|
Despite comprising a
mere 3% of cancer cases
in women, ovarian cancer
is the fifth leading
cause of cancer deaths
in women in the US.
According to the
National Cancer
Institute, there will be
22,280 new cases and
15,500 deaths from
ovarian cancer in 2012
in the US. The relative
5-year survival rate is
46% but decreases to 28%
if diagnosed after the
disease has spread to
distant organs and lymph
nodes. Little progress
has been made in
diagnosing or treating
this disease: in 1975,
the relative survival
was 34.8%. The lack of
progress is due in part
to the constellation of
symptoms that are also
found in a variety of
other common conditions;
the lack of simple,
accurate diagnostics;
the persistence of
dormant cancer cells;
and the lack of
anatomical barriers to
prevent ovarian cancer
cells from disseminating
to the peritoneal
cavity.
More than 90% of ovarian
cancers are epithelial
cancers (EOC), which
arise from cells that
cover the surface of the
ovaries or those that
line the inclusion
cysts. The tumors have a
great deal of
heterogeneity. Germ cell
ovarian cancers compose
roughly 5% of cases and
stromal ovarian tumors
make up another 5% of
cases. Primary
peritoneal cancer looks
like and is treated like
ovarian cancer but
derives from the
peritoneum.
Patients diagnosed with
stage 1 cancer (disease
confined to the ovaries)
have a 90% cure rate.
Unfortunately, only 20%
of patients are
diagnosed so early in
the disease. Stages 2–4
describe disease that
has metastasized to the
pelvic organs (stage 2),
abdomen (stage 3), or
beyond the peritoneal
cavity (stage 4).
Although CA125 (cancer
antigen 125) levels are
tested to diagnose
ovarian cancer or to
determine how well
therapy is working, its
usefulness is limited.
CA125 levels can
increase due to other
conditions (i.e.,
endometrial, peritoneal,
or fallopian tube
cancer) and can be
released by some normal
cells. Furthermore,
non-epithelial ovarian
cancers do not show an
increase in CA125
levels. A recent study
tried to increase
sensitivity by combining
CA125 screening with
screening for seven
markers derived from
proteomic analysis, but
the added markers failed
to improve the
sensitivity of
pre-clinical diagnosis
of ovarian cancer.
In the January 25, 2012,
issue of JAMA, Paul
Pharoah’s group
published results
showing that patients
with a mutation in the
BRCA2 gene were more
likely to survive to 5
years after diagnosis
(52%) than patients with
a mutation in BRCA1
(44%). Both groups had a
survival advantage over
patients who had
wild-type copies of the
genes (36%).
Tumor debulking is used
even in patients for
whom complete resection
is impossible. For
patients with advanced
ovarian cancer, it
becomes difficult for
surgeons to extract all
of the cancerous tissue;
therefore, most patients
(except those with stage
1A grade 1 or stage 1B
grade 1 tumors) receive
chemotherapy. Currently,
first-line chemotherapy
consists of paclitaxel
plus cisplatin or
carboplatin.
Unfortunately, most
patients become
resistant to therapy and
most patients are
encouraged to enroll in
clinical trials.
BioNumerik
Pharmaceuticals is
conducting a Phase III
trial on patients with
stage III or IV
platinum-/taxane-resistant
EOC. Its drug,
Karenitecin, is a novel
compound of the
camptothecin class but
with fewer side effects,
improved efficacy, less
susceptibility to drug
resistance mechanisms,
and an improved safety
profile. Its trial pits
Karenitecin against
topotecan in terms of
safety and efficacy, PFS,
OS, and severity and
incidence of
hematological
toxicities.
The folate receptor is
expressed at high levels
on 90%–95% of ovarian
cancers but not on
normal tissues.
Morphotek is targeting
the folate receptor with
its monoclonal antibody
MORAb-003 (farletuzumab)
in the FAR131 Phase III
trial. The trial is
enrolling patients with
EOC that relapsed 6–24
months after first-line
platinum-containing
therapy. The trial will
assess the safety and
efficacy of treating
patients with MORAb-003
in combination with
carboplatin and taxane.
Endocyte is also
targeting the folate
receptor. Its drug EC145
conjugates folate to a
super potent vinca
alkaloid.
|
The Phase III trial,
“study for women with
platinum resistant
ovarian cancer
evaluating EC145 in
combination with Doxil
(PROCEED),” is enrolling
platinum-resistant
patients to assess PFS
in patients treated with
pegylated liposomal
doxorubicin (PLD) +
placebo compared with
patients treated with
PLD + EC145. Endocyte
has a companion imaging
diagnostic, EC20, which
also targets the folate
receptor.
The anti-angiogenic
peptide, AMG-386
(Amgen), inhibits the
interaction between the
Tie receptor and its
ligands – angiopoietins
1 and 2. The drug is
being tested in the
TRINOVA-1 study to
determine whether
AMG-386 + paclitaxel
shows superiority to
placebo + paclitaxel in
partial
platinum-sensitive or
platinum-resistant
cancers. The TRINOVA-2
study will assess
whether AMG-386 + PLD is
superior to placebo +
PLD in partial
platinum-sensitive or
platinum-resistant
cancers. The results of
this study should be
interesting as a Phase
I/II trial testing
pazopanib, an oral
angiogenesis inhibitor
that targets VEGFRs,
PDGRs, and c-kit, was
discontinued due to
disappointing results.
The results were
published in the British
Journal of Cancer, in
which pazopanib was
tested in combination
with carboplatin and
paclitaxel. Overall, 10
of 12 patients
discontinued treatment
and 67% experienced
serious
treatment-related
adverse events.
PARP inhibitors took the
cancer world by storm
several years ago when
it was shown that cancer
cells carrying a mutant
BRCA1 or BRCA2, which
are components of the
homologous recombination
pathway, were
susceptible to drugs
that inhibited poly
(ADP-ribose) polymerase
(PARP), a gene important
in an alternative DNA
repair pathway. Stan
Kaye and colleagues
published the results of
a Phase II trial
comparing the safety and
efficacy of two
different doses of
olaparib with PLD in
patients with BRCA1 or
BRCA2 mutations and
recurrent ovarian
cancer. Patients were
assigned in a 1:1:1
ratio to olaparib 200 mg
twice per day or 400 mg
twice per day
continuously or PLD 50
mg/m2 IV every 28 days. ORRs were not
significantly different:
25% for olaparib 200 mg,
31% for olaparib 400 mg,
and 18% for PLD. Median
PFS was not
statistically
significant for either
dose of olaparib when
compared with PLD (6.5
months for 200 mg, 8.8
months for 400 mg, and
7.1 months for PLD).
Interestingly, a lower
percentage of patients
developed new lesions in
the olaparib 200 mg and
olaparib 400 mg groups
(28.1% and 34.4%,
respectively) than in
the PLD group (45.5%).
The authors noted that 8
of 25 patients in the
study who have crossed
over from PLD have
continued on treatment
with olaparib,
indicating the potential
for continued benefit in
patients with
BRCA1/2-mutated ovarian
cancer and suggesting
that future trials in
PLD-treated patients
would be of interest.
In December 2011, the
European Commission
approved bevacizumab in
combination with
standard chemotherapy (carboplatin
and paclitaxel) as a
frontline (first line
following surgery)
therapy for advanced
ovarian cancer. Roche
submitted the related
marketing authorization
on the basis of results
from the GOG 0218 and
ICON7 clinical trials.
Genentech filed for
approval in the US for
this indication in
mid-2011.
Source:
Cancer.gov;
Ovariancancer.org;
Oncolink.org;
emedicine;
ADDIN EN.REFLIST Bast
RC, Jr., Hennessy B,
Mills GB. The biology of
ovarian cancer: New
opportunities for
translation. Nat Rev
Cancer (2009) 9:415-28;
Moore LE, Pfeiffer RM,
Zhang Z, et al.
Proteomic biomarkers in
combination with CA 125
for detection of
epithelial ovarian
cancer using
prediagnostic serum
samples from the
Prostate, Lung,
Colorectal, and Ovarian
(PLCO) cancer screening
trial. Cancer.
2012;118:91-100; Bolton
KL, Chenevix- Trench G,
Goh C, et al.
Association between
BRCA1 and BRCA2
mutations and survival
in women with invasive
epithelial ovarian
cancer. JAMA.
2012;307:382-9; Bionumerik;
Morphotek;
Endocyte;
du Bois A, Vergote I,
Wimberger P, et al.
Open-label feasibility
study of pazopanib,
carboplatin, and
paclitaxel in women with
newly diagnosed,
untreated, gynaecologic
tumours: A phase I/II
trial of the AGO study
group. Br J
Cancer. Advance online
publication January 12,
2012; Kaye SB, Lubinski
K, Matulonis U, et al.
Phase II, open-label,
randomized, multicenter
study comparing the
efficacy and safety of
olaparib, a poly
(ADP-ribose) polymerase
inhibitor, and pegylated
liposomal doxorubicin in
patients with BRCA1 or
BRCA2 mutations and
recurrent ovarian
cancer. J Clin Oncol.
|
