Management of Epithelial Ovarian Cancer Mohamed Abdulla (M.D.) Department of Clinical Oncology Kasr El-Aini School of Medicine Cairo University Egyptian.

Management of Epithelial Ovarian Cancer

Mohamed Abdulla (M.D.)Department of Clinical OncologyKasr El-Aini School of Medicine

Cairo University

Egyptian Cancer Society Meeting, Demiat Cancer Center

– June, 2009

Magnitude of The Clinical Problem:

Jelic S, et al. 2002 Congress of the European Society for Medical Oncology. Mocharnuk R. Available at: http://www.medscape.com/viewarticle/444134.

Stage I II III IV

Description Confined to ovaries

Confined to pelvis

Confined to abdomen/lymph

nodes

Distant metastases

Incidence 20% 5% 58% 17%

Survival 73% 45% 21% < 5%

01020304050607080

I II III IV

Steep Survival Gradient of Ovarian Cancer and Stage at Diagnosis

Magnitude of The Clinical Problem:

FDA-Approved Drugs in Ovarian Cancer

• 1978 Cisplatin

• 1989 Carboplatin

• 1990 Altretamine

• 1992 Paclitaxel

• 1996 Topotecan

• 1999 Liposomal doxorubicin (accelerated)

• 2005 Liposomal doxorubicin (full)

• 2006 Gemcitabine

1978

2008

Magnitude of The Clinical Problem:

Magnitude of The Clinical Problem:

• Stage I/II– Essentially all patients will achieve a clinical CR after surgery

and chemotherapy– 20% to 25% will relapse

• Optimal stage III– > 90% will achieve a clinical CR – 75% will recur

• Suboptimal stage III/IV– 50% will achieve a clinical CR– > 90% will recur

Ovarian Carcinoma--Symptoms

Abdominal bloating, increased girth, pressure Abdominal / pelvic pain Fatigue GI (nausea, gas, constipation, diarrhea) Urinary frequency/ incontinence Weight loss/ gain Shortness of breath

Vague and often non-gynecologic-- NOT Silent

Magnitude of The Clinical Problem:

Ovarian Carcinoma--Signs

Palpable pelvic mass Abdominal mass Abdominal distension Decreased breath sounds due to effusions Adenopathy -- groin, supraclavicular

Magnitude of The Clinical Problem:

Spreads by local growth, bloodstream and lymphatic routes

Ovarian Cancer Risk Factors• 50 years of age or older• Familial factors

– Family history of breast, ovarian, or colon cancer

– Personal history of breast or colon cancer

– BRCA (breast cancer) gene mutation

– Hereditary nonpolyposis colon cancer (HNPCC)

• Other potential risk factors– Early menarche (younger than 12

years of age)– Late menopause (older than 52

years of age)– Hormone replacement therapy or

fertility drugs– First pregnancy at older than 30

years of age– Infertility

How Much Cancer Is Hereditary?

90% not hereditary

~5% to 10% of breast, colon,

endometrial, and ovarian

cancers are hereditary

90% not hereditary

Lifetime Risk of Cancers Associated With Specific Genes

*MMR (mismatch repair) = HNPCC.

Chen S, et al. J Clin Oncol. 2007:25:1329-1333. Aarnio M, et al. Int J Cancer. 1999:81:214-218.

Cancer, % BRCA1 BRCA2 MMR*

Breast 35-60 30-55 0

Ovarian 30-40 15-25 6-20

Endometrial 0 0 40-60

Whittemore AS, et al. Am J Epidemiol. 1992;136:1212-1220.

Duration of Oral

ContraceptiveUse (Yrs)

Durationof Breast-Feeding

(Mos)

Numberof Term

Pregnancies

0.0 0.5 1.0

0

2

4

> 6

1-5

12-23

0

2-3

> 5

Relative Risk of Ovarian Cancer

Ovarian Cancer: Ovulation

*Rate ratio estimates adjusted for age and race. †Models adjusted for age at baseline, race, duration of oral contraceptive use, number of live births, age at menopause, body mass index, age at menarche, and tubal ligation.

Estrogen Use No. of Deaths

No. ofPerson-Years

Rate Ratio(95% CI)*

Rate Ratio(95% CI)†

Never 689 2,185,876 1.00 (referent) 1.00 (referent)

Ever 255 625,984 1.21 (1.05-1.41) 1.23 (1.06-1.43)

Frequency

• Current (baseline) 62 151,880 1.45 (1.11-1.88) 1.51 (1.16-1.96)

• Former 193 474,103 1.15 (0.98-1.36) 1.16 (0.99-1.37)

Current users, yrs

• < 10 31 110,379 1.07 (0.74-1.54) 1.14 (0.79-1.65)

• ≥ 10 31 41,396 2.13 (1.48-3.06) 2.20 (1.53-3.17)

Former users, yrs

• < 10 158 416,823 1.09 (0.92-1.30) 1.10 (0.92-1.31)

• ≥ 10 35 57,281 1.55 (1.10-2.18) 1.59 (1.13-2.25)

Rodriguez C, et al. JAMA. 2001;285:1460-1465.

Limiting HRT May Reduce Ovarian Cancer Risk:

Transvaginal ultrasound: poor sensitivity in early-stage disease, cannot reliably distinguish benign from malignant changes

CA-125: poor sensitivity in CA-125: poor sensitivity in early stage diseaseearly stage disease

Pelvic examPelvic exam

Ovarian Screening Methods for Average-Risk Women

• Insufficient evidence to recommend population-based screening

• Low prevalence of ovarian cancer in general population

• Not cost-effective• Difficult to screen premenopausal women • Appropriate screening is undefined

Ovarian Screening Methods for Average-Risk Women (cont’d)

1. Finch A, et al. JAMA. 2006;296:185-192.2. Narod SA, et al. Lancet. 2001;357:1467-1470.

• Chemoprevention– Oral contraceptive pills– Limit clomifene citrate– Limit hormone replacement therapy

• Surgical prevention– Oophorectomy: 80% risk reduction in high-risk

women[1]

– Bilateral tubal ligation: 72% risk reduction when used with oral contraception[2]

Prevention of Ovarian Cancer

• Medical risks– Loss of endogenous

estrogen (effect on heart, bones, sexual function)

• Effect of hormone replacement therapy on breast cancer risk

• Emotional risks– Issues around castration

• Medical benefits– Prevention of ovarian

cancer (unknown risk of peritoneal cancer)

– Decreases risk of recurrent breast cancer

• Emotional benefits– Relief from fear of

developing ovarian cancer

Prophylactic Oophorectomy: Counseling about Risks/Benefits

At What Age Should a Patient Undergo Surgery?• Limited data available

– Decision often relies on pedigree information

• National Institutes of Health consensus panel recommendation: 35 years of age or older or after childbearing is complete[1]

1. JAMA. 1995;273:491-497

Epithelial Ovarian Cancer

Standards of Care

Goals of Therapy:

• Manage symptomatic patients.• Better durability of response.• Survival improvement.• Maintain Quality of Life.

GOG 111: Standard of Care

• Study design

Cisplatin 135 mg2 IV over 24 hours + Paclitaxel 75 mg/m2 x 6 cycles

(n = 184)

Cisplatin 75 mg/m2 x 6 cycles + Cyclophosphamide 750 mg/m2 IV

(n = 202)

Patients with suboptimally debulked, stage III/IV

epithelial ovarian cancer within 6 weeks of

surgery(N = 386)

McGuire W, et al. N Engl J Med. 1996;334:1-6.

GOG 111: PFS and OS

McGuire W, et al. N Engl J Med. 1996;334:1-6.

Treatment No. Progression

Free

No. With Treatment

Failure

Total Median PFS, mos

Cisplatin + cyclophosphamide

28 174 202 13

Cisplatin + paclitaxel 45 139 184 18

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months After Entry Into Study

Pro

po

rtio

n S

urv

ivin

g P

rog

ress

ion

F

ree

0 6 24 36 4212 18 30 48

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months After Entry Into Study

Pro

po

rtio

n S

urv

ivin

g

0 6 24 36 4212 18 30 48

Treatment No. Alive No. Dead Total Median Survival, mos

Cisplatin + cyclophosphamide

65 137 202 24

Cisplatin + paclitaxel 86 98 184 38

PFS (P < .001) OS (P < .001)

NCCN Guidelines: v2.2009

• Stage IA & IB:

1. Grade 1 & 2: Observe.

2. Grade 3: 3-6 Courses Paclitaxel/Carboplatin.• Stage IC: 3-6 Courses Paclitaxel/Carboplatin.

• Stages II, III & IV:

1. Stage II: Intraperitoneal Chemotherapy vs Systemic 6-8 Courses of Paclitaxel/Carboplatin.

2. Stage III (< 1 cm Residual): Intraperitoneal Chemotherapy vs Systemic 6-8 Courses of Paclitaxel/Carboplatin.

3. Stages III (> 1 cm Residual) & IV: Systemic 6-8 Courses of Paclitaxel/Carboplatin.

4. Completion of Surgery.

New Agents for the Clinical Management of Ovarian Cancer

Diagnosis

Staging

Progression

Death

SecondarySurgery

1. Bevacizumab

Symptoms Chemotherapy #1 Maintenance Chemo #2 Chemo #3+

1. Paclitaxel poliglumex2. Oregovomab3. Abagovomab

1. Canfosfamide2. Patupilone3. Phenoxodiol4. Karenitecin5. Trabectedin

GOG 218: Potential New Standard of Care

• Primary endpoint: PFS measured by RECIST

• Secondary endpoints: OS, safety, QoL, translational objectives, response

*Beginning in course 2 of chemotherapy.†Beginning in course 7 of chemotherapy.

ClinicalTrials.gov. NCT00262847.

Patients with stage III/IV ovarian or primary peritoneal cancer and

GOG PS 0-2 entered 1-12 weeks after initial surgery

(N = 2000)

Paclitaxel + Carboplatin + Placebo*

Paclitaxel + Carboplatin + Bevacizumab*

Paclitaxel + Carboplatin + Bevacizumab*

Placebo† x 15 months

Placebo† x 15 months

Bevacizumab† x 15 months

GC vs TC Induction Regimens Followed by T Consolidation: Study Design

Gordon A, et al. ASCO 2008. Abstract 5536.

Anything other than CR(PR, SD, PD)

Anything other than CR(PR, SD, PD)

Clinical CR

Single-agent crossoverPaclitaxel 175 mg/m2 Day 1

Single-agent crossoverGemcitabine 1000 mg/m2 Days 1, 8

ElectiveT Consolidation Therapy

Paclitaxel 135 mg/m2 every 28 days for 12 cycles

Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal,

or fallopian tube carcinoma

Induction GCGemcitabine 1000 mg/m2 Days 1, 8

+ Carboplatin AUC 5 Day 1x 6 cycles every 21 days

Induction TCPaclitaxel 175 mg/m2 Day 1+ Carboplatin AUC 6 Day 1

x 6 cycles q 21 days

Conventional vs Dose-Dense TC (NOVEL): Study Design

Ovarian epithelial, primary peritoneal, or fallopian tube cancer with

FIGO stage II-IV

Conventional TC (c-TC)Paclitaxel 180 mg/m2 Day 1 +Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles

Dose-dense weekly TC (dd-TC)Paclitaxel 80 mg/m2 Days 1, 8, 15 +

Carboplatin AUC 6.0 Day 1every 21 days for 6-9 cycles

Dose-dense weekly TC (dd-TC)Paclitaxel 80 mg/m2 Days 1, 8, 15 +

Carboplatin AUC 6.0 Day 1every 21 days for 6-9 cycles

Stratified by residual disease ≤ 1 cm vs > 1 cm;

FIGO stage II vs III vs IV;histology: clear cell/mucinous vs serous/others

Isonishi S, et al. ASCO 2008. Abstract 5506.

Treatment n Event Median PFS, mos P Value HR 95 %CI

c-TC 319 200 17.2

dd-TC 312 160 28.0 .0015 0.714 0.581-0.879

Conventional vs Dose-Dense TC (NOVEL): PFS

0.0

0.2

0.4

0.6

0.8

1.0

0 12 30 54

Mos From Randomization

Pro

po

rtio

n S

urv

ivin

g

Pro

gre

ssio

n F

ree

0.1

0.3

0.5

0.7

0.9

6 18 4224 4836

Isonishi S, et al. ASCO 2008. Abstract 5506.

dd-TC

c-TC

• Toxicity profile.• GOG III :

1. Systemic Paclitaxel/Cisplatin.

2. Intraperitoneal Paclitaxel.

3. Intraperitoneal Cisplatin.

Intra-Peritoneal Chemotherapy:

ClinicalTrials.gov/ct2/show/NCT00003322. August 2008

• Serologic relapse– Rising CA-125 only evidence of disease

• Localized recurrence• Disseminated intraperitoneal disease• Extraperitoneal metastases• Recurrences can be symptomatic or asymptomatic

Patterns of Recurrence

• Rising CA-125 is highly predictive of a clinical relapse– Median time of 4-6 months before symptoms develop

and/or a clinical recurrence (physical exam or imaging studies) is documented[1,2]

• Patient/physician preference about instituting chemotherapy is similar (~ 50%)– No evidence that delaying chemotherapy until clinical

relapse is detrimental

• Randomized trial in progress in Europe1. Niloff JM, et al. Am J Obstet Gynecol. 1986;155:56-60. 2. Vergote IB, et al. Tumour Biol. 1992;13:168-174.

Management of a Rising CA-125 in a Patient Who Is Clinically Disease Free

• No RCT establishing clinical benefit– Gynecologic Oncology Group trial in progress[1]

• Easier to define patients who should not undergo secondary cytoreduction– Short disease-free interval

– Intraperitoneal carcinomatosis precludes complete resection

– Ascites

– Drug-resistant disease

1. ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov/ct2/show/ NCT00002568?term=GOG+cytoreduction&rank=1. Accessed February 4, 2008.

Role of Secondary Cytoreduction

Platinum-Sensitive Recurrent Ovarian Cancer:• Carboplatin is key drug• Carboplatin combinations are superior to single-

agent carboplatin• Choice of carboplatin/gemcitabine vs

carboplatin/paclitaxel based on toxicity considerations

• Results of carboplatin/PLD vs carboplatin/paclitaxel will be available soon

• No evidence that combinations of cytotoxic agents superior to single agents– RCT of canfosfamide + carboplatin vs PLD: negative– PLD + trabectedin vs PLD in progress

• No RCTs of in vitro sensitivity/resistance assays have shown improvement

• Biologic agents– Bevacizumab

• ? single agent or in combination with chemotherapy

Strategies to Improve Outcomes in Platinum-Resistant Disease

How Long to Treat Patients With Recurrent Disease?• No RCTs in recurrent disease directly address this

issue

• In previously untreated patients, RCTs have failed to show any benefit for either continuing with the same chemotherapy or switching to a non–cross-resistant regimen– In recurrent disease, the same could be expected

• Currently, this is a personal choice issue with patient/physician– Toxicity is key

– Some patients will choose more therapy as long as there is evidence they are not in a remission—“psychochemotherapy”

– Benefit of “drug holidays”