Ovarian Cancer Summary
Epidemiology
·
5th most common
cancer among women.
·
Leading cause of
gynecologic cancer death.
·
4% of cancers among women
in the U.S.
·
Epithelial ovarian cancer
accounts for 90% of all cases.
·
Fallopian tube cancer and
primary peritoneal cancer are much rare, but share histologic, prognostic and
treatment response features with epithelial ovarian cancer.
·
25% of women presents with
stage I, 15% with stage II, 42% with stage III and 17% with stage IV.
·
10% of cancers of the ovary
are non-epithelial. They are classified as either sex cord stromal cell tumors
or germ cell tumors
Risk factors and presentation
·
Non-specific discomfort,
Urinary frequency, persistent bloating and constipation.
·
Mean age at diagnosis of
ovarian cancer in 59.
·
Increasing age is one of
the strongest risk factor for developing ovarian cancer.
·
Family history is the next
strongest risk factor.
·
A woman with a 1st
degree relative with ovarian cancer has a lifetime risk of 5%.
·
Families with multiple
cases of breast and/or ovarian cancer should consider genetic testing.
·
Deleterious BRCA1 or BRCA2 mutation carriers have a lifetime
risk of ovarian cancer estimated at 16% to 60%, with the higher risk among
BRCA1 mutation heterozygous women with strong family histories of the disease
·
Women with genetic mutations
that are part of the HNPCC syndrome also have an increased risk of ovarian
cancer.
·
Other risk factors include
white race, diets high in animal fat, nulliparity or first birth after age 35
yrs, involuntary infertility, late menopause and early menarche.
·
Oral contraceptive use is
associated with a decreased risk.
Screening
·
No data to support the
routine use of ovarian cancer screening of any type in the general population
·
A randomized trial of
screening with Ca125 and transvaginal sonogram compared with usual care
enrolled 78,216 women age 55 to 74. Screening did not decrease mortality, and
there was evidence of harm from interventions required for women with false
positive screening results.
·
No prospective data to
demonstrate longer survival with screening of women at high risk for developing
ovarian cancer, however the prevalence of the disease in these populations
makes screening a reasonable choice for women who wish to preserve fertility
Risk reduction
·
Prophylactic BSO may
substantially reduce the risk of ovarian cancer for women who are carries of
deleterious BRCA1 or BRCA2 mutations
·
Approximately 80% lower
risk of ovarian and fallopian tube cancers with follow up of less than 10 yrs
from surgical procedure.
·
A meta-analysis of 10
studies confirmed this level of risk reduction across a large population of
high risk women.
Diagnosis and surgical staging
·
Transvaginal ultrasound can
assist in the differential diagnosis.
·
CT scan chest, abdomen and
pelvis are helpful for staging.
·
CA 125 is elevated in more
than 80% of patients with advanced ovarian cancer but only 50% of patients with
early stage.
·
Definitive diagnosis by
surgical exploration
·
Prognosis is linked to the
amount of residual tumor after surgical cytoreduction.
·
Optimal cytoreduction is
defined as no residual tumor measuring > 1cm.
·
In patients whom there is
clear evidence that optimal cytoreduction will not be possible, neoadjuvant
chemotherapy should be used but a biopsy of accessible tissue may be performed
to confirm diagnosis prior.
o
One phase III randomized
trial showed equivalent outcomes for patients with stage III or IV ovarian
cancer whether treated with neoadjuvant chemotherapy followed by surgery or
with cytoreductiove surgery followed by Chemotherapy. (NEJM 2010;363;943)
·
Patients who have a
complete resection of all macroscopic disease have superior survival outcomes
with patients in whom the disease cannot be completely resected.
·
Ctyoreduction surgery
includes TAH BSO, pelvic & para-aortic lymph node sampling, infra-colic
omentectomy, pelvic and peritoneal biopsies, and pelvic and peritoneal
washings.
Treatment overview and
estimates of overall survival
Stage
|
Definition
|
Treatment overview
|
5 yr survival
|
I
|
Tumor confined to the ovaries
|
Complete surgical resection/staging + see below
|
85-90%
|
IA
|
Limited to 1 ovary, capsule intact, no tumor on surface, no malignant
cells in ascites or washing
|
·
No adjuvant chemotherapy
for grade 1 or 2.
·
Adjuvant chemotherapy for
grade 3 and clear cell.
|
|
IB
|
Limited to both ovaries, rest as 1A
|
||
1C
|
Limited to 1 or both ovaries but with capsule rupture or tumor on
ovarian surface or malignant cells in ascites or peritoneal washing
|
Adjuvant chemotherapy
|
|
II
|
Involves 1 or both ovaries with pelvic extension
|
Adjuvant chemotherapy
|
80%
|
IIA
|
Extension and/or implants on uterus and/or fallopian tubes, no
malignant cells in ascites or peritoneal washings
|
||
IIB
|
Extension to other pelvic tissue, rest as IIA
|
||
IIC
|
Pelvic extension with malignant cells in ascites or peritoneal
washing
|
||
III
|
Involves 1 or both ovaries with peritoneal metastasis outside the
pelvis and/or retroperitoneal or inguinal LNs
|
Adjuvant chemotherapy
|
15-50%
|
IIIA
|
Microscopic peritoneal metastasis beyond the pelvis
|
||
IIIB
|
Macroscopic peritoneal metastasis beyond the pelvis, measuring <2
cm
|
||
IIIC- optimally debulked
|
Macroscopic peritoneal metastasis beyond the pelvis measuring > 2
cm and/or regional LN metastases;
No residual disease >1 cm at completion of cytoreductive surgery
|
Intraperitoneal cisplatin plus intraperitoneal and intravenous
paclitaxel
|
30-50%
|
IIIC- suboptimally debulked
|
Same as above but residual disease > 1 cm at completion of
cytoreductive surgery
|
IV platinum + taxane chemotherapy
|
10-20%
|
IV
|
Distant metastases (excluding peritoneal) to liver or malignant
pleural effusion
|
IV adjuvant chemtherapy
|
5-10 %
|
Chemotherapy for early stage ovarian cancer
·
Stage IA or IB grade 1 or 2
are considered favorable prognostic group.
·
2 randomized trials for
this favorable group failed to show a DFS or OS benefit from chemotherapy.
(NEJM 1990;322;1021)
·
Stage IA or IB grade 3, all
stage IC, All clear cell tumors and Stage II have a less favorable prognosis.
·
A number of randomized
trials have demostrated that adjuvant chemotherapy can prolong the time to
progression for women with high risk early stage ovarian cancer.
·
An analysis of data from
more than 900 patients with high risk, early stage disease showed that adjuvant
platinum based chemotherapy administered postoperatively led to 11% improvement
in 5 yr PFS and 8% improvement in 5 yr OS, compared with a strategy of
observation until evidence of recurrent disease. (J Natl Cancer Inst.
2003;95;105)
·
The optimal duration of
therapy for early stage disease has not been defined.
·
A large phase III trial
showed that adding 24 weeks of maintenance paclitaxel after 3 cycles of IV
paclitaxel plus carboplatin did not improve PFS or OS.
Chemotherapy for advanced ovarian cancer
·
Standard 1st
line therapy is Platinum + Taxane combination chemotherapy.
·
Patients with optimally
cytoreduced, stage III ovarian cancer have a significant survival advantage
when receiving a combination of IP Cisplatin + IP & IV Paclitaxel.
·
Carboplatin and Cisplatin
are equally efficacious when delivered IV for advanced ovarian cancer but
important differences in adverse effect profiles.
·
Systematic review of 1st
line chemotherapy for stage II, III or IV Ovarian cancer: (Gynecal
Oncol;2002;85;71)
o
A published meta-analysis
found that, compared with non-platinum-based regimens, platinum, alone or in
combination with other agents, improved survival.
o
The meta-analysis did not
detect a difference in efficacy between cisplatin and carboplatin.
o
Carboplatin is more myelosuppressive,
but Cisplatin has a greater risk of nausea, vomiting, neurotoxicity, and
nephrotoxicity.
o
In 2 randomized trials,
treatment with paclitaxel + cisplatin resulted in improved OS compared with
cyclophosphamide + cisplatin.
o
Conclusion is IV
carboplatin + paclitaxel is the recommended postoperative regimen. IV cisplatin
+ paclitaxel may be considered a treatment option.
o
Single agent carboplatin
can be considered in patients whom paclitaxel is contraindicated.
·
GOG 132 trial: (JCO
2000; 18;106)
o
Phase III Randomized Study
of Cisplatin Versus Paclitaxel Versus Cisplatin and Paclitaxel in Patients with
Suboptimally debulked Stage III or IV Ovarian Cancer.
o
Cisplatin alone or in
combination yielded superior response rates and PFS relative to paclitaxel.
However, OS was similar in all three arms, and the combination therapy had a
better toxicity profile. Therefore, the combination of cisplatin and paclitaxel
remains the preferred initial treatment option
·
Approximately 60-80% of
patients with advanced ovarian cancer experience objective response.
·
Median PFS is about 26
months, and OS is about 60 months, for women with advanced disease who had
optimal debulking.
·
Median PFS is about 18
months, and OS is about 38 months, for women with advanced disease who had
suboptimal debulking.
·
Bevacizumab was tested
for 1st line therapy in stage III & IV ovarian cancer:
o
GOG 218 trial: (JCO
2010;28;18s)
§
Phase III trial of 1873
patients with advanced ovarian cancer
§
Paclitaxel + Carboplatin
with bevacizumab followed by bevacizumab maintenance had a PFS of 14.1 months
compared to 10.3 months for patients assigned to chemotherapy without bevacizumab.
§
OS didn’t seem to be
improved.
o
ICON7 trial: (JCO
2011;29; suppl;LBA5006)
§
European similarly designed
study of 1528 patients with advanced ovarian cancer
§
Employed a lower dose and
shorter duration of bevacizumab
§
Showed a similar PFS
advantage and trend towards improvement of OS.
·
Weekly Paclitaxel +
every 3 weeks Carboplatin was compared with standard every 3 weeks
Paclitaxel + Carboplatin in a phase III trial of 637 women with stage II-IV
ovarian cancer, and it was associated with an OS advantage of 72% vs 65% at 3
years. (Lancet;2009;374;9698;1331)
·
Liposomal doxorubicin
+Carboplatin were not superior to Paclitaxel + Carboplatin as 1st
line therapy in patients with stage IC to IV disease in terms of survival
outcomes or quality of life.
·
Intraperitoneal
chemotherapy for stage III disease with optimal cytoreduction:
o
Because drug delivery is by
diffusion, intraperitoneal therapy is limited to patients with small volume
residual disease.
o
GOG 172 trial:
(NEJM;2006;354;34)
§
Phase III trial of 429 patients
with optimally debulked stage III patients randomized to receive IV Cisplatin +
Paclitaxel or IP Cisplatin + IV & IP Paclitaxel.
§
Patients assigned to the IP
treatment had significantly longer PFS (23.8 months vs 18.3 months) and OS
(65.6 months vs 49.7 months)
§
Toxicity was greater in the
IP arm with initial decrease in quality of life, however at 1 year; there were
no quality of life differences.
·
Early vs delayed
treatment of relapsed ovarian cancer:
o
MRC OV05/EORTC 55955
trial (Lancet;2010;376;9747;1155)
§
A randomized trial of Women
with ovarian cancer in complete remission after first-line platinum-based
chemotherapy and a normal CA125 concentration.
§
Clinical examination and
CA125 measurement were done every 3 months.
§
If
CA125 concentration exceeded twice the upper limit of normal, patients were
randomly assigned (1:1) to early treatment group which starts within 28 days of
the CA125 elevation or the delayed group which starts treatment only at
clinical or symptomatic relapse.
§
All patients were treated
according to standard local practice. 265 women in early group and 264 women in
the delayed one.
§
there was no evidence
of a difference in overall survival between early and delayed treatment
§
The value of routine
measurement of CA125 in the follow-up of patients who attain a complete
response after first-line treatment is not proven.
·
Secondary surgical
procedures:
o
GOG 152 trial: (NEJM;2004;351;24;2489)
§
Randomized phase III trial
of 550 women with residual tumor >1 cm after primary cytoreduction surgery.
§
Patients who were stable or
improved after 3 cycles of Cisplatin + Paclitaxel we randomly assigned to
continue with chemotherapy or to have a 2nd attempt at cytoreduction
followed by additional chemotherapy.
§
Patients didn’t benefit
from a 2nd attempt at cytoreduction in terms of PFS or OS; rather
treatment with chemotherapy should continue.
·
Consolidation therapy:
o
Disease will recur in
almost 70% of women with advanced disease who have a clinically defined
complete response to standard chemotherapy with a platinum agent and a taxane.
o
GOG 178 trial:
(JCO;2003;21;13;2460)
§
Phase III trial of 277
women with advanced ovarian cancer after complete response to platinum and
Taxol based chemotherapy randomly assigned to 12 vs 3 months of maintenance
Paclitaxel.
§
Patients assigned to
receive 12 cycles of consolidation Paclitaxel had a markedly improved PFS of 28
months vs 21 months for patients receiving 3 cycles only.
§
The study was early closed.
As of the date of study closure, there was no difference in OS.
Treatment of
recurrent or resistant disease
·
20% of women with advanced
ovarian cancer do not respond to 1st line platinum/taxane therapy.
·
Platinum refractory:
o
Progressing during
treatment with platinum based regimen.
o
Very poor prognosis.
·
Platinum resistant:
o
Progressing within 6 months
of completing 1st line platinum based regimen.
o
Objective response can be
achieved in a minority of patients (10-20%)
o
Liposomal doxorubicin,
topotecan, gemcitabine, docetaxel, weekly Paclitaxel, oral Etoposide,
irinotecan and vinorelbine can be used.
o
Bevacizumab as a single
agent can achieve objective responses.
·
Potentially/intermediate
platinum sensitive:
o
Progressing >6 months
but <12 months from completing 1st line platinum based regimen.
o
Response rate to platinum
based regimen is higher than 20%.
o
Treatment with platinum or
nonplatinum single agents is appropriate.
·
Platinum sensitive:
o
Recurrence > 12
months from completion of 1st line platinum based therapy.
o
Platinum sensitive patients
have a high likelihood of response to retreatment with platinum based therapy.
o
2 randomized trials have
shown that platinum based combination therapy (carbo/gemzar) or (carbo/Taxol)
is superior to single agent platinum.
o
Liposomal doxorubicin +
Carboplatin were superior to Paclitaxel + Carboplatin in terms of PFS (11.3
months vs 9.4 months) and toxicity profile in a large phase III randomized
trial. ( JCO 2010;28;3323)
o
Another phase III trial
comparing gemzar + Carboplatin with or without bevacizumab, showed PFS advantage
in the group assigned to receive bevacizumab (12.4 months vs 8.4 months). (JCO
2012;30;2039)
·
Patients with recurrent
ovarian cancer who receive 2nd line chemotherapy, in general the
median time for disease control with any given agent in approximately 4 months.
Low malignant
potential tumors of the ovary (LMP)
·
Patients with LMP who wish
to preserve fertility can undergo fertility sparing surgery.
·
Most women with LMP have
early stage disease.
·
5 yr OS rates exceed 95%,
and PFS exceeds 80%.
·
There is no evidence that
adjuvant therapy (chemo or RT) is beneficial in any stage if pathology review
confirms there is no evidence of invasive implants.
·
5 yr OS rates for patients
with stage III or IV are around 90%, and PFS > 65%.
Sex-cord stromal cell
tumors of the ovary
·
Subclassifed as granulosa cell tumors, and the androgen producing tumors
such as Sertoli-Leyding cell tumors
·
Granulosa cell tumors:
o
Generally stage I at diagnosis.
o
Diagnosed in women age 40-70.
o
Produce estrogen which may cause abnormal uterine bleeding, endometrial
hyperplasia and even endometrial cancer.
o
Endometrial cancers that are found concurrently with granulosa cell
tumors are typically early stage and low grade.
o
The treatment is surgical resection
o
If patient desire fertility preservation and fertility sparing surgery
was done. Then an endometrial biopsy should be done to rule out a concurrent
endometrial cancer
o
Routine lymphadenectomy is not routinely recommended
o
Adjuvant chemotherapy is not routinely recommended.
o
There are some data supporting the use of combination platinum based
chemotherapy for patients with recurrent or unresectable disease.
(JCO;2007;25;20;2944)
·
Sertoli-Leydig tumors:
o
Commonly present before age 40.
o
More than 90% of cases are stage I at diagnosis.
o
Androgen leads to virilization.
o
5 yr survival rates are 70-90% depending on stage and degree of tumor
differentiation
o
Platinum based chemotherapy may be considered for patients with poorly
differentiated tumors and for patients with advanced or recurrent disease.
Germ cell tumors of
the ovary
·
Affect adolescent girls and young women
·
Fertility sparing surgery is appropriate for most patients.
·
50% of germ cell tumors are dysgerminomas.
·
Other histologies included yolk sac tumors, immature teratomas, embryonal
cell, nongestational choriocarcinomas, and mixed tumors.
·
HCG and AFP may be elevated in some germ cell tumors at diagnosis and can
be used in follow up monitoring.
·
Dysgerminomas are likely to be confined to 1 ovary at diagnosis (stage
I), and carry a favorable prognosis
·
Patients with stage I dysgerminoma and stage I, grade I immature
teratomas can be treated with surgery alone.
·
All other nondysgerminomas and high stage dysgerminomas should be treated
with chemotherapy after surgical resection.
·
Standard treatment is combination platinum/etoposide-based chemotherapy,
with most data supporting 3 to 4 cycles of bleomycin, etoposide and cisplatin.
o
GOG 78 trial:
(JCO;1994;12;4;701)
§
93 patients with completely resected germ cell tumors nondysgerminoma,
received 3 cycles of bleomycin, etoposide and cisplatin
§ Disease free survival
was 96%
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