This document discusses several topics related to the treatment of ovarian cancer including adjuvant chemotherapy, assessment of treatment response, and management of recurrent/resistant disease. It summarizes several key studies comparing different chemotherapy regimens for advanced ovarian cancer, including the use of carboplatin versus cisplatin, dose-dense versus conventional schedules, intraperitoneal versus intravenous administration, and the addition of bevacizumab. It also reviews options for recurrent platinum-sensitive and platinum-resistant disease, secondary cytoreduction surgery, and the potential role of targeted therapies, immunotherapy and radiation.

2. Topics Covered
 Adjuvant Treatment in Advanced Ovarian Cancer
 Treatment Assessment
 Management of Recurrent/ Resistant/ Refractory disease
 Carcinoma Ovary in Pregnancy

5. Adjuvant Chemotherapy in
Advanced Ovarian Cancer

7. Cyclophosphamide and Cisplatin compared with
Paclitaxel and Cisplatin in patients with Stage III
and Stage IV Ovarian Cancer : GOG 111
McGuire etal
 N = 386
 Cisplatin (75 mg per square meter) with either
cyclophosphamide (750 mg per square meter) or
paclitaxel (135 mg per square meter over a period of 24
hours)

9. Phase III trial of carboplatin and
paclitaxel compared with cisplatin and
paclitaxel in patients with optimally
resected stage III ovarian cancer: a
Gynecologic Oncology Group study (GOG
158).
Ozols etal

10.  N = 792
 Received cisplatin 75 mg/m2 plus a 24-hour infusion of
paclitaxel 135 mg/m2 (arm I), or carboplatin area under the
curve 7.5 intravenously plus paclitaxel 175 mg/m2 over 3
hours (arm II)
 Gastrointestinal, renal, and metabolic toxicity, as well as grade
4 leukopenia, were significantly more frequent in arm I.
 Grade 2 or greater thrombocytopenia was more common in arm
II.
 Neurologic toxicity was similar in both regimens.

11.  Median progression-free survival and overall survival
were 19.4 and 48.7 months, respectively, for arm I
compared with 20.7 and 57.4 months, respectively, for
arm II.
 CONCLUSION: In patients with advanced ovarian
cancer, a chemotherapy regimen consisting of carboplatin
plus paclitaxel results in less toxicity, is easier to
administer, and is not inferior, when compared with
cisplatin plus paclitaxel.

12. Carboplatin Plus Paclitaxel Versus
Carboplatin Plus Pegylated Liposomal
Doxorubicin As First-Line Treatment
for Patients With Ovarian Cancer: The
MITO-2 Randomized Phase III Trial

13.  Chemotherapy-naive patients with stage IC to IV
ovarian cancer were randomly assigned to carboplatin
area under the curve (AUC) 5 plus paclitaxel 175
mg/m2 or to carboplatin AUC 5 plus PLD 30 mg/m2 ,
every 3 weeks for six cycles.

15. Conclusion
 Carboplatin/PLD was not superior to
carboplatin/paclitaxel, which remains the
standard first-line chemotherapy for
advanced ovarian cancer.

16. Current acceptable practice
Berek & Hacker’sGynecologic Oncology Sixth Edition

17. What is new in Chemotherapy in
Advanced Stage Ovarian Cancer??

18. Dose Dense Paclitaxel
 Strategy to enhance antitumor activity and prolong the survival
of patients.
 Theoretical basis : Smaller tumors grow faster and so tumor
regrowth between treatment cycles is more rapid when cell kill
is greatest.
 Increased dose density is achieved by reducing the interval
between each dose of chemotherapy.
 The cumulative drug dose remains constant.
Berek & Hacker’sGynecologic Oncology Sixth Edition

19. Long-term results of dose-dense paclitaxel and
carboplatin versus conventional paclitaxel and
carboplatin for treatment of advanced epithelial
ovarian, fallopian tube, or primary peritoneal
cancer (JGOG 3016): a randomised, controlled,
open-label trial.
Katsumata etal

20. 631 patients (Stage II-IV)
Dose Dense (312) Conventional dose (319)
Carboplatin :AUC 6
Paclitaxel 180 mg/m(2)
Carboplatin AUC 6 Paclitaxel 80
mg/m(2) on days 1, 8, and 15
PFS : 28.2 months
OS : 100.5 months
PFS : 17.5 months (p = 0.0037)
OS : 62.2 months (p=0.039)
Treatments were repeated every 3 weeks for six cycles
Median follow-up was 76·8 months

22. Dose Intensification
Assessment of dose-intensive therapy in
suboptimally debulked ovarian cancer: a
Gynecologic Oncology Group study.
McGuire etal

23.  N= 458
 Residual masses more than 1 cm following surgery or
any stage IV
 Standard therapy : Cyclophosphamide 500 mg/m2 and
Cisplatin 50 mg/m2 iv every 3 weeks for eight courses
 Intense therapy : Cyclophosphamide 1,000 mg/m2
and cisplatin 100 mg/m2 intravenously every 3 weeks
for four courses

24. Results
 Clinical and pathologic response rates; response
duration, and survival were similar
 Hematologic, gastrointestinal, febrile episodes, septic
events, and renal toxicities were significantly more
common and severe in the dose-intensive group.
 This study provides no evidence to support the
hypothesis that modest increases in dose-intensity
without increasing total dose are associated with
significant improvement in overall survival or PFS.

25. Intraperitoneal Chemotherapy
Rationale :
 Direct tumor penetration
 Clearance from a body cavity is delayed compared to the
systemic circulation, achieving more prolonged exposure
to higher regional concentrations of active agents.
 Tumor size < 1cm

26. Intraperitoneal Cisplatin Plus Intravenous
Cyclophosphamide versus Intravenous
Cisplatin Plus Intravenous Cyclophosphamide
For Stage III Ovarian cancer
Alberts etal

27. Study Design
 The patients underwent an initial exploratory laparotomy
and resection of all tumor masses larger than 2 cm.
 Within four weeks after surgery, six courses of
intravenous cyclophosphamide (600 mg per square meter)
plus either intraperitoneal cisplatin (100 mg per square
meter) or intravenous cisplatin (100 mg per square meter)
were administered at three-week intervals.

30. Phase III trial of standard-dose intravenous cisplatin plus
paclitaxel versus moderately high-dose carboplatin
followed by intravenous paclitaxel and intraperitoneal
cisplatin in small-volume stage III ovarian carcinoma: an
intergroup study of the Gynecologic Oncology Group,
Southwestern Oncology Group, and Eastern Cooperative
Oncology Group
Markman etal

31.  Arm 1: IV paclitaxel 135 mg/m(2) over 24 hours followed
by IV cisplatin 75 mg/m(2) every 3 weeks for six courses
 Arm 2: IV carboplatin (area under curve 9) every 28 days
for two courses, then IV paclitaxel 135 mg/m(2) over 24
hours followed by intraperitoneal (IP) cisplatin 100
mg/m(2) every 3 weeks for six courses.

32.  N =462
 Progression-free survival was superior for patients
randomized to the experimental treatment arm (median, 28
v 22 months P =.01)
 Neutropenia, thrombocytopenia, and gastrointestinal and
metabolic toxicities were greater in the experimental arm
 There was a borderline improvement in overall survival
associated with this regimen (median, 63 v 52 months; P
=.05).

33. Intraperitoneal Cisplatin and
Paclitaxel in Ovarian Cancer :
GOG 172
Armstrong etal

34.  Intravenous-therapy group : 135 mg of intravenous
paclitaxel per square meter over a 24-hour period followed
by 75 mg of intravenous cisplatin per square meter on day
2
 Intraperitoneal-therapy group : 135 mg of intravenous
paclitaxel per square meter over a 24-hour period followed
by 100 mg of intraperitoneal cisplatin per square meter on
day 2 and intraperitoneal paclitaxel 60 mg per square
meter on day 8.
 Treatment was given every three weeks for six cycles

37. NCI ALERT
 Based on the results of these randomized phase III trials, a
combination of IV and IP administration of chemotherapy
conveys a significant survival benefit among women with
optimally debulked epithelial ovarian cancer, compared to
IV administration alone.
 While it is not possible to specify a precise regimen, the
three largest studies with the greatest survival advantage
delivered cisplatin 100 mg/m2 IP

38. Hyperthermic Perioperative
Chemotherapy (HIPEC)
 Highly concentrated, heated chemotherapy treatment that
is delivered directly to the abdomen during surgery.
 HIPEC is a treatment option for people who have
advanced surface spread of cancer within the abdomen,
without disease involvement outside of the abdomen.
Principles and Practice of Gynaecologic Oncology 6th Edition

39. Principle of HIPEC
 Increase in the number of lysosomes  more labile in
malignant cells
 Vascular stasis of microcirculation occurs in neoplastic
cells at temperatures produced by HIPEC, while normal
cells experience increased flow.
 More penetration, more DNA damage and depression or
complete inhibition of oxidative metabolism leads to
accumulation of lactic acid and lower pH
 This results in accelerated cell death of the malignant cells
Principles and Practice of Gynaecologic Oncology 6th Edition

40. Cytoreductive Surgery
Chemotherapy solution (41-42⁰ C)
Circulation through abdomen for 1-1.5
hours
Drainage of fluid and incision
closure
Principles and Practice of Gynaecologic Oncology 6th Edition

41. Drugs Used
 CISPLATIN
 Mitomycin
 Doxorubicin
 Melphalan
 Gemcitabine
 Oxaliplatin
Principles and Practice of Gynaecologic Oncology 6th Edition

42. Bidirectional Hyperthermic
Perioperative Chemotherapy : HIPEC
plus
 Concurrent administration of intraperitoneal and
intravenous chemotherapy
 Drugs used :
 Ifosfamide
 5 FU
Principles and Practice of Gynaecologic Oncology 6th Edition

43. Early Postoperative Intraperitoneal
Chemotherapy : EPIC
 May gain access to all peritoneal surfaces because no
significant wound healing has occurred at this point in
time
 Distribution within the peritoneal space may be
augmented by gravity distribution.
 This means that the patient turns from an extreme
right lateral to left lateral position postoperatively in a
repeated manner.
Principles and Practice of Gynaecologic Oncology 6th Edition

44. Drugs Used
 Paclitaxel
 Docetaxel
 5 FU
 Floxuridine
 Pemetrexed

45. Molecular Targeted Therapies
 Bevacizumab : humanized anti–vascular endothelial
growth factor monoclonal antibody
 GOG 218
 ICON 7

46. Incorporation of Bevacizumab
in the Primary Treatment of
Ovarian Cancer : GOG 218
Burger etal

48. Results
 The median progression-free survival was 10.3 months in
the control group, 11.2 in the bevacizumab-initiation
group, and 14.1 in the bevacizumab-throughout group.
 The use of bevacizumab during and up to 10 months after
carboplatin and paclitaxel chemotherapy prolongs the
median progression-free survival by about 4 months in
patients with advanced epithelial ovarian cancer.

49. A Phase 3 Trial of Bevacizumab
in Ovarian Cancer : ICON 7

50. 1528 patients
Control 764 Experimental 764
Control + bevacizumab (7.5 mg/kg),
given concurrently every 3 weeks for
5 or 6 cycles and continued for 12
additional cycles
Carboplatin (AUC 5 or 6) and
paclitaxel (175 mg /m²) given
every 3 weeks for 6 cycles
PFS : 22.4 months
OS : 28.8 months
PFS : 24.1 months (p = 0.04)
OS : 36.6 months

52. Maintenance Therapy
 Paclitaxel
 Topotecan
 Cochrane meta analysis : There was no evidence to
suggest that maintenance chemotherapy was more
effective than observation alone

53. Radiation Therapy
 No apparent benefit seen by adding WAR after
chemotherapy
 Renewed interest in potential role of radiation in selected
subsets of patients with clear cell and endometrioid cancer
Dose-intensive induction therapy with cyclophosphamide, cisplatin, and consolidative abdominal
radiation in advanced-stage epithelial ovarian cancer.
M L Rothenberg,

54. Immunotherapy
 Gamma Interferon : More adverse events and no survival
benefits
 OvaRex : monoclonal antibody against CA 125. No PFS
benefit seen
 Monoclonal antibody against HMGF (Human milk fat
globulin) : No survival benefit
Berek & Hacker’sGynecologic Oncology Sixth Edition

55. Treatment Assessment

57. Approach to Recurrence

58. Platinum
chemotherapy
Sensitive Refractory Resistant
Recurrence of
active disease in a
patient who has
achieved a
documented
response to initial
platinum-based
treatment and has
been off therapy
for 6 months
Disease that has
responded to initial
chemotherapy but
demonstrates
recurrence within 6
months following the
completion of
treatment.
Patients who have
failed to achieve at
least a partial
response to therapy.
This includes
patients with either
stable disease or
actual disease
progression during
primary therapy

59. Secondary Cytoreduction

60. DESKTOP I & DESKTOP II TRIALS
Selection criteria for secondary debulking :
 Disease-free interval longer than 12 months
 Platinum sensitive disease with additional chemotherapy
options
 Oligometastatic or localized disease with the absence of
ascites and carcinomatosis
 Good performance status

61.  Can be considered in patients with recurrent ovarian
cancer who recur more than 6-12 months since completion
of initial chemotherapy, have an isolated focus (or limited
foci) of disease amenable to complete resection and do not
have ascites
NCCN

62. Platinum Sensitive Disease

63. CALYPSO
 Pegylated Liposomal Doxorubicin and Carboplatin
Compared With Paclitaxel and Carboplatin for Patients
With Platinum-Sensitive Ovarian Cancer in Late Relapse

64.  N = 976
 CD Arm : Carboplatin [AUC 5] plus PLD 30 mg/m2
every 4 weeks
 CP Arm : Carboplatin [AUC 5] plus paclitaxel 175 mg/m2
every 3 weeks for at least 6 cycles

67. Conclusion
 In this largest randomized phase III trial in ROC, CD
provides a more effective, less toxic alternative to the
current standard for patients who relapse more than 6
months after platinum based chemotherapy.

69. Platinum resistant and Refractory
disease

70. Drugs Available
 Paclitaxel
 Docetaxel
 Topotecan
 Liposomal Doxorubicin
 Gemcitabine
 Ifosfamide
 Oral Etoposide
 Tamoxifen
 Bevacizumab

71. Long-term survival advantage for women
treated with pegylated liposomal
doxorubicin compared with topotecan in a
phase 3 randomized study of recurrent and
refractory epithelial ovarian cancer
Gordon etal

72.  Randomized to receive pegylated liposomal doxorubicin
50 mg/m2 every 28 days (n = 239) or topotecan 1.5
mg/m2 per day for 5 days every 21 days (n = 235)
 There was an 18% reduction in the risk of death for
patients treated with pegylated liposomal doxorubicin
(median survival 62.7 weeks for pegylated liposomal
doxorubicin and 59.7 weeks for topotecan-treated
patients; P = 0.050)

73. Liposomal Doxorubicin vs Paclitaxel
 Study comparing liposomal doxorubicin with single-agent
paclitaxel in 214 platinum-treated patients who had not
received prior taxanes
 The overall response rates for liposomal doxorubicin and
paclitaxel were 18% and 22%, respectively, and median
survivals were 46 and 56 weeks, respectively.
 Neither was significantly different.
Berek & Hacker’sGynecologic Oncology Sixth Edition

75. Hormonal Therapy
 Tamoxifen
 Leuprolide acetate
 Aromatase inhibitors
 NO DEFINITE ROLE

76. Targeted Therapies
 Bevacizumab
 Pazopanib
 Cediranib

77. OCEANS: A Randomized, Double-Blind,
Placebo-Controlled Phase III Trial of
Chemotherapy With or Without
Bevacizumab in Patients With Platinum-
Sensitive Recurrent Epithelial Ovarian,
Primary Peritoneal, or Fallopian Tube
Cancer

78.  Randomly assigned to GC plus either BV or placebo (PL)
for 6 -10 cycles.
 Patients received G 1,000mg/m2 on days 1 and 8 and C
(AUC 4) on day 1
 BV or PL 15 mg/kg day 1
 BV or PL was continued until PD or unacceptable toxicity
 N = 484
 PFS for the BV arm was superior to that for the PL arm (P
= .0001); median PFS was 12.4 v 8.4 months, respectively

79. Bevacizumab Combined With
Chemotherapy for Platinum-
Resistant Recurrent Ovarian Cancer:
The AURELIA Open-
Label Randomized Phase III Trial

80.  After investigators selected chemotherapy (pegylated
liposomal doxorubicin, weekly paclitaxel, or topotecan),
patients were randomly assigned to single-agent
chemotherapy alone or with bevacizumab (10 mg/kg
every 2 weeks or 15 mg/kg every 3 weeks) until
progression, unacceptable toxicity, or consent withdrawal
 Median PFS was 3.4 months with chemotherapy alone
versus 6.7 months with bevacizumab-containing therapy P
<0.001
 OS : P= 0.174

81. Cediranib in patients with relapsed
platinum-sensitive ovarian cancer
(ICON6): a randomised, double-
blind, placebo-controlled phase 3
trial
 Cediranib is an oral antiangiogenic vascular endothelial
growth factor receptor 1–3 inhibitor

82.  Participants received up to six cycles of platinum-based
chemotherapy (once every 3 weeks) then entered a
maintenance phase.
 Arm A (reference) : Received placebo alongside
chemotherapy and then placebo only maintenance
 Arm B (concurrent) : Received cediranib 20 mg once-
daily alongside chemotherapy then placebo only
maintenance
 Arm C (maintenance) : Received cediranib 20 mg once-
daily alongside chemotherapy then cediranib 20 mg once-
daily maintenance

84. Approach to Carcinoma Ovary in
Pregnancy

85. Gynecologic cancers in pregnancy:
guidelines of a second international
consensus meeting.
 Cancer treatment in pregnancy should follow a standard
treatment protocol as for non pregnant patients
 Most standard regimens of chemotherapy can be
administered from 14 weeks gestational age onward
Int J Gynecol Cancer. 2014 Mar;24(3):394-403

86.  Diagnosed at an early stage because of the routine ultrasonic
scanning.
 Early Stage : Unilateral salpingo oophorectomy + Surgical
Staging in 2nd trimester
 Advanced stage : Poor maternal prognosis makes termination
of pregnancy a viable option.
 Neoadjuvant chemotherapy until fetal maturity and complete
cytoreduction after delivery
 A combination of paclitaxel and carboplatin should be the
treatment of choice

87. THANK YOU