Download Ovarian Cancer (2)

Treatment of Refractory
Ovarian Cancer
OVARIAN CANCER
Worldwide incidence*
Western
Europe
10.0
Eastern
Europe
11.5
Japan
6.4
Australia
New Zealand
9.6
South Central
Asia
5.4
Northern
Africa
2.8
Southern
Africa
5.3
Central
America
7.6
North
America
11.2
*Incidence per 100,000 population.
Parkin DM, et al. CA Cancer J Clin. 1999;49:61.
OVARIAN CANCER
Risk factors

Increasing age

Nulliparous history

Non-use of oral contraceptives

Personal history of breast cancer

Family history

Genetic cancer syndrome

BRCA 1/BRCA 2

Hereditary non-polyposis colon cancer
American Cancer Society. Cancer Facts & Figures—1999;13.
Lynch HT et al. Semin Oncol. 1998;25:265-280.
OVARIAN CANCER
Early detection
Early detection is rare due to:

Lack of accurate screening methods

Late appearance of signs and symptoms

Insidious, 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.
OVARIAN CANCER
Screening

Currently available techniques

Pelvic exam

Transvaginal ultrasound

Serum CA 125

None sufficiently accurate for general screening

Routine screening not recommended

Evaluation of a panel of more sensitive tumor markers
(eg, CA 125, M-CSF, OVX-1) may improve detection
of early-stage disease
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/

NCI PLCO trial evaluating TVUS + CA 125
OVARIAN CANCER
Pathogenesis

Common epithelial tumors account for

60% of ovarian neoplasms

80%-90% of ovarian malignancies

Most common form of tumor spread:
exfoliation of malignant cells through
the epithelial surface of ovarian capsule

Malignant cells circulate in peritoneal
fluid and through lymphatics
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 CANCER
Prognostic factors

FIGO Stage

Patient’s age

Postsurgical volume of residual disease

Postsurgical CA 125

Histologic subtype

Histologic grade
Ozols RF, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1510.
OVARIAN CANCER
Survival by stage
FIGO Stage
5-Year Survival
I
> 90%
II
 80%
III
15% to 20%
IV
< 5%
Ozols RF, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1510-1511.
Current Management for
Epithelial Ovarian Cancer



Surgical staging and cytoreduction at diagnosis
Postoperative chemotherapy for high-risk
limited stage and all advanced stage patients
Chemotherapy


IV paclitaxel (175 mg/m2 over 3 hrs) plus IV
carboplatin (AUC 6.0-7.5) for 6 cycles
Vast majority of patients with advanced stage
ovarian cancer will relapse
1. National Cancer Institute. NCI Clinical Announcement. January 2006.
Treatment Considerations
in Recurrent Ovarian Cancer

Definitions
Refractory disease: no response or incomplete response
to platinum-based therapy
 Relapsed disease: progression after clinical complete
response

Platinum sensitive:  12 month platinum-free interval
 Partially Platinum sensitive: 6-12 month platinum-free
interval
 Platinum resistant:  6 month platinum-free interval

Treatment Modalities for
Recurrent Ovarian Cancer

Chemotherapy


Primary modality
Surgery
Late relapse with potential for complete resection
 Bowel obstruction


Radiation

Palliation for drug-resistant, symptomatic, isolated
lesions
Chemotherapy Principles in
Recurrent Ovarian Cancer

Combinations are superior to single-agent
platinum in platinum-sensitive patients
Multiple agents have clinical activity
 Activity superior in platinum-sensitive patients



No established role for combinations in platinumresistant disease
Management considerations




Length of treatment and “drug holidays”
Choice of combination in platinum-sensitive patients
Choice of drug in platinum-resistant patients
Maintenance chemotherapy
Active Agents in
Recurrent Ovarian Cancer


Carboplatin
Taxanes

Topotecan
Liposomal
doxorubicin
Gemcitabine




Paclitaxel
Docetaxel
Less commonly
used
 Oral etoposide
 Altretamine
 Tamoxifen
 Vinorelbine
Platinum-sensitive
ovarian cancer
Chemotherapy for PlatinumSensitive
Recurrent Ovarian Cancer

“Old standard”


Single-agent carboplatin
“New standard”
Paclitaxel plus carboplatin
 Gemcitabine plus carboplatin


Other combinations under evaluation
Liposomal doxorubicin plus carboplatin
 Biologic agents plus chemotherapy

GINECO: phase II Carboplatin (PA) and PLD (CA;
PACA regimen) in patients with AOC in late (>6 ms)
relapse (AOCLR): trial. 2004 ASCO Abstract No: 5022 J.M. Ferrero et al. Published in Annals of Oncology,
November 15, 2006

Methods:


105 pts received a q4w schedule of CA (30
mg/m², d1) followed by PA (AUC 5 mg.ml1.mn, d1) median 6 cycles
Patients and methods:
 The
median age was 61 years (23-79), 47%
had PS 1-2 66% had serous histology; 54% had
MD; and 86% had CA-125 levels >40 IU/ml.
GINECO: phase II Carboplatin (PA) and PLD (CA;
PACA regimen) in patients with AOC in late (>6 ms)
relapse (AOCLR): trial. 2004 ASCO Abstract No: 5022
J.-M. Ferrero et al. Published in Annals of Oncology,
November 15, 2006
 Results:





The ORR is 63% (65/105 pts) including 38% with CR
Median PFS is 9 months. Median OS 31.1-month
NCI G 3-4 neutropenia (23% of cycles), anemia (4%) and
thrombocytopenia (8%).
G 2-3 nausea/vomiting (32%), G 2 PPE (11%), and G 2-3
mucositis (12%).
Conclusions:

PLD plus Carboplatin is highly effective, prolongs OS, and is
well tolerated in women with AOC in late relapse previously
treated with both platinum and taxanes.
Platinum-refractory
ovarian cancer

Management of PlatinumResistant
Recurrent Ovarian Cancer
Remissions are achievable in about 20% of patients using the
most active single agents:





tubulin interacting agents (taxans, vinorelbine)
Liposomal doxorubicin
topoisomerase-II-inhibitors (anthracyclines, etoposid)
Topotecan
Gemcitabine
Which is better?
 Few randomized trials have been performed




Topotecan vs paclitaxel
Liposomal doxorubicin vs topotecan
Gemcitabine vs liposomal doxorubicin
Until today, no combination regimen has shown superior results
compared with an active single agent in comparative trials
30-49 Study Design
Enrollment
- recurrent epithelial ovarian
cancer
- 474 patients
- 104 US and international
sites
Endpoints
Primary
- time to progression
Secondary
- overall survival
- response rate
- toxicity
R
A
N
D
O
M
I
Z
A
T
I
O
N
Gordon AN, et al. J Clin Oncol. 2001;19:3312-3322.
CAELYX® (PLD) 50 mg/m2 q 4 wks
Topotecan 1.5 mg/m2/day for
5 consecutive days, q 3 wks
PLD vs Topotecan in
Recurrent/Refractory Ovarian Cancer
100
Median Survival
Pegylated liposomal doxorubicin: 62.7 wks
Topotecan: 59.7 wks
Hazard ratio: 1.23 (95% CI: 1.01-1.50); P = .038
Overall Survival (%)
90
80
70
60
50
Pegylated liposomal
Doxorubicin (n = 240)
40
30
20
10
Topotecan (n = 241)
0
0
20
40
60
80
100
120
140
160
180
Weeks Since Randomization
Gordon AN, et al. Gynecol Oncol. 2004;95:1-8.
200
220
240
260
PLD vs Topotecan: Patients With
Platinum-Refractory Disease
100
Overall Survival (%)
90
No significant difference in survival
80
HR: 1.069 (95% CI: .823-1.387); P = .618
70
60
50
Pegylated liposomal
doxorubicin (n = 130)
40
30
20
Topotecan (n = 125)
10
0
0
20
40
60 80
100 120 140 160 180 200 220 240 260
Weeks Since First Dose
Gordon AN, et al. Gynecol Oncol. 2004;95:1-8.
PLD vs Topotecan: Patients With
Platinum-Sensitive Disease
100
Median Survival
Pegylated liposomal doxorubicin: 107.9 wks
Topotecan: 70.1 wks
HR: 1.432 (95% CI: 1.066-1.923); P = .017
90
Overall Survival (%)
80
70
60
50
Pegylated liposomal
doxorubicin (n = 109)
40
30
20
Topotecan (n = 110)
10
0
0
20
40
60
80 100 120 140 160 180 200 220 240 260
Weeks Since First Dose
Gordon AN, et al. Gynecol Oncol. 2004;95:1-8.
Related Adverse Events: All Grades
Neutropenia
PEG Liposomal
doxorubicin
Topotecan
%
%
35
81
p value
0.001
Anaemia
35
72
0.001
Thrombocytopeni
a
13
65
0.001
Leukopenia
36
64
0.001
Alopecia
16
49
0.001
PPE
49
0
0.001
PPE, palmar-plantar erythema.
Stomatitis
40
15
0.001
Related Adverse Events:
Grades 3/4
Neutropenia
Anaemia
Thrombocytopen
ia
Leukopenia
Alopecia
PPE
Stomatitis
PLD
%
12
5
Topotecan
%
p value
77
0.001
28
0.001
1
34
0.001
10
1
23
8
50
6
0
0
0.001
0.007
0.001
0.001
Growth Factor Support/
Blood Transfusions
G-CSF or GMCSF
Erythropoietin
Blood transfusions
PEG
Liposomal
doxorubicin Topotecan
%
%
p value
5
29
0.001
6
23
0.001
16
59
0.001
PLD vs Topotecan

In conclusion:


This long-term follow up analysis demonstrates that
treatment with pegylated liposomal doxorubicin significantly
prolongs survival compared with Topotecan in patients with
recurrent or refractory epithelial ovarian cancer.
The results of this analyses, as well as the ease of
administration and adverse event profile, suggest that PLD is
the treatment of choice among non-platinum agents for
patients with relapsed ovarian cancer, especially those with
platinum-sensitive disease.
Gordon AN, et al. Gynecologic Oncology 95 (2004) 1-8.
Thank you!