Plain language summary
Are DNA repair inhibitors as effective and
harmless compared to conventional chemotherapy in the treatment of
ovarian cancer?
Ovarian cancer is the sixth commonest cancer
in women world-wide and remains a leading cause of death, with an annual
incidence
of 6.6 cases per 100,000 women and an annual mortality rate of
4.0 deaths per 100,000 women. Most ovarian cancers (90%) are
epithelial ovarian cancer and arise from the surface of the
ovary. Epithelial ovarian cancer typically occurs in post-menopausal
women, with a peak incidence around the age of 60, although it
does occur in younger women, often associated with genetic
predispositions. The onset of this disease is insidious and 75%
of women present with advanced stage disease (stage III or
IV) when the 5 year survival is around 30%. Treatment consists
of debulking surgery and platinum-based chemotherapy, with
or without taxanes. Although initial response to chemotherapy
is good, most women will relapse, requiring further chemotherapy
treatment and develop cancer that is resistant to chemotherapy.
Conventinal
chemotherapy acts on all rapidly dividing cells by damaging DNA. Cancer
cells divide very rapidly, which is why
chemotherapy works better on cancer cells than normal cells.
However, there is no inherent selectivity for normal calls and
so rapidly dividing cells, such as gut lining, hair follicles
and bone marrow, are also affected, leading to diarrhoea, mouth
ulcers, hair loss, anaemia and susceptibility to infections.
All
cells are equipped with a number of systems or pathways that repair DNA
damage. If cells are unable to repair their DNA,
the cell undergoes programmed cell death (apoptosis) in order
to prevent an abnormal cell from dividing. Because being able
to repair DNA is vital to cell survival, normal cells have more
than one DNA-repair pathway, so that if one is lost cells
can still repair themselves. Cancer cells often develop defects
in these pathways, due to mutations, which may promote development
of cancer (e.g. BRCA mutations). However, these same mutations
mean that these cancer cells are more susceptible to DNA damage,
such as that caused by chemotherapy, than normal cells. Novel
therapeutical agents have been developed to inhibit DNA-repair
pathways, which makes cells that already have faults in another
DNA repair pathway due to a mutation, exquisitely sensitive
to DNA damaging chemotherapy agents. The most common target for
this type of novel anti-cancer agent are the DNA-repair enzymes
called poly (ADP-ribose) polymerases (
PARPs). PARPs are a
family of related enzymes, which are involved in regulating various
cellular processes, including DNA repair, cell death, and
inflammation. PARP inhibitors therefore have a potentially wide
range of applications.
Our objective was to compare
effectiveness and side effects of PARP inhibitors compared to
conventional chemotherapy in women
with ovarian cancer. The identification of a safe dose of
AZD2281 (a PARP inhibitor) has been found by small non randomised
trials, with encouraging results. For ovarian cancer, there are
currently two ongoing RCTs, but outcome data are not yet available.
Results of these trials are awaited to determine if DNA repair
inhibitors have a role in addition to conventional chemotherapy
in the treatment of ovarian cancer.
