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Outcome Issues in Ovarian Cancer

Outcome Issues in Ovarian Cancer

ABSTRACT: Ovarian cancer is the leading cause of death from a gynecologic malignancy in the United States. Most patients present with advanced disease and are treated with a combination of surgery and chemotherapy. Recently, paclitaxel has been identified as a highly active agent in this disease, and has produced a meaningful impact upon survival for patients with advanced disease. However, numerous questions remain regarding the optimal combination chemotherapy regimen and the integration of surgery into overall management. Furthermore, while patients with early-stage disease have an improved prognosis, there currently is no evidence that screening the general population is beneficial. Similarly, there is no evidence that any form of additional therapy for patients with advanced disease following their surgery and chemotherapy is beneficial. Controversy exists with regard to the benefit of second-look procedures to assess the impact of therapy and of close surveillance to select patients who may be candidates for additional therapy. [ONCOLOGY 9(Suppl):135-139, 1995]

Introduction

Ovarian cancer is a complex disease that requires knowledge of
its biology and clinical course in order to select necessary diagnostic
tests and to embark upon an appropriate treatment course. It is
a disease of the elderly population and generally produces no
specific signs or symptoms. Most patients are in their mid 60s
when they are diagnosed, after a prolonged period of having vague
abdominal complaints. Patients frequently undergo extensive radiologic
studies unnecessarily, since a definitive diagnosis usually requires
surgery, most frequently a laparotomy [1]. A careful laparotomy
is mandatory to stage the disease and to remove as much disease
as possible.

At the time of diagnosis, most patients already have advanced-stage
disease such that the disease has spread throughout the peritoneal
cavity to involve multiple sites on peritoneal surfaces. About
75% of all patients will present with stage III disease. Stage
IV disease, in which there is spread to the pleural or extraperitoneal
sites such as the liver, has an even worse prognosis and, like
stage III disease, is not curable by surgery. Subsequently, the
vast majority of patients with ovarian cancer are treated immediately
with chemotherapy following their initial surgery. Appropriate
chemotherapy for ovarian cancer remains controversial. However,
it appears that paclitaxel (Taxol) has made a significant impact
upon the survival of patients with advanced disease, and the investigators
in the Gynecologic Oncology Group (GOG) have now adopted the combination
of paclitaxel plus a platinum compound as their standard therapy
for ovarian cancer patients.

Such a combined modality approach using surgery and chemotherapy
produces an approximately 70% to 85% response rate in patients
with advanced disease [2]. Unfortunately, the vast majority of
these patients will ultimately recur, and 5-year survival rates
for patients with advanced disease are somewhere around 25% to
30%. The appropriate treatment of patients at the time of recurrence
and the follow-up of patients who do undergo a complete remission
are also areas of controversy.

Because ovarian cancer has a markedly superior survival rate in
patients who present with early-stage disease, a major effort
has been underway to diagnose the disease in asymptomatic women
with appropriate screening tests. However, this too has led to
controversy: Some investigators are strong advocates of screening
while others are concerned about its cost and potential deleterious
effects.

Critical quality of life studies and outcomes analyses have not
been frequently performed in ovarian cancer patients. This review
points out those areas where such studies are needed. Clinical
pathways need to be developed that give the patient the greatest
opportunity for long-term survival and, at the same time, produce
acceptable morbidity. Furthermore, outcomes analyses must be linked
with economic studies to determine the cost effectiveness of practices
and procedures used in the management of ovarian cancer patients.

This review examines current approaches to diagnosis, screening,
initial treatment, follow-up, and management of recurrent disease,
to focus on those areas that require further outcomes analyses
and quality of life studies.

Diagnosis

As noted, most patients with ovarian cancer are elderly with a
protracted history of vague abdominal complaints. Unfortunately,
many of these patients do not undergo pelvic examination at the
time of their first visit to a physician or caregiver. When the
patient does present with an adnexal mass, an upper abdominal
mass, ascites, and/or pleural effusion, often an expensive diagnostic
work-up is begun. Patients frequently undergo CT scans, ultrasound
examinations, cystoscopies, barium enemas, and colonoscopies [1].
The justification often given is to help the surgeon define the
extent of normal tissue invasion prior to debulking surgery. Since
most of these patients will go to surgery, it is unclear exactly
how these preoperative studies are routinely beneficial. In addition,
if there is any question about the diagnosis, a CA 125 test done
in the presence of a pelvic mass in a postmenopausal woman has
a high degree of specificity in correctly diagnosing epithelial
ovarian cancer [3,4].

Most physicians would, at a minimum, require a chest x-ray and
a CT scan of the abdomen prior to surgery, and reserve barium
studies and in-depth examinations of the bowel for those patients
in whom there is suspected involvement of the gastrointestinal
tract.

Screening

Since patients who are diagnosed with early-stage ovarian cancer
(ie, the disease has not spread beyond the pelvis) have a markedly
higher survival rate, screening has been proposed to decrease
morbidity and mortality from this disease [5,6]. The current screening
tests being studied include transvaginal ultrasound, serum CA
125, and pelvic palpation. It should be emphasized that screening
does not diagnose ovarian cancer. It only identifies patients
who are at potential high risk for the disease, in whom a surgical
procedure such as laparotomy is required to determine if they
indeed have ovarian cancer.

The primary requirement for any screening procedure for ovarian
cancer is that it have a high specificity, to avoid an excess
of false-positive results leading to numerous unnecessary laparotomies.
Although perhaps somewhat arbitrary, a minimum criterion for an
acceptable screening procedure is a positive predictive value
of 10% [7]. (Positive predictive value is the ratio of true positives
to true positives plus false negatives.) Even such a low positive
predictive value means that there will be nine false-positive
laparotomies for each diagnosed case of ovarian cancer.

Several large screening studies have been done [8-10], and these
have recently been reviewed at the National Institutes of Health
Consensus Conference on ovarian cancer [11]. Due to the inadequate
sensitivity and specificity of available screening tests, the
current recommendation is that screening not be employed for the
general population. This decision reflects three major factors:

1. The high rate of false-positive test results would lead to
unnecessary operations and has the potential for doing harm in
the screened population [12]. Among patients undergoing unnecessary
laparotomies, some would experience complications, and some, however
small the number, might die from an unnecessary procedure. These
deaths would likely outweigh any possible benefit from identifying
a few patients with early-stage ovarian cancer in the screening
protocol.

2. An elevated CA 125 level induces a great deal of anxiety in
the patient and consequently leads to an unnecessary and expensive
diagnostic workup, which often results in a negative laparotomy.

3. The cost of screening has been estimated to be about $15 billion
if applied to the general US population [13]. Consequently, while
there may be a role for screening in patients with hereditary
familial syndrome, women who are desirous of screening should
participate in the ongoing National Cancer Institute PLCO trial
in which 75,000 women will be randomized to screening with ovarian
palpation, transvaginal ultrasound, and serum CA 125 or to routine
follow-up. The study began in 1993, and initial results will be
presented by the end of 1995. Dr. John Gohagan is coordinating
the trial at the NCI.

The accepted surgical approach when the diagnosis of ovarian cancer
is expected is a comprehensive laparotomy with a large midline
incision that extends above the umbilicus. This will allow the
gynecologic oncologist to adequately stage the cancer and at the
same time perform cytoreduction. The standard operation includes
a bilateral salpingo-oophorectomy and omentectomy as well as removal
of any masses in the upper abdomen. The goal of cytoreductive
surgery is to leave no tumor mass greater than 1 cm in diameter;
if this is achieved, it is termed an optimal cytoreductive procedure.

Approximately 50% to 60% of all patients with advanced disease
can undergo effective cytoreduction. However, controversy remains
regarding the impact of cytoreductive surgery on the overall survival
of these patients [14,15]. Nevertheless, it is accepted practice,
since patients who undergo successful cytoreduction have a subsequently
improved quality of life with decreased symptoms from large masses,
and also respond more favorably to postoperative chemotherapy.

Postoperative Chemotherapy

There has been substantial recent progress made in defining more
effective chemotherapy for advanced ovarian cancer. Until recently,
the combination of cyclophosphamide (Cytoxan, Neosar) and a platinum
compound was considered standard care. This type of combination
produced a response rate of approximately 55% to 60% in patients
with suboptimal stage III and IV disease, and in this group of
patients, median survival usually was 21 to 22 months. Carboplatin
(Paraplatin) is a less toxic analog of cisplatin (Platinol), and
many investigators have used carboplatin instead of cisplatin
in combination with cyclophosphamide. A series of randomized trials
and a metaanalysis have failed to demonstrate any significant
difference in survival between patients treated with cisplatin
or carboplatin [16-18]. Patients treated with carboplatin have
a better quality of life due to decreased nausea and vomiting,
less neurotoxicity, and less anorexia.

The taxanes represent a new family of antineoplastic agents that
have altered the standard approach to ovarian cancer. The greatest
clinical experience available is with paclitaxel (Taxol). This
drug was initially derived from bark of the Western yew (Taxus
brevifolia
). Interest in this compound was heightened by its
marked in vitro and in vivo activity in preclinical models of
human cancer and by its novel mechanism of cytotoxicity [19].
In contrast to other drugs that interfere with tubulin, paclitaxel
leads to a polymerization of the microtubules, thereby disrupting
mitoses.

Initial phase I trials with this agent were hampered by hypersensitivity
reactions. Subsequently, by increasing the length of infusion
to 24 hours and by premedicating the patients with steroids, diphenhydramine,
and cimetidine (Tagamet), hypersensitivity reactions became infrequent
[20].

In early phase II trials, paclitaxel was shown to induce a high
response rate (approximately 30% to 40%) in previously untreated
patients with advanced ovarian cancer [21,22]. Of particular note
in these trials was the finding that even cisplatin-resistant
patients were responding to paclitaxel. A subsequent phase I trial
demonstrated that paclitaxel could be combined with cisplatin
at full doses, and this led to a prospective randomized trial
in untreated patients [23].

The GOG protocol 111 is a pivotal study in ovarian cancer in which
patients with suboptimal stage III and IV disease were randomized
to receive either six cycles of standard cisplatin plus cyclophosphamide
or six cycles of cisplatin plus paclitaxel [24]. After the completion
of chemotherapy, patients were reassessed clinically, and those
patients in a clinical complete remission underwent a second-look
procedure to surgically assess their response to therapy. The
patients randomized to the paclitaxel combination had a higher
overall response rate (77% vs 62%), a higher clinical complete
remission rate (54% vs 33%), a higher negative second-look or
microscopic positive second-look rate (26% vs 41%), a longer time
to disease progression (18 months vs 14 months), and, most important,
a marked prolongation in median survival (37 months vs approximately
23 months). On the basis of these results, the GOG has accepted
paclitaxel plus cisplatin as the standard chemotherapy regimen.

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