Gynecology Abstracts Gynecology Abstracts Susana M. Campos, MD, MPH - - PowerPoint PPT Presentation

Gynecology Abstracts Gynecology Abstracts

Susana M. Campos, MD, MPH Susana M. Campos, MD, MPH Dana Farber Cancer Institute Dana Farber Cancer Institute Dana Farber Cancer Institute Dana Farber Cancer Institute Boston Mass Boston Mass

Gynecological Abstracts: ASCO 2009

Abstract Abstract # Author Author Title Title 1 Rustin G.J. Rustin G.J. A Randomized trial in ovarian cancer of early treatment of relapse A Randomized trial in ovarian cancer of early treatment of relapse based on CA125 level alone versus delayed treatment based on based on CA125 level alone versus delayed treatment based on y y conventional clinical indicators conventional clinical indicators 5504 5504 Karam A Karam A Influence of residual disease and extreme drug resistance assays on Influence of residual disease and extreme drug resistance assays on

• utcome in patients with epithelial ovarian cancer
• utcome in patients with epithelial ovarian cancer

5505 5505 Levenback Levenback CF CF Sentinel node biopsy in patients with vulvar cancer : a GOG study Sentinel node biopsy in patients with vulvar cancer : a GOG study 5507 5507 Duenas Duenas-

• Gonzalez A

Gonzalez A A phase II study comparing concurrent gemcitabine plus cisplatin and A phase II study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant Gem plus Cis vs concurrent Cis and radiation followed by adjuvant Gem plus Cis vs concurrent Cis and Gonzalez A Gonzalez A radiation followed by adjuvant Gem plus Cis vs. concurrent Cis and radiation followed by adjuvant Gem plus Cis vs. concurrent Cis and radiation in patients with stage IIB to IVA carcinoma of the cervix radiation in patients with stage IIB to IVA carcinoma of the cervix 5508 5508 Pignata S Pignata S Carboplatin plus paclitaxel ( CP) versus carboplatin plus CLD) in Carboplatin plus paclitaxel ( CP) versus carboplatin plus CLD) in patients with advanced ovarian cancer: MITO 2 patients with advanced ovarian cancer: MITO 2 5509 5509 Pujade Pujade-

• Lauraine E

Lauraine E Randomized phase III study of carboplatin and pegylated liposomal Randomized phase III study of carboplatin and pegylated liposomal doxorubicin vs. carboplatin and paclitaxel in relapsed platinum doxorubicin vs. carboplatin and paclitaxel in relapsed platinum sensitive ovarian cancer: CALYPSO study of the GCIG sensitive ovarian cancer: CALYPSO study of the GCIG 5510 5510 Herrstedt J Herrstedt J A randomized phase II study of gem A randomized phase II study of gem-

• paclitaxel

paclitaxel-

• carboplatin versus

carboplatin versus p y g p y g p p paclitaxel paclitaxel-

• carboplatin as first line treatment of ovarian cancer:

carboplatin as first line treatment of ovarian cancer: Survival of FIGO stage I Survival of FIGO stage I-

• IIA patients

IIA patients

Ovarian Ovarian Cancer Cancer

GOG111: Survival By Treatment GOG111: Survival By Treatment

Ali Di d M di PFS R l ti Cisplatin/ cyclophosphamide Treatment Alive (N) 28 174 Died (N) Median PFS Survival (mo) 13.0 Relative Risk – Cisplatin/paclitaxel y p p 45 138 18 0.69

Adapted with permission from McGuire WP, et al. N Engl J Med. 1996;334:1-6.

Role of IP Chemotherapy for Optimally Debulked Role of IP Chemotherapy for Optimally Debulked py p y py p y Advanced Advanced-

• Stage Ovarian Cancer

Stage Ovarian Cancer

Imp d t m i Imp d t m i GOG GOG 104 1041 Improved outcome in Improved outcome in CP CP-

• treated patients when

treated patients when cisplatin administered IP cisplatin administered IP (relative risk, 0.76) (relative risk, 0.76) GOG GOG 114 1142 Improved outcome in Improved outcome in TP TP-

• treated patients when

treated patients when cisplatin administered IP cisplatin administered IP (relative risk, 0.78) (relative risk, 0.78) GOG GOG 172 1723 Improved outcome in Improved outcome in TP TP-

• treated patients when

treated patients when paclitaxel and cisplatin paclitaxel and cisplatin 172 172 p p p p administered IP administered IP (relative risk, 0.73) (relative risk, 0.73)

CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1 Alberts DS et al N Engl J Med 1996;335:1950 1955

• 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955.
• 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007.
• 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43.

Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006.

Carboplatin plus Paclitaxel versus Carboplatin Carboplatin plus Paclitaxel versus Carboplatin l St lth Li l D bi i i ti t l St lth Li l D bi i i ti t plus Stealth Liposomal Doxorubicin in patients plus Stealth Liposomal Doxorubicin in patients with Advanced Ovarian Cancer with Advanced Ovarian Cancer

• S. Pignata
• S. Pignata et al

et al Abstract 5508 Abstract 5508

St d d si n St d d si n

Abstract 5508 Abstract 5508

R Control arm

C b l ti AUC 5 d 1

Study design Study design

a n d

Carboplatin AUC 5, day 1 Paclitaxel 175 mg/m2, day 1 Treatment repeated every 21 days, for 6 cycles 1:1

d

• m

p y y y

Experimental arm

Strata:

• Center

Experimental arm

Carboplatin AUC 5, day 1 PLD 30 mg/m2, day 1

• PS (0-1, 2)
• Stage (IC, II, III, IV)
• Residual disease after surgery

(absent, 1 cm, 1 cm, no surgery)

Treatment repeated every 21 days, for 6 cycles

( , , , g y)

Study population/Endpoint Study population/Endpoint y p p p y p p p

Inclusion criteria Inclusion criteria

• Cyto/histological diagnosis of ovarian cancer

Cyto/histological diagnosis of ovarian cancer

• FIGO Stage IC

FIGO Stage IC – – II II – – III III – – IV IV

• Age

Age  75 75 ECOG P f ECOG P f 0 2

• ECOG Performance Status 0

ECOG Performance Status 0-2

• No previous chemotherapy

No previous chemotherapy Main exclusion criteria Main exclusion criteria Main exclusion criteria Main exclusion criteria

• ANC

ANC  2000 2000/ /L, platelets , platelets  100000 100000/ / L L

• Creatinine

Creatinine  1.25 x UNL, SGOT and SGPT 1.25 x UNL, SGOT and SGPT  1.25 x UNL 1.25 x UNL

• Life expectancy of less than 3 months

Life expectancy of less than 3 months p y p y

Primary Endpoint: Primary Endpoint:

Progression Progression free survival (PFS) free survival (PFS) Progression Progression-free survival (PFS) free survival (PFS)

Baseline characteristics Baseline characteristics Baseline characteristics Baseline characteristics

Carbo + Paclitaxel Carbo + Paclitaxel Carbo + PLD Carbo + PLD Carbo + Paclitaxel Carbo + Paclitaxel Carbo + PLD Carbo + PLD (n = 410) (n = 410) (n=410) (n=410) Age Age median (range)

median (range)

57 57 (21 (21-

• 77)

77) 57 57 (25 (25-

• 77)

77) ECOG Performance Status ECOG Performance Status 0-

• 1

1 398 398 (97%) (97%) 397 397 (97%) (97%) 2 12 12 (3%) (3%) 13 13 (3%) (3%) FIGO Stage FIGO Stage IC IC 38 38 (9%) (9%) 38 38 (9%) (9%) II II 40 40 (10%) (10%) 37 37 (9%) (9%) III III 243 243 (59%) (59%) 247 247 (60%) (60%) IV IV 89 89 (22%) (22%) 88 88 (22%) (22%) IV IV 89 89 (22%) (22%) 88 88 (22%) (22%) Residual disease after surgery Residual disease after surgery Absent Absent 152 152 (37%) (37%) 150 150 (37%) (37%)  1 cm 1 cm 68 68 (17%) (17%) 69 69 (19%) (19%)  1 cm 1 cm 68 68 (17%) (17%) 69 69 (19%) (19%)  1 cm 1 cm 117 117 (28%) (28%) 114 114 (28%) (28%) No surgery No surgery 73 73 (18%) (18%) 67 67 (16%) (16%)

Objective response Objective response – – RECIST RECIST W i h l i W i h l i Women with target lesions Women with target lesions

Carbo Carbo Carbo Carbo Carbo Carbo + Paclitaxel + Paclitaxel (n=156) (n=156) Carbo Carbo + PLD + PLD (n=134) (n=134) p p (2)* )*

Obj ti Obj ti % % 0 70 0 70 Objective response Objective response 92 (59%) 92 (59%) 76 (57%) 76 (57%) 0.70 0.70 Complete response Complete response 24 (15%) 24 (15%) 22 (16%) 22 (16%) Partial response Partial response 68 (44%) 68 (44%) 54 (40%) 54 (40%) p 68 (44%) 68 (44%) 54 (40%) 54 (40%) No response No response 64 (41%) 64 (41%) 58 (43%) 58 (43%) Stable disease Stable disease 45 (29%) 45 (29%) 41 (31%) 41 (31%) Progressive disease Progressive disease 9 (6%) 9 (6%) 7 (5%) 7 (5%) Not evaluated Not evaluated 10 (6%) 10 (6%) 10 (7%) 10 (7%) *Objective response vs no response

Toxicity Toxicity

Any grade Any grade Severe (G Severe (G3) ) C+P C+P C+PLD C+PLD p* p* C+P C+P C+PLD C+PLD p* p* Toxic deaths Toxic deaths 0.8% 0.8% 0.5% 0.5% 1 1 Anemia Anemia 59% 59% 68% 68% 0.007 0.007 4% 4% 10% 10% 0.001 0.001 RBC transfusions RBC transfusions 2% 2% 6% 6% 0.002 0.002 Neutropenia Neutropenia 73% 73% 80% 80% 0.04 0.04 49% 49% 43% 43% 0.09 0.09 p Febrile neutropenia Febrile neutropenia 2% 2% 1% 1% 0.21 0.21 Thrombocytopenia Thrombocytopenia 19% 19% 48% 48% 0.001 0.001 2% 2% 16% 16% 0.001 0.001 Platelet transfusions Platelet transfusions 0.3% 0.3% 2% 2% 0.06 0.06 Platelet transfusions Platelet transfusions 0.3% 0.3% 2% 2% 0.06 0.06 Bleeding Bleeding 0.3% 0.3% 1% 1% 0.37 0.37

• 1%

1% 0.24 0.24 C+P: carboplatin + paclitaxel, 399 patients; C+PLD: carboplatin + PLD, 386 patients *Chi square or Fisher exact test as appropriate

Progression free survival Progression free survival Progression free survival Progression free survival

1.0

Patients Patients Events Events Median PFS Median PFS (months) (months) 1-

• yr

yr PFS PFS 2-

• yr

yr PFS PFS 820 820 531 531 17.7 17.7 (95%CI (95%CI 65.0% 65.0% 41.9% 41.9%

0.6 0.8 sion-free survival

(95%CI (95%CI 16.3 16.3-

• 19.9)

19.9)

0.4 ability of progress 1 2 2 4 3 6 4 8 6 0 7 2 0.0 0.2 Prob

Patients at risk Patients at risk

Months

1 2 2 4 3 6 4 8 6 0 7 2

Patients at risk Patients at risk 820 820 531 531 258 258 134 134 69 69 21 21

• Months

O ll i l O ll i l

Patients Events Median OS (months) 1-yr OS 2-yr OS

Overall survival Overall survival

1.0

Patients Events (months) OS OS 820 269 56.3 (95%CI 48.3-n.a.) 88.8% 73.8%

0.8 0.6 all survival 2 0.4 Overa 0.0 0.2

atients at risk 820 712 413 228 90 38

• Months

*M 2009

12 24 36 48 60 72

Abstract :5510

GOG 182 GOG 182— —Primary Therapy Primary Therapy y py y py

Paclitaxel 175 mg/m Paclitaxel 175 mg/m2 3 hours 3 hours All regimens = 8 cycles Interval cytoreduction allowed Paclitaxel 175 mg/m Paclitaxel 175 mg/m2 3 hours 3 hours b l / b l / g Carboplatin AUC 6 mg/mL•min Carboplatin AUC 6 mg/mL•min No second-look surgery Endpoints: PFI, survival, response N > 4,000 patients FIGO III FIGO III-

• IV

IV All residuum All residuum Paclitaxel 175 mg/m Paclitaxel 175 mg/m2 3 hours 3 hours Carboplatin AUC 5 mg/mL Carboplatin AUC 5 mg/mL•min min Gemcitabine 800 mg/m Gemcitabine 800 mg/m2 days 1, 8 days 1, 8 Paclitaxel 175 mg/m Paclitaxel 175 mg/m2 3 3 hours hours Carboplatin AUC 5 Carboplatin AUC 5 mg/mL mg/mL•min min

ALTERNATING ALTERNATING

EOC or PPC EOC or PPC International International g Carboplatin AUC 5 mg/mL Carboplatin AUC 5 mg/mL•min min mg/mL mg/mL min min Doxorubicin 30 mg/m Doxorubicin 30 mg/m2

COURSES COURSES

Paclitaxel 175 mg/m Paclitaxel 175 mg/m2 3 3 h Topotecan 1.5 mg/m Topotecan 1.5 mg/m2 days 1 days 1 -

• 3

3 C b l ti AUC 5 / L C b l ti AUC 5 / L i THEN THEN hours hours Carboplatin AUC 6 Carboplatin AUC 6 mg/mL mg/mL•min min,

x4 cycles x4 cycles

Carboplatin AUC 5 mg/mL Carboplatin AUC 5 mg/mL•min min,

, x4 cycles x4 cycles

Paclitaxel 175 mg/m Paclitaxel 175 mg/m2 3 3 hours hours Gemcitabine 1,000 mg/m Gemcitabine 1,000 mg/m2 days 1, 8 days 1, 8 Carboplatin AUC 6 mg/mL Carboplatin AUC 6 mg/mL•min min THEN THEN THEN THEN hours hours Carboplatin AUC 6 Carboplatin AUC 6 mg/mL mg/mL•min min, x4 cycles

, x4 cycles

Carboplatin AUC 6 mg/mL Carboplatin AUC 6 mg/mL•min min,

, x4 cycles x4 cycles

THEN THEN

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.

GOG GOG— —Frontline Trials Frontline Trials

GOG GOG-

• 218

218

Suboptimal (> 1 cm) Suboptimal (> 1 cm) EOC, PPC, FT cancer EOC, PPC, FT cancer Paclitaxel Paclitaxel Carboplatin Carboplatin Placebo Placebo Paclitaxel Paclitaxel Carboplatin Carboplatin Bevacizumab Bevacizumab Paclitaxel Paclitaxel Carboplatin Carboplatin Bevacizumab Bevacizumab Placebo Placebo Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab Placebo Placebo Placebo Placebo ×15 months 15 months N = 1,200 N = 1,200 -

• 1,400 patients

1,400 patients Survival, PFS primary endpoints Survival, PFS primary endpoints ×15 months 15 months ×15 months 15 months Biologic & QOL endpoints Biologic & QOL endpoints

EOC = Epithelial ovarian cancer; PPC = Primary peritoneal cancer; FT = Fallopian tube; PFS = Progression-free survival; QOL = Quality of life.

Recurrent Ovarian Cancer Recurrent Ovarian Cancer— — D fi iti f Di S iti it D fi iti f Di S iti it Definition of Disease Sensitivity Definition of Disease Sensitivity

P R E V I O

3 6 12 18 24

Refractory Refractory

O U S T R E A

Resistant Resistant

A T M E N

Sensitive Sensitive Very sensitive Very sensitive

N T

y

A Randomized trial in ovarian cancer of early treatment A Randomized trial in ovarian cancer of early treatment

• f relapse based on CA125 level alone versus delayed
• f relapse based on CA125 level alone versus delayed

f p y f p y treatment based on conventional clinical indicators treatment based on conventional clinical indicators

D l i t ti i ti t ith D l i t ti i ti t ith Does early intervention in patients with Does early intervention in patients with a rising CA125 have merit ? a rising CA125 have merit ? Abstract 1 : Trial OV05/55955 Abstract 1 : Trial OV05/55955 Rustin et al Rustin et al

Results: No evidence of difference between the two arms Results: No evidence of difference between the two arms HR 1.01 HR 1.01

Commentary Commentary Commentary Commentary

Strengths Strengths Weakness Weakness Strengths Strengths

– Randomized trial Randomized trial – Large study Large study

Weakness Weakness

– Lack of second/third Lack of second/third line therapy line therapy g y g y – Balanced for stage Balanced for stage – Endpoints Endpoints – Lack of surgical Lack of surgical considerations considerations Heterogeneous patient Heterogeneous patient

Overall survival Overall survival Quality of Life Quality of Life

– Heterogeneous patient Heterogeneous patient population population

Platinum Sensitive Platinum Sensitive Platinum Resistant Platinum Resistant

Recurrent Disease Recurrent Disease

Platinum Sensitive Platinum Sensitive Platinum Resistant Platinum Resistant Platinum Resistant Platinum Resistant

ICON IV ICON IV— —Survival Survival

Median PFI: 9 vs. 12 months Median PFI: 29 vs. 24 months

Median follow-up: 42 months OR: 54 vs. 66% (P = .06)

PFI = Progression-free interval; OR = Objective response; CI = Confidence interval; Pac = Paclitaxel; Plat = Platinum-based chemotherapy. Reprinted with permission from Ledermann JA. Lancet. 2003;361:2099-2106.

Carboplatin/Gemcitabine Carboplatin/Gemcitabine D i D i Design Design

Gemcitabine 1000 mg/m² d1, 8 R A N Stratified at central AGO office by 8 Carboplatin AUC 4 d1 q 3w for 6 cycles N D O M I

Platinum-free interval (PFI) (6-12 or >12 mos) Type of 1st-line platinum therapy (platinum/paclitaxel

Carboplatin AUC 5 d1 q 3w for 6 cycles I Z E D

therapy (platinum/paclitaxel

• r other platinum therapy)

Bidimensionally measurable disease (yes or no)

!

PFS Gemcitabine /Carboplatin vs Carboplatin PFS Gemcitabine /Carboplatin vs Carboplatin: : p p p p Summary of Subgroup Analysis Summary of Subgroup Analysis

Median PFS Median PFS Gemcitabine/carboplatin Gemcitabine/carboplatin Carboplatin Carboplatin Progression Progression-

• free interval

free interval (6 (6-

• 12 mos)

12 mos) 7.9 mos 7.9 mos 5.2 mos 5.2 mos Progression Progression-

• free interval

free interval (>12 mos) (>12 mos) 9.7 mos 9.7 mos 6.7 mos 6.7 mos Prior platinum and paclitaxel Prior platinum and paclitaxel 9.7 mos 9.7 mos 5.9 mos 5.9 mos Prior platinum (no paclitaxel) Prior platinum (no paclitaxel) 7.6 mos 7.6 mos 5.7 mos 5.7 mos

CALYPSO trial Carboplatin & Pegylated Liposomal Carboplatin & Pegylated Liposomal CALYPSO trial Carboplatin & Pegylated Liposomal Carboplatin & Pegylated Liposomal Doxorubicin (PLD) Doxorubicin (PLD) C b l & P l l C b l & P l l versus Carboplatin & Paclitaxel versus Carboplatin & Paclitaxel in Relapsed, Platinum in Relapsed, Platinum-sensitive sensitive in Relapsed, Platinum in Relapsed, Platinum sensitive sensitive Ovarian Cancer Ovarian Cancer

Eric Pujade Eric Pujade-

• Lauraine

Lauraine Ab t t 5509 Ab t t 5509 Abstract 5509 Abstract 5509

CALYPSO Study Schema CALYPSO Study Schema CALYPSO Study Schema CALYPSO Study Schema

International, Intergroup, Open-label, Randomized Phase III Study Ovarian cancer in late relapse (> 6 months) after 1st- or 2nd-line R A

Experimental arm: CD PLD 30 mg/m2 IV d 1

after 1

• r 2

line platinum-based therapy (previous taxane required) N D O M

LD 3 mg/m V d Carboplatin AUC 5 d 1 Q 28 days x 6 courses*

q )

Stratification:

• Therapy-free interval

(6 12 mo vs > 12 mo)

M I Z E

Control arm: CP Paclitaxel 175 mg/m2 IV d 1 courses

(6-12 mo vs > 12 mo)

• Measurable disease

(yes vs no)

• Center

E

Carboplatin AUC 5 d 1 Q 21 days x 6 courses*

*or progression in patients with SD or PR nt r

• r progression in patients with SD or PR

Key Eligibility/Objectives Key Eligibility/Objectives

Age ≥ 18 years Age ≥ 18 years ECOG performance status ≤ 2 ECOG performance status ≤ 2 ECOG performance status ≤ 2 ECOG performance status ≤ 2 Histologically proven diagnosis of cancer of the ovary, fallopian tube, or Histologically proven diagnosis of cancer of the ovary, fallopian tube, or extra extra-

• ovarian papillary serous tumors
• varian papillary serous tumors

Disease progression > 6 months after 1st Disease progression > 6 months after 1st-

• or 2nd
• r 2nd-
• line platinum

line platinum-

• based

based h therapy therapy Previous taxane exposure Previous taxane exposure Measureable disease (RECIST criteria) or CA 125 assessable disease Measureable disease (RECIST criteria) or CA 125 assessable disease (GCIG criteria) or histologically proven diagnosis of relapse (GCIG criteria) or histologically proven diagnosis of relapse (GCIG criteria) or histologically proven diagnosis of relapse (GCIG criteria) or histologically proven diagnosis of relapse

Primary : Progression free survival y g

Hematologic Toxicity Hematologic Toxicity Hematologic Toxicity Hematologic Toxicity

Toxicity, grade(gr) Toxicity, grade(gr) CD CD (n=464) (n=464) CP (n=500) CP (n=500) P Value P Value %

• c ty, gra

(gr)

• c ty, gra

(gr) Number of patients (%) Number of patients (%) Neutropenia, gr 3 Neutropenia, gr 3 144 (31) 144 (31) 121 (24) 121 (24) <0.01 <0.01 gr 4 gr 4 20 (4) 20 (4) 108 (22) 108 (22) F b il i F b il i 10 (2) 10 (2) 21 (4) 21 (4) NS NS Febrile neutropenia, gr Febrile neutropenia, gr 3-

• 4

4 10 (2) 10 (2) 21 (4) 21 (4) NS NS Infection, gr 3 Infection, gr 3-

• 4

4 11 (3) 11 (3) 14 (3) 14 (3) NS NS Thrombocytopenia, gr 3 Thrombocytopenia, gr 3-

• 4

73 (16) 73 (16) 31 (6) 31 (6) <0.01 <0.01 Bleeding gr 3 Bleeding gr 3 4 3 (0 6) 3 (0 6) 0 (0) 0 (0) NS NS Bleeding, gr 3 Bleeding, gr 3-4 3 (0.6) 3 (0.6) 0 (0) 0 (0) NS NS Anemia, gr 3 Anemia, gr 3-

• 4

4 37 (8) 37 (8) 27 (5) 27 (5) NS NS

NS=not significant.

Progression Progression-Free Survival (ITT) Free Survival (ITT) Progression Progression Free Survival (ITT) Free Survival (ITT)

CD CD CP CP Median PFS, mo Median PFS, mo 11.3 11.3 9.4 9.4 HR (95% CI) HR (95% CI) 0.82 (0.72, 0.82 (0.72, 0.94) 0.94) 0.94) 0.94) Log Log‐rank p rank p‐value value (superiority) (superiority) 0.005 0.005 P l ( l ( i f i it ) i f i it ) <0 001 <0 001 P‐value (non value (non‐inferiority) inferiority) <0.001 <0.001

Conclusions Conclusions Conclusions Conclusions

Carboplatin Carboplatin-

• PLD demonstrated a superior

PLD demonstrated a superior p p therapeutic index (benefit/risk ratio) versus therapeutic index (benefit/risk ratio) versus current standard, carboplatin current standard, carboplatin-

• paclitaxel

paclitaxel PLD PLD-

• carboplatin offers an evidence

carboplatin offers an evidence-

• based

based

• ption for patients with platinum
• ption for patients with platinum-
• sensitive

sensitive recurrent ovarian cancer recurrent ovarian cancer recurrent ovarian cancer recurrent ovarian cancer

PARP inhibitors PARP inhibitors

PARP: poly (ADP PARP: poly (ADP-

• ribose) polymerases

ribose) polymerases ribose) polymerases ribose) polymerases – Critical Critical regulatory regulatory components in components in DNA damage DNA damage DNA damage DNA damage repair repair and other and other cellular processes cellular processes Deficit in PARP Deficit in PARP-

• 1

1 :delayed DNA repair :delayed DNA repair function function u c o u c o Therapeutic Therapeutic E l it ti E l it ti Exploitation Exploitation

Phase II trial of oral PARP inhibitor AZD2281 in Phase II trial of oral PARP inhibitor AZD2281 in BRCA BRCA d fi i t i d fi i t i BRCA BRCA-deficient ovarian cancer deficient ovarian cancer

AZD 2281 (Olaparib) : PARP inhibitor AZD 2281 (Olaparib) : PARP inhibitor ( p ) ( p ) Phase I : 400 mg was the MTD Phase I : 400 mg was the MTD Phase II study: 100 mg BID vs 400 mg BID Phase II study: 100 mg BID vs 400 mg BID Endpoint : Best objective response rate Endpoint : Best objective response rate N: 57 patients N: 57 patients ORR 400 BID 33% ORR 400 BID 33% ORR : 400 mg BID : 33% ORR : 400 mg BID : 33% ORR : 100 BID :12.5 % ORR : 100 BID :12.5 % Toxicity : mild nausea diarrhea and fatigue Toxicity : mild nausea diarrhea and fatigue Toxicity : mild, nausea, diarrhea and fatigue Toxicity : mild, nausea, diarrhea and fatigue

Audeh MW et al ASCO 2009 Abstract 5500

Agents For Second Agents For Second-

• Line Therapy

Line Therapy Cumulative Toxicities Cumulative Toxicities Cumulative Toxicities Cumulative Toxicities

C b l ti C b l ti lt lt

Vi lbi Vi lbi WBC WBC

Carboplatin Carboplatin - plts plts

Cisplatin Cisplatin - neuro

neuro Paclitaxel q1wk or Paclitaxel q1wk or

Vinorelbine Vinorelbine - WBC WBC Tamoxifen Tamoxifen -

• none

none 5-

• FU/leucovorin

FU/leucovorin -

• GI

GI

Paclitaxel q1wk or Paclitaxel q1wk or q3wk q3wk -

• neuro

neuro Doxirubicin Doxirubicin -

• Irinotecan

Irinotecan -

• GI

GI Ifosfamide Ifosfamide -

• neuro, bone

neuro, bone marrow, renal marrow, renal

hand/foot (PPE) hand/foot (PPE) Gemcitabine Gemcitabine -

• none

none Et id l Et id l AML AML

, Hexamethylmelamine Hexamethylmelamine -

• neuro, GI

neuro, GI Epirubicin ( wbc Epirubicin ( wbc)

Etoposide, oral Etoposide, oral - AML AML Topotecan Topotecan -

• none

none Docetaxel Docetaxel - neuro neuro

Epirubicin ( wbc Epirubicin ( wbc)

Docetaxel Docetaxel - neuro neuro

Selecting therapy… Selecting therapy…

Chemotherapy Assays Chemotherapy Assays

Karam et al Karam et al

Abstract 5504 Abstract 5504

Kern and Weisenthal, JNCI 1990

Aims and Methods Aims and Methods Aims and Methods Aims and Methods

Aims: Aims: m

– Effects of EDR assay Effects of EDR assay-

• guided therapy in EOC

guided therapy in EOC – Outcomes in the primary and recurrent setting Outcomes in the primary and recurrent setting

Retrospective review Retrospective review

– 377 EOC patients 377 EOC patients EDR assays between 1995 and 2005 EDR assays between 1995 and 2005 – EDR assays between 1995 and 2005 EDR assays between 1995 and 2005

End points End points

– Time to first recurrence (TTP) Time to first recurrence (TTP) Time to first recurrence (TTP) Time to first recurrence (TTP) – Overall survival (OS) Overall survival (OS) – Survival after recurrence (RS) Survival after recurrence (RS)

Univariate Analysis OS and TTP Univariate Analysis OS and TTP

U i i t U i i t M di OS M di OS M di TTP M di TTP Univariate Univariate Median OS Median OS Median TTP Median TTP Characteristic Characteristic Months Months p p Months Months p p Age group, yrs Age group, yrs <40 <40 153.9 153.9 <0.001 <0.001 49.2 49.2 0.008 0.008 40 40 153.9 153.9 0.001 0.001 49.2 49.2 0.008 0.008 40 40-

• 50

50 59.5 59.5 33.8 33.8 50 50-

• 60

60 59.5 59.5 26.0 26.0 60 60-

• 70

70 46.3 46.3 19.5 19.5 >70 >70 42 5 42 5 19 9 19 9 >70 >70 42.5 42.5 19.9 19.9 Stage Stage <III <III 88.8 88.8 0.002 0.002 55.5 55.5 <0.001 <0.001 ≥III III 48.6 48.6 21.3 21.3 ≥III III 48.6 48.6 21.3 21.3 Residual at 1 Residual at 1° ° CRS CRS Microscopic Microscopic 66.8 66.8 0.03 0.03 37.0 37.0 <0.001 <0.001 0.1 0.1-

• 1.0 cm

1.0 cm 45.0 45.0 19.0 19.0 1 0 1 0 39 5 39 5 10 2 10 2 >1.0 cm >1.0 cm 39.5 39.5 10.2 10.2 Grade Grade 1 133.7 133.7 0.005 0.005 100.0 100.0 0.008 0.008 2 or 3 2 or 3 45.0 45.0 20.7 20.7 EDR Assay at 1 EDR Assay at 1° ° CRS CRS No No 61.9 61.9 0.002 0.002 27.0 27.0 0.1 0.1 Yes Yes 44.1 44.1 23.7 23.7

Multivariate Analysis Multivariate Analysis

Multivariate Multivariate Disease progression Disease progression Death Death Characteristic Characteristic HR HR 95% CI 95% CI p p HR HR 95% CI 95% CI p p Age decades Age decades 1.12 1.12 0.98 0.98 1.28 1.28 0.1 0.1 1.33 1.33 1.13 1.13 1.56 1.56 0.001 0.001 Stage Stage Stage Stage Stage <III Stage <III 1.0 1.0 1.0 1.0 Stage Stage ≥III III 3.61 3.61 0.86 0.86 6.4 6.4 0.09 0.09 2.78 2.78 0.68 0.68 11.3 11.3 0.15 0.15 Tumor grade Tumor grade Grade 1 Grade 1 1.0 1.0 1.0 1.0 Grade 2 or 3 Grade 2 or 3 1.87 1.87 0.68 0.68 5.14 5.14 0.23 0.23 5.41 5.41 0.73 0.73 40.1 40.1 0.10 0.10 1° ° CRS residual CRS residual Microscopic Microscopic 1 00 1 00 1 00 1 00 Microscopic Microscopic 1.00 1.00 1.00 1.00 0.1 to 1.0 cm 0.1 to 1.0 cm 1.94 1.94 1.33 1.33 2.84 2.84 0.001 0.001 1.59 1.59 1.03 1.03 2.45 2.45 0.04 0.04 >1.0 cm >1.0 cm 3.61 3.61 2.07 2.07 6.29 6.29 <0.001 <0.001 2.14 2.14 1.09 1.09 4.20 4.20 0.03 0.03 Adjuvant chemotherapy Adjuvant chemotherapy Platinum and taxane Platinum and taxane 1.00 1.00 Other Other 0.94 0.94 0.23 0.23 3.86 3.86 0.93 0.93 EDR assay EDR assay None None 1.0 1.0 None None 1.0 1.0 At primary surgery At primary surgery 1.13 1.13 0.75 0.75 1.72 1.72 0.55 0.55

Conclusion Conclusion

EDR did not predict outcomes in EOC EDR did not predict outcomes in EOC EDR did not predict outcomes in EOC EDR did not predict outcomes in EOC patients patients Age and disease residual important for Age and disease residual important for Age and disease residual important for Age and disease residual important for

• utcome
• utcome

R ti l f i t R ti l f i t Rationale for assays remains strong Rationale for assays remains strong

– Continued research Continued research – Gene Gene-

• expression/microarray profiles

expression/microarray profiles

Limitations and Strengths Limitations and Strengths Limitations and Strengths Limitations and Strengths

Limitations: Limitations: Limitations: Limitations:

– Retrospective nature Retrospective nature – Selection and ascertainment bias Selection and ascertainment bias – Selection and ascertainment bias Selection and ascertainment bias – Incomplete information on salvage Incomplete information on salvage chemotherapy chemotherapy chemotherapy chemotherapy

V l C V l C Vulvar Cancer Vulvar Cancer

Sentinel Node Biopsy in Patients with Squamous Cell Sentinel Node Biopsy in Patients with Squamous Cell Carcinoma of the Vulva: Carcinoma of the Vulva: a Gynecologic Oncology Group Study a Gynecologic Oncology Group Study Abstract 5505 Abstract 5505 Abstract 5505 Abstract 5505 Charles F. Levenback, MD Charles F. Levenback, MD GOG 173 GOG 173

Modern Sentinel Lymph Modern Sentinel Lymph

Regional nodes Regional nodes

Modern Sentinel Lymph Modern Sentinel Lymph Node Concept Node Concept

SN Team: SN Team: DI, Surg, Path DI, Surg, Path S ti l d fi t it S ti l d fi t it Sentinel node: first site Sentinel node: first site

• f metastasis
• f metastasis

Injection of blue dye or Injection of blue dye or

Tumor Tumor

Inject on of blue dye or Inject on of blue dye or radiocolloid around tumor radiocolloid around tumor

Eligibility criteria Eligibility criteria g y g y

Squamous cancer only Squamous cancer only Greater than 1 mm invasion Greater than 1 mm invasion Greater than 1 mm invasion Greater than 1 mm invasion Clinical stage II Clinical stage II

– T2 (Tumor size 2 T2 (Tumor size 2-

• 6 cm)

6 cm) – N0/1 (Clinically negative lymph nodes) N0/1 (Clinically negative lymph nodes) N0/1 (Clinically negative lymph nodes) N0/1 (Clinically negative lymph nodes)

No imaging or surgeon skill No imaging or surgeon skill ifi ti i d ifi ti i d verification required verification required

Protocol Protocol Protocol Protocol

Blue dye lymphscintigraphy (LSG) Blue dye lymphscintigraphy (LSG) Blue dye, lymphscintigraphy (LSG) Blue dye, lymphscintigraphy (LSG)

• ptional
• ptional

Unilateral or bilateral SLNB Unilateral or bilateral SLNB Unilateral or bilateral SLNB Unilateral or bilateral SLNB Inguinal femoral lymphadenectomy Inguinal femoral lymphadenectomy Ultra staging of SLN Ultra staging of SLN

– Serial sectioning with H&E staining of SLN Serial sectioning with H&E staining of SLN – Cytokeratin IHC staining if H&E negative Cytokeratin IHC staining if H&E negative

Results: Sensitivity and FNPV Results: Sensitivity and FNPV Results: Sensitivity and FNPV Results: Sensitivity and FNPV

SLN Status SLN Status Yes Yes No No Total Total Positive Positive 116 116 116 116 Negative Negative 13 13 282 282 295 295 Total Total 129 129 282 282 411 411

Sensitivity: 89.9% False Negative Predictive Value: 4 4% False Negative Predictive Value: 4.4%

Neg Predictive Value = TN/(TN+FN) 282/282+13 95 6% Sensitivity = TP/(TP+FN) 116/(116+13) 89 9% 282/282+13=95.6% 90% CI=93.6%-97.6% 116/(116+13)=89.9% 90% CI=84.2%-93.9% False neg predictive value = 1-NPV False neg predictive value = 1-NPV FNPV=1-95.6%=4.4% 90% CI=2.4%-6.4%

Conclusions Conclusions Conclusions Conclusions

GOG met its predetermined goal of >88% sensitivity GOG met its predetermined goal of >88% sensitivity GOG met its predetermined goal of 88% sensitivity GOG met its predetermined goal of 88% sensitivity and a FNPV of ≤ 5% and a FNPV of ≤ 5% Future GOG studies should include SLNB in the Future GOG studies should include SLNB in the Futur GOG stu s shou nc u SLNB n th Futur GOG stu s shou nc u SLNB n th management of patients with early vulvar cancer management of patients with early vulvar cancer SLNB should be limited to patients with tumors < 4 cm SLNB should be limited to patients with tumors < 4 cm p The combined technique is recommended The combined technique is recommended S kill ifi ti d d S kill ifi ti d d Surgeon skill verification recommended Surgeon skill verification recommended

Cervical Cancer ? Cervical Cancer ?

Have we not cured this Have we not cured this disease? disease? disease? disease?

Cervical Cancer

FIGO Stage FIGO Stage Carcinoma in situ Carcinoma in situ I Cervical carcinoma confined to the cervix Cervical carcinoma confined to the cervix IA: Invasive carcinoma diagnosed by microscopy IA: Invasive carcinoma diagnosed by microscopy IA: Invasive carcinoma diagnosed by microscopy IA: Invasive carcinoma diagnosed by microscopy IA1: Stromal invasion 3.0 mm or less in depth and 7.0 mm or less in horizontal spread IA1: Stromal invasion 3.0 mm or less in depth and 7.0 mm or less in horizontal spread IA2: Stromal invasion more than 3.0 mm and not more than 5.0 mm with a horizontal spread IA2: Stromal invasion more than 3.0 mm and not more than 5.0 mm with a horizontal spread

• f 7.0 mm or less
• f 7.0 mm or less

IB: Clinically visible lesion confined to the cervix or microscopic IB: Clinically visible lesion confined to the cervix or microscopic IB1:Clinically visible lesion 4.0 cm or less in greatest dimension IB1:Clinically visible lesion 4.0 cm or less in greatest dimension IB2: Clinically visible lesion more than 4.0 cm in greatest dimension IB2: Clinically visible lesion more than 4.0 cm in greatest dimension y m . m g m y m . m g m II II Tumor invades beyond the uterus but not to pelvic wall or lower third of the vagina Tumor invades beyond the uterus but not to pelvic wall or lower third of the vagina IIA: No parametrial invasion IIA: No parametrial invasion IIB: Parametrial invasion IIB: Parametrial invasion III III Tumor extends to pelvic wall and /or involves the lower third of the vagina and / or causes Tumor extends to pelvic wall and /or involves the lower third of the vagina and / or causes p g p g hydronephrosis hydronephrosis IIIA: Tumor involves the lower third of the vagina withpout extension to the pelvic wall IIIA: Tumor involves the lower third of the vagina withpout extension to the pelvic wall IIIB: Tumor extends to the pelvic wall and causes hydronephrosis or renal compromise IIIB: Tumor extends to the pelvic wall and causes hydronephrosis or renal compromise IVA IVA Tumor invades the mucosa of the bladder or rectum, and or extends beyond the true pelvis Tumor invades the mucosa of the bladder or rectum, and or extends beyond the true pelvis

Chemo-Radiation

Metastatic Cervical Cancer

Author Author GOG trial GOG trial Agents Agents Response Response McGuire et al McGuire et al31

31

GOG 76S GOG 76S paclitaxel paclitaxel ORR :17 % ORR :17 % Rose et al Rose et al32

32

GOG 76X GOG 76X cisplatin + cisplatin + paclitaxel paclitaxel ORR: 46% ORR: 46% p Moore et al Moore et al28

28

GOG169 GOG169 cisplatin + paclitaxel vs cisplatin cisplatin + paclitaxel vs cisplatin RR: 36 % vs 19 % RR: 36 % vs 19 % Long et al Long et al27

27

GOG 179 GOG 179 MVAC vs cisplatin vs MVAC vs cisplatin vs cisplatin + topotecan cisplatin + topotecan MVAC:D/C MVAC:D/C Combination of cisplatin and topotecan has Combination of cisplatin and topotecan has improve RR, median PFS and median OS improve RR, median PFS and median OS Patients w/o prior cisplatin Patients w/o prior cisplatin Patients w/o prior cisplatin Patients w/o prior cisplatin

1. 1.vs 20 %

vs 20 % Patients with prior cisplatin Patients with prior cisplatin 15 vs 8 % 15 vs 8 % Sill et al Sill et al33

33

GOG 204 GOG 204 cisplatin+ paclitaxel cisplatin+ paclitaxel ispl tin in lbin ispl tin in lbin Closed early: study arms had no difference Closed early: study arms had no difference ispl tin p lit x l ispl tin p lit x l cisplatin+ vinorelbine cisplatin+ vinorelbine cisplatin+ gemcitabine cisplatin+ gemcitabine cisplatin+ topotecan cisplatin+ topotecan

• ver cisplatin + paclitaxel
• ver cisplatin + paclitaxel

Tiersten et al Tiersten et al34

34

paclitaxel + topotecan paclitaxel + topotecan RR: 59 % RR: 59 % OS 8.6 mo OS 8.6 mo Symonds R et al Symonds R et al35

35

SCOT SCOT-

• CERV

CERV Docetaxel + gemcitabine Docetaxel + gemcitabine 1 CR ; 4 PR, 6SD and 11 PD 1 CR ; 4 PR, 6SD and 11 PD Monk et al Monk et al30

30

GOG 227C GOG 227C Bevacizumab Bevacizumab 5 PR 5 PR 11 patients PFS > 6 mo 11 patients PFS > 6 mo

R d i d Ph III d C i R d i d Ph III d C i A Randomized Phase III Study Comparing A Randomized Phase III Study Comparing Concurrent Gemcitabine (Gem) plus Cisplatin Concurrent Gemcitabine (Gem) plus Cisplatin (Cis) and Radiation (Cis) and Radiation (Cis) and Radiation (Cis) and Radiation Followed by Adjuvant Gem plus Cis Followed by Adjuvant Gem plus Cis versus versus versus versus Concurrent Cis and Radiation Concurrent Cis and Radiation in Patients with Stage IIB to IVA Carcinoma in Patients with Stage IIB to IVA Carcinoma

• f the Cervix :
• f the Cervix :

Abstract 5009 Abstract 5009

lf D ñ lf D ñ G ál G ál l l Alfonso Dueñas Alfonso Dueñas-

• González

González, et al , et al

Study Design Study Design

Randomization Chemoradiation BCT Randomization Chemoradiation BCT Adjuvant chemotherapy Adjuvant chemotherapy

Eligibility: Eligibility: Arm A Arm A N 259 N 259

Arm A Arm A 2 cycles of: 2 cycles of: cisplatin 50 mg/m cisplatin 50 mg/m2 (day 1) + (day 1) +

g y g y CC histology; CC histology; stage IIB to stage IIB to IVA; IVA; clear PA LNs; clear PA LNs; CTy/RTy CTy/RTy i N=259 N=259 cisplatin 40 mg/m cisplatin 40 mg/m2 + + gemcitabine 125 mg/m gemcitabine 125 mg/m2 weekly for 6 weeks weekly for 6 weeks

All All ti t ti t All All patients patients p mg m p mg m ( y ) ( y ) gemcitabine 1 g/m gemcitabine 1 g/m2 (days 1 (days 1 and 8) and 8) given q3 weeks given q3 weeks

naive; naive; KPS KPS 70 70 Randomized Randomized and and sstratified stratified: pelvic XRT 50.4 Gy 1.8 pelvic XRT 50.4 Gy 1.8 Gy/day in 5.4 weeks (Co Gy/day in 5.4 weeks (Co60

60 or

• r

LinAc) LinAc) Arm B Arm B

patients patients 30 30 35 35 patients patients

REST REST

Arm B Arm B NO ADJUVANT NO ADJUVANT

sstratified stratified: stage; stage; tumor size; tumor size; investigator investigator site; site; radiation radiation N=256 N=256 cisplatin 40 mg/m cisplatin 40 mg/m2 weekly for 6 weeks weekly for 6 weeks l i XRT 50 4 G 1 8 l i XRT 50 4 G 1 8

30 30-35 35 Gy Gy (low or (low or IM dose IM dose rate) rate)

REST REST Week 0 Weeks 1 to 6 Week 7 Weeks 8 to 9 Weeks 10 to Week 0 Weeks 1 to 6 Week 7 Weeks 8 to 9 Weeks 10 to

CHEMOTHERAPY CHEMOTHERAPY

radiation radiation equipment equipment (Co (Co60

60 or

• r

LinAc); LinAc); age age pelvic XRT 50.4 Gy 1.8 pelvic XRT 50.4 Gy 1.8 Gy/day in 5.4 weeks (Co Gy/day in 5.4 weeks (Co60

60 or

• r

LinAc) LinAc)

Week 0 Weeks 1 to 6 Week 7 Weeks 8 to 9 Weeks 10 to Week 0 Weeks 1 to 6 Week 7 Weeks 8 to 9 Weeks 10 to 15 15N=515

N=515 patients patients

Primary objective Primary objective Progression Progression-

• free survival (PFS) at 3 years

free survival (PFS) at 3 years

Progression Progression-

• Free Survival at 3 Years

Free Survival at 3 Years

0.9 1.0 0.9 1.0 PFS b bili 0.6 0.7 0.8

Gem/cis/rad Cis/rad

PF b b l 0.6 0.7 0.8

Gem/cis/rad Cis/rad

PFS probability 0.3 0.4 0.5 Log-rank p=0.023 PFS probability 0.3 0.4 0.5 6 12 18 24 30 36 42 48 54 60 0.0 0.1 0.2 Hazard ratio = 0.68 95% CI = 0.49-0.95 6 12 18 24 30 36 42 48 54 60 0.0 0.1 0.2

PFS overall was statistically superior PFS overall was statistically superior

months 6 6 6 months 6 12 18 24 30 36 42 48 54 60

PFS at 3 years: PFS at 3 years: PFS at 3 years: 74.4% versus 65.0% (p=0.029) PFS at 3 years: 74.4% versus 65.0% (p=0.029)

Overall Survival Overall Survival

0.8 0.9 1.0

Gem/cis/rad

l

0.6 0.7

Gem/cis/rad Cis/rad

OS probability

0.3 0.4 0.5 0.1 0.2 Log-rank p = 0.022 Hazard ratio = 0.68 95% CI = 0.49-0.95

months

6 12 18 24 30 36 42 48 54 60 66 0.0

• OS was statistically superior for Gem/cis/rad over Cis/rad

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

OS at 3 years: 78.2% in Gem/cis/rad versus 69.1% in Cis/rad Cis/rad

Overall Study Drug Overall Study Drug-

• Related Toxicity

Related Toxicity

Drug Drug-

• related CTCAE Grade 3/4 toxicity

related CTCAE Grade 3/4 toxicity (on (on-

• study or within 30 days of last study

study or within 30 days of last study drug dose) drug dose) Arm A Arm A N=260 N=260 Grade 3 (%) Grade Grade 3 (%) Grade 4 (%) 4 (%) Arm B Arm B N=255 N=255 Grade 3 (%) Grade 4 Grade 3 (%) Grade 4 (%) (%) p p-

• value

value Neutropenia Neutropenia 45.0 45.0 6.2 6.2 5.1 5.1 0.8 0.8 <0.001 <0.001 p Anemia Anemia 7.7 7.7 1.5 1.5 1.6 1.6 0.4 0.4 <0.001 <0.001 Thrombocytopenia Thrombocytopenia 5.4 5.4 0.8 0.8 1.2 1.2 0.0 0.0 0.004 0.004 Febrile neutropenia Febrile neutropenia 1.5 1.5 0.8 0.8 0.4 0.4 0.0 0.0 0.123 0.123 Di h Di h 17 7 17 7 0 0 0 0 4 7 4 7 0 0 0 0 0 001 0 001 Diarrhea Diarrhea 17.7 17.7 0.0 0.0 4.7 4.7 0.0 0.0 <0.001 <0.001 Nausea Nausea 3.8 3.8 0.4 0.4 2.7 2.7 0.0 0.0 0.473 0.473 Vomiting Vomiting 7.7 7.7 0.0 0.0 2.4 2.4 0.4 0.4 0.016 0.016 Fatigue Fatigue 3.1 3.1 0.8 0.8 1.6 1.6 0.0 0.0 0.174 0.174 Radiation dermatitis Radiation dermatitis 11.2 11.2 0.0 0.0 10.6 10.6 0.0 0.0 0.888 0.888 Abdominal pain/cramping Abdominal pain/cramping 2.7 2.7 0.0 0.0 0.4 0.4 0.0 0.0 0.068 0.068 Anorexia Anorexia 0.4 0.4 0.0 0.0 0.0 0.0 0.0 0.0 1.000 1.000 Proctitis Proctitis 2 7 2 7 0 8 0 8 0 4 0 4 0 0 0 0 0 020 0 020 Proctitis Proctitis 2.7 2.7 0.8 0.8 0.4 0.4 0.0 0.0 0.020 0.020 AST AST 0.8 0.8 0.0 0.0 0.0 0.0 0.0 0.0 0.499 0.499 ALT ALT 0.8 0.8 0.0 0.0 0.0 0.0 0.0 0.0 0.499 0.499 Creatinine Creatinine 1.5 1.5 0.0 0.0 0.4 0.4 0.4 0.4 0.686 0.686 Other* Other*

Future For Gynecological Cancers Future For Gynecological Cancers Future For Gynecological Cancers Future For Gynecological Cancers

Ovarian Ovarian

– VEGF VEGF – EGFR EGFR – MTOR MTOR MTOR MTOR – AURORA KINASE AURORA KINASE – HEDGEHOG HEDGEHOG

CERVICAL CERVICAL CERVICAL CERVICAL

– VEGF VEGF

ENDOMETRIAL ENDOMETRIAL ENDOMETRIAL ENDOMETRIAL

– VEGF VEGF – MTOR MTOR