recentupdated management in ovarian cancer as per NCCN

1. EPITHELIAL OVARIAN
CANCER : AN UPDATED
MANAGEMENT
DR. LIZA KHOSHIN
PHASE B RESIDENT
DEPARTMENT OF ONCOLOGY

2. CONTENTS
1) EPIDEMIOLOGY
2) ANATOMY
3) CLASSIFICATION
4) RISK FACTORS
5) DIAGNOSIS
6) STAGING
7) MANAGEMENT

3. EPIDEMIOLOGY
• 12th most common cancer in Bangladesh as per GLOBOCAN 2018
• 11th most common cancer-related cause of death in Bangladesh
• Average life time risk : 1 in 70
• Median age at diagnosis : 63 years
• Epithelial tumors : 90% of ovarian tumors
• Common histologic subtype : High grade serous Endometrioid 
Clear cell  Mucinous tumors

4. ORIGIN OF THE OVARIAN TUMORS

5. WHO CLASSIFICATION OF MALIGNANT OVARIAN TUMORS
A) COMMON EPITHELIAL TUMORS: B) SEX CORD STROMAL TUMORS:
MALIGNANT SEROUS TUMOR :
• Adenocarcinoma, papillary adenocarcinoma,
• papillary cystadenocarcinoma
• Surface papillary carcinoma
• Malignant adenofibroma, cystadenofibroma
MALIGNANT MUCINOUS TUMOR
• Adenocarcinoma, cystadenocarcinoma
• Malignat adenofibroma, cystadenofibroma
MALIGNANT ENDOMETRIOID TUMOR:
• Adenocarcinoma
• Adenoacanthoma
• Malignant adenofibroma, cystadenofibroma
• Endometrioid stromal sarcoma
• Mesodermal (mullerian) mixed tumor
OTHER :
• Clear cell (mesonephroid) tumor, malignant
• Brenner tumor, malignant
• Mixed epithelial tumor
• Undifferentiated carcinoma
GRANULOSA – STROMAL TUMOR :
• Granulosa cell tumor
• Tumor in the thecoma-fibroma group
• Fibroma
• Unclassified
ANDROBLASTOMA : SERTOLI - LEYDIG
CELL TUMOR
• Well differentiated
• Tubular androblastoma, Sertoli leydig tumor (Tubular
adenoma of Pick)
• Tubular androblastoma with lipid storage, Sertoli cell
tumor with lipid storage
• Sertoli – Leydig cell tumor (tubular adenoma with
Leydig cells)
• Leydig cell tumor, hilus cell tumor
• Of intermediate differentiation
• Poorly differentiated (sarcomatoid)
• With heterologous elements
• Gynandroblastoma
• Lipid (lipoid) cell tumors
• Unclassified

6. C) GERM CELL TUMOR :
• Dysgerminoma
• Endodermal sinus tumor
• Embryonal carcinoma
• Polyembryoma
• Choriocarcinoma
• Immature teratoma
• Mature dermoid cyst with malignant transformation
• Monodermal and highly specialized
• Struma ovarii
• Carcinoid
• Struma ovarii and carcinoid
• Others
• Mixed forms
D) GONADOBLASTOMA :
• Pure
• Mixed with dysgerminoma or other form of germ cell tumor

7. RISK FACTORS
Increased risk factors Decreased risk factors :
Patient characteristics:
o Increasing age
o Personal history of breast cancer
o Inflammatory- PID, Endometriosis
Hormonal :
o OCP
o Progestins
Genetic factor :
o Family h/o Ovarian cancer
o BRCA 1 / 2 mutations
o Hereditary non polyposis colorectal cancer
Surgery
o Hysterectomy
o Tubal ligation
Reproductive factors :
o Nulliparity
o Early menarche / late menopause
o Infertility
o PCOS
o Endometriosis
o Ovulation inducing drugs
o HRT
Reproductive factors :
o Multiparity
o Breast feeding
Environmental factors:
o Obesity and high fat diet
o Talc exposure
o Cigarette smoking (for mucinous ovarian cancer)

8. DIAGNOSIS
 Usually asymptomatic
 Acute presentation :
Pleural effusion - SOB
Bowel obstruction – severe nausea vomiting
 Subacute presentation :Adnexal mass
Pelvic and abdominal symptoms :
Bloating
Urinary urgency or frequency
Difficulty eating or feeling full quickly
Pelvic or abdominal pain
Palpable inguinal/cervical lymphadenopathy uncommon
 Paraneoplastic syndromes : Cerebellar degeneration, polyneuritis, dermatomyositis,
hemolytic anemia, DIC, acanthosis, nephrotic syndrome

9. INVESTIGATION
• For diagnosis: Tumor marker
Transabdominal / Transvaginal ultrasonography
• For confirmation of diagnosis : Surgical exploration & biopsy
• Tumor molecular testing (BRCA1/2, MSI, dMMR)
• For staging : CT scan of abdomen, pelvis and chest
MRI of abdomen
PET CT scan
• Routinely: CBC
CXR P/A view
RFT
LFT

10. TUMOR MARKER IN OVARIAN MASSES
TUMOR MARKER OVARIAN NEOPLASM
CA 125 Epithelial ovarian cancer
CEA Mucinous ovarian cancer
HCG Embryonal carcinoma
Choriocarcinoma
INHIBIN A OR INHIBIN B Granulosa cell tumor
LDH Dysgerminoma
AFP Endodermal sinus tumor
Embryonal carcinoma

11. FIGO staging
FIGO STAGE
I Tumor limited to ovaries (one or both) or fallopian tube(s)
IA Tumor limited to one ovary (capsule intact) or fallopian tube, no tumor on ovarian
or fallopian tube surface; no malignant cells in ascites or peritoneal washings
IB Tumor limited to both ovaries; (capsule intact) or fallopian tube surface ; no
malignant cells in ascites or peritoneal washings
IC Tumor limited to one or both ovaries or fallopian tubes, with any of the following:
IC1 Surgical spill
IC2 Capsule ruptured before surgery or tumor on ovarian or fallopian tube surface
IC3 Malignant cells in ascites or peritoneal washings
II Tumor involves one or both ovaries or fallopian tubes with pelvic extension below
pelvic brim or primary peritoneal cancer
IIA Extension and/or implants on the uterus and / or fallopian tube(s) and/or ovaries
IIB Extension to and/or implants on other pelvic tissues

12. III Tumor involves one or both ovaries or fallopian tubes, or primaryperitoneal cancer, with
microscopically confirmed peritoneal metastasis outside the pelvis and/oor metastasis to
the retroperitoneal (pelvic and/or para-aortic) lymph nodes
IIIA1 Positive retroperitoneal lymph nodes only (histologically confirmed)
IIIA2 Microscopic extrapelvic (above the pelvic brim)peritoneal involvement +/- retroperitoneal
lymph nodes
IIIB Macroscopic peritoneal metastasis beyond pelvis 2cm or less in greatest dimension +/-
metastasis to the retroperitoneal lymph nodes
IIIC Macroscopic peritoneal metastasis beyond the pelvis >2cm in greatest dimension +/-
metastasis to the retroperitoneal lymph nodes (includes extension of tumor to capsule of
liver and spleen without parenchymal involvement of either organ)
IV
IVA Pleural effusion with positive cytology
IVB Liver or splenic parenchyma metastases, metastases to extraabdominal organs (including
inguinal LN and lymph nodes outside the abdominal cavity); transmural involvement of
intestine

15. MANAGEMENT
Epithelial Ovarian
tumor
Primary peritoneal
carcinomatosis
Fallopian tube cancer

16. TREATMENT MODALITY
SURGERY SYSTEMIC THERAPY
CHEMOTHERAPY
TARGETED THERAPY
HORMONAL THERAPY
IMMUNOTHERAPY

17. SURGERY
AIMS:
• Histopathological confirmation of the disease (primary/ secondary)
• Staging laparatomy (to determine the extent)
• Debulking : Primary debulking
Interval debulking
Second cytoreduction
Goal of surgery Ro resection margins or optimal cytoreduction (≤1cm
diameter residual tumor) / debulking

18. PRIMARY CYTOREDUCTION :
• Debulking surgery prior to administration of 1st line CT
• Standard approach for suspected epithelial ovarian cancer
INTERVAL CYTOREDUCTION :
• Debulking procedure performed after several cycles of
chemotherapy have been administered
• Done in those who had a suboptimal cytoreduction at the time of
initial surgery

19. EXPLORATORY LAPATOROTOMY
• A large midline incision required to inspect the peritoneal cavity,
including the upper abdomen, retroperitoneal spaces and lymph nodes
• Fluid sample from ascitic fluid, peritoneal surfaces, pelvic and
paracolic spaces collected and sent for cytological examination
• If intraperitoneal carcinomatosis absent, ovarian tumor is resected first
and surgical staging done to avoid the rupturing of ovarian mass

20. • Grossly normal opposite ovary biopsy or excision of any benign appearing
cyst
• Pelvic and paraaortic retroperitoneal lymph nodes sampling if not
involved. But if involved, should be removed
• An infracolic omentectomy if gross disease is not present in omentum. But
if present (omental cake) completely excised as completely as possible
• Careful examination of both diaphragm, liver serosa, liver parenchyma,
spleen

21. • Paracolic spaces and large bowel are inspected and if there is threat for
intestinal obstruction then resection may be required
• The small intestine and mesentery are evalutaed and any tumor implants are
removed as much as possible
• Hysterectomy and Salpingoophorectomy –
If fertility is not needed then TAH + BSO done
If fertility is desired in case of young women with stage I A(early), low
malignant potential lesion, then unilateral salpingo-ophorectomy or
bilateral salpingo ophorectomy

22. ROLE OF APPENDICECTOMY
• Routinely for mucinous ovarian tumor as primary mucinous
appendiceal tumor may metastasize to ovary
• Routine appencectomy for all staging procedure for ovarian cancer is
controversial

23. • The standard staging procedure is Extrafascial hysterectomy with
BSO with omentectomy with pelvic and paraaortic lymph node
dissection with cytology of peritoneal cavity and any suspected
lesions either by laparotomy (preferred) or laparoscopy

24. TIMING OF TREATMENT INITIATION
• Started as soon as feasible, usually within 2-4 weeks from the surgery
• No high-quality data about the optimal timing for the initiation of first-
line chemotherapy, but limited data suggest that a delay of greater than
approximately 1 month in instituting chemotherapy associated with a
poorer outcome

25. SYSTEMIC THERAPY
CHEMOTHERAPY :
 Neoadjuvant-
oFor women with advanced EOC who are poor candidates to
withstand an aggressive initial surgery
oFor those with extensive disease where optimal cytoreduction is
not possible
oUnresectable disease
 Adjuvant chemotheapy : Stage 1A/B(grade3,clear cell ),1C, II, III,
IV ovarian cancer
 Palliative chemotherapy

26. UNRESECTABLE DISEASE
Most experts agree that criteria for unresectability include patients with
the following :
●Diffuse and/or deep infiltration of the small bowel mesentery.
●Diffuse carcinomatosis involving the stomach and/or large parts of the
small or large bowel
●Infiltration of the duodenum and/or parts of the pancreas (not limited
to the pancreatic tail)
●Involvement of the large vessels of the hepatoduodenal ligament,
celiac trunk or behind the porta hepatis
●Involvement of the liver parenchyma

27. ANGIOGENESIS INHIBITORS
• Angiogenesis inhibitors not used in combination with initial CT for
advanced EOC, as only modest benefits have been demonstrated in
randomized trials .
• Bevacizumab is approved by the US Food and Drug Administration
and used in addition to conventionally dosed IV CT (Cat 2B), in select
patients without a known mutation in BRCA1 / BRCA2 who have a high
risk of recurrence (eg: those with pleural effusions or ascites)

28. BEVACIZUMAB :
• First targeted agent to show significant single agent activity in ovarian
carcinoma
• Used during adjuvant carboplatin /paclitaxel and for maintenance
therapy (Cat 2B)

29. GOG 218
FOR BEVACIZUMAB AS AN ADJUVANT AFTER SURGERY
Bevacizumab+ standard ct vs
Bevacizumab alone
PFS 14.1vs 10.3 month, (p value < 0.001)
PFS was not significantly increased in patient who did not receive maintenance Bevacizumab
vs chemotherapy alone
There was no improvement in OS with bevacizumab

30. IMMUNOTHERAPY
OLAPARIB : (PARP inhibitor)
• In December 2014, olaparib was approved for use as a single
agent by FDA.
• The FDA approval is for
• germline BRCA mutated (gBRCAm) advanced ovarian
cancer as a maintenance
• who has received 3 or more prior lines of
chemotherapy(recurent/progressive disease)

31. RADIOTHERAPY
Limited use only for :
- Palliative setting for symptom control in patients with
recurrent disease

32. SUSPICIOUS OVARIAN MASS
Abdominal and pelvic examination
Imaging study- TVS / USG / CT / MRI
CBC and complete metabolic panel
Tumor marker
GI evaluation as indicated and family history for germline mutation
Clinical staging

33. C
L
I
N
I
C
A
L
S
T
A
G
I
N
G
Stage IA
(Fertility
desired)
Stage IB
(Ferility
desired)
Stage IA – IV ,
surgical candidate,
optimal
cytoreduction
(fertility not
desired)
Poor surgical candidate or
low likelyhood of optimal
cytoreduction
USO + CSS
BSO + CSS
TAH + BSO + CSS +
debulking as required
Neoadjuvant
therapy
Further
treatment as
Pathological
staging
Clinical stage Primary treatment

34. INCIDENTALLY DIAGNOSED OVARIAN CANCER BY PREVIOUS SURGERY
Suspected grade I
or low grade stage
I disease
Surgical staging
Completion
surgery/Surgical staging
Reductive
surgery
CT f/b IDS
Findings Primary treatment
Obtain family
history, genetic
risk evaluation,
pathological
review if
required, imaging
study if not done
, tumor marker if
indicated
Incomp
lete
previou
s
surgery
or
staging
Suspected grade II
stage I disease (non
serous)
Suspected stage I, high
grade serous or clear
cell or stage IC
Completion
surgery/surgical staging/
chemotherapy
Stage II - IV
No residual disease
Potentially resectable
residual disease
Potentially
unresectable residual
disease
Patholo
gical
staging

35. Disease diagnosed by Surgery (Pathological staging) (Stage I)
Stage I A / IB / IC
disease
Grade II
endometrioid Observe or Platinum
based CT (3-6 cycle)
Grade III
Endometrioid / High
risk serous carcinoma IV platinum based CT
Clear cell carcinoma,
carcinosarcoma
Observe (IA)
IV platinum based
therapy
Mucinous carcinoma
Observe or fertility
sparing surgery
CT (IC)
Monitoring and
follow up
Pathological staging Primary CT/Primary
Adjuvant therapy

36. Stage II / III
/IV
• Platinum based CT
• Completion surgery as
indicated by tumor
response and potential
resectability
Maintenance
therapy
Pathological
staging
Primary CT / Adjuvant
therapy

37. POST PRIMARY TREATMENT (STAGE II – IV)
Monitorin
and follow
up
Imaging as
clinically
indicated
(TVS/USG/C
T/MRI/PET
CT
Complete remission
Partial remission
Progression
Stable disease
Observed or Orlaparib for BRCA I/II
mutation or if Bevacizumab is used in
primary therapy then post remisssion
Bevacizumab
Orlaparib for BRCA I mutation or
post remisssion Bevacizumab if used
in primary therapy
Or
treatment as persistent disease
Treatment as persistent disease
Post remission Bevacizumab
Bevacizumab if used in primary
therapy
or
treatment
Maintenance therapy

38. MONITORING / FOLLOW UP (STAGE I – IV AFTER
PRIMARY TREATMENT)
• Visit every 2-4 monthly for 2 year  3-6 monthly for 3 year 
annnually after 5 year
• Physical examination include pelvic examination
• Imaging study of the chest , abdomen and pelvis as indicated
• BCC and chemistry profile
• Tumor marker
• Genetic risk evaluation if not done previously

39. PERSISTANT DISEASE OR RECURRANCE
Disease status Therapy
Progression on primary,maintenance or recurrance therapy
Or
Stable or persistant disease(if not on maintenance therapy)
Or
Complete remission and relapse<6 months after completing
chemotherapy
Clinical trial
And/or
Best supportive care
And/or
Recurrance therapy as platinum resistant
Complete remission and
relapse≥6 mo after completing
prior chemotherapy
Radiographic and or
clinical relapse
Biochemical relapse
Consider 2ND
cytoreductive
therapy
Clinical trial OR
Delay treatment until clinical relapse OR
Immediate platinum based CT (2B) OR
Best supportive care
Clinical trial AND/OR
Platinum based CT (cat1) for
first recurrance OR
Recurrance therapy OR
Best supportive care

40. NEOADJUVANT VS PRIMARY CYTOREDUCTIVE
SURGERY
[As compared by Surveillance, Epidemiology and End-Results (SEER) database]
NACT PRIMARY CYTOREDUCTIVE
SURGERY
Ostomies placed 8% 19%
Small bowel resections 4% 6%
Large bowel resections 11% 21%
Reduction in postoperative complications :
- Infection
- Gastrointestinal complications
- Pulmonary problems
18%
35%
11%
11%
29%
4%

41. European Organization for the Research and Treatment of Cancer
(EORTC) 55971 trial
NACT for 3 cycles f/b
interval surgical
cytoreduction and ACT
Primary debulking
surgery (PDS) f/b 6 cycles
of platinum-based CT
Fewer postoperative deaths 0.7% 2.5%
Infections 2% 8%
Grade 3/4 hemorrhage 4% 7%
Thrombotic events O% 2.6%
Optimal cytoreduction 81% 42%
Median free survival No difference No difference
Overall survival (OS) :
- If no residual disease at the time of
surgery
- if microscopic residual disease only
(ie, <10 mm residual disease
38 months
27 months
45 months
32 months

42. CHEMOTHERAPY REGIMEN

44. WOMEN WITH OPTIMALLY CYTOREDUCED DISEASE
• For patients with optimally cytoreduced EOC, combined
(IV/IP therapy) rather than IV treatment alone, IV chemotherapy
remains an appropriate alternative
• Preferred IV/IP therapy regimen — The most commonly
used IV/IP regimen consists of six cycles of
•IV paclitaxel (135 mg/m2 over 24 hours) on day 1
•IP cisplatin (100 mg/m2) on day 2
•IP paclitaxel (60 mg/m2) on day 8
Repeat every 3 weekly for 6 cycles

45. • Support for IV/IP chemotherapy comes from randomized data comparing
standard IV therapy with IV/IP treatment following primary
cytoreductive surgery In one meta-analysis that included nine randomized
trials and over 2100 women, IV/IP therapy was associated with :
• A reduction in the risk of dying compared with IV treatment (HR 0.81,
95% CI 0.72-0.90)
• Improvement in disease-free survival (HR for recurrence 0.78, 95% CI
0.70-0.86)

46. WOMEN WITH SUBOPTIMALLY CYTOREDUCED
DISEASE
• Are not appropriate candidates for IP treatment as it results in
limited penetration into larger tumors and reduced effectiveness of
treatment. Therefore, IV therapy is recommended

47. DOSE-DENSE VERSUS CONVENTIONALLY DOSED IV THERAPY
• Dose-dense IV therapy  Administering CT in a weekly schedule
• It typically refers to one of two regimens:
A) Carboplatin and paclitaxel 3 weekly
B) Carboplatin and paclitaxel administered weekly
• In general, trials have suggested similar or improved efficacy with
dose-dense regimens relative to conventionally dosed therapy,
though toxicities are typically higher
• Mucinous or clear cell carcinoma  does not have improved disease
outcomes with dose-dense therapy, so conventionally dosed regimen
suggested

48. MAINTENANCE THERAPY (POST REMISSION
THERAPY)
• Limited data to support the routine administration of maintenance for
patient with stages II-IV EOC , who have had complete clinical
remission after 1st line therapy
• Paclitaxel(cat 2B)
• Pazopanib (Cat 2B),
• Bevacizumab -frontline setting, along with chemotherapy and as
maintenance for select patients with a high risk of recurrence
• Olaparib - for women with a germline mutation
in BRCA1 or BRCA2 and a response to frontline platinum-based
therapy has also found to be benifited.

49. Paclitaxel(4 weekly for 12 cycle)(category 2B)
PFS : 28 vs 21 month(improved)
but no improvement in OS

50. Olaparib vs placebo
(SOLO1 trial phase 3 trail)
Median follow up At 41 month (60 versus 27 percent; hazard ratio [HR for
disease progression or death 0.30, 95% CI 0.23-
0.41
three-year rate of freedom from death 84 versus 80 percent (HR for death 0.95, 95% CI
0.60-1.53

51. MAINTENANCE
• Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe
Ovarialkarzinom group (AGO-OVAR 16)
Pazopanib vs placebo
PFS (18 versus 12 months, respectively;
hazard ratio [HR] 0.766, 0.64-0.91)
significant grade 2 or greater
hypertension
(52 versus 17 percent)
grade 3 or 4 diarrhea (8 versus 1 percent)
grade 3 or 4 hepatotoxicities (9 versus <1 percent).
only prospective trial to evaluate maintenance angiogenesis inhibition as a single agent at the
completion of first-line chemotherapy. However, it provides more evidence that maintenance therapy
using an angiogenesis inhibitor can prolong PFS. However, until this is shown to also improve OS, we
do not administer angiogenesis inhibitors in this context as part of standard clinical practice.

52. MAINTENANCE
Nintedanib vs placebo
PFS (17.3 versus 16.6 months; HR 0.84, 95% CI
0.72-0.98)
Thrombocytopenia
Anemia
●Hypertension
●Hepatic transaminitis
(18 versus 6 percent with placebo)
(14 versus 7 percent)
(5 versus 0.4 percent)
(16 versus 3 percent)
Further follow-up is ongoing for its impact on OS

53. RECURENCE
• Likelihood of relapse after initial therapy for all stage EOC 62%
• 80-85% of stage III and IV relapse even after initial treatment
• Management of relapse cases are stratified as:
• Platinum free interval
» PFI ≥ 6 month indicate Platinum sensitive disease
» PFI < 6 month indicate Platinum Resistant cases
• BRCA mutation status
• Hisological variety

54. RECURRENCE THERAPY

57. REFERENCES
• NCCN Guidelines Version 1.2019 Epithelial Ovarian cancer /
Fallopian tube cancer / Primary peritoneal cancer
• DeVita, Hellman, and Rosenbergs Cancer Principles and Practice of
Oncology - 10E (2015) [PDF] [UnitedVRG]
• AJCC Cancer staging manual, 8th edition
• The MD Anderson Manual of Medical Oncology, 3rd edition
• Uptodate