Gynecologic Cancer Update 2010

Eric L. Eisenhauer, M.D.

Assistant ProfessorDivision of Gynecologic Oncology

James Cancer Hospital and Solove Research InstituteOhio State University School of Medicine

Conflict of Interest

Objectives

• Review current guidelines for cervical cancer treatment

• Discuss changes to 2009 FIGO staging system for cervical and endometrial cancer

• Understand rationale for current surgical and medical treatment of endometrial cancer

• Review recent data for the treatment of primary and recurrent ovarian cancer

Jemal, A. et al. CA Cancer J Clin 2010; 60:277-300

28% Breast

14% Lung and bronchus

10% Colon and rectum

6% Uterine corpus

5% Thyroid

4% Non-Hodgkin lymphoma

4% Melanoma

3% Kidney

3% Ovary

3% Pancreas

Cancer Statistics – 2010

Estimated Deaths

43,470

207,090

Estimated New Cases

26% Lung and bronchus

15% Breast

9% Colon and rectum

7% Pancreas

5% Ovary

4% Non-Hodgkin lymphoma

3% Leukemia

3% Uterine corpus

2% Liver

2% Brain

7,950

39,840

21,880

13,850

Estimated New Gynecologic Cancers: 2010

Uterus 43,470 Vulva 3,900

Ovary 21,880 Vagina & Other 2,300

Cervix 12,200

Jemal, A. et al. CA Cancer J Clin 2010; 60:277-300

Estimated Gynecologic Cancer Deaths: 2010

Ovary 13,850 Vulva 920

Uterus 7,950 Vagina & Other 780

Cervix 4,210

Jemal, A. et al. CA Cancer J Clin 2010; 60:277-300

Cervical Cancer

Year Cases Deaths %

2006 9,710 3,700 38

2007 11,150 3,670 33

2008 11,070 3,870 35

2009 11,270 4,070 36

2010 12,200 4,210 35

Jemal A, et al. CA Cancer J Clin 2006-2010

Cervical Cancer

• Most common gyn cancer worldwide• Clinical rather than surgical staging• Correlation of FIGO to TNM is poor• Minor changes to 2009 FIGO staging

– Deletion of Stage 0– Subdivision of Stage IIA

• IIA1: tumor ≤ 4 cm with involv. < 2/3 upper vag• IIA2: tumor > 4 cm with involv. <2/3 upper vag

Cervical Carcinoma

Stage Distribution of Patients

Five-year Survival

I 62% 85%

II 18% 60%

III 11% 35%

IV 9% 15%

Stage Distribution and Survival

Cervical Cancer

• Poor prognostic factors:– Positive lymph nodes– Parametrial involvement– Positive resection margins

• 1999 NCI Clinical Alert– Noted results of 5 randomized trials showing

benefit of chemoradiation (cisplatin) over radiation alone

Cervical Cancer

• Since 1999, few frameshifts in thinking about cervical cancer therapy

• Ongoing HPV vaccine trials

• Attempts at consolidation therapy

• Trials of targeted agents

• New combinations for advanced or recurrent disease

Chemotherapy for Advanced or Recurrent Cervical Cancer

• Combination chemotherapy– GOG 76X; Cisplatin + paclitaxel, 46% RR (Rose et al, 1999)– GOG 169; cisplatin + paclitaxel vs cisplatin; improved RR

not OS (Moore et al 2004)– GOG 179; topotecan + cisplatin; improved OS (Long et al,

2005)– GOG 204; topotecan, gemcitabine, vinorelbine, paclitaxel

• Interim analysis: so sig benefit; RR, PFS and OS favors cisplatin + paclitaxel (Monk et al, 2009)

• Favored regimen: cisplatin + paclitaxel

• Role of carboplatin + paclitaxel?

Uterine Cancer

Year Cases Deaths %

2006 41,200 7,350 18

2007 39,080 7,400 19

2008 40,100 7,470 19

2009 42,160 7,780 18

2010 43,470 7,950 18

Jemal A, et al. CA Cancer J Clin 2006-2010

Uterine Neoplasia

SarcomaAdenocarcinoma

Sporadic Inherited

Type IIType I

•Estrogen-dependent•Endometrioid•MMR/MSI•PTEN, KRAS

•Estrogen-independent•Serous, clear cell•TP53, HER-2/neu, p16

•Lynch syndrome (HNPCC)•Cowden’s disease•BRCA syndrome?

Hyperplasia

Endometrial cancer incidence and mortality by histologic

type

Hamilton CA et al. Br J Cancer, 2006

Risk Factors

**INCREASED ESTROGEN:PROGESTERONE**

Characteristic Increased Risk

Late Menopause (age 52) 2.4 x

Nulliparous 3 x

Unopposed Estrogen 10 x

Obesity

>30 lbs

>50 lbs

3 x

10 x

Hyperplasia-WHO Classification

RECENT EVIDENCE CHALLENGES THESE RATES OF PROGRESSION

Types of HyperplasiaProgressing to

Cancer (%)

Simple 1

Complex 3

Simple with Atypia 8

Complex with Atypia 29

Kurman et al, Cancer 56:403,1985

Rates of progression HC

Lacey JV Jr. Absolute risk of endometrial carcinoma during 20-year follow-up among women with endometrial hyperplasia. J Clin Oncol. 2010 Feb 10;28(5):788-92

If an endometrial biopsy shows complex atypical hyperplasia, what is the risk that an underlying endometrial cancer is present?

Concurrent Carcinoma with Complex Atypical Hyperplasia

GOG 167• Pre-op diagnosis of CAH on EMB

• 306 patients

• 43% had carcinoma on final pathology

– 16% high grade histologic cell types

• serous, clear cell, undifferentiated

– 30% had myometrial invasion

– 10% stage IC

CL Trimble, Concurrent endometrial carcinoma in women with biopsy of atypical endometrial hyperplasia: A GOG study, Cancer. 106 (4): 812-819, Feb 2006

Complex atypical hyperplasia

– 48% found to have cancer– Invasive disease in 27%

• 8% with deeply invasive and/or grade 3 disease

Suh-Burgmann E, et al. Complex atypical endometrial hyperplasia: the risk of unrecognized

adenocarcinoma and value of pre-operative dilation and curettage. Obstet Gynecol 2009;114:523-529.

Surgery for CAH

• At time of surgery, CONSIDER:– Perform Pelvic Washings– Intra-op Frozen Section– Have capability to perform surgical

staging if needed– Surgical staging (modified or not)

Revised FIGO stagingFIGO 1988

STAGE I

A. Limited to the endometrium

B. Invasion to < half myometrium

C. Invasion ≥ half myometrium

STAGE II

A. Endocervical glandular involvement B. Cervical stromal invasion

STAGE III

A. Invades serosa or adnexa or

positive cytology

B. Vaginal metastases

C. Positive pelvic or aortic nodes

STAGE IV

A. Invades bladder or bowel mucosa

B. Distant metastases, including intra-

abdominal or inguinal

FIGO 2009

STAGE IA. Invasion < half myometriumB. Invasion ≥ half myometrium

STAGE II-Cervical stromal invasion

STAGE IIIA. Invades serosa or adnexaB. Vaginal or parametrial involvementC1. Positive pelvic nodesC2. Positive aortic nodes

STAGE IVA. Invades bladder or bowel mucosaB. Distant metastases, including intra- abdominal or inguinal

Stage I

Modified from Disaia, Clinical Gynecologic Oncology, sixth edition

New IA

New IB

Stage II

Modified from Disaia, Clinical Gynecologic Oncology, sixth edition

New II

Stage III

Modified from Disaia, Clinical Gynecologic Oncology, sixth edition

New IIIC1 New IIIC2

So What?????

Survival outcomes

Stage Distribution (%) 5 year survival

Confined to uterus 69% 95.5%

Regional spread (lymph nodes)

19% 67.5%

Distant 8% 17.1%

Unknown (unstaged)

4% 55.5%

Treatment

• Surgical Staging– Peritoneal Washings– Hyst/BSO– Pelvic and Paraaortic lymph nodes

• Not sampling….lymphadenectomy is required

– Option of minimally invasive surgery • LS, Robotic

• Adjuvant Therapy

Who to Surgical Stage?

• Without Debate– Grade ≥ 2 lesions– Myometrial Invasion > ½ – Cervical extension– Extra-uterine spread– Serous, clear-cell, undifferentiated cell

types or squamous – Enlarged lymph nodes

ACOG Practice Bulletin

• Who to surgically stage?– Most women should be staged– Exceptions “include young or

perimenopausal women with grade 1 endometrioid adenocarcinoma associated with atypical hyperplasia and women at increased risk of mortality secondary to comorbidities.”

ACOG Practice Bulletin No. 65. Obstet Gynecol 2005

And Why?

Accuracy of pre-operative sampling

• Pre-operative grade 1 endometrial cancer– The Ohio State experience

• Histology upgraded in 19%• 18% (32/181) had stage II or greater• Lymphatic metastases in 4%• Extra-uterine disease in 10.5%

– Overall 26% of patients were found to have high risk factors

– MSKCC experience• Histology upgraded in 15% (+1.2% serous/clear cell) • 14% (69/490) had stage II or greater

– Overall 18.5% of patients were found to have high risk factors

– Affects ~ 20-25% of patients

Ben-Shacar I, et al. Surgical staging for patients presenting with grade 1 endometrial carcinoma. Obstet Gynecol 2005;105:487-493.Leitao MM, et al. Accuracy of preoperative endometrial sampling diagnosis of FIGO grade 1 endometrial adenocarcinoma. Gynecol Oncol. 2008;111(2):244-8.

Grade 1

NCCNNational Comprehensive Cancer Network

• Current Recommendations– Comprehensive surgical staging of all

tumors greater than Grade I, IA

– Consider comprehensive surgical staging of Grade I, IA

• © National Comprehensive Cancer Network, Inc. 2009/2010. NCCN and NATIONAL COMPREHENSIVE CANCER NETWORK are registered trademarks of National

Comprehensive Cancer Network, Inc.

Minimally-invasive staging

• GOG LAP2– 2616 women with early EMCA– Randomized to laparoscopy vs laparotomy– Early endpoints: QoL, complications,

staging– Later endpoints: PFS, OS

Minimally-invasive staging

• GOG LAP2– Lpsc conversion rate ~25%– Lpsc may be safer

• 14% vs 21% mod-severe postop events (P<0.001)

– Lpsc is adequate for staging• Same rate of detection of advanced disease

– Lpsc has lower pain scores– Lpsc had shorter hosp stay and faster return to work– Lpsc had overall improved QoL for first 6 mo

Walker JL et al. J Clin Oncol 2009, 27:5331.Walker JL et al. J Clin Oncol 2009, 27:5337.

Limitations of Laparoscopy

• 2-D vision • Counterintuitive

movements• Limited manipulation• Few degrees of

freedom• Steep learning curve

Robotic Surgery for Endometrial Cancer at OSU

• Began Spring 2006– 97 patients with endometrial carcinoma

• 9% laparotomy required• 91% completed robotically

– 84 with pelvic and aortic LND– 4 without LND (BMI range = 47-60)– BMI = 34 kg/m2, LOS = 1 day– One severe intraoperative complication

– Robotic surgical staging for endometrial cancer is feasible

Fowler JM et al. J Robotic Surg 2008

Endometrial CancerRobotic (n=105) LS (n=76) LAP2

Room Time 305 min 336 min

Skin to Skin 242 min 287 min

Staging 86% 89% 77%

Conversion 10% 26% 23%

BMI (kg/m2) 34 29 27

BMI >30 60% 38%

BMI >40 26% 3%

LOS 1 day 2 days

Transfusion 3% 18%

Seamon LG et al. Gynecol Oncol 2008

Robotics and Obesity

Seamon LG et al. Obstet Gynecol 2008 and Gynecol Oncol 2009

BMI Conversion

40 15%

45 24%

50 34%

55 48%

Outcome BMI

Converted 40

Completed 34

Laparoscopy

Robotic

Post Operative Treatment

Uterine Risk Factors and Recurrence Rate

Uterine Factor Recurrence Rate (%)

Grade 1, 2, 3 4%, 9%, 16%

Deep myometrial invasion

15%

Isthmus/cervix involvement

16%

Lympho/vascular space involvement

27%

After surgical staging, which early stage patients benefit from further therapy?

Intermediate risk

• GOG 99– Phase III RCT– 392 women– Staging with or without post-op WPRT– Defined “intermediate risk”

• Stage IB, IC, IIA/IIB (occult)• 5 year recurrence rate of 20-25%• Excluded serous and clear cell

Keys HM et al. Gynecol Oncol 2004

Adjuvant WPRT: GOG 99

No Adjuvant

TreatmentAdjuvant

WPRT P Value

Progression Free : 2 yrs

88% 96% 0.004

Survival: 3 yrs

89% 96% 0.09

Keys HM et al. Gynecol Oncol 2004

PORTEC-2

• Phase III RCT• 427 women high-intermediate risk after

hysterectomy• Randomized to WPRT vs vag brachy• Defined high-intermediate risk:

1) >60 y.o. stage IC gr 1-2

2) >60 y.o. stage IB gr 33) any age, stage IIA

Nout RA et al. Lancet 2010

PORTEC-2

WPRT VBT P

Vaginal recur 1.6% 1.8% 0.74

Local recur 2.1% 5.1% 0.17

Distant mets 5.7% 8.3% 0.46

DFS (45 mo) 78% 83% 0.74

OS (45 mo) 80% 85% 0.57

Nout RA et al. Lancet 2010

So how to treat high-intermediate risk?

• GOG 249?

Eligible: Stage I-IIA endometrial carcinoma, with high-intermediate risk factorsStage IIB (occult) endometrial carcinoma (any histology), with or without risk factors, and

Stage I-IIB (occult) serous or clear cell endometrial carcinoma, with or without other risk features

TREATMENT RANDOMIZATION

Regimen I: Pelvic Radiation Therapy (4500/25 fractions-5040 cGY/28 fractions) over 5-6 weeksOptional Vaginal Cuff Boost ONLY for Stage II patients and Stage I patients with

papillary serous and clear cell carcinomas

OR

Regimen II: Vaginal Cuff Brachytherapy + 3 cycles of chemotherapy consisting ofPaclitaxel 175 mg/m2 (3hr) + Carboplatin AUC 6 q 21 days

chemotherapy to start within 3 weeks of initiating brachytherapy

Extra-Uterine Involvement

• Stage IIIA

• Stage IIIC

• Stage IV

Extra-uterine Risk Factors for Recurrence

(%)Extra-uterine Factor Recurrence Rate

Adnexal Metastasis 14

+ Peritoneal Cytology 19

+ Peritoneal Disease 25

Pelvic Nodal Metastases 28

Para-aortic Nodal Metastases

40

Advanced Disease

• GOG 122• RCT compared cis/adria (AP) vs WAI

– 5 yr PFS 50% vs 38% for chemo arm– 5 yr OS 60% vs 43% for chemo arm

• Recurrence WAI APPelvic 13% 18%Extrapelvic 38% 32%

Remaining questions:-Best systemic chemotherapy?-Risk for local recurrence: role of combined chemoRT?

Marcus E. Randall, et al; Randomized Phase III Trial of Whole-Abdominal Irradiation Versus Doxorubicin and Cisplatin Chemotherapy in Advanced Endometrial Carcinoma: A Gynecologic Oncology Group Study. JCO, 2006.

Advanced Disease

• GOG 184• Optimal stage III and IVA• All received volume-directed RT• cis/adria (AP) vs cis/adria/paclitaxel (TAP)• 3 yr PFS 64% vs 62%• Recurrence

Local 8%Distant 28%

Homesley H et al Gynecol Oncol 2009

Remaining questions

• Systemic chemotherapy better than WAI for a systemic disease (GOG 122)

• Most recurrences are systemic, not locoregional (GOG 122 and GOG 184)

• Best chemotherapy: TAP no better than AP (GOG 184)

• 16% of pts receiving volume-directed RT did not make it to chemotherapy (GOG 184)

• TAP vs carbo/paclitaxel (GOG 209 – closed)• Role of RT in combination with chemo

– GOG 258 – Carbo/paclitaxel (CT) x6 vs. RT + CT x4

Adjuvant Treatment Summary

Low Risk

Inter-mediate Risk

High Risk

Stage/ Grade IA G1/2 IA (G3)

IB (all grades)

IIA

IIB

Stage III

Stage IV

UPSC (all stages)

CCC (all stages)

Undiff (all stages)

Post-operative

(complete

surgical

staging)

None Vaginal Cuff Brachy Therapy or Observation

(*exception is in stage IIB)

Chemotherapy consider RT (Vaginal Cuff Brachy Therapy vs. whole pelvic)

Endometrial Cancer: James Cancer HospitalTreatment Recommendations

Stage I, A-B; any grade No further therapy (NFT) +/- vaginal brachytherapyStage II, any grade Radical hyst w/LND then observation Otherwise consider XRTStage IIIA Individualized mgmtStage IIIB-IVA Clinical trial Chemotherapy +/- XRTStage IV B Clinical trial or chemotherapy

SEER Cancer Statistics Review, 1975-2001

Ovarian CancerGradual Therapy Changes Improve Survival

Ovarian Cancer

Year Cases Deaths %

2006 20,180 15,310 76

2007 22,430 15,280 68

2008 21,650 15,520 71

2009 21,550 14,600 67

2010 21,880 13,850 63

Jemal A, et al. CA Cancer J Clin 2006-2010

Pathology

Epithelial (65%)Serous (80%) – Tubal Mucinous (10%) – IntestinalClear cell – EndocervicalEndometrioid – EndometrialBrenner – Transitional cell

Benign = Cystadenoma Invasive = Cystadenocarcinoma Borderline = Tumor of LMP

Survival by Stage

Stage Percent 5-year Survival

I 24% 90%

II 6% 80%

III 55% 15-50%

IV 15% 5-15%

What is My Risk of Ovarian Cancer?

-Ovarian CA

Dx 6161 yr

Baseline 1.5% risk

2+ relatives 3% risk

One 1o relative 5% risk

Two 1o relatives 7% risk

BRCA2 mutation 25% risk

BRCA1 mutation 40% risk

Risk of Ovarian Cancer

Interventions to Mortality?

Time

Dis

ea

se V

olu

me

Prevention

Screening

Current point of diagnosis and initiation of treatment

Prevention– Pedigree Analysis

– Medical: Oral Contraceptives

– Surgical: Risk-Reducing Oophorectomy

Screening– Pelvic Examination

– Ultrasonography

– CA125 and other (OvaSure) Serum Testing

– Proteomics (OvaCheckTM)

Interventions to Mortality?

NIH Consensus Development Panel, 1994

“…there is no evidence available yet

that the current screening modalities

of CA 125 and ultrasonography can

be effectively used for widespread

screening to reduce mortality from

ovarian cancer…”

Screening – US and CA 125

Screening - OvaCheckTM

Society of Gynecologic Oncologists, 2004

“In the opinion of SGO, more

research is needed to validate

the test’s effectiveness before

offering it to the public”

Screening - OvaSureTM

Society of Gynecologic Oncologists, 2008

“In the opinion of SGO,

additional research is needed

to validate the test’s

effectiveness before offering it

to women”

Ovarian Cancer Staging

Stage I – Confined to the ovaries Stage II – Confined to the pelvis Stage III – Implants out of the pelvis or

positive lymph nodes Stage IV – Distant metastases

Positive pleural effusion or intraparenchymal liver disease

Cytoreductive Surgery

Goal is elimination of all tumor• No gross residual (microscopic)• Optimal (<1 cm)• Suboptimal (>1 cm)

Operative Technique• Resection of urinary or intestinal tract

Surgical Outcomes• Optimal in ~75% of cases• Does it matter?

Does Cytoreduction Matter?

Optimal Suboptimal

Response Rate

Clinical CR 95% 75%

Pathologic CR 50% 25%

Progression free interval (mo) 34 13

Survival (mo) 50 36

10-yr survival 35% 15%

Stage IIIC Ovarian Cancer

Microscopic – 40-75%

Optimal – 30-40%

Suboptimal – 5-10%

Practical Management of Advanced Cancer

Advanced (stage III or IV)Ovarian Cancer

Surgical Candidate?

Debulkable disease

Medically fit

Yes No

Yes

Chemotherapy

No

Optimal Cytoreduction? (<1cm)3 cycles of chemotherapy, then consider interval cytoreduction, then complete chemotherapy

Neoadjuvant Chemotherapy

GCIG Collaboration 14 European centers, 1998-2006 718 patients with stage IIIC-IV EOC 670 randomized Primary surgery vs 3 cycles NACT Non-inferiority trial Primary endpoint: overall survival Secondary: PFS, QoL, adverse events

Vergote I et al. New Engl J Med 2010; 363:943-55

Neoadjuvant Chemotherapy

Results Optimal cytoreduction: 42% vs 81% Adverse events higher in primary surgery arm NACT Hazard Ratio = 0.98 (P = 0.01 non-inf) Complete resection of all macroscopic disease was

strongest predictor of overall survival

Conclusion NACT followed by interval cytoreduction was not

inferior to primary surgery

Vergote I et al. New Engl J Med 2010; 363:943-55

Neoadjuvant Chemotherapy

Criticism Primary cytoreduction rate only 42% Long enrollment period Median PFS was only 12 months Median OS was only 29 months Were second-line therapies available to these patients?

Takeaway Interesting, but unlikely to replace US standard

Vergote I et al. New Engl J Med 2010; 363:943-55

Survival lower than GOG trials of sub-optimal only patients

How did we arrive at the current standard and what have we done to improve it?

Primary Treatment of Ovarian Cancer

1995 1997 1999

Cyclophosphamide + Cisplatin

STANDARD OF CARE

GOG 111 establishes Taxol-CDDPas standard 1st line

2001

GOG 158 shows Taxol-carboplatin = Taxol-CDDP, with improved toxicity and QoL

GOG 178 demonstrates improved DFS with longer duration of maintenance Taxol – No

data on overall survival

GOG 172 confirms IP therapy leads to a survival

advantage compared with IVNEW STANDARD OF CARE?

SWOG 8501 demonstrates improved survival with IP therapy

2003 2005 2008

GOG 182 demonstrates no survival advantage to triplet or sequential

doublet therapy

Advanced Ovarian Cancer

cisplatincisplatin paclitaxelpaclitaxelmulti-drugmulti-drug AlkeranAlkeran

Median Survival: 1975 - 2005Median Survival: 1975 - 2005

IP therapyIP therapy

(optimal)(optimal)(optimal)(optimal)

mon

ths

mon

ths

1212 14142424

37375252

57576666

00

2020

4040

6060

8080

19751975 19831983 19861986 19961996 19981998 20032003 20052005

GOG 158: Carboplatin vs. Cisplatin

RANDOMIZE

• FIGO stage III epithelial ovarian or peritoneal cancer

• Optimal (<1 cm) cytoreduction

Paclitaxel 135 mg/m2 24 hr IV q21 d x6Cisplatin 75 mg/m2 IV D2 q 21 d x6

Arm 1

Arm 2

Paclitaxel 175 mg/m2 3 hr IV q21 d x6Carboplatin AUC 7.5 IV D1 q21 d x6

Ozols RF et al. J Clin Oncol 2004;21:3194-200

• EfficacyP + CDDP P + Carbo

Median recurrence-free 21.7 22.0 survival, moNegative SLS, % 45.2 51.5

• ToxicityMore frequent with paclitaxel/carboplatin:

– Grade III/IV thrombocytopenia

– Grade I/II pain

More frequent with paclitaxel/cisplatin:

– Grade IV neutropenia

– Grade III/IV gastrointestinal

– Fever

– Metabolic

Ozols RF et al. J Clin Oncol 2004;21:3194-200

SLS = second-look surgery.

GOG 158: Carboplatin vs. Cisplatin

Improvements in Primary Therapy

• Intraperitoneal Chemotherapy

• Weekly (dose-dense) taxanes ?

• Bevacizumab consolidation ?

Improvements in Primary Therapy: Intraperitoneal Therapy

RANDOMIZE

• FIGO stage III epithelial ovarian or peritoneal cancer

• Optimal (<1 cm) cytoreduction

Paclitaxel 135 mg/m2 24 hr IV q21 d x6Cisplatin 75 mg/m2 IV D2 q 21 d x6

IV

IP

Armstrong DK. Proc Am Soc Clin Oncol 2002;21:201a.

Paclitaxel 135 mg/m2 24 hr IV q21 d x6Cisplatin 100 mg/m2 IP D2 q 21 d x6Paclitaxel 60 mg/m2 IP D8 q 21 d x6

GOG 172

GOG 172: Intraperitoneal Therapy

Significantly increased toxicity with IP:

● Neutropenia, thrombocytopenia, GI, renal, infection,

fatigue, metabolic and pain

Outcomes:

● RR recurrence 0.73 in IP arm compared with IV arm

(23 versus 18 months, P=0.05)

● Overall survival 65 versus 49.7 months (P=0.03)

● Confirmed findings of SWOG 8501 and GOG 114

(survival advantage with IP therapy)

Armstrong DK et al. N Engl J Med 2006

Intraperitoneal Therapy?

GOG Trial Regimen PFI Median Survival

GOG 104 IV: CDDP/CTX Not reported 41 moAlberts et al IP: CDDP/CTX Not reported 49 mo

Risk of Death Hazard Ratio = 0.76

GOG 114 IV: CDDP/Taxol 22mo 52 mo.Markman et al IP: CDDP then 28 mo 63 mo

IV Carbo/Taxol x2 Risk of Death Hazard Ratio = 0.81

GOG 172 IV: Taxol/CDDP 18 mo 50 moArmstrong et al IP: Taxol/CDDP and 23 mo 65 mo IV Taxol

Risk of Death Hazard Ratio = 0.73

Toxicity with IP chemotherapy

• Presence of an IP catheter

– Infection, fever

• IP administration of chemotherapy

–Abdominal pain, nausea, vomiting

• Chemotherapy

–Greater hematologic, metabolic, and neurologic toxicity

IV CDDP 100 mg/m2

PlasmaPeritoneal

fluid

AU

C

IP CDDP 90 mg/m2

Peritoneal fluid

Plasma

AU

C

Pharmacokinetics

Intravenous versus Intraperitoneal Administration of Cisplatin

Improvements in Primary Therapy: Weekly Taxane

RANDOMIZE

• FIGO stage II-IV EOC

• Optimal or suboptimal

• 1º endpoint = PFS

• N = 631

Paclitaxel IV 180 mg/m2 q21 d x6Carboplatin IV AUC 6 q 21 d x6

Arm 1

Arm 2

Katsumata N et al. Lancet 2009;374:1331-1338

Paclitaxel IV 80 mg/m2 q7 d x18Carboplatin IV AUC 6 q 21 d x6

JGOG

JGOG: Weekly Taxane

• Rationale:– Duration of exposure is an important determinant of paclitaxel

cytotoxicity

– Preclinical evidence of anti-angiogenic effect

• Results:– Median PFS longer in dose-dense (28 vs 17 mo)

– 3 yr OS higher in dose dense (HR=0.75, P=0.03)

– Heme and non-heme toxicities similar

• Conclusions:– PFS and OS improved with dose-dense primary taxane therapy

– GOG has incorporated weekly taxane arms in several trials

Katsumata N et al. Lancet 2009;374:1331-1338

GOG 218

RANDOMIZE

• FIGO stage III/IV epithelial ovarian or peritoneal cancer

• Optimal/Suboptimal

• 1º endpoint: PFS

• N = 1873

Carboplatin IV AUC 6 (6 cycles)Paclitaxel IV 175 mg/m2 (6 cycles)Placebo IV (5 cycles)+ maintenance placebo up to 15 mo

Arm 1

Burger R et al, ASCO 2010

Arm 2

Carboplatin IV AUC 6 (6 cycles)Paclitaxel IV 175 mg/m2 (6 cycles)Bevacizumab IV 15 mg/kg (5 cycles)+ maintenance placebo up to 15 mo

Arm 3

Carboplatin IV AUC 6 (6 cycles)Paclitaxel IV 175 mg/m2 (6 cycles)Bevacizumab IV 15 mg/kg (5 cycles)+ maintenance bevacizumab up to 15 mo

Results: Women in Arm 3 (T/C/B + B) had median PFS 14 months

compared to 10 months in Arm 1 (T/C); (HR = 0.72, P<0.0001)

Women in Arm 2 (T/C/B) did not have significant increase in PFS compared to Arm 1 (T/C)

Adverse events consistent with previous trials of bevacizumab

Criticism: Is bevacizumab necessary with primary treatment if Arms 1 and

2 are similar?

OS data not yet mature

GOG 218 Results

Burger R et al, ASCO 2010

ICON7

RANDOMIZE

• FIGO stage II/IV epithelial ovarian or peritoneal cancer

• Optimal/Suboptimal

• 1º endpoint: PFS

• N = 1528

Carboplatin IV AUC 6 (6 cycles)Paclitaxel IV 175 mg/m2 (6 cycles)

Arm 1

Perren T et al, ESMO 2010

Arm 2

Carboplatin IV AUC 6 (6 cycles)Paclitaxel IV 175 mg/m2 (6 cycles)Bevacizumab IV 15 mg/kg (5 cycles)+ maintenance bevacizumab up to 15 mo

*10/11/2010 Press release: PFS reduced by 15% at 12 months* Mature data will not be available for another 2 years

Response to Chemotherapy

Overall response rate = 75-80%

with chemotherapy

66% of patients will recur and die

of their advanced ovarian cancer

Treatment Options for Recurrent Ovarian Cancer

• Chemotherapy– Cytotoxic

– Empiric versus assay-directed

– Non-cytotoxic (“targeted”) therapy

– High-dose with marrow transplant

• Surgery (2o cytoreduction)

• Immunotherapy

• Radiation therapy

Secondary Cytoreduction

Best Candidates Response to 1st line Rx DFI > 6-12 months Platinum sensitive Isolated recurrent disease Good performance status Further Rx options Previous optimal

cytoreduction

Poor Candidates Progressive disease Platinum resistant Short DFI Exhausted further Rx Poor surgical candidate Ascites Extensive disease

Treatment-free IntervalResponse to Platinum Retreatment

6 m

onth

s

Fini

sh 1

o Tx

24 m

onth

s

18 m

onth

s

12 m

onth

s

10% RR

30% RR

50% RR

75% RR

About 50% of recurrences are >6 months

Platinum-Sensitive Recurrence

• Recurrence diagnosed > 6 months from completion of primary therapy

• Generally retreat with platinum combination

• Evidence for both paclitaxel (ICON4) and gemcitabine (AGO-OVAR) in combination with carboplatin

• New evidence for carboplatin-PLD

Platinum-Sensitive Recurrence

• GCIG– European consortium

– RCT non-inferiority trial

– 976 women with plat-sensitive recurrence

– Carboplatin + PLD vs carboplatin + paclitaxel

– Primary endpoint: PFS

– Results: • PFS superior in PLD arm (HR=0.82, P=0.005)

• Severe non-heme tox higher in paclitaxel arm

Pujade-Lauraine E et al. J Clin Oncol 2010;28:3323-3329

RANDOMIZATION•Epithelial ovarian cancer or

primary peritoneal cancer•Recurrent disease•Platinum sensitive•+/- Cytoreduction

Paclitaxel Doublet Carboplatin Paclitaxel

I

Gemcitabine Doublet Carboplatin Gemcitabine

II

Doxil Doublet Carboplatin Doxil

III

Topotecan Doublet Carboplatin Topotecan

V

GOG 213: Doublets for Recurrence

IV

VISequential Doublet Paclitaxel

Sequential Doublet Carboplatin

Docetaxel Doublet Carboplatin Docetaxel

To treat or not to treat….

Early vs delayed treatment of recurrent ovarian cancer

• MRC OV05/EORTC 55955

– 9 European centers

– RCT of 1442 women of EOC in complete remission

– Clinical exam and CA125 q 3 mo

– Pts/investigators blinded to these results

– If CA125 >2X ULN, pt randomized to early treatment (within 28 days) or delayed treatment (not until clinical or symptomatic relapse)

– 529 women randomized: 265 early, 264 delayed

– Primary endpoint: overall survival

Rustin GJS et al. Lancet 2010;376:1155-1163

Early vs delayed treatment of recurrent ovarian cancer

• Results– No difference in overall survival (HR = 0.98)

• Conclusions– Value of routine CA125 measurement not proven

• Criticism– Long enrollment (1996-2005)

– Large number of early stage (20%) but overall survival poor (26-27 mo from randomization)

– Contemporary therapy for recurrence not available to many patients

• Takeaway– Provocative, but not likely to be uniformly adopted

Rustin GJS et al. Lancet 2010;376:1155-1163

The Future?

Proge

stin

s

MM

PIs

Erlotinib

AngiostatinSorafenib

PARP inhibitorsPertuzumab

Trastuzum

abTKIsTam

oxife

nBevacizumab

Imatinib