C+P C+PLD p* C+P C+PLD p*
Toxic deaths 0.8% 0.5% 1
Anemia 59% 68% 0.007 4% 10% 0.001
RBC transfusions 2% 6% 0.002
Neutropenia 73% 80% 0.04 49% 43% 0.09
Febrile neutropenia 2% 1% 0.21
Thrombocytopenia 19% 48% 0.001 2% 16% 0.001
Platelet transfusions 0.3% 2% 0.06
Bleeding 0.3% 1% 0.37 - 1% 0.24
C+P: carboplatin + paclitaxel, 399 patients; C+PLD: carboplatin + PLD, 386 patients
*Chi square or Fisher exact test as appropriate
Toxicity (2)
Any grade Severe (G3)
C+P C+PLD p* C+P C+PLD p*
Allergy 6% 5% 0.60 2% 2% 0.86
Heart 2% 4% 0.26 0.3% 2% 0.06
Fatigue 44% 43% 0.86 3% 3% 0.94
Constipation 32% 32% 0.99 1% 1% 0.73
Nausea 47% 51% 0.21 2% 2% 0.95
Vomiting 29% 30% 0.83 2% 3% 0.42
Diarrhoea 13% 6% 0.001 1% - 0.25
Hair loss 63% 14% 0.001
Skin toxicity 6% 20% 0.001 - 2% 0.01
Stomatitis 9% 20% 0.001 0.3% 0.5% 0.62
Neurotoxicity 47% 15% 0.001 3% 0.2% 0.004
*Chi square or Fisher exact test as appropriate
C+P: carboplatin + paclitaxel, 399 patients; C+PLD: carboplatin + PLD, 386 patients
Preliminary conclusions (1)
• Toxicity profile of carboplatin plus PLD as first-line
treatment of advanced ovarian cancer is markedly
different from carboplatin plus paclitaxel
• Carboplatin plus PLD is associated with:
– Higher incidence of anemia and
thrombocytopenia (rarely requiring transfusions)
– Higher incidence of stomatitis and cutaneous
toxicity (that are rarely severe)
– Lower incidence of hair loss and neurotoxicity
Preliminary conclusions (2)
• There was no statistically significant difference in
response rate between carboplatin plus PLD and
carboplatin plus paclitaxel
• Final analysis for the primary endpoint (PFS) will
be performed as soon as the required number of
events will be reached
40
GINECO, Paris, France; AGO-OVAR, Hamburg, Germany; NSGO, Oslo, Norway;
ANZGOG, Sydney, Australia; NCIC Clinical Trials Group, Vancouver, BC, Canada;
ANZGOG, Queensland, Australia; AGO-Austria, Vienna, Austria; EORTC, Leuven,
Belgium; MITO, Napoli, Italy; MANGO, Torino, Italy
A randomized, phase III study of
carboplatin and pegylated liposomal
doxorubicin versus carboplatin and
paclitaxel in relapsed platinum-sensitive
ovarian cancer (OC): CALYPSO study of the
Gynecologic Cancer Intergroup (GCIG)
E. Pujade-Lauraine, S. Mahner, J. Kaern, V. Gebski,
M. Heywood, P. Vasey, A. Reinthaller, I. Vergote,
S. Pignata, A. Ferrero
J Clin Oncol 27:15s, 2009 (suppl; abstr LBA5509)
CALYPSO Study Schema
Ovarian cancer in late
relapse (> 6 months)
after 1st- or 2nd-line
platinum-based therapy
(previous taxane
required)
International, Intergroup, Open-label, Randomized Phase III Study
Stratification:
•Therapy-free interval
(6-12 mo vs > 12 mo)
•Measurable disease
(yes vs no)
•Center
RANDOMIZE
Experimental arm: CD
PLD 30 mg/m2 IV d 1
Carboplatin AUC 5 d 1
Control arm: CP
Paclitaxel 175 mg/m2 IV d 1
Carboplatin AUC 5 d 1
Q 28 days x 6 courses*
Q 21 days x 6 courses*
*or progression in patients with SD or PR
Baseline Characteristics (1)
CharacteristicCD (n=466) CP (n=508)
Number of patients (%)
Age, medianECOG performance status*
012
Primary site of diseaseOvarian
Papillary/Serous histology FIGO stage*
I/IIIIIIV
Size of residual disease*≤ 1 cm> 1 cm
60.5
286 (61)159 (34)
13 (3)
415 (89)334 (72)
52 (11)339 (73)62 (13)
251 (54)129 (28)
61.0
317 (62)164 (32)
15 (3)
451 (89)366 (72)
59 (12)373 (73)54 (11)
262 (52)129 (26)
* Missing values to attain 100%.
Baseline Characteristics (2)
CharacteristicCD (n=466) CP (n=508)
Number of patients (%)
Number of previous lines OneTwo
Prior taxane
Interval since prior therapy, median
6-12 months> 12 months
Measurable diseaseYesNo
408 (88)58 (12)
462 (99)
162 (35)304 (65)
330 (71)136 (29)
421 (83)87 (17)
500 (99)
182 (36)326 (64)
370 (73)138 (27)
Early Treatment Discontinuation
ReasonCD (n=466) CP (n=501)
Number of patients (% of total)
Toxicity*
Patient/investigator choice
Progressive disease
Intercurrent disease
TOTAL*
27 (6)
16 (3)
26 (6)
1 (<1)
70 (15)
73 (15)
14 (3)
22 (4)
1 (<1)
110 (22)
* P< 0.001
Hematologic Toxicity
Toxicity, grade(gr)
CD
(n=464)
CP (n=500) P Value
Number of patients (%)
Neutropenia, gr 3
gr 4
144 (31)
20 (4)
121 (24)
108 (22)
<0.01
Febrile Neutropenia, gr 3-4 10 (2) 21 (4) NS
Infection, gr 3-4 11 (3) 14 (3) NS
Thrombocytopenia, gr 3-4 73 (16) 31 (6) <0.01
Bleeding, gr 3-4 3 (0.6) 0 (0) NS
Anemia, gr 3-4 37 (8) 27 (5) NS
NS=not significant.
Overall Non-Hematologic
Safety Profile
Overall non-
hematologic toxicity
CD (n=465) CP (n=498) P Value
Number of patients (%)
Grade 0-1 72 (15) 14 (3)
<0.01Grade 2 257 (55) 298 (59)
Grade 3-5 136 (29) 189 (38)
Severe Adverse Event 64 93 0.034
Selected Non-Hematologic
Toxicities During Treatment
CD (n=466) CP (n=501)
Grade 2 Grade 3/5 Grade 2 Grade 3/5
Hypersensitivity* 3% 2% 10% 9%
Treatment partially stopped - 4%
Study treatment stopped 1% 4%
Hypersensitivity Reactions
*P< 0.001
Protocol included EORTC guidelines for re-challenge
after a hypersensitivity reaction to carboplatin
Selected Non-Hematologic
Toxicities During Treatment
CD (n=466) CP (n=501)
Grade 2Grade3/
4Grade 2 Grade 3/4
Nausea/vomiting* 31% 4% 20% 4%
Constipation 19% 2% 20% 2%
Diarrhea 4% 2% 6% 2%
Arthralgia/myalgia* 4% 0% 18% 1%
Hand-foot syndrome* 11% 2% 2% 0%
Mucositis* 13% 2% 6% 1%
Cardiac disorders 2% 1% 3% 1%
*P< 0.001
Selected Non-Hematologic
Toxicities During Treatment
CD (n=466) CP (n=501)
Alopecia grade 2* 7% 84%
Alopecia
*P< 0.001
Long-Lasting ToxicitiesCD (n=466) CP (n=501)
Grade 2Grade
3/5Grade 2 Grade 3/5
Fatigue 31% 7% 34% 7%
Neuropathy* 4% 1% 24% 4%
*P< 0.001
Long-Lasting
Neuropathy
Progression-Free Survival (ITT)
Carbo-
PLD
Carbo-
pacli
Median PFS, mo 11.3 9.4
HR (95% CI) 0.82 (0.72, 0.94)
Log-rank p-value
(superiority)
0.005
P-value
(non-inferiority)
<0.001
52
University of Texas M. D. Anderson Cancer Center, Houston, TX; GOG Statistical and Data
Center, Buffalo, NY; Oklahoma University Health Science Center, Oklahoma City, OK;
Columbus Cancer Council, Columbus, OH; University of Minnesota, Minneapolis, MN
Sentinel node (SN) biopsy in patients with
vulvar cancer: A Gynecologic Oncology
Group (GOG) study.
C. F. Levenback, C. Tian, R. L. Coleman,
M. A. Gold, J. M. Fowler, P. L. Judson
J Clin Oncol 27:15s, 2009 (suppl; abstr 5505)
Lymphedema
Excellent Target for SLNB
Concept
Conclusions
• Future GOG studies should include SLNB in the
management of patients with early vulvar cancer
– FNPV < 5%
– Sensitivity >88%
• SLNB is best limited to patients with tumors < 4 cm
• The combined technique is recommended
56
Unidad de Investigacion Biomédica en Cáncer, Mexico City, Mexico; Medical Centre San
Roque, Tucuman, Argentina; National Institute of Oncology, Panama, Panama; Siriraj
Hospital, Bangkok, Thailand; Institute of Oncology, Sarajevo, Bosnia and Herzegovina;
Postgraduate Institute of Medical Education and Research, Chandigarh, India; National
Institute of Oncology, Lima, Peru; Eli Lilly and Company, Sydney, Australia; Eli Lilly
Interamerica, Buenos Aires, Argentina
A phase III study comparing concurrent
gemcitabine (Gem) plus cisplatin (Cis) and
radiation followed by adjuvant Gem plus
Cis versus concurrent Cis and radiation in
patients with stage IIB to IVA carcinoma of
the cervix
A.Dueñas-González, J. J. Zarba, J. C. Alcedo, P.
Pattarunataporn, S. Beslija, F. Patel, L. Casanova,
B.H. Barraclough, M. Orlando
J Clin Oncol 27:15s, 2009 (suppl; abstr CRA5507 )
Study Design
Week 0 Weeks 1 to 6 Week 7 Weeks 8 to 9 Weeks 10 to 15
Randomization Chemoradiation BCT Adjuvant Chemotherapy
Arm A
2 cycles of:cisplatin 50 mg/m2 (day 1) +
gemcitabine 1 g/m2 (days 1 and 8)given q3 weeks
Stratified by:
stage;tumor size;investigator
site;radiation
equipment (Co60 or LinAc);
age
N=515 patients
Arm AN=259
cisplatin 40 mg/m2 + gemcitabine 125 mg/m2
weekly for 6 weeks
pelvic EBRT 50.4 Gy 1.8 Gy/day in 5.4 weeks
Arm BN=256
cisplatin 40 mg/m2
weekly for 6 weeks
pelvic EBRT 50.4 Gy 1.8 Gy/day in 5.4 weeks
30-35 Gy(low orIM DR)
REST
30-35 Gy(low or IM DR)
Patient baseline characteristics
Abbreviations: N = total number of patients; n = number of patients per category. P-values determined by (e) Fisher‟s exact test or (t) t test.
CharacteristicArm AN=259
Arm BN=256
OverallN=515 p-value
Age, yearsMedian (range) 45.0 (22 – 68) 46.0 (18 – 70) 46.0 (18 – 70) 0.377 (t)
Karnofsky Performance StatusMedian (range) 90.0 (80 – 100) 90.0 (70 – 100) 90.0 (70 – 100) 0.734 (t)
Pathological Diagnosis, n (%)AdenocarcinomaNon-adenocarcinoma
17 (6.6)242 (93.4)
15 (5.9)241 (94.1)
32 (6.2)483 (93.8)
0.856 (e)
Stage of Disease, n (%)IIBIIIAIIIBIVA
160 (61.8)1 (0.4)
94 (36.3)4 (1.5)
156 (60.9)1 (0.4)
94 (36.7) 5 (2.0)
316 (61.4)2 (0.4)
188 (36.5)9 (1.7)
0.973 (e)
Maximum Diameter of the Largest Lesion, cmMedian (range) 6.00 (2.0 – 20.0) 5.90 (2.8 – 11.0) 6.00 (2.0 – 20.0) 0.494 (t)
Hemoglobin at Baseline, g/dLMedian (range) 12.00 (7.9 – 15.8) 12.05 (8.5 – 15.9) 12.00 (7.9 – 15.9) 0.893 (t)
Country, n (%)BosniaPakistanThailandArgentinaPanamaPeruIndiaMexico
33 (12.7)27 (10.4)34 (13.1)17 (6.6)31 (12.0)29 (11.2)60 (23.2)28 (10.8)
28 (10.9)29 (11.3)33 (12.9)18 (7.0)30 (11.7)31 (12.1)56 (21.9)31 (12.1)
61 (11.8)56 (10.9)67 (13.0)35 (6.8)61 (11.8)60 (11.7)
116 (22.5)59 (11.5)
0.997 (e)
Enrolment: 10 sites, 8 countries (May „02 to March ‟04) -
follow-up completed April ‟08.
months
0 6 12 18 24 30 36 42 48 54 60
PFS probability
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Log-rank p=0.023
Hazard ratio = 0.68
95% CI = 0.49-0.95
Gem/cis/rad
Cis/rad
Progression-Free Survival at 3 YearsPFS at 3 years:
74.4% in Gem/cis/rad versus 65.0% in Cis/rad (p=0.029)
Abbreviations: CI = confidence interval; cis = cisplatin; Gem = gemcitabine; PFS = progression-free survival; Rad = radiation.
months
0 6 12 18 24 30 36 42 48 54 60
PFS probability
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Gem/cis/rad
Cis/rad
Overall Survival
OS was statistically superior for Gem/cis/rad over Cis/rad
OS at 3 years: 78.2% in Gem/cis/rad versus 69.1% in Cis/rad
months
0 6 12 18 24 30 36 42 48 54 60 66
OS probability
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Log-rank p = 0.022
Hazard ratio = 0.68
95% CI = 0.49-0.95
Gem/cis/rad
Cis/rad
Abbreviations: CI = confidence interval; cis = cisplatin; Gem = gemcitabine; OS = overall survival; Rad = radiation.
Overall Study Drug-Related Toxicity
Drug-related CTCAE Grade 3/4 toxicity (on-study or within 30 days of last study drug dose)
Arm A N=260
Grade 3 (%) Grade 4 (%)
Arm B N=255
Grade 3 (%) Grade 4 (%) p-value
Neutropenia 45.0 6.2 5.1 0.8 <0.001
Anemia 7.7 1.5 1.6 0.4 <0.001
Thrombocytopenia 5.4 0.8 1.2 0.0 0.004
Febrile neutropenia 1.5 0.8 0.4 0.0 0.123
Diarrhea 17.7 0.0 4.7 0.0 <0.001
Nausea 3.8 0.4 2.7 0.0 0.473
Vomiting 7.7 0.0 2.4 0.4 0.016
Fatigue 3.1 0.8 1.6 0.0 0.174
Radiation dermatitis 11.2 0.0 10.6 0.0 0.888
Abdominal pain/cramping 2.7 0.0 0.4 0.0 0.068
Anorexia 0.4 0.0 0.0 0.0 1.000
Proctitis 2.7 0.8 0.4 0.0 0.020
AST 0.8 0.0 0.0 0.0 0.499
ALT 0.8 0.0 0.0 0.0 0.499
Creatinine 1.5 0.0 0.4 0.4 0.686
Other*
Abbreviations: ALT = alanine aminotransaminase; AST = aspartate aminotransaminase; CTCAE = Common
Toxicity Criteria Adverse Event; N = total number of patients.
* Other = low incidence of toxicity overall or for Grade 3/4 – also includes toxicities deemed not to be clinically
significant.
Late ToxicityArm A
(N=260)
Arm B
(N=255)
Maximum toxicity score Maximum toxicity score
3 4 3 4
Toxicity N* n (%) n (%) N* n (%) n (%) p-value**
Any 222 1 (0.5) 8 (3.6) 216 1 (0.5) 2 (0.9) 0.176 (e)
Skin 211 0 (0.0) 0 (0.0) 207 0 (0.0) 0 (0.0) 0.730 (e)
SC tissue 210 1 (0.5) 0 (0.0) 206 0 (0.0) 0 (0.0) 0.646 (e)
Mucous
membrane 210 0 (0.0) 1 (0.5) 208 0 (0.0) 1 (0.5) 0.450 (e)
Spinal cord 207 0 (0.0) 0 (0.0) 204 0 (0.0) 0 (0.0) 0.857 (e)
Small/large
intestine 213 0 (0.0) 5 (2.3) 209 1 (0.5) 0 (0.0) 0.044 (e)
Bladder 209 0 (0.0) 3 (1.4) 204 0 (0.0) 1 (0.5) 0.067 (e)
Abbreviations: SC = subcutaneous; N = total number of patients; n = number of patients within category.
Because of rounding, not all percentages add up to 100. Late toxicity measured using Radiotherapy Oncology Group/European Organization
for Research and Treatment of Cancer (RTOG/EORTC) criteria.
*Some data were missing. This table includes only toxicities occurring more than 30 days after last study drug dose.
** Comparison was for incidence of toxicity of all severities.
(e) Fisher‟s exact test.
Conclusions
• When compared with the current standard of care, inclusion of
gemcitabine significantly improves survival outcomes for patients
with locally advanced cervical cancer at the expense of increased,
but clinically acceptable and manageable, toxicity
• Further studies are required to define the optimal application of this
regimen and to delineate the relative contributions of multi-agent
chemoradiation and adjuvant chemotherapy to survival outcomes
and toxicity
ASCO 2009 Gyn Cancer Summary
• Ovarian Cancer
– CA125 surveillance questioned
– EDR assay not validated
– First-line IV carboplatin + paclitaxel still standard
– First-line IV Carboplatin + PLD (or + Gem ASCO 2008) encouraging RR with unique toxicities, PFS and OS pending
– Second-line carboplatin + PLD improves PFS compared to carboplatin + paclitaxel, OS pending
• Vulvar Cancer– Sentinel node biopsies with combined technique if tumor <4cm
confrimed
• Locally Advanced Cervical Cancer– RT + cisplatin + Gemcitabine may be better than RT + cisplatin