gynecologic cancers

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


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


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


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



Gemcitabine 800 mg/m2 days 1, 8 Paclitaxel 175 mg/m2 3 hours

Carboplatin AUC 5

mg/mL•min

PLD 30 mg/m2ALTERNATING

COURSES


Carboplatin AUC 6

mg/mL•min,

x4 cycles

Topotecan 1.5 mg/m2 days 1 - 3

Carboplatin AUC 5 mg/mL•min,

x4 cycles


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



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


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


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 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


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


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



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



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


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

gynecologic cancers

Documents

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