ppt on metastatic ovarian cancer

1. Metastatic Ovarian
Cancer
5/8/2018

2. HPI
 56 F PMH asthma glaucoma, was first seen by her gynecologist for a right ovarian mass
palpable on her routine gynecologic exam in May, 2015 for DUB and underwent ultrasound.
 Showed bilateral complex adnexal masses with the left ovary with 9.5 x 8 cm solid and cystic
mass and a 7.8 x 7.4 cm mass at the left ovary. Fluid and implants were also seen in the cul-de-
sac.
 In retrospect, she had noted abdominal bloating and had to get larger pants.
 Patient also reported a decreased appetite.

3. History
PMH : Glaucoma, asthma, fibroid, chronic back ache
PSH : D&C fibroids, wisdom teeth extraction
Social history: Occasional alcohol drinker, non-smoker. No
children, (because of late marriage). She works at Macy’s.
Family History: Father with bladder and lung Ca, +h/o
smoking, 2 brothers- no h/o cancer

4. Physical Exam
 General: Well-developed, well-nourished 55
y.o. female in no apparent distress
 HEENT: Pupils are equal and reactive to light,
extraocular movement intact, sclera is anicteric. No
lymphadenopathy
 Neck: Supple, no JVD
 Respiratory: Clear to auscultation..
 Cardiovascular: Regular rate and rhythm, normal S1
and S2
 Abdomen: Soft, nontender. No hepatosplenomegaly is
appreciated, no masses.
 Extremities: No edema, clubbing or cyanosis is noted.
 Skin: Unremarkable
 Lymph Nodes: No lymphadenopathy is noted.
 Neuro: Alert and oriented ×3, nonfocal.

8. Epidemiology
 Fifth most common cause of cancer related
mortality in women
 Most common gynecologic cancer in the US
 In 2018, estimated 22,240 new diagnoses
expected
 14,070 deaths expected
 <40% are cured
 5 year survival 46%
 Median age- 63
 70% cases are diagnosed with advanced
disease

9. Epidemiology
 Nulliparity
 Older age at first pregnancy (>35yrs)
 PID
 Postmenopausal hormone therapy
 BRCA1/BRCA2; Lynch Syndrome
 Inverse correlation with-
 Younger age at first pregnancy (<25yrs)
 No association with obesity

10. Symptoms
 Bloating,
 Pelvic or abdominal pain,
 Difficulty eating/early satiety,
 Urinary symptoms (urgency or frequency),
 If these symptoms are new and frequent (>12 d/mo)
 Literature does not support routine screening for
ovarian cancer in the general population

12. Workup
Abdominal/pelvic
ultrasound (Initial
evaluation)
1
Abdominal/pelvic
CT/MRI scan (to
assess for metastasis)
2
Tumor markers
3
Biopsy (?)
4

13. Tumor Markers (young women <35)
CA-125, Inhibin,
Alpha-fetoprotein
[AFP],
Beta– human chorionic
gonadotropin [beta-
hCG])

14. Caution
 Fine-needle aspiration (FNA) should be avoided for
presumed early-stage disease if possible
 To prevent rupturing the cyst and spilling malignant
cells into the peritoneal cavity; however,
 FNA may be necessary in patients with bulky disease

17. Primary Treatment
 TAH/BSO + Debulking  Systemic chemotherapy
 Surgeon should describe the following in the
operative report:
 1) the extent of initial disease;
 2) the amount of residual disease; and
 3) whether a complete or incomplete resection
(including a description of the lesions) was achieved

18. Fertility
Preservation
Unilateral salpingo-oophorectomy (USO) (preserving the uterus
and contralateral ovary) may be adequate for
Unilateral stage I tumors (stage 1A and 1C, but not stage 1B)
low-risk ovarian tumors (ie, early-stage, grade 1 tumors;
borderline tumors).
Stage IB tumors who wish to maintain fertility, a BSO (preserving
the uterus) and comprehensive surgical staging are needed.

19. Debulking
Surgery
Remove all gross disease,
Aspiration of ascites with
peritoneal lavage
Hysterectomy and BSO
should be performed.
Encapsulated mass should
be removed intact,
Omentectomy.
Suspicious and/or enlarged
nodes should be resected, if
possible.
Bilateral pelvic and para-
aortic lymph node
is recommended for those
patients with tumor

20. Neoadjuvant
Chemotherapy
Stage III to IV disease deemed
unlikely to be completely
cytoreduced to R0
Gynecologic oncologist should make
this assessment
Before initiation of neoadjuvant
chemotherapy-
Histologic confirmation of ovarian
cancer should be obtained (by FNA,
biopsy, or paracentesis);
Core biopsy is preferred.

22. OV21/PETROC
 Multicenter, two-stage, phase II trial. Eligible patients with stage IIB–IVA
EOC treated with platinum-based intravenous (i.v.) NACT followed by
optimal (<1 cm) debulking surgery were randomized to
 treatment arms: (i) i.v. carboplatin/paclitaxel, or (ii) i.p. carboplatin plus
i.v./i.p. paclitaxel.
 The primary end point was 9-month progressive disease rate (PD9).
 The analysis compared i.v. carboplatin/paclitaxel (n = 101) with i.p.
carboplatin, i.v./i.p. paclitaxel (n = 102).
 The intention to treat PD9 was lower in the i.p. carboplatin arm
compared with the i.v. carboplatin arm: 24.5% (95% CI 16.2% to 32.9%)
versus 38.6% (95% CI 29.1% to 48.1%) P = 0.065.
 The study was underpowered to detect differences in PFS: HR PFS 0.82
(95% CI 0.57–1.17); P = 0.27 and OS HR 0.80 (95% CI 0.47–1.35) P = 0.40.

25. Retrospective analysis of the EORTC-NCIC
trial
 Stage IIIC patients with metastatic tumours
⩽45 mm benefited more from primary surgery
 Stage IV patients with metastatic tumours >45 mm
benefited more from neoadjuvant chemotherapy.
 Stage IIIC patients with larger metastatic tumors
and in stage IV patients with less extensive
metastatic tumours both treatments were equally
effective.
 We estimated that the potential five-year survival
rate in the population of treated patients would be
27.3% (95% confidence interval (CI) 21.9–33.0),
7.8% higher than if all were treated with primary
surgery, and 5.6% higher if all were treated with
neoadjuvant chemotherapy.

26. Neoadjuvant vs PDS
Large (586 patients) single-institution study in the United States
reported that patients with advanced ovarian cancer who had
standard debulking surgery had improved median overall survival
(71.7 months) when compared with those who had neoadjuvant
chemotherapy (42.9 months).
A report of more than 14,000 patients reported that median
survival is improved by almost 2 years in those receiving
upfront debulking surgery when compared with those
receiving neoadjuvant chemotherapy (69 vs. 45 months).
A recent retrospective Italian study in women in complete response
after primary treatment reported better outcomes with upfront surgery
(n = 322) when compared with neoadjuvant therapy followed by surgery
(n = 62); overall survival at 2 years, 5 years, and 7 years was 96.4%,
69.3%, and 50.4% for upfront surgery versus 87.1%, 41.8%, and 32.6%
for neoadjuvant therapy (P =.001)

29. Adjuvant Chemotherapy
IV/IP chemotherapy regimen (IP
chemotherapy) is recommended for
patients with stage III cancer with
optimally debulked (<1 cm residual)
disease based on randomized
controlled trials (category 1).1
In women with stage III cancer,
survival was increased by 16 months
after IP therapy using
cisplatin/paclitaxel when compared
with standard intravenous therapy
GOG 172 trial

37. Postremission Therapy
Paclitaxel (category 2B) is a postremission
therapy option for patients with stages II
to IV epithelial ovarian cancer, Fallopian
tube cancer, or primary peritoneal cancer
who have had complete clinical remission
after first-line therapy.
Maintenance (or postremission) therapy
an option based on the results from GOG
178 (No OS difference)

41.  Median overall survival was no different between the groups, at 54.8
months with surveillance, 51.3 months with paclitaxel, and 60 months with
PP. The hazard ratio (HR) for paclitaxel vs surveillance was 1.104 (97.5% CI,
0.884–1.38); for PP vs surveillance, it was 0.979 (97.5% CI, 0.781–1.23).

45. Management of an Increasing CA-125 Level
A multi-institutional European trial
assessed the use of CA-125 for
monitoring for ovarian cancer
recurrence after primary therapy
The data suggest that treating
recurrences early (based on detectable
CA-125 levels in patients who are
asymptomatic) is not associated with
increase in survival and is associated
with a decrease in quality of life

48. Rising CA-125
Refer for a clinical trial
Delaying treatment (ie, observation) until clinical symptoms arise,
or
Immediate treatment (category 2B)
Tamoxifen, other hormonal agents are acceptable
recommendations for this clinical situation (category 2B for all)

49.  105 patients with Stage III or IV epithelial ovarian cancer
 Tamoxifen (20 mg orally twice daily) and evaluated for response.
 18% responded: 10% demonstrated a complete response (CR) and 8%
showed a partial response (PR).
 38% had short-term disease stabilization.
 CR had a median duration of 7.5 months, with the longest lasting 17
months.
 Patient with CR- 89% had elevated estrogen receptor levels.
 This contrasts with patients who had stable or progressive disease as only
59% of them had measurable estrogen receptors (P = 0.16)

50. Recurrent
Disease
 Prognosis is poor either
 1) for patients who progress after 2 consecutive
chemotherapy regimens without ever sustaining
a clinical benefit (refractory)
 2) for those whose disease recurs in less than 6
months (platinum resistant)
 Patients who relapse 6 months or more after
initial chemotherapy are termed platinum
sensitive.
 Combination platinum-based chemotherapy for
a total of 6 cycles is preferred for first recurrence
(category 1) in patients with platinum-sensitive
disease

51.  Secondary cytoreductive surgery can be considered for patients
who recur (ie, radiographic and/or clinical relapse) after a long
disease-free interval (6 months or more)
 Re-evaluation should follow after 2 to 4 cycles of
chemotherapy (depending on the agent) to determine if
patients benefited from chemotherapy.
 Patients who primarily progress on 2 consecutive
chemotherapy regimens without evidence of clinical benefit
may not benefit from additional therapy.
 Platinum-based combination chemotherapy is recommended
(category 1) for a total of 6 cycles for platinum-sensitive
recurrence
 For patients with platinum-sensitive disease who cannot
tolerate combination therapy, the preferred single agent is
carboplatin or cisplatin.

52. Preferred
combinations
 carboplatin/paclitaxel (category 1),
 carboplatin/liposomal doxorubicin (category 1)
 carboplatin/weekly paclitaxel,
 carboplatin/albumin-bound paclitaxel (for
taxane hypersensitivity),
 carboplatin/docetaxel,
 carboplatin/gemcitabine (which has been
shown to improve PFS)
 cisplatin/gemcitabine, or
 carboplatin/gemcitabine/bevacizumab.

55. PFS favored platinum and paclitaxel
1-year progression-free
survival of 10% (50 vs
40% [4-15])
Median progression-free
survival of 3 months (13
vs 10 months [1-5]).

61. Conclusions
 Carboplatin/liposomal doxorubicin has a
better PFS compared to
carboplatin/paclitaxel.
 Carboplatin/liposomal doxorubicin is
easier to tolerate; (women tend to
discontinue therapy with
carboplatin/paclitaxel more often than
they do with carboplatin/liposomal
doxorubicin. )

62. Platinum resistant disease
 Sequential therapy using single agents is typically used
 Response rate of the following agents appears to be similar:
 Topotecan, 20%;
 Gemcitabine, 19%;
 Liposomal doxorubicin, 26%;
 Oral etoposide, 27%.356
 Docetaxel is 22% and for
 Weekly paclitaxel is 21%.

63. MITO-11
 PFS was increased in the
paclitaxel/pazopanib arm when
compared with paclitaxel alone
(median 6.35 months [95% CI,
5.36–11.02] vs. 3.49 months
[2.01–5.66]

72. BRCA  The most common type of ovarian cancer, high
grade serous ovarian cancer, frequently has
defects in the genes involved in the DNA repair
pathway, homologous recombination.
 Mutations of BRCA1 and BRCA2 occur in 20-
25% of high grade serous carcinomas of the
ovary.
 Sporadic, non-hereditary tumors with defects in
homologous recombination display similar
features to BRCA mutant tumors, so called
“BRCAness

73. BRCA  BRCA mutated and BRCA like tumors have
higher response rates to platinum based
chemotherapy than non-BRCA ovarian cancers,
with improved overall survival and prolonged
treatment-free intervals.
 With deficient homologous recombination, the
other DNA repair pathways become more
important and PARP is an integral part of the
other pathways.

74. Who Should
Get Genetic
Testing
Young age, < 50
Triple negative breast cancer
Bilateral breast cancer, or breast and ovarian cancer
Ovarian cancer
Male breast cancer
Ashkenazi Jewish Ancestry
Strong family history, two first or second degree relatives > 50, or one < 50.

75. PARP inhibitors
 Poly (ADP Ribose) Polymerase (PARP) is a group
of enzymes important in DNA repair.
 BRCA mutations result in defects in homologous
recombination.
 Tumors with defects in homologous
recombination require PARP for cell survival.
 PARP inhibitors are active in BRCA mutated
tumors and tumors with defects in homologous
recombination.

77. PARP inhibitors
 There are currently three PARP inhibitors approved
for use in different indications in high grade serous
ovarian cancer.
 Olaparib is approved for breast cancer patients with
BRCA mutations.
 There are over 100 clinical trials investigating PARP
inhibitors, and taking advantage of synergistic anti-
tumor activity.

85. Common
adverse
reactions
(≥20%)
 Anemia,
 nausea,
 fatigue (including asthenia),
 Nasopharyngitis,
 Diarrhea,
 Aarthralgia/myalgia,
 Headache,
 Cytopenias

90. Back to our
case
Neoadjuvant chemotherapy with carboplatin and
weekly paclitaxel x6 , and had an excellent response
She underwent debulking surgery,
Her CA 125 normalized and her post-treatment CT
and PET scans were negative.

91.  CT followed by PET showed recurrence after her CA 125 was slowly going
up.

92. Treatment
Consented to Carboplatin and Doxil, which
she started 10/7/16.
She completed 6 full cycles, and her re-
staging showed a complete response.
Maintenance Niraparib

93. Thank you