Treatment of CA Ovary

TREATMENT OF OVARIANTREATMENT OF OVARIAN
CARCINOMACARCINOMA
By Dr Anil Gupta
Moderator Dr Budhi Singh

Includes ovarian, fallopian tube and primary peritoneal
carcinomatosis

Is not a not a single entity but instead represents tumors of
epithelial, germ cell or sex cord stromal origin

Age-standardized (to the world
population) incidence rates of ovarian
cancer among women- Globacon 2012
Epidemiology
Indian Cancer Registry: Female (ASR per100,000)
Indian Cancer
Registry
All sites Breast Cervix Uterus Ovary
Relative proportion of ten leading sites of
cancer- females – HBCR, PGIMER 2011-13
Breast 20.3%
Cervix 15.4%
Ovary 7%

● Median age of diagnosis- 63 yr
● 30% of all cancers of the female genital organs
● Epithelial- older woman
● Germ cell- younger woman
● Sex cord tumors- any age
● 90% are epithelial tumors

Pattern of spread
Transcoelomic spread
direct exfoliation of cells into peritoneal cavity- circulatory
path of peritoneal fluid- pelvis →paracolic gutters→mesentry→r
hemidiaph→perit surf of liver, ints, omentum--- rarely invades
bowel
Direct extension
Lymphatic spread (20 %)
pelvic &paraaortic,
Haematogenous
lungs, liver (2-3%)
bone,brain

Symptoms
● Asymptomatic- in initial stages
● Abdominal discomfort
● Bloating
● Early satiety
● Pelvic mass- firm, fixed, multiple nodularities
● Ascites
● Ocassionally umblical nodule(Sister Mary Joseph nodule)
● Pleural effusion
Signs

Adenexal mass without ascites
● Complete Physical Examination
● Detailed family history
● Tumor Markers, based on clinical judgment
(CA125/AFP/BHCG/LDH/CEA/CA19.9)
● Trans Abdominal Ultrasound
● Trans Vaginal Ultrasound Risk of Malignancy
● CBC, LFT, KFT, Stool for Occult Blood
● Chest X ray
● Calculate Risk of Malignancy Index
● Biopsy/FNAC with IHC

Adenexal mass with ascites
● Complete Physical Examination
● Trans Abdominal Ultrasound
● Trans Vaginal Ultrasound
● Ultrasound score for calculation of Risk of Malignancy
● Appropriate Tumour Markers, based on clinical judgment
(CA125/AFP/BHCG/LDH)
● CECT Abdomen + Pelvis
● Chest X ray, and diagnostic thoracentesis, if pleural effusion detected
● Biopsy/FNAC with IHC
● Paracentesis
● Repeat diagnostic paracentesis, if initially negative for
malignant cytology

Ascites without adenexal mass
● Evaluate Ascites as per protocol
● If positive → cell block for IHC
● Consider Endoscopy (UGIE + LGIE), especially if GIT related
symptoms such as
➔ Occult blood in stool
➔ Elevated CEA levels
➔ CEA/CA125 ratio
➔ Bilateral tumors (mobile)
➔ Suspicious family history
➔ Neo-adjuvant chemotherapy is planned (without surgical
assessment)

CA-125
Mucin like glycoprotein, 200-250 kDa.
Chromosome 17.
Site of production : Epithelial ovarian cancer cells,
pleura, pericardium, peritoneum
HALF LIFE: 5-7 days
REFERENCE VALUE: < 35 U/ML
>200 U / ml
(Benign disease unlikely )
Elevated: 1% of healthy blood donors,
6% of patients with benign disease,
28% of non gynaecological malignancy and
82% of proven epithelial ovarian cancer.

Gynaecological
Benign:
●
Endometriosis
●
Acute pelvic inflammatory
disease
●
Adenomyosis
●
Benign ovarian neoplasm
●
Functional ovarian cyst
●
Ovarian fibroma with ascites
●
Menstruation
●
Uterine myomata
●
Unexplained infertility
Malignant:
●
Ovarian carcinoma
●
Primary peritoneal
carcinoma
●
Endometrial carcinoma
Non-gynaecological
Benign:
Acute hepatitis
Acute pancreatitis
Chronic liver disease
Cirrhosis
Non malignant ascites
Mesothelioma
Polyarteritis nodosa
Systemic lupus
erythematosus
Renal disease
Sarcoidosis
Malignant:
Carcinoma of
pancreas
Hepatocellular
carcinoma
Ca breast
Not a reliable
diagnostic
test...
Malignant:
Carcinoma of
pancreas
Hepatocellular
carcinoma
Ca breast
Malignant:
Carcinoma of
pancreas
Hepatocellular
carcinoma
Ca breast

Preop (baseline)- burden of disease- >65u/ml---↓5 yr
survival
post menopausal women – adnexal mass +↑CA 125 (>200)–
96 % ppv for malignancy
During t/t
●
—immediate post op period- 3-4 wks– elevated owing to peritoneal
inflammation
●
Declining level correlate with t/t response
●
Disease progression can also occur without ↑CA 125
●
DURING SALVAGE THERAPY doubling values associated with
progression & t/t failure >90% cases
●
CA125 after 3 cycles of CCT- lack predictive power- cant be a guide for
decision
●
After t/t
●
Persistent elevation – poor prognosis
●
Elevated, rising or doubling CA 125 predict relapse
●
Negative values do not exclude disease presence
●
Elevation in CA125 can precede clinical, radiological evidence of recurrence with
median time of 2-6 months

● Trans vaginal ultrasonography
- more sensitive in detecting ovarian tumors compared to CT
- Complex cyst containing solid and cystic components sometimes
with septations and internal echogenicity
Signssymptoms and raised tumor markers
Strong suspicion of malignancy
Requires surgery for further evaluation
● Avoid percutaneous biopsy → may lead to cyst rupture and spillage
of malignant cells into peritoneal cavity
● Simple cyst with normal CA-125 do not always require surgical
evaluation

● Colour Doppler imaging
- evaluates blood flow to an ovarian mass and can potentially
identify a malignant process on the basis of abnormal
neovascularization
- In premenopausal women simple cyst may be funcional
( corpus luteum) or benign serous cystadenoma which may
resolve spontaneously
→ Simple cyst with raised CA-125 of >5 to 10 cm in diameter
with abnormal colour doppler flow studies in postmenopausal
women requires surgical evaluation

● Complex cyst
● Simple cyst with raised CA-125 of >5 to 10 cm in diameter with
abnormal colour doppler flow studies in postmenopausal
women
SURGICAL EVALUATION

● CT
- helpful in defining the extent of peritoneal disease
- may also assist in surgical planning by locating the site of
suspected bowel obstruction
CT chest to evaluate pleural effusion which occur in 10% of
patients with epithelial origin
● MRI
- not added advantage over CT except in pregnant woman
● PET
- No proven role in diagnosis/disease extension/follow up

Risk of Malignancy Index
● RMI score= ultrasound score;H* menopausal score* CA
level125 in U mL
● The RMI II score more sensitive than the RMI I system
● specificity of 89%- 92% and PPV of 80%.
● Score >200 indicate maignancy
● Essential for surgical planning

Criteria for Inoperability
● Medical Inoperability
- Poor G.C
- Multiple comorbidities
● Surgical inoperability
-Stage III with deposits> 3cm and stage IV
- technical inoperablility

Surgical exploration
● Done by Exploratory laparotomy plus Trans abdominal hysterectomy
and bilateral oosalphingorectomy
● Serves three purpose
1) Determine extent of disease
2) Debulking of tumor
3) Permits histological confirmation
GOAL of Surgery → R0
resection margins or optimal
cytoreduction/debulking
● Extent of disease
● Optimal cytoreduction
- defined as having <_ 1 cm diameter residual tumor
-have a better prognosis compared to those with greater amounts of
residual disease

Ideal exploratory laparatomy
● Requires a midline incision large enough to permit inspection of
peritoneal cavity, including the upper abdomen, retroperitoneal
spaces and lymph nodes
● Fuid sample from ascitic fluid, peritoneal surfaces, pelvic and
paraclolic spaces should be collected and sent for cytologic
examination
● If intraperitoneal carcinomatosis is absent, first resect ovarian
tumor and then proceed to surgical staging to avoid rupturing
the mass
● Grossly normal opposite ovary biopsy or excision of any benign
appearing cysts

● Pelvic and para aortic retroperitoneal lymph node sampling if
no involvement ,If involved, should be removed
● An infra colic omentectomy if gross disease is not present in
omentum, if present (omentum cake), it should be completely
excise from as completely as possible
● Careful examination of right hemi diaphragm, liver serosa, liver
parenchyma.
● Then spleen is carefully examined as well as left diaphragm
● If tumor appears to invade large bowel and pose a threat to
intestinal obstruction resection may be required.
● The small intestine and mesentry are evaluated and any tumor
implants are removed as much as possible

● For women who wish to preserve fertility staging may be
performed by preserving uterus alongwith contralateral ovary
and tube
DiSaia and coworkers outlined criteria for preserving childbearing function in a young
woman with stage IA, grade 1 ovarian epithelial carcinoma, as follows:
1. Tumor confined to one ovary
2. Tumor well differentiated (grade 1) with no invasion of capsule, lymphatics, or
mesovarium
3. Peritoneal washings negative
4. Omental biopsy specimen negative
5. Young woman of childbearing years with strong desire to preserve reproductive
function
● If initial surgical staging is incomplete due to lack of lymph node or
upper abdominal evaluation in a patient with presumptive stage I
disease, it is reasonable to complete surgical staging if the
findings would alter postoperative management.
● For instance , if a patient has stage IA Grade I or II no further
treatment is required, therefore in this scenario complete surgery
is mandatory

Histo pathological confirmation
● The World Health Organization Histological Classification for
ovarian tumors
-separates ovarian neoplasms according to the most probable
tissue of origin:
➢ surface epithelial (65%)
➢ germ cell (15%)
➢ sex cord-stromal (10%)
➢ metastases (5%)
➢ miscellaneous

Epithelial-stromal tumours
 Serous Tumors
 Benign- Serous cystadenoma
 Borderline tumour- Serous borderline tumor
 Malignant- Serous Adenocarcinoma
 Mucinous Tumors
 Benign Tumor- Mucinous cystadenoma
 Borderline Tumor- Mucinous borderline tumor
 Malignant -Mucinous Adenocarcinoma
 Endometroid Tumors
Benign Tumor
Borderline Tumor
Malignant- Adenocarcinoma
Clear cell tumors:
Benign
Borderline tumors
Malignant (clear cell adenocarcinoma)
Transitional cell tumors:
Benign-Brenner tumor
Borderline-Brenner tumor of borderline malignancy
Malignant Brenner tumor
Transitional cell carcinoma (non-Brenner type)
Epithelial-stromal:
Adenosarcoma
Carcinosarcoma (formerly mixed
Mullerian tumors)

Evolution of chemotherapy in CA
Ovary

Timeline
● Pre-1970s
Involving single agent such as melphalan chlorambucil and
cyclophosphamide . 5-year survival for advanced-stage disease was
7 percent
● 1978
First combination chemotherapy of hexamethylmelamine,
cyclophosphamide (Cytoxan), methotrexate and 5-fluorouracil
(HEXACAF) extends survival by more than 12 months over single-
drug chemotherapy. However,it causes significantly more side
effects.
Cisplatin approved for ovarian cancer. Combination regimen of
cyclophosphamide (Cytoxan) plus cisplatin and a regimen called
CHAP

● 1989
Carboplatin became available as a 2nd
line of therapy,later
becomes the preferred initial chemotherapy, after it was shown
to be as effective as cisplatin with fewer side effects
● 1992-1994
Taxanes Emerge As Vital Chemotherapy Option. Later replaced
by a regimen involving paclitaxel and carboplatin which results
in fewer side effects
● 1996
Topotecan approved to after other treatments have failed

● 1999
Liposomal Doxorubicin approved Ovarian Cancer that has
progressed after prior treatment
● 2003
Docetaxel is as effective as the standard paclitaxel in
combination with carboplatin, with different side effects
● 2006
Intraperitoneal chemotherapy introduced
● 2010
Pre-surgery chemotherapy proven an effective option or women
with advanced ovarian cancer

Cisplatin
●
Covalently binds to DNA with preferential binding to the N-7 position
of guanine and adenine and produces cross links
●
potent emetogenic agent
●
Nephrotoxic
●
Myelosuppression
●
Neurotoxic
●
Ototoxic
●
Less nephrotoxic,neurotoxic,emetogenic
●
No need for forced hydration
●
Should be given in chloride free solutions- over 30 mins
●
Only dose limiting myelosuppression
●
Rapidly excreted by kidney
Linear correlation with renal excretion- directly related to GFR
GFR- creatinine clearance
Major dose limiting toxicity- low platelets - nadir at 17- 21 days
severity best accounted for by a measure of drug exposure to an individual, the AUC
(Calvert et al )
Carboplatin – 2nd
gen platinum analogue

PACLITAXEL
●
Binds to microtubules- β tubulin- stabilizing against depolymerization
●
Extensive plasma protein binding- 95%-high volume of distribution
peripheral edema & 3rd
space fluid
collections don’t require
dose modifications
●
Disposition related to BSA
●
Non linear pharmacokinetic behaviour-tissue saturation- at <175 mg/m2
over 3 hrs
●
Principal toxicity- neutropenia
●
Hypersensitivity- 30%
--- taxane moiety / polyoxyethylated castor oil vehicle----- complement mediated
---- reduced to < 1 % with prior premedication
dexamethasone orally / IV- 20 mg 4- 6 hr before
H1 & H2 antagonist 30 min before
Administration- avoid PVC lined devices
should be given through polyethylene lined sets that
include an in – line filter of micropore- < 200μ m

Liposomal doxorubicin
● Inhibits topoisomerase II by forming a cleavable complex with
DNA and topoisomerase II. This creates uncompensated DNA
helix torsional tension, leading to eventual DNA breaks
● Liposomal encapsulation of doxorubicin
- Protected from chemical and enzymatic degradation
- reduced plasma protein binding
- decreased uptake in normal tissues
- Penetrates tumor tissue into which doxorubicin is released
● Toxicity
- Myelosupression
- cardiotoxic
- hand foot syndrome

● 2006 study showed no significant difference
● A recent subset analysis showed that 5 yr recurrence free
survival with 6 cycles is 83% and 60% with three cycles in
serous epithelial ovarian cancer
● Therefore six cycles is considered reasonable in early stage,
high risk

Dose regimen
● Standard dose regimen
Paclitaxel 175 mg/m2
IV over 3 hrs f/b carboplatin AUC 5/6 over 1 hr
day 1. 3 weekly 6 cycles (if docetaxel 60-75 mg/m2
IV over 1 hr)
The maximum allowed doses of carboplatin are:
AUC 6 = 900 mg
AUC 5 = 750 mg (If cisplatin 60 mg/m2
IV over 1 hr)
● Dose- dense regimen
Paclitaxel 80mg/m2
IV over 1 hr day 1,8,15 f/b carboplatin AUC 5-6 IV
over 1 hr day 1 . 3 weekly 6 cycles

Role of Radiotherapy
● Ovarian cancer has a unique pattern of dissemination
compared with other solid tumors
● Transperitoneal spread is the most common route of
dissemination and at relapse regardless of therapy
● techniques that encompass the whole peritoneal cavity,
rather than just the pelvis or lower abdomen alone, are
likely to be most beneficial

Post operative radiation therapy
● Abdominopelvic radiation was superior to pelvic radiation alone or
followed by chlorambucil, with respect to long-term survival and
control of abdominal disease
● The benefit applied only to patients with small or no macroscopic
tumor remaining

OPEN FIELD●
Field-single field
AP PA portal
Energy- 1.25 Mv, 4,6 Mv
WHOLE ABD
Margins
Sup- 1.5 margin above domes of diaphgram
Inf- obturator foramen
Lat-extends beyond skin
Size 45 *30 cm
Shield – liver 1 HVL 1500 cGy
(ant & post)
kidney 2 HVL 1050 cGy
(post)
Dose 2250- 2500 cGy/20-22#/4.5 wks
PELVIC BOOST
Margins
Sup- L5- S1
lat- 1.5 cm beyond bony pelvis
Inf - obt foramen
Dose 2000 cGy/10# / 2 wks

●
Concept arose in an era
(1963- Delclos)
when RT equipment could not
adequately irradiate large volume on 1
portal
●
Major justification- delivery of a
biologically higher dose than OFT
●
Technique-
lines drawn at 2.5 cm regular intervals
●
Total dose 28Gy/30-40#@ 10#/strip
●
Shielding-
both kidneys from post field 2HVL
R half of liver from ant & post 1HVL
●
Followed by PELVIC BOOST
15*15cm
20 Gy/10#/2 wks
MOVING STRIP

limitations
● The dose of radiation that can be delivered safely to this large
volume, which includes the upper abdomen, is low in
comparison to that considered necessary to eradicate most
solid tumors
● RT would benefit only patients in whom the volume of residual
tumor remaining postoperatively in the upper abdomen is less
than macroscopic,i.e. microscopic.

● Careful adherence to simple technical principles by radiologic
verification that the entire peritoneal contents are included within the
treatment portals.
● The dose to the abdomen, which should be within tolerance of the
liver
● In the abdomen only microscopic amounts of tumor and in the pelvis
only small macroscopic lesions would be expected to be controlled
CONCLUSION
Small subset of patients with high risk of relapse can be considered
for abdomino pevic irradiation
● Renal, bowel and hepatic toxicity limits use of WAR in present
scenario
● Presence of good chemotherapy regimens limits use of irradiation

● Despite the initial promise for a curative benefit of cisplatin based
chemotherapy the cure rate in ovarian cancer has not changed
appreciably during the last decade
● more than 67% of intermediate-risk patients were alive and disease-
free 10 years after treatment with minimal late morbidity
● high risk in have only a 20% 10-year failure-free rate when
treated with WART alone

Adjuvant Intraperitoneal Phosphorous32

● Debulking surgery
Theoretical benefits include
- Removal of large necrotic tumors with blood supply that might
lead to impaired chemotherapy delivery
- Permits residual tumor to proliferate, thereby enhancing
senstitivity to chemotherapy
● Can be
- Primary debulking surgery
- Interval debulking surgery

● Primary debulking surgery
- Prior to chemotherapy
- Is standard approach
● Not possible in some patients in due to
- poor performance status
- extensive bulky intra-abdominal disease
● Interval surgery approach

Interval debulking surgery
- adminstering neoadjuvant chemotherapy followed by surgery
● Theoretical advantage of neo adjuvant chemotherapy
includes ::
- rapid improvement in QOL
- technically more feasible operation with shorter hospitalization
- less morbidity
● Confirmation of ovarian primary is mandatory

● Neoadjuvant f/b IDS is non inferior to PDS
●
EORTC 55971 randomized trialEORTC 55971 randomized trial
Stage IIIC and less extensive metastatic tumours had higher survival with
primary surgery
stage IV disease and large metastatic tumours had higher survival with
neoadjuvant chemotherapy.
Who did not meet these criteria, both treatment options led to comparable
survival rates.

● Advanced stage is chemo responsive
● Although relapse eventually occurs
● Platinum based compounds remain the single most active
drugs
● Carboplatin has similar survival advantage as cisplatin, but with
less survival advantage, less neuropathy, nephropathy and
emesis
● Response rate is 70% for suboptimal debulked disease, and
over 80% for optimally cytoreduced

Intraperitoneal chemotherapy
● Ovarian cancer is largely
confined to the peritoneal space
● Permits a several-fold increase
in drug concentration to be
achieved within the abdominal
cavity
● Efforts made to directly instill
chemotherapy into the
peritoneal cavity
● May be possible to achieve
more effective cytoreduction
Tenchoff catheter

● IV has more survival than IP
● Cause more frequent and more severe side effects than IV
chemotherapy, including abdominal pain, nausea, and vomiting.
IP/IV significantly improves survival and has significantly fewer
toxic effects in patients with stage III
Complications
Obstruction
inadequate distribution
Infections
peritonitis
Bowel perforation

● Histopathologic scoring of tissue removed at IDS represents an
ideal means of assessing response to antineoplastic treatments.
● Based on omental assessment

Maintenance therapy
● Aim → To increase PFS subsequenly OS and QOL
●
Single agent Pacitaxel(175 mg/m2
) monthly
SWOG/GOG
PFS was 28 and 21 months in 12 month and 3 month maintenance
therapy
● Maintenance Bevacizumab
GOG 218- PFS improved by 3.8 months
ICON-7--> PFS improved by 2.4 months
● Pazopinib
Du Bois- PFS improved by 5.6 months
No improvement in OS or QOL

Treatment follow up
●
Assessment
●
Early detection of reurrences
●
Monitoring response to therapy
persistence/ regression
Clinical assessment
Radiological assessmect
Tumour marker- CA 125
Clinical assessment
persistence of symptoms- abd pain, heaviness, distension
Signs- P/A mass , ascites
P/R – NODULE- pesistence, regression, reappearance
Radiologic assessment
Early stage- limited value in assessing response to subclinical disease
USG- tumour , ascites, hepatomegaly ( correlation with raised enzyme
levels)
CT- added information : retroperitoneum, omental mets

CA 125●
1) After treatment completion
●
If level normal than 4-6 monthly
If Elevated (>35 U/ml)
persistence – poor prognosis
(PPV- 100%, NPV- 53%)
Normal values do not exclude disease absence
Elevation may precede clinical or radiologic evidence of recurrence with a median
time of 2-6 months
asymptomatic & clinically non palbable disease P/A or P/R
USG/CECT abd pelvis
- no residual disease
↑ CA 125-
Close follow up- monthly
PET (if available)
sudden doubling of CA125
- correlate with regular 2-6 monthly CT scan
-if evidence of persistent/ recurrent disease
- no evidence (↑ uptake in PET)

Asymptomatic but ↑CA 125
●
In asymptomatic & clinically non palbable disease P/A or P/R
USG/CECT abd pelvis
- no residual disease
↑ CA 125-
- Close follow up- monthly
- PET (if available)
sudden doubling of CA125
- correlate with regular 2-6 monthly CT scan
-if evidence of persistent/ recurrent disease
- no evidence (↑ uptake in PET)
If no radiological evidence- continue follow up

Recurrence/relapse
● Most patients with advanced ovarian cancer wil reccur after first
line chemotherapy
● Relapse can be either marker only(biochemical) or with some
objective evidence( clinical or radiological)
● Categorization based on interval of relapse
● 0 (progression during chemotherapy) : Platinum Refractory
relapse
● < 6 months : Platinum Resistant relapse
● > 6 months : Platinum Sensitive relapse

Early versus delayed treatment of relapsed ovarian cancer (MRC
OV05/EORTC 55955): a randomised trial. Lancet, 2010
No evidence to
suggest survival
advantage with
early initiation of
chemotherapy
based on raising CA-
125 levels
Adverse effect on
QOL
MRC05 study
Recommend retreatment based on signs and/or
symptoms of relapsed EOC and not on treating
a rising Ca-125 alone

Aims of Treatment for Relapsed Ovarian Cancer
Maintain Quality
of Life
Extend Survival
Control Disease
●
Considering the balance between efficacy and toxicity is a
key skill for ovarian cancer management
AIMS

Hormonal therapy
In serous cancers presence of progesterone receptors is a favorable factor of
prognosis and, as a rule, associates with a high degree of tumour
differentiation indicate the efficiency of hormonotherapy and chemotherapy.
Heightened androgenicity is linked to the pathogenesis and tumor biology of
epithelial ovarian cancer.
Indications
Patients with biochemical relapse and no
objective evidence of significant disease or
symptoms can be kept on hormonal therapy
In poor G.C.- not been able to tolerate
chemotherapy

●
AGENTS-
●
progestational agents
●
Antiandrogens
●
Gonadotropin agonists
●
Tamoxifen
Response depends on grade of tumour
10-20 % response rates
- High dose oral megestrol acetate
Sequentially administered ethinyl estradiol +medroxyproges- 17 % response rate
Oral medroxy progesterone acetate 100/ 200/400 mg / d – no significant benefit
Oral tamoxifen 20 mg once daily – 3.2 % - RR
6.4 % PR
No correlation with ER PR status
IN PGI- oral tamoxifen 20 mg OD + ORAL MELPHALAN 5 mg twice daily – 3 days– 6
cycles in inoperable cases with poor G . C.
when chemotherapy cannot be given

● Platinum free interval(PFI) <_ 6 months
- are less likely to respond to platinum based chemotherapy
- treated with various single agent such as liposomal
doxorubicin(40 mg/m2 IV 3 weekly 6 cycles), paclitaxel,
docetaxel, topotecan, gemcitabine
● Response <20%( median PFS 4 to 6 months)

● Patients with PFI between 6 and 24 months have 30%
chance of benefit from 2nd
line chemotherapy
● In PFI> 24 months chance of benefit is 60 to 70%
● Strong evidence in support of platinum based combination
over platinum alone in increasing Progression free survival and
overall survival.

GCIG CALYPSO Trial
Ovarian Cancer
Platinum Sens.
N: 976
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
Which Platinum Combination to Use
Non inferiority trial
Primary end point : PFS

Key findings
●
In patients with platinum-sensitive relapsing ovarian cancer, the
combination of PLD-carboplatin was not inferior in term of PFS to
paclitaxel-carboplatin, and even was found significantly superior
– 18% reduction in risk of recurrence (HR 0.82; P=0.005).
No improvement in OS
●
Paclitaxel-carboplatin associated with more severe toxicity
(carboplatin hypersensitivity), alopecia, and long-lasting
toxicity (neuropathy)
●
Moderate reversible HFS, mucositis, and nausea/vomiting more
frequent with PLD.
Conclusion:
CP and CD were equally effective treatment regimens for
patients with very platinum-sensitive ROC. The favourable
risk-benefit profile suggests carboplatin-PLD as treatment of
choice for these patients

Advanced Ovarian Cancer: A ‘Chronic’ Disease with
Multiple Relapses

Ø
Vascular endothelial growth factor (VEGF) and vascular
endothelial growth factor receptor inhibitors.
Ø
Rationale
VEGF over-expressed in epithelial ovarian
cancers, associated with Ascites formation,
Malignant progression Poor prognosis
Preclinical models of solid tumors using Anti-
VEGF therapy:
Slowing of tumor progression
Resolution of malignant effusions
Synergy with cytotoxic agents

No improvement
in OS
O
C
E
A
N
S
Platinum
sensitive
recurrent
ovarian
cancer
Carbo + Gem+ Bevacizumab
(15mg/kg)
Carbo + Gem+ Placebo
response rate of 21%
(OR 78.5% versus 57.4%,
P < 0.0001)
Progression free
survival
J Clin Oncol 30, 2012
Bevacizumab in combination with this chemotherapy has
been licensed by the EMA and is a recommended treatment
for patients with ‘platinum-sensitive’ relapsed ovarian
cancer who have not previously received bevacizumab.

Up to 50% of patients with high-grade serous ovarian cancer could be deficient in
Homologous recombination repair due to:
- BRCA1 or BRCA2 mutations
- BRCA1-/BRCA2-independent defects in the HR pathway
PARP inhibitors prevent DNA repair in BRCA1/BRCA2
PARP – HRD deficiency - Implications
‘BRCA syndrome’/ ‘BRCAness’
●
Younger age at onset
●
HGS histologic type
●
Advanced stage at presentation,
●
High probability of durable remission with platinum therapy
●
Better prognosis
- olaparib 400 mg bd approved for proven BRCA mutation after 3 or more lines of
chemotherapy

Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of
ovarian cancer. Cochrane Database Syst Rev. 2015
PARP inhibitors appear to improve PFS in women with recurrent
platinum-sensitive disease
US approval:
Olaparib as
monotherapy in
patients with
germline BRCA
mutation treated with
> 3 lines
chemotherapy.
Dose 400 bd
European approval: Olaparib monotherapy for adult platinum sensitive,
relapsed BRCA mutated ( somatic/ germline, HGS, who are in response to
platinum based therapy
●
Rucaparib, in 2016 accelerated approved for previously treated BRCA-
mutant ovarian cancer
●
Niraparib (MK-4827) In a phase III trial

Investigational agents
MINIMAL RESPONSE
● EGFR inhibitor- shown minimal response
- cetuximab, trastuzumab, lapatinib, pertuzumab
● Tyrosine kinase inhibitors- minimal response
- geftinib, erlotinib
NO RESPONSE
● Vandetanib TKI with VEGF and EGFR inhibitor
● Farletuzumab anti alfa foate receptor
UNDER TRIAL
● IGF- AMG 479 under trial
● mTOR inhibitors- everolimus, temsirolimus

Surgery in relapse
● Attempt at surgical debuking at the time if relapse in selected
patients pror to 2nd
line chemotherapy- Second cytoreductive
surgery
● Successful is cytoreduction is no gross residual diesase >1cm
trials
● More chances of success with biologically less aggressive
disease and lower tumor burden
● No randomized trial performed yet
● Ongoing prospective trials:- GOG 213 and AGOD III study
● Other operations- colostomy for large bowel obstruction, lysis of
adhesions, palliative gastrostomy tube for small bowel
obstruction

Role of radiotherapy in relapse
● Minority of patients with localized recurrences may experience
prolonged survival after whole abdominal radiation or limited
field irradiation
● Palliative pelvic radiotherapy can provide rapid relief in in cases
of growing pelvic mass causing pain, bleeding and rectal
narrowing.
● May prevent or delay the need for diverting colostomy as well.
● Can also be used in rare brain or bone metastasis as well
● Dose 8 Gy single fraction, 20 Gy/5# or 30 Gy/10#

Borderline tumors
● Differsfrom invasive cancer bt the absence of stromal invasion
● Serous or mucinous borderline tumors
● Mucinous can be present with pseudomyxoma peritonei
● Surgery is the mainstay of treatment
● TAH+BSO or fertility sparing conservative surgery aparing CL
ovary,FT and uterus
● If found during surgery conservative surgery is usually
performed
● Careful examination of tissue block is necessary to exclude a
component of invasive carcinoma

Adjuvant treatment in borderline
ovarian tumors
● Currently no convincing evidence suggest any role of
chemotherapy or radiotherapy
● Simple observation with serial monitoring is reasonable
● Late relapses may occur and often reveal persistent borderline
histology, and sometimes with low grade invasive cancer
● Surgery is the mainstay during recurrence as well
● Some patients with borderline histology also respond to
tamoxifen
● If low grade invasive cancer than adjuvant chemotherapy is
recommended

Sex cord stromal tumor
● Represent about 5% of ovarian cancers
● Often present in stage I, which has excellent prognosis
● Granulosa cell tumors
- are mc type
- presents as solid mass with occasional cytci features
- secrete inhibin, mullerian inhibiting substance
- thus may present as precocius puberty in premenarchal girl
and abnormal menses with infertility mimicing ectopic
pregnancy in reproductive age, postmenopausal women with
postmenopausal bleeding due to endometrial hyperplasia
● Sertoli-leydig tumors present as virilization, pelvic mass

● Surgey is the mainstay
● Often managed conservative unilateral salpingo oopherectomy to
preserve fertility
● TAH and BSO for women who have competed family
● Staging similar to epithelial ovarian carcinoma
● Stage II onwards adjuvant treatment is required
● Selected patients of stage I with high risk features such as large
tumor size(>10cm), high mitotic count, rupture , surface
involvement may be considered for adjuvant treatment
● 30 to 50 % respond to platinum based chemotherapy
● Most common combination used - BEP and PVB
● Associated with toxicities bleomycin- induced lung damage,
etoposide induced leukemia, renal dysfunction, hypertension and
raynaud phenomenon

Current Scenario
two-pathway model of ovarian carcinogenesis
● The fallopian tube is now regarded as the precursor site for high
grade serous cancer carcinogenesis
● Further subclassification on the basis of molecular genetics is
being attempted

CONCLUSION
● Not a not a single entity but represents tumors of epithelial, germ cell
or sex cord stromal origin
● Early stage
Surgery f/b adjuvant therapy
● Locally advanced
surgery f/b adjuvant therapy PDS)
neoadjuvant f/b surgery f/b adjuvant therapy(IDS)
● Indications for adjuvant therapy
✔ Suboptimal resection
✔ Stage Ic
✔ High grade
✔ Pathological stage II, III

● Radiotherapy was used previously but declined due to availability
better chemotherapy which are less toxic
● Recurrence in a locally advanced cancer is common
● Recurrent disease follows a frequent relapse-response with
subsequent shorter disease-free intervals resistant to treatment with
A ‘Chronic’ Disease with Multiple Relapses
● A multipronged approach integrating genomics, sub type specific
maintenance therapy, and other directions that will be used alongside
increasingly sensitive disease detection tools is warranted

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