The document discusses treatment options for relapsed ovarian cancer, noting that combination chemotherapy with paclitaxel plus platinum shows improved response rates and progression-free survival over platinum alone based on the ICON4 trial. Secondary cytoreduction surgery may provide a benefit for highly selected patients with isolated recurrence and long treatment-free interval. Emerging anti-angiogenic therapies targeting VEGF/VEGFR pathways such as bevacizumab are also being investigated in relapsed ovarian cancer.

1. How I treat Relapsed Ca. Ovary
CK Das MD, DM
Assistant Professor Medical Oncology
Regional Cancer Center, PGIMER, Chandigarh

3. Ovarian Cancer Staging
Stage I - Limited to ovaries
A. Unilateral ovary
B. Bilateral ovaries
C. Positive cytology
Stage II - Limited to pelvis
A. Extends to uterus or tubes
B. other pelvic organs
C. Positive cytology
Stage III – Spread to upper abdomen or regional lymph nodes
A. Microscopic spread
B. Macroscopic < 2 cm
C. Macroscopic > 2 cm
Stage IV - Spread outside peritoneum, pleura or parenchymal
liver metastases

4. Ovarian Cancer
FIGO Staging System
Stage Description Incidence Survival
I Confined to ovaries 20% 73%
II Confined to pelvis 5% 45%
III Confined to abdomen/ 58% 21%
lymph nodes
IV Distant metastases 17% <5%
Jelic S, et al. Program and abstracts of the 27th Congress of the European
Society for Medical Oncology; 2002; Nice, France.
Mocharnuk R. Medscape Web site.
http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007.
FIGO = International
Federation of Gynecology
and Obstetrics

5. Ovarian Carcinoma:
Clinical Course
Symptoms
Diagnosis
Chemotherapy #1
Staging
Primary cytoreduction
Interval
Cytoreduction
Progression
Chemo #2 Chemo #3+
Supportive
Care
Death
Consolidation/
Maintenance
Cure
Secondary
CytoreductionSecond-Look

6. Ovarian Cancer Patients in Remission
• Second-look laparotomy
• Physical examination
– Include pelvic examination
• CA-125
• Imaging
– CT scan
CT = computed tomography
MRI = magnetic resonance imaging
PET = positron emission tomography

7. TP

8. Biology of Relapse

9. Goals of Treatment:
Relapsed Ovarian Cancer
Prolong Survival
Delay Time to Progression
Control Disease-Related Symptoms
Minimize Treatment-Related Symptoms
Maintain or Improve Quality of Life

10. Population Study Treatment PFS
Optimal St III GOG 114 IV Carb & Pac, IP Cis 28 mos
GOG 172 IV Pac, IP Cis & Pac 24 mos
GOG 158 IV Pac & Carb 21 mos
GOG 114 IV Pac & Cis 22 mos
GOG 158 IV Pac & Cis 19 mos
GOG 172 IV Pac & Cis 18 mos
Suboptimal III & IV GOG 111 IV Pac & Cis 18 mos
GOG 162 IV Pac Cis 12 mos
GOG 152 IV Pac Cis 11 mos
Stage IC-IV SCOTROC Doc Carbo 15 mos
Stage IC-IV SCOTROC Pac Carbo 15 mos
All Stage III & IV GOG 182 IV Pac/Carbo x 8 16 mos
When Does Ovarian Cancer Recur?
Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel;
GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel

11. Ovarian Cancer:
How is Relapse Defined?
Continuous rise in CA-125
CA-125 above 100
Radiographic recurrence
Symptomatic recurrence
Physical examination findings
Combination of above

12. Issues Impacting Therapy for
Recurrent Ovarian Cancer
• Treatment-free interval
– Impact of consolidation/maintenance therapy
• Number of prior regimens
– Response to prior therapy
• Toxicity from prior therapy
– Prior use of growth factors
– Transfusion requirements
– Neuropathy
• Volume and site(s) of disease
– Ascites/GI symptoms
– Performance status

13. Platinum Sensitivity

14. Effect of Platinum-Free Interval
on Response Rate
% Response to Second-line
Platinum Therapy
Platinum-Free
Interval (mos)
Markman Gore Blackledge
0-6
17%
10%
7-12 27% 29%
13-18
33% 27%
63%
19-24 94%
>24 59% 57%
Non-Platinum
Therapy
15%
20%
30%
30%
Markman M, et al. J Clin Oncol. 1991;9(3):389-393.
Gore ME, et al. Gynecol Oncol. 1990;36:207-211.
Blackledge G, et al. Br J Cancer. 1989;59:650-653.

15. Options we have: NCCN

17. ICON 4 :TP
• Relapsed ovarian or primary
• Peritoneal requiring
chemotherapy
• Previous platinum-based
chemotherapy
Conventional
platinum-based
chemotherapy
Paclitaxel plus
platinum
chemotherapy
R
A
N
D
O
M
I
Z
E
Prior chemotherapy
• Carboplatin (31%)
• Paclitaxel/platinum (40%)
• Other (30%)
TFI > 12 months for 75%
Parmar MK, et al. Lancet. 2003;361:2099-2106.
ICON = International Collaborative Ovarian Neoplasm Group
TFI = treatment-free interval

18. ICON 4 Response
Plat
(n = 128)
Pac-Plat
(n = 119)
CR or PR 54% 66%
(Difference of 12%; 95% CI -0.1% to 24%; p=0.06)
CR = complete response; ICON = International Collaborative
Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum;
PR = partial response;Parmar MK, et al. Lancet. 2003;361:2099-2106.

19. Proportionaliveand
progression-free
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4
Patients at risk
Pac-Plat 392 179 52 25 17
Plat 410 157 45 17 7
Years from randomization
Pac-Plat
Plat
Hazard ratio = 0.76
(95% CI 0.66 - 0.89; p < 0.001)
Absolute difference at 1 year = 10%
(40% to 50%; 95% CI 4% to 15%)
Ovarian Carcinoma:
ICON 4 Progression-Free Survival
Parmar MK, et al. Lancet. 2003;361:2099-2106.
ICON = International Collaborative Ovarian Neoplasm Group;
Pac = paclitaxel; Plat = platinum

20. Hazard ratio = 0.82
(95% CI 0.69 - 0.97; p = 0.023)
Absolute difference 2 years = 7%
(50% to 57%; 95% CI 1% to 12%)
Patients at risk
Pac-Plat 392 306 167 96 43
Plat 410 295 150 68 33
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4
Years from randomization
Proportion
alive
Pac-Plat
Plat
ICON 4: Overall Survival
Parmar MK, et al. Lancet. 2003;361:2099-2106.
ICON = International Collaborative Ovarian Neoplasm Group;
Pac = paclitaxel; Plat = platinum

21. R
A
N
D
O
M
I
Z
E
Gemcitabine 1,000 mg/m2
days 1 + 8 Plus
Carboplatin AUC 4 day 1
every 21 days × 6
• Recurrent ovarian cancer
• 6+ months after platinum
• Strata
– PFI (6 - 12, >12 months)
– 1st-line therapy (platinum
± paclitaxel)
– Measurable vs evaluable
• Primary endpoint = PFS
AGO OVAR 2.5 :Gem/Carbo
Carboplatin AUC 5 day 1
every 21 days × 6
Carbo = carboplatin
Gem = gemcitabine
PFI = progression-free interval
PFS = progression-free survivalPfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707.

22. AGO OVAR 2.5 Primary Endpoint: Progression-
Free Survival
0 3 6 9 12 15 18 21 24 27 30 33 36 39
0.0
0.2
0.4
0.6
0.8
1.0
Progression-Free Survival Time (mo)
Progression-FreeProbability
GCb: median = 8.6 mo
Censoring: 12.4%
Cb: median = 5.8 mo
Censoring: 12.9%
Cb Arm (N=178)
GCb Arm (N=178)
Log-rank p-value = 0.0038
Unadjusted HR = 0.72 (0.57 to 0.90)
Adjusted HR* = 0.71 (0.57 to 0.89)
* Adjusted for PFI, Tumor size
Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707.
AGO = Arbeitsgemeinschaft Gynaekologische
Onkologie; GCb = gemcitabine; Cb = carboplatin

23. AGO OVAR 2.5 Efficacy Results:
Overall Survival
0.0
0.8
0.2
0.3
0.4
0.5
0.6
0.7
0.9
1.0
0.1
0 6 12 18 60544842363024
ProportionSurviving
Months
Median = 18.0 mo
Censoring: 18.5%
Median = 17.3 mo
Censoring: 22.5%
Cb Arm (N=178)
GCb Arm (N=178)
* Adjusted for PFI, Tumor size and performance status
Log-rank p-value = 0.7349
Unadjusted HR = 0.96 (0.75 to 1.23)
Adjusted* HR = 0.92 (0.72 to 1.16)
Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707.
AGO = Arbeitsgemeinschaft
Gynaekologische Onkologie; GCb = gemcitabine;
Cb = carboplatin

24. GCIG :CALYPSO PLD-CARBO
Ovarian Cancer
Platinum Sens.
Stratify:
< 0.5 cm
> 0.5-2 cm
R
A
N
D
O
M
I
Z
E
PLD
30 mg/m2
Carboplatin AUC = 5
q 28 days x 6
Paclitaxel 175 mg/m2
Carboplatin AUC = 5
q 21 days x 6
GCIG = Gynecologic Cancer Intergroup
PFS = progression-free survival
PLD = pegylated liposomal doxorubicin
Accrual Completed
(Target accrual 864 pts)
PFS 1° endpoint

25. Secondary
Cytoreduction
• Controversial
• Inconsistent definitions
• Benefit appears confined to
patients likely to respond
to additional chemo:
• >12 month PFI
• Isolated site of
recurrence
• Disease completely
resectable
Kidney
Resected Liver
Diaphragm
Kidney
Vena Cava
Tumor Mass
Renal Vein
PFI = progression-free interval

26. TTP
mos
>12
>12
>12
>17.5
>36
>24
12-24
>24
Ovarian Cancer Secondary Cytoreduction:
Post-Surgery Survival
Author
Janicke
Segna
Zang
Gadducci
Eisenkop
Munkarah
Scarabelli
Tay
Total/Range
Year
1992
1993
2000
2000
2000
2001
2001
2002
N
30
100
60
30
114
25
148
46
553
Survival
Median
mos
16
16.6
13
21
16.8
26
13-26
TTP
mos
<12
<12
<12
<17.5
<12
<24
<12
<12
Survival
Median
mos
8
8.8
8
15
25
42
12
6
6-42
Survival
Median
mos (P)
29 (0.002)
22.9 (0.007)
12 (0.02)
25 (0.04)
56.8 (0.005)
57 (NS)
32 (0.001)
39 (0.001)
12-56
TTP = time to progression

27. Cochrane Review of Tamoxifen for
Relapsed Ovarian Cancer
• 13 studies (11non-randomized series, 1 non-
randomized phase II and 1 randomized trial)
• 59 of 568 women (10.4%) treated with tamoxifen
achieved an objective response (RR)
– RR varied from 0% to 56%
– Stable disease, for variable periods of 4 weeks or more, in
109 of 356 (30.6%) from 8 studies
– Not enough data to assess duration of RR, survival, or the
effect of tamoxifen on quality of life
• No reliable data from randomized controlled trials
Williams CJ. Cochrane Database Syst Rev. 2000;(2):CD001034. RR = response rate

28. Rationale for Targeting VEGF in Treatment
of Epithelial
Ovarian Cancer
• Human tumors
– VEGF over-expressed in epithelial ovarian cancers,
associated with
• Ascites formation
• Malignant progression
• Poor prognosis
• Preclinical models of solid tumors
– Anti-VEGF therapy:
• Slowing of tumor progression
• Resolution of malignant effusions
• Synergy with cytotoxic agents
Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345.
Burger RA. J Clin Oncol. 2007;25(20):2902-2908. VEGF = vascular endothelial growth factor

29. Antiangiogenic Agents in Testing
for Treatment of Ovarian Cancer
Agent Targets
Ligand binding:
Bevacizumab VEGF-A
VEGF-Trap VEGF-A, -B, -C, -D, -E, PIGF-1 and -2
Receptor binding:
Volociximab 51 integrin
IMC-1121B VEGFR-2
Receptor tyrosine kinase inhibition:
Valatanib VEGFR-1, -2, -3, PDGFR, and c-kit
Sunitinib PDGFR, VEGFR-1, -2, -3, c-kit, Flt-3
AMG-706 VEGFR-1, -2, -3, PDGFR, and c-kit
Sorafenib Raf, VEGFR-2, -3, Flt-3, c-kit, PDGFR- 
Non-receptor kinase inhibition:
Temsirolimus, everolimus mTOR
Enzastaurin PKC- 
Dasatinib Src kinase
EGFR = epidermal growth factor receptor;
Mab = monoclonal antibody; mTOR =
mammalian target of rapamycin; PDGF-R =
platelet derived growth factor receptor;
PKC-b = protein kinase C-beta;
VEGF = vascular endothelial growth factor

30. Agents Targeting the VEGF Pathway
VEGFR-2VEGFR-1
P
PP
PP
PP
P
Endothelial Cell Small-Molecule Inhibitors
Anti-VEGFR
Antibodies
VEGF
Anti-VEGF
Antibodies
(bevacizumab)
Soluble
VEGFRs
(VEGF-TRAP)
Podar K, et al. Blood. 2005;105(4):1383-1395.
VEGF = vascular endothelial growth factor
VEGFR = VEGF receptor

31. Anti-VEGF Toxicities

32. PLATINUM RESISTANT/REFRACTORY
CA OVARY

33. Options

35. PFS

36. Published in: Eric Pujade-Lauraine; Felix Hilpert; Béatrice Weber; Alexander Reuss; Andres Poveda; Gunnar Kristensen; Roberto Sorio; Ignace Vergote; Petronella Witteveen; Aristotelis
Bamias; Deolinda Pereira; Pauline Wimberger; Ana Oaknin; Mansoor Raza Mirza; Philippe Follana; David Bollag; Isabelle Ray-Coquard; JCO 2014, 32, 1302-1308.
DOI: 10.1200/JCO.2013.51.4489
Copyright © 2014

37. Paclitaxel+Pazopanib: MITO-11
paclitaxel :80 mg/m²1, 8, and 15 in a 28-day cycle
pazopanib 800 mg given daily
Progression-free survival :6·35 months [95% CI 5·36–11·02] vs 3·49 months

38. Pemetrexed in Platinum-Resistant EOC: Phase
II GOG Study Schema
Miller DS, et al. ASCO 2008. Abstract 5524.
Day
-7
Folic
acid,
Vitamin
B12
Day
-6
Folic
acid
Day
-5
Stop
NSAID,
folic
acid
Days
-4,-3
Folic
acid
Day
-2
Stop
NSAID,
folic
acid
Day
-1
Dexamethasone,
folic acid
Day
1
Chemotherapy,
dexamethasone,
folic acid
Day
2
Dexamethasone,
folic acid
Patients with persistent or recurrent platinum-resistant
EOC or primary peritoneal cancer who have failed on
higher priority treatment protocols
Pemetrexed 900 mg/m2 IV every 21 days for 1 cycle;
patients who have received previous radiotherapy will initiate
pemetrexed at level I reduction dose until disease progression or
adverse effect prohibits further therapy

39. Phase II GOG Study Evaluation of Pemetrexed:
Clinical Responses
Miller DS, et al. ASCO 2008. Abstract 5524.
Category No. of Cases Pts, %
Response
• CR 1 2.1
• PR 9 18.8
• SD 17 35.4*
• Increasing disease 18 37.5
• Not evaluable 3 6.3
Total 48 100
*1 patient remains on therapy.

41. Take home message