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Clinical Trials in Ovarian Cancer, Part 1

Clinical Trials in Ovarian Cancer, Part 1

The American Cancer Society has estimated
that in 2002 ovarian cancer will strike 23,300 women, and 13,900 women will die
from the disease.[1] Five-year survival is about 80% for women with stage I
disease, 50% for women with stage II disease, 25% for women with stage III
disease, and 15% for women with stage IV disease. Among women with
advanced-stage disease, optimal debulking surgery, as well as platinum/taxane-based
adjuvant therapy prolongs disease-free and median survival.[2,3]
Population-based data suggests that guidelines for therapy are not uniformly
followed in community practice.[4] In addition, older patients appear to receive
less aggressive treatment than younger patients.

Part 1 of this two-part series will discuss prevention,
screening, adjuvant treatment, neoadjuvant chemotherapy, and adjuvant
chemotherapy trials for ovarian cancer. Part 2, to be published in next month’s
issue of ONCOLOGY, will detail diagnosis and treatment trials for
recurrent disease.

Epidemiology

About 5% of ovarian cancer appears linked to an inherited
predisposition. The most common genetic syndromes are mutations at the BRCA1 and
BRCA2 loci.[5] The risk of ovarian cancer is higher with BRCA1 mutations than
BRCA2 mutations. Other known risk factors for ovarian cancer include northern
European descent, nulliparity, and advancing age.[6] Protective factors include
pregnancy, lactation, and use of hormonal contraceptives. In the United States,
ovarian cancer is more common in the northern states than the southern
states.[7] It has been hypothesized that higher levels of sun exposure in
southern latitudes, resulting in increased vitamin D levels, may also be
protective against the development of ovarian cancer.

Prevention Trials

There is no consensus yet as to the existence or the nature of
premalignant ovarian neoplasia.[8] Reliable intermediate biomarkers for use in
prevention studies have not been identified. Several prevention studies are
underway evaluating retinoids/progestins, which appear to have activity in
primate models.[9-11] Phase II studies are being conduced in women at high
genetic risk for ovarian cancer, who have decided to undergo prophylactic
oophorectomy (Gynecologic Oncology Group [GOG]-0190). The intervention is given
during a defined window of opportunity between the decision to undergo surgical
removal of the ovaries and the actual procedure.

Screening Trials

To date, an effective screening algorithm for ovarian cancer has
not been identified. The best imaging modality for the adnexa, transvaginal
ultrasound, lacks both adequate sensitivity and specificity for diagnosing early
ovarian cancer.[12] The serum marker CA-125, which is used to monitor response
to therapy among women with advanced ovarian cancer, similarly lacks both
sensitivity and specificity[13]; up to 50% of women with early ovarian cancer
have CA-125 levels in the normal range. Aggressive efforts are under way through
the NCI’s Early Detection Research Network, Ovarian Cancer Specialized
Programs of Research Excellence, Cancer Diagnosis Program (Diagnostic Research
Branch, Program for the Assessment of Clinical Cancer Tests), and Center for
Cancer Research, to identify more effective markers, marker combinations, and
screening algorithms. Proteomics appear particularly promising in this
regard.[14]

The NCI has recruited 74,000 women to the Prostate, Lung,
Colorectal, and Ovarian Cancer Screening Trial (PLCO), which is evaluating
screening for prostate, lung, colon, and ovarian cancer.[15] In this trial,
women are randomized to yearly monitoring of their CA-125 level and transvaginal
ultrasound, or normal clinical care. They are to undergo such evaluation for 6
years, then are followed for an additional 7 years. The United Kingdom, under
the leadership of Drs. Ian Jacobs and Usha Menon, has recently started an even
larger screening trial (in 100,000 women), evaluating both transvaginal
ultrasound and serial, individualized CA-125 levels.[16]

The NCI’s Cancer Genetics Network has recently undertaken a
screening trial for women at high risk for familial ovarian cancer
(Massachusetts General Hospital [MGH]-000084). The trial, led by Dr. Steven
Skates, has already accrued 1,000 patients. Dr. Mark Greene, of the NCI’s
Division of Cancer Epidemiology and Genetics and the GOG, has developed a
complementary study to quantitate the benefit of prophylactic oophorectomy in
women at high familial risk (GOG-0199).

Primary Treatment Trials

Recent studies have documented the importance of surgery in the
treatment of ovarian cancer.[17] Comprehensive surgical exploration, accompanied
by systematic biopsies of intra-abdominal tissues and retroperitoneal lymph
nodes, must be performed to accurately stage ovarian cancer. In addition,
removal of gross disease via surgical debulking significantly improves outcome
for women with advanced (stage III and IV) ovarian cancers.

Patients found to have stage IA/IB, grade 1 or 2 epithelial
ovarian cancer may not require adjuvant therapy. In general, women with stage I,
grade 3, stage IC, and stage II ovarian cancer are recommended to undergo
adjuvant chemotherapy. However, recent European data suggested that this
treatment improves recurrence-free survival, but not overall survival in women
with accurate surgical staging.[18] Adjuvant therapy is generally based
empirically on regimens with documented activity in women with recurrent or
advanced ovarian cancer. Most regimens are based on platinum or the combination
of a platinum and taxane, generally for three to six courses. The GOG has
completed a trial in which women with early-stage ovarian cancer were randomized
to three vs six cycles of carboplatin (Paraplatin)/paclitaxel (GOG-0157). The
current GOG trial randomizes the same population of women to three courses of
carboplatin/paclitaxel with or without weekly low-dose paclitaxel
(40 mg/m2) for 24 weeks, which is thought to have an antiangiogenic effect
(GOG-0175).

For women with advanced (ie, stage III/IV) ovarian cancer,
adjuvant chemotherapy generally consists of six to eight courses of intravenous
platinum/taxane therapy. Although several trials suggest that concomitant
intravenous and intraperitoneal therapy of the same agents may improve survival,
intraperitoneal therapy has gone out of vogue in the community setting and is
rarely employed.[19-21] Similarly, despite promising data associated with the
use of whole abdominal radiation, radiation therapy is rarely, if ever, used in
primary adjuvant therapy for epithelial ovarian cancer.[22]

Several trials are under way to evaluate the addition of another
agent to the platinum/taxane combination. Despite advances in our understanding
of the molecular biology of ovarian cancer, we have yet to define a
comprehensive set of molecular targets or determine how best to optimize
individual therapy based on the molecular characteristics of a patient’s
cancer. The agents currently under evaluation in phase III trials are primarily
cytotoxic agents that have demonstrated activity in women with recurrent,
platinum-resistant ovarian cancer. Agents currently under evaluation include the
topoisomerase I inhibitor topotecan (Hycamtin), gemcitabine (Gemzar), and two
anthracyclines, epirubicin (Ellence) and liposomal doxurubicin.

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