Landmark chemotherapy trials in advanced ovarian cancer established platinum-based combinations as the standard of care. GOG 47 (1986) showed cisplatin improves response rates and progression-free survival compared to cyclophosphamide alone. GOG 111 (1996) found the combination of paclitaxel and cisplatin improved progression-free and overall survival over cyclophosphamide and cisplatin. Subsequent trials determined carboplatin as an effective alternative to cisplatin, with fewer side effects.

1. .
LANDMARK CHEMOTHERAPY
TRIALS IN ADVANCED OVARIAN
CANCER
Dr Sathiyaseelan B
MCh surgical oncology resident
Govt kilpauk medical College
Chennai

2. PROF S.SUBBIAH et al
The alkylating agent CYCLOPHOSPHAMIDE got approval
in 1959.
In advanced ovarian cancer for next 2 decades,
CYCLOPHOSPHAMIDE / MELPHALAN along with either
DOXORUBICIN or 5Fu was used.
In 1978 FDA approved platins (cisplatin) for germ cell
tumor , this leads to initiation of various trials in use of
platins in ovarian cancer.
Till then most widely used regimen for ovarian cancer is
CYCLOPHOSPHAMIDE and DOXORUBICIN

3. PROF S.SUBBIAH et al
GOG 47(1986)
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

4. PROF S.SUBBIAH et al
• The addition of cisplatin improves
response rate( 51 vs 25%), progression
free interval(13.3 vs 7.7 months) in
patients with advanced ovarian cancer
in all patients compared to CA alone.
• A SIGNIFICANT MILESTONE
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

5. PROF S.SUBBIAH et al
GOG 52 (1989)
Randomized trial of cyclophosphamide plus
cisplatin with or without doxorubicin in ovarian
carcinoma.
Arm 1: CP (cyclophosphamide + Cisplatin)
Vs
Arm 2: CAP (Cyclophosphamide + Adriamycin +
Cisplatin)
J Clin Oncol. 1989;7(4):457-465. PMID: 2926470.
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

6. PROF S.SUBBIAH et al
• Doxorubicin does not improve outcomes in
stage III ovarian cancer.
• Progression free interval 22.7 months in CP
and 24.7 Months in CAP.
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

7. PROF S.SUBBIAH et al
GOG 97 (1995)
• The standard therapy at the time of this trial
was the 2-drug regimen of
cyclophosphamide and cisplatin.
• This trial was designed to evaluate
chemotherapy dose intensity on ovarian
cancer patients based on response rate.
• J Clin Oncol. 1995;13(7):1589-1599. PMID:
7602348
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

8. PROF S.SUBBIAH et al
In this trial they doubled the dose of
cyclophosphamide and cisplatin and
reduced the number of cycles.
The median overall survival is about 19.5
months in standard and 21.3 months in dose
intense group with no statistical significance
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

9. PROF S.SUBBIAH et al
• Clinical and pathologic response rates,
and survival were similar between
treatment arms.
• But adverse events (hematologic,
gastrointestinal, febrile episodes,
sepsis, and renal toxicities) were more
common and severe in the dose-
intensive therapy group
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

10. PROF S.SUBBIAH et al
GOG 111 (1996)
• Till now the standard of care for advanced
epithelial ovarian cancer was
cyclophosphamide and cisplatin without
dose intensification.
• However, long- term disease control with
this regimen was less than 10% in stage 3
ovarian cancer
• N Engl J Med. 1996;334(1):1-6. PMID:
7494563.
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

11. PROF S.SUBBIAH et al
• In 1989, a phase II trial reported that
paclitaxel produced a 24% response
rate in patients with advanced ovarian
cancer.
• This made paclitaxel the most active
single- agent drug ever evaluated by
the GOG in a phase II study in ovarian
cancer.
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

12. PROF S.SUBBIAH et al
Arm 1: Standard Therapy Group—
cyclophosphamide + Cisplatin
Vs
Arm 2: Experimental Therapy
Group—
Paclitaxel and Cisplatin
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

13. PROF S.SUBBIAH et al
• Incorporation of paclitaxel into first- line
chemotherapy for patients stage III and IV
epithelial ovarian cancer improved both
progression- free interval (18 vs 13
months)and overall survival (38 vs 24
months)
• Paclitaxel and cisplatin are associated
with an estimated 40% reduction in the
risk of death compared to CP.
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

14. PROF S.SUBBIAH et al
ICON 1 (2001)
Whether platinum-based adjuvant
chemotherapy can improve outcomes in
patients with early-stage epithelial ovarian
cancer (stage l and ll)
Arm 1 : ADJUVANT
CHEMOTHERPY
Vs
Arm 2 : NO CHEMOTHERAPY
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

15. PROF S.SUBBIAH et al
Results suggest that platinum-based
adjuvant chemotherapy improves survival
and delays recurrence and increases the
progression free interval in patients with
early-stage ovarian cancer.
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

16. PROF S.SUBBIAH et al
ICON 2(1998)
Randomised trial of single- agent
carboplatin against three-drug combination of
CAP (cyclophosphamide, doxorubicin, and
cisplatin)
Trial started before the results of GOG 111
hence CAP regimen was used
Lancet. 1998;352(9140):1571-1576. PMID:
9843101
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

17. PROF S.SUBBIAH et al
CONCLUSION
There was no difference in PFS or OS
between CAP and single agent carboplatin.
Single agent carboplatin is a safe
and effective standard treatment option for
patients with advanced ovarian cancer
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

18. PROF S.SUBBIAH et al
ICON 3 (2002)
Its a Randomised control study with 3arms
Control Group— Carboplatin
Control Group— CAP
Vs
Experimental Group— Paclitaxel +
Carboplatin
Lancet. 2002;360 (9332):505-515. PMID:
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

19. PROF S.SUBBIAH et al
• The combination of paclitaxel + carboplatin
is not superior to single agent carboplatin or
CAP.
• ICON3 suggests that single- agent
carboplatin, CAP, and paclitaxel +
carboplatin are all safe and have similar
efficacy as first line treatments for ovarian
cancer.
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

20. PROF S.SUBBIAH et al
DANISH NETHERLANDS TRIAL (Neijt, JCO
2000)
Phase III study of paclitaxel
and cisplatin vs paclitaxel and carboplatin in
advanced ovarian cancer.
Arm 1: Paclitaxel + Cisplatin (Administered
as Inpatient)
Vs
Arm 2: Paclitaxel + Carboplatin
(Administered as Outpatient)
JClin Oncol. 2000;18(17):3084-3092. PMID:
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

21. PROF S.SUBBIAH et al
• feasibility when administered to
outpatients?
• Is neurotoxicity less with carboplatin
compared to cisplatin?
• Are the regimens equal in efficacy?
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

22. PROF S.SUBBIAH et al
• The paclitaxel + carboplatin combination is
safe and easy to administer to outpatients
and is less toxic than paclitaxel + cisplatin.
• Due to the small number of patients the
survival outcomes, conclusions about
efficacy cannot be made with this group.
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

23. PROF S.SUBBIAH et al
GOG 158 (2003)
Phase III trial of carboplatin
and paclitaxel compared with cisplatin and
paclitaxel in patients with optimally resected
stage III ovarian cancer
Control Arm: Paclitaxel + Cisplatin
Vs
Experimental Arm: Paclitaxel +
Carboplatin
. . J Clin Oncol. 2003;21(17):3194-200. PMID:
12860964
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

24. PROF S.SUBBIAH et al
• The combination of paclitaxel plus
carboplatin is not inferior to the
combination of paclitaxel plus cisplatin in
patients stage III epithelial ovarian cancer.
• Median OS 48.7 months (cisplatin group
)57.4 months (carboplatin group)
• There is a 16% reduced risk of death
with carboplatin compared to cisplatin
group.
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

25. PROF S.SUBBIAH et al
AGO/OVAR3 (2003)
Median overall survival 30.7 months
(cisplatin group) 31.4 months carboplatin
group)
Since the carboplatin is more tolerable
than cisplatin with equal treatment efficacy,
the combination of carboplatin with paclitaxel
may be used in patients with advanced
ovarian cancer.
J Natl Cancer Inst. 2003;95(17):1320-9. PMID: 12953086.
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

26. PROF S.SUBBIAH et al
TRIALS CARBOPLATN
GROUP
CISPLATIN
GROUP
OVERALL
SURVIVAL
OVERALL
SURVIVAL
GOG 158 57.4 months 48.7months
AGO/
OVAR3
31.4 months 30.7 months
DANISH NA NA

27. PROF S.SUBBIAH et al
SCOTROC (2004)
Phase II trials of docetaxel in ovarian
cancer demonstrate activity comparable to
paclitaxel
The combination of docetaxel and
carboplatin was found to be feasible.
Arm 1: Paclitaxel + Carboplatin
vs
Arm 2: Docetaxel + Carboplatin
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

28. PROF S.SUBBIAH et al
• Median progression free survival 14.8 months (paclitaxel)
15 months docetaxel)
• 2- year survival 68.9% (paclitaxel) 64.2%(docetaxel)
without statistical significance.

29. PROF S.SUBBIAH et al
CONCLUSION
• Docetaxel- carboplatin is an alternative to
treatment with paclitaxel-carboplatin in the
treatment of patients with stage IC to IV
ovarian cancer.
• Compared to paclitaxel- carboplatin,
docetaxel- carboplatin resulted in greater
myelo suppression but less neurotoxicity
during therapy and follow up.
• J Natl Cancer Inst. 2004;96(22):1682-1691. PMID: 15547181.
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

30. .
How often we should use?

31. PROF S.SUBBIAH et al
JGOG 3016 (2009)
Standard first- line chemotherapy for
advanced ovarian cancer consists of paclitaxel
and carboplatin given every 3 weeks.
As the dose intensification leads to
more toxicity Dose- dense weekly
administration of paclitaxel may be a
strategy to improve survival.
Lancet. 2009;374(9698):1331-1338. PMID: 19767092
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG 3016
MITO7
GOG 218
ICON 7

32. PROF S.SUBBIAH et al
Arm 1:
Conventional Paclitaxel + Carboplatin
• Paclitaxel 180 mg/m2 iV over 3 hours on day 1.
• Carboplatin AUC 6 IV over 1 hour on day 1;
Vs
Arm 2:
Dose- Dense Paclitaxel + Carboplatin
• Paclitaxel 80 mg/m2 IV over 1 hour on days 1, 8, and
15.
• Carboplatin AUC 6 IV over 1 hour on day 1.
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG 3016
MITO7
GOG 218
ICON 7

33. PROF S.SUBBIAH et al
• Dose- dense paclitaxel with carboplatin
improved survival compared to the
conventional 3- week regimen with a 29%
lower risk of disease progression and a 25%
lower risk of death.
• With long- term follow-up, dose- dense
treatment improves survival (100 vs 62
months) compared to conventional
treatment.
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG 3016
MITO7
GOG 218
ICON 7

34. PROF S.SUBBIAH et al
MITO 7( 2014)
Carboplatin plus paclitaxel once a
week versus every 3 weeks in patients with
advanced ovarian cancer.
Arm 1: Standard Regimen Every 21
Days
Vs
Arm 2: Standard Weekly Regimen
18wks.
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

35. PROF S.SUBBIAH et al
Weekly carboplatin and paclitaxel.
• Does not improve progression- free survival
and overall survival( 2yr survival rate 78 vs
77%)
• More frequent and severe hematologic
toxicity, vomiting, neuropathy, hair loss.
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

36. .
Is there a need for third drug?

37. PROF S.SUBBIAH et al
OV 16 (2010)
Advanced ovarian cancer: phase III randomized study of addition
of TOPOTECAN to standard therapy vs carboplatin- paclitaxel.
CONCLUSION
The addition of topotecan to paclitaxel and carboplatin does not improve
outcomes and adds to the toxicity profile in the treatment of advanced
ovarian cancer.
J Natl Cancer Inst. 2010;102(20):1547-1556. PMID: 20937992.

38. PROF S.SUBBIAH et al
AGO OVAR 9 (2010)
Phase III trial of carboplatin plus paclitaxel with or without
gemcitabine in first- line treatment of epithelial ovarian cancer.
The addition of gemcitabine to the paclitaxel and carboplatin
backbone increased treatment burden, increased toxicities,
and reduced PFS in patients with advanced epithelial ovarian
cancer
J Clin Oncol. 2010;28(27):4162-4169. PMID:
20733132.

39. PROF S.SUBBIAH et al
GOG 218 (2011)
Incorporation of bevacizumab in the
primary treatment of ovarian cancer.
VEGF and angiogenesis promote
ovarian cancer progression and are inversely
correlated with survival.
•. Bevacizumab is a humanized anti- VEGF
monoclonal antibody that inhibits tumor
angiogenesis and has single- agent activity
against epithelial ovarian cancer in phase II trials
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

40. PROF S.SUBBIAH et al
Arm 1: Standard Chemotherapy (PC)
Vs
Arm 2: Standard Chemotherapy + Initiation
Bevacizumab (PCB)
Vs
Arm 3: Standard Chemotherapy + Initiation
Bevacizumab + 15 Months of Bevacizumab Maintenance
(PCB + B)

41. PROF S.SUBBIAH et al
The addition of bevacizumab during and up
to 10 months after paclitaxel and carboplatin chemotherapy
extends median PFS by 4 months
But does not have an impact on OS in patients
with advanced epithelial ovarian cancer

42. PROF S.SUBBIAH et al
ICON 7 (2015)
A phase 3 trial of bevacizumab use in
ovarian cancer.
Arm 1: Standard Chemotherapy (PC)
Vs
Arm 2: Standard Chemotherapy +
Bevacizumab (PCB)
Lancet Oncol. 2015;16(8):928-936. PMID:
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

43. PROF S.SUBBIAH et al
Bevacizumab improved PFS by about 2
months and increased the response rate by
about 20% in patients with ovarian cancer.
No difference in overall survival in the
trial population as a whole.
GOG 47
GOG 52
GOG 97
GOG 111
ICON 1
ICON 2
DANISH
GOG 158
ICON 3
AGO OVAR
SCOTROC
JGOG3016
MITO7
GOG 218
ICON 7

44. PROF S.SUBBIAH et al
SOLO 1 (2018)
Use of OLAPARIB ((oral poly adenosine
diphosphate–ribose polymerase inhibitor)) in
maintainence therapy in advanced ovarian cancer patients
with BRCA 1and BRCA2 mutation.
Patients who had a complete or partial clinical
response after platinum-based chemotherapy were
randomised with olaparib tablets (300 mg twice daily)vs
placebo
Progression free survival was the primary endpoint.

45. PROF S.SUBBIAH et al
• In the phase 3 SOLO 1 trial, the use of maintenance
therapy with olaparib provided a substantial benefit
with regard to progression-free survival (69% vs 35%)
among women with newly diagnosed advanced ovarian
cancer and a BRCA1/2 mutation, with a 70% lower risk
of disease progression or death with olaparib than with
placebo

46. PROF S.SUBBIAH et al
CONSOLIDATION
CYCLOPHOSPHAMIDE WITH DOXORUBICIN
CYCLOPHOSPHAMIDE DOXORUBICIN AND
CISPLATIN
CYCLOPHOSPHAMIDE and CISPLATIN

47. PROF S.SUBBIAH et al
Dose INTENSIFICATION OF CP
CISPLATIN WITH PACLITAXEL
Introduction of CARBOPLATIN

48. PROF S.SUBBIAH et al
CARBOPLATIN WITH PACLITAXEL
DOSE DENSE REGIMENS
ADDITION OF THIRD DRUG

49. PROF S.SUBBIAH et al
ONLINE LINKS FOR ARTICLES
• Icon 7,-
https://www.nejm.org/doi/full/10.1056/nejmoa1103799
• Gog 218
.https://www.nejm.org/doi/pdf/10.1056/nejmoa1104390
• MITO 7.
https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-
2045(14)70049-X.pdf
• JGOG 3016
https://www.thelancet.com/journals/lanonc/article/PIIS147
0-2045(13)70363-2/fulltext.

50. PROF S.SUBBIAH et al
• SCOTROC TRIAL ..
https://pubmed.ncbi.nlm.nih.gov/15547181/AGO
• AGO OVAR3
https://academic.oup.com/jnci/article/95/17/1320/252042
4
• ICON 2 https://pubmed.ncbi.nlm.nih.gov/12241653/
• ICON 1
https://academic.oup.com/jnci/article/95/2/105/2964945
• ICON 3 https://pubmed.ncbi.nlm.nih.gov/12241653/

51. PROF S.SUBBIAH et al
• GOG 158 https://pubmed.ncbi.nlm.nih.gov/12860964/
• GOG 111
https://ascopubs.org/doi/10.1200/jco.2000.18.1.106
• SOLO 1
https://www.nejm.org/doi/full/10.1056/nejmoa1810858

52. .
THANK YOU