Treatment of Treatment of Refractory Ovarian Refractory Ovarian

CancerCancer

OVARIAN CANCEROVARIAN CANCERWorldwide incidence*Worldwide incidence*

*Incidence per 100,000 population.Parkin DM, et al. CA Cancer J Clin. 1999;49:61.

10.010.0

11.511.5

6.46.4

9.69.6

5.45.4

2.82.8

5.35.3

7.67.6

11.211.2

Eastern Eastern EuropeEurope

JapanJapan

AustraliaAustraliaNew ZealandNew Zealand

South CentralSouth CentralAsiaAsia

Northern Northern AfricaAfrica

Southern Southern AfricaAfrica

Central Central AmericaAmerica

WesternWestern Europe Europe

NorthNorthAmericaAmerica

OVARIAN CANCEROVARIAN CANCERRisk factorsRisk factors

Increasing ageIncreasing age

Nulliparous historyNulliparous history

Non-use of oral contraceptivesNon-use of oral contraceptives

Personal history of breast cancerPersonal history of breast cancer

Family historyFamily history

Genetic cancer syndromeGenetic cancer syndrome BRCA 1/BRCA 2BRCA 1/BRCA 2 Hereditary non-polyposis colon cancerHereditary non-polyposis colon cancer

American Cancer Society. Cancer Facts & Figures—1999;13.

Lynch HT et al. Semin Oncol. 1998;25:265-280.

OVARIAN CANCEROVARIAN CANCEREarly detectionEarly detection

Early detection is rare due to: Early detection is rare due to: Lack of accurate screening methods Lack of accurate screening methods Late appearance of signs and symptomsLate appearance of signs and symptoms Insidious, nonspecific symptomsInsidious, nonspecific symptoms

American Cancer Society. Cancer Facts & Figures—1999;13.

NCI. A 16-year randomized screening study for prostate, lung, colorectal, and ovarian cancer—PLCO trial. http://Cancernet.nci.nih.gov/

Rosenthal A, Jacobs I. Semin Oncol. 1998;25:315-325.

Stern JL. Everyone’s Guide to Cancer Therapy. 1997;602.

OVARIAN CANCEROVARIAN CANCERScreeningScreening

Currently available techniquesCurrently available techniques Pelvic examPelvic exam Transvaginal ultrasoundTransvaginal ultrasound Serum CA 125Serum CA 125

None sufficiently accurate for general screeningNone sufficiently accurate for general screening

Routine screening not recommendedRoutine screening not recommended

Evaluation of a panel of more sensitive tumor markers Evaluation of a panel of more sensitive tumor markers (eg, CA 125, M-CSF, OVX-1) may improve detection of (eg, CA 125, M-CSF, OVX-1) may improve detection of early-stage diseaseearly-stage disease

NCI PLCO trial evaluating TVUS + CA 125NCI PLCO trial evaluating TVUS + CA 125

Ozols RF, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1509.

NCI. A 16-year randomized screening study for prostate, lung, colorectal, and ovarian cancer—PLCO trial. http://Cancernet.nci.nih.gov/

OVARIAN CANCEROVARIAN CANCERPathogenesisPathogenesis

Common epithelial tumors account forCommon epithelial tumors account for 60% of ovarian neoplasms60% of ovarian neoplasms 80%-90% of ovarian malignancies80%-90% of ovarian malignancies

Most common form of tumor spread: Most common form of tumor spread: exfoliation of malignant cells through the exfoliation of malignant cells through the epithelial surface of ovarian capsuleepithelial surface of ovarian capsule

Malignant cells circulate in peritoneal fluid Malignant cells circulate in peritoneal fluid and through lymphaticsand through lymphatics

Late presentation with metastatic disease Late presentation with metastatic disease outside the peritoneumoutside the peritoneum

Ozols RF, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1503-1504.

Berek JS, Hacker NF. Cancer Treatment. 4th ed. 1995;628-661.

OVARIAN CANCEROVARIAN CANCERPrognostic factorsPrognostic factors

FIGO StageFIGO Stage

Patient’s agePatient’s age

Postsurgical volume of residual diseasePostsurgical volume of residual disease

Postsurgical CA 125Postsurgical CA 125

Histologic subtypeHistologic subtype

Histologic gradeHistologic grade

Ozols RF, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1510.

OVARIAN CANCEROVARIAN CANCERSurvival by stageSurvival by stage

FIGO StageFIGO Stage 5-Year Survival5-Year Survival

II > 90%

IIII 80%

IIIIII 15% to 20%

IVIV < 5%

Ozols RF, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1510-1511.

Current Management for Current Management for

Epithelial Ovarian Epithelial Ovarian CancerCancer Surgical staging and cytoreduction at Surgical staging and cytoreduction at

diagnosisdiagnosis Postoperative chemotherapy for high-risk Postoperative chemotherapy for high-risk

limited stage and all advanced stage limited stage and all advanced stage patientspatients

ChemotherapyChemotherapy IV paclitaxel (175 mg/mIV paclitaxel (175 mg/m22 over 3 hrs) plus IV over 3 hrs) plus IV

carboplatin (AUC 6.0-7.5) for 6 cyclescarboplatin (AUC 6.0-7.5) for 6 cycles

Vast majority of patients with advanced Vast majority of patients with advanced stage ovarian cancer will relapsestage ovarian cancer will relapse

1. National Cancer Institute. NCI Clinical Announcement. January 2006.

Treatment Treatment ConsiderationsConsiderations

in Recurrent Ovarian in Recurrent Ovarian CancerCancer DefinitionsDefinitions

Refractory diseaseRefractory disease: no response or : no response or incomplete response to platinum-based incomplete response to platinum-based therapytherapy

Relapsed diseaseRelapsed disease: progression after clinical : progression after clinical complete responsecomplete response

Platinum sensitive: Platinum sensitive: 12 month platinum-free 12 month platinum-free intervalinterval

Partially Platinum sensitive: 6-12 month platinum-Partially Platinum sensitive: 6-12 month platinum-free intervalfree interval

Platinum resistant: Platinum resistant: 6 month platinum-free 6 month platinum-free intervalinterval

Treatment Modalities for Treatment Modalities for Recurrent Ovarian Recurrent Ovarian

CancerCancer ChemotherapyChemotherapy

Primary modalityPrimary modality SurgerySurgery

Late relapse with potential for complete Late relapse with potential for complete resectionresection

Bowel obstructionBowel obstruction RadiationRadiation

Palliation for drug-resistant, Palliation for drug-resistant, symptomatic, isolated lesionssymptomatic, isolated lesions

Chemotherapy Principles in Chemotherapy Principles in Recurrent Ovarian CancerRecurrent Ovarian Cancer

Combinations are superior to single-agent Combinations are superior to single-agent platinum in platinum in platinum-sensitiveplatinum-sensitive patients patients Multiple agents have clinical activityMultiple agents have clinical activity Activity superior in platinum-sensitive Activity superior in platinum-sensitive

patientspatients No established role for combinations in No established role for combinations in

platinum-resistant diseaseplatinum-resistant disease Management considerationsManagement considerations

Length of treatment and “drug holidays”Length of treatment and “drug holidays” Choice of combination in platinum-sensitive patientsChoice of combination in platinum-sensitive patients Choice of drug in platinum-resistant patientsChoice of drug in platinum-resistant patients Maintenance chemotherapyMaintenance chemotherapy

Active Agents in Active Agents in Recurrent Ovarian Recurrent Ovarian

CancerCancer CarboplatinCarboplatin TaxanesTaxanes PaclitaxelPaclitaxel DocetaxelDocetaxel TopotecanTopotecan Liposomal Liposomal

doxorubicindoxorubicin GemcitabineGemcitabine

Less commonly Less commonly usedused

Oral Oral etoposideetoposide

AltretamineAltretamine TamoxifenTamoxifen VinorelbineVinorelbine

Platinum-Platinum-sensitive ovarian sensitive ovarian

cancercancer

Chemotherapy for Chemotherapy for Platinum-SensitivePlatinum-SensitiveRecurrent Ovarian Recurrent Ovarian

CancerCancer ““Old standard”Old standard” Single-agent carboplatinSingle-agent carboplatin

““New standard”New standard” Paclitaxel plus carboplatinPaclitaxel plus carboplatin Gemcitabine plus carboplatinGemcitabine plus carboplatin

Other combinations under evaluationOther combinations under evaluation Liposomal doxorubicin plus carboplatinLiposomal doxorubicin plus carboplatin Biologic agents plus chemotherapyBiologic agents plus chemotherapy

GINECO:GINECO: phase II Carboplatin (PA) and phase II Carboplatin (PA) and PLD (CA; PACA regimen) in patients with PLD (CA; PACA regimen) in patients with

AOC in late (>6 ms) relapse (AOCLR): AOC in late (>6 ms) relapse (AOCLR): trial. trial. 2004 ASCO 2004 ASCO Abstract No: 5022 Abstract No: 5022 J.-M. J.-M.

Ferrero et al.Ferrero et al. Published in Published in Annals of Annals of OncologyOncology, November 15, 2006, November 15, 2006

Methods:Methods: 105 pts received a q4w schedule of CA (30 105 pts received a q4w schedule of CA (30

mg/m², d1) followed by PA (AUC 5 mg.ml-mg/m², d1) followed by PA (AUC 5 mg.ml-1.mn, d1) 1.mn, d1) median 6 cycles median 6 cycles

Patients and methods:Patients and methods: The median age was 61 years (23-79), 47% The median age was 61 years (23-79), 47%

had PS 1-2 had PS 1-2 66% had serous histology; 54% had 66% had serous histology; 54% had MD; and 86% had CA-125 levels >40 IU/ml. MD; and 86% had CA-125 levels >40 IU/ml.

ResultsResults:: The ORR is 63% (65/105 pts) including 38% with CR The ORR is 63% (65/105 pts) including 38% with CR Median PFS is 9 months. Median OS 31.1-monthMedian PFS is 9 months. Median OS 31.1-month NCI G 3-4 neutropenia (23% of cycles), anemia (4%) and NCI G 3-4 neutropenia (23% of cycles), anemia (4%) and

thrombocytopenia (8%). thrombocytopenia (8%). G 2-3 nausea/vomiting (32%), G 2 PPE (11%), and G 2-3 G 2-3 nausea/vomiting (32%), G 2 PPE (11%), and G 2-3

mucositis (12%).mucositis (12%). ConclusionsConclusions: :

PLD plus Carboplatin is highly effective, prolongs OS, and is PLD plus Carboplatin is highly effective, prolongs OS, and is well tolerated in women with AOC in late relapse previously well tolerated in women with AOC in late relapse previously treated with both platinum and taxanes.treated with both platinum and taxanes.

GINECO: phase II Carboplatin (PA) and GINECO: phase II Carboplatin (PA) and PLD (CA; PACA regimen) in patients with PLD (CA; PACA regimen) in patients with

AOC in late (>6 ms) relapse (AOCLR): AOC in late (>6 ms) relapse (AOCLR): trial. trial. 2004 ASCO 2004 ASCO Abstract No: 5022 Abstract No: 5022 J.-M. J.-M.

Ferrero et al.Ferrero et al. Published in Published in Annals of Annals of OncologyOncology, November 15, 2006, November 15, 2006

Platinum-Platinum-refractory refractory

ovarian cancerovarian cancer

Management of Management of Platinum-Resistant Platinum-Resistant Recurrent Ovarian Recurrent Ovarian

CancerCancer Remissions are achievable in about 20% of Remissions are achievable in about 20% of patients using the most active single agents:patients using the most active single agents: tubulin interacting agents (taxans, vinorelbine)tubulin interacting agents (taxans, vinorelbine) Liposomal doxorubicinLiposomal doxorubicin topoisomerase-II-inhibitors (anthracyclines, etoposid)topoisomerase-II-inhibitors (anthracyclines, etoposid) TopotecanTopotecan GemcitabineGemcitabine

Which is better?Which is better? Few randomized trials have been performedFew randomized trials have been performed

Topotecan vs paclitaxelTopotecan vs paclitaxel Liposomal doxorubicin vs topotecanLiposomal doxorubicin vs topotecan Gemcitabine vs liposomal doxorubicinGemcitabine vs liposomal doxorubicin

Until today, no combination regimen has shown Until today, no combination regimen has shown superior results compared with an active single superior results compared with an active single agent in comparative trialsagent in comparative trials

CAELYX® (PLD) 50 mg/m2 q 4 wks

Topotecan 1.5 mg/m2/day for5 consecutive days, q 3 wks

RRAANNDDOOMMIIZZAATTIIOONN

Enrollment- recurrent epithelial ovarian cancer

- 474 patients- 104 US and international sites

Endpoints

Primary- time to progression

Secondary- overall survival - response rate- toxicity

Gordon AN, et al. J Clin Oncol. 2001;19:3312-3322.

30-49 Study Design30-49 Study Design

PLD vs Topotecan in PLD vs Topotecan in Recurrent/Refractory Ovarian Recurrent/Refractory Ovarian

CancerCancer

Gordon AN, et al. Gynecol Oncol. 2004;95:1-8.

100

90

80

70

60

50

40

30

20

10

0

0 20 40 60 80 100 120 140 160 180 200 220 240 260

Weeks Since Randomization

Pegylated liposomalDoxorubicin (n = 240)

Topotecan (n = 241)

Ove

rall

Su

rviv

al (

%)

Median Survival

Pegylated liposomal doxorubicin: 62.7 wks

Topotecan: 59.7 wks

Hazard ratio: 1.23 (95% CI: 1.01-1.50); P = .038

PLD vs Topotecan: PLD vs Topotecan: Patients With Platinum-Patients With Platinum-

Refractory DiseaseRefractory Disease100

90

80

70

60

50

40

30

20

10

0

Weeks Since First Dose

Ove

rall

Su

rviv

al (

%)

Pegylated liposomaldoxorubicin (n = 130)

Topotecan (n = 125)

No significant difference in survival

HR: 1.069 (95% CI: .823-1.387); P = .618

0 20 40 60 80 100 120 140 160 180 200 220 240 260

Gordon AN, et al. Gynecol Oncol. 2004;95:1-8.

PLD vs Topotecan: PLD vs Topotecan: Patients With Platinum-Patients With Platinum-

Sensitive DiseaseSensitive Disease100

90

80

70

60

50

40

30

20

10

00 20 40 60 80 100 120 140 160 180 200 220 240 260

Weeks Since First Dose

Ove

rall

Su

rviv

al (

%)

Pegylated liposomaldoxorubicin (n = 109)

Topotecan (n = 110)

Median Survival

Pegylated liposomal doxorubicin: 107.9 wks

Topotecan: 70.1 wks

HR: 1.432 (95% CI: 1.066-1.923); P = .017

Gordon AN, et al. Gynecol Oncol. 2004;95:1-8.

PEG PEG Liposomal Liposomal

doxorubicin doxorubicin

%%TopotecTopotec

an %an % p valuep value

NeutropeniaNeutropenia 3535 8181 0.0010.001

AnaemiaAnaemia 3535 7272 0.0010.001

ThrombocytoThrombocytopeniapenia 1313 6565 0.0010.001

LeukopeniaLeukopenia 3636 6464 0.0010.001

AlopeciaAlopecia 1616 4949 0.0010.001

PPEPPE 4949 00 0.0010.001

StomatitisStomatitis 4040 1515 0.0010.001

Related Adverse Events: All Related Adverse Events: All GradesGrades

PPE, palmar-plantar erythema.

Related Adverse Events: Related Adverse Events: Grades 3/4 Grades 3/4

PLDPLD%%

TopotecTopotecanan%%

p p valuevalue

NeutropeniaNeutropenia 1212 7777 0.0010.001

AnaemiaAnaemia 55 2828 0.0010.001

ThrombocytoThrombocytopeniapenia 11 3434 0.0010.001

LeukopeniaLeukopenia 1010 5050 0.0010.001

AlopeciaAlopecia 11 66 0.0070.007

PPEPPE 2323 00 0.0010.001

StomatitisStomatitis 88 00 0.0010.001

Growth Factor Support/Growth Factor Support/Blood Transfusions Blood Transfusions

PEG PEG LiposomLiposom

al al doxorubidoxorubi

cincin%%

TopotecTopotecanan%%

p p valuevalue

G-CSF or GM-G-CSF or GM-CSFCSF

55 2929 0.0010.001

ErythropoietiErythropoietinn

66 2323 0.0010.001

Blood Blood transfusionstransfusions

1616 5959 0.0010.001

PLD vs TopotecanPLD vs Topotecan

In conclusion:In conclusion: This long-term follow up analysis demonstrates This long-term follow up analysis demonstrates

that treatment with pegylated liposomal that treatment with pegylated liposomal doxorubicin significantly prolongs survival doxorubicin significantly prolongs survival compared with Topotecan in patients with compared with Topotecan in patients with recurrent or refractory epithelial ovarian cancer.recurrent or refractory epithelial ovarian cancer.

The results of this analyses, as well as the ease The results of this analyses, as well as the ease of administration and adverse event profile, of administration and adverse event profile, suggest that PLD is the treatment of choice suggest that PLD is the treatment of choice among non-platinum agents for patients with among non-platinum agents for patients with relapsed ovarian cancer, especially those with relapsed ovarian cancer, especially those with platinum-sensitive disease.platinum-sensitive disease.

Gordon AN, et al. Gynecologic Oncology 95 (2004) 1-8.

Thank you!