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The Management of Early Ovarian Cancer

The Management of Early Ovarian Cancer

ABSTRACT: Approximately one third of patients with epithelial ovarian cancer present with localized or early-stage disease. Prognostic features identify certain subsets of patients with good risk characteristics who do not require adjuvant treatment after comprehensive surgical staging and cytoreduction. Only a minority of patients undergo such a complete procedure, which often results in understaging of these patients. In the United States, patients with poor prognostic features, such as stage IC to II disease, poorly differentiated histologic grade, clear cell histology, dense adhesions, and large volume ascites, have received adjuvant chemotherapy. Single-agent or combination chemotherapy, whole abdominal irradiation, and intraperitoneal phosphorus 32 have been evaluated, although no modality has been shown to improve overall survival. Randomized trials investigating the optimal therapy or whether any therapy is truly effective are in progress. Until the completion of these trials, the most common postoperative adjuvant therapy in these patients in this country remains combination chemotherapy. [ONCOLOGY 9(2):171-187]

Introduction

In the past year, ovarian cancer ranked as the fifth most common
cause of malignancy among women in the United States [1]. There
will be an estimated 21,000 new ovarian cancer cases this year,
and approximately 13,500 deaths, which is more deaths than from
endometrial and cervical cancers combined. Despite advances in
cytoreductive surgery and dose-intense combination chemotherapy,
overall survival in patients with ovarian cancer has not changed
in the past 2 decades, because more than two thirds of women continue
to be diagnosed with advanced bulky disease. Patients with localized
ovarian cancer, however, have been reported to have a 5-year disease-free
survival of approximately 80% [2]. This article focuses on the
management of early-stage ovarian cancer, which has been surgically
defined by the staging system of the International Federation
of Gynecologists and Obstetricians (FIGO) as stage I and stage
II disease (Table 1).

Surgical Implications in Early-Stage
Ovarian Cancer

Staging--Over the past decade, a great deal has been learned
about the potential for occult extra-ovarian disease, which occurs
in a significant proportion of women with apparent early-stage
epithelial ovarian carcinoma. Comprehensive surgical staging is
the single most important factor in deciding appropriate management
of early-stage disease. It allows for a more accurate determination
of prognosis and correctly identifies those patients whose survival
may be improved by adjuvant therapy. The appropriate procedures
that constitute a complete staging laparotomy for ovarian cancer
are listed in Table 2 [3].

Unfortunately, many women who are explored for pelvic masses undergo
their initial surgery in a community hospital by a general obstetrician/gynecologist
or a general surgeon. Oftentimes, a comprehensive staging procedure
is not performed, since ovarian cancer often is not suspected
at the time of the patient's initial surgery. McGowan and coworkers
[4] found that only 54% of 291 women with ovarian carcinoma had
a complete comprehensive surgical staging at their initial laparotomy.
In this series, 97% of the patients initially explored by gynecologic
oncologists had complete surgical staging documented, compared
with 52% and 35% of patients explored by obstetrician/gynecologists
and general surgeons, respectively. In another series, only 25%
of patients had an incision at the time of their initial surgery
that would allow a thorough exploration and staging of the upper
abdomen [5]. When a second laparotomy was performed, approximately
30% of the patients were upstaged, and approximately 75% of these
patients actually had stage III ovarian carcinoma. Another study
evaluated 59 women who were explored in a community hospital setting
for a pelvic mass [6]. Only 15% had a comprehensive surgical staging
procedure. Complete surgical staging was performed in 5% of cases
managed by an obstetrician/gynecologist, and only 38% of patients
were completely staged when a vascular surgeon was consulted.

Preoperative consultation with a gynecologic oncologist obviously
is imperative. In addition, since age and menopausal status are
important risk factors, we recommend that any patient who is peri-
or postmenopausal and who has a pelvic mass should also have a
gynecologic oncologist available at the time of her laparotomy,
regardless of the value of the preoperative CA-125. Any postmenopausal
woman with a pelvic mass and an elevated serum CA-125 level should
be referred directly to a gynecologic oncologist for appropriate
surgical staging and cytoreduction, as her risk of malignancy
is exceedingly high (95%) [7].

Conservative Surgery--If an apparent stage IA ovarian carcinoma
is encountered intraoperatively in a young woman desiring fertility,
or in a woman whose desires are unknown, conservative surgery
may be possible following careful inspection of the upper abdomen
and retroperitoneum. The contralateral ovary should also be carefully
inspected. Unless an obvious lesion is noted, random biopsies
or wedge resections are not recommended, because they may compromise
future fertility. If, on gross inspection, there appears to be
no extra-ovarian disease, the surface of the ovary is smooth without
excrescences, and there are no adhesions between the mass and
the pelvic side walls, then a unilateral salpingo-oophorectomy
with adequate resection of the ipsilateral infundibulopelvic ligament
may be performed. A thorough surgical staging procedure as shown
in Table 2 should be undertaken, except that the contralateral
ovary and uterus are not removed. If, on the final histopathology
review, adverse prognostic factors are discovered, the benefits
of a second operation to remove the uterus and the retained ovary
may be discussed and safely performed after careful consideration
has been given to every alternative. Consideration should be given
to a "completion" total abdominal hysterectomy and unilateral
salpingo-oophorectomy following the patient's childbearing, although
it has not been established that there is any benefit from this
procedure.

Although not common, early epithelial ovarian carcinoma does occur
in younger women who have not completed childbearing. In these
circumstances, it is crucial to review with the patient, prior
to surgery if possible, the risks and possible benefits of conservative
surgery with preservation of reproductive function. Several studies
have documented compromised survival for patients with stage I
ovarian carcinoma treated with unilateral salpingo-oophorectomy.
In one series, the contralateral ovaries of 65 women with apparent
stage IA ovarian carcinoma were pathologically evaluated, and
14% had cancers in the normal-appearing ovary [8]. Additional
reports have documented poor survival in women undergoing unilateral
oophorectomy (50%), compared with women undergoing total abdominal
hysterectomy and bilateral salpingo-oophorectomy and complete
comprehensive surgical staging (80%) [9]. These studies are flawed
by nonrandomized small numbers of patients, many of whom did not
have comprehensive surgical staging. In contrast, Williams and
coworkers [10] retrospectively reviewed 29 patients with apparent
stage I ovarian carcinoma treated with unilateral salpingo-oophorectomy.
No recurrences were documented after initial surgery in 19 patients
with grade 1 or 2 lesions that did not have capsular rupture,
pelvic adhesions, or surface excrescences. Among these 19 patients,
seven were successful in achieving pregnancy. If the dominant
ovarian mass was adherent, ruptured, or had excrescences, 50%
of these patients eventually died.

Ovarian Tumors of Low Malignant Potential--Borderline tumors
of the ovary or tumors of low malignant potential constitute a
distinct, well-defined pathologic entity with several characteristic
microscopic findings that distinguish it from its invasive counterpart.
These tumors have characteristic papillary fronds, epithelial
tufts, and a pseudostratification of their nuclei, but do not
exhibit any stromal invasion microscopically. Clinically, borderline
tumors are more indolent than typical ovarian cancers.

Unlike invasive epithelial ovarian cancer, approximately 75% of
these tumors are diagnosed in early stages and represent approximately
15% of all ovarian malignancies. If these tumors are encountered
intraoperatively, a gynecologic oncologist should be consulted,
and every effort should be made to fully stage the patient, just
as in invasive epithelial ovarian cancer. It should be noted,
however, that these cancers are not usually chemosensitive, and
the surgeon should attempt to remove all gross evidence of disease.
In younger women who desire the preservation of their fertility,
conservative surgery should be attempted in exactly the same fashion
as previously described for women with invasive early epithelial
ovarian cancers who desire preservation of their childbearing
potential. Recurrence rates are higher in women who have conservative
surgery than in women who have definitive surgery, but there is
no difference in overall survival, due to effective salvage surgery.

In one series, approximately 24% of apparent early-stage epithelial
ovarian cancers of low malignant potential were upstaged by a
comprehensive surgical staging procedure [3]. Obviously, upstaging
has important prognostic implications, though not as significant
as with invasive disease. In addition, an experienced gynecologic
pathologist should be consulted in all cases because of the unusual
nature of the tumor and the difficulty in making accurate diagnoses
and differentiating it from its malignant counterpart. Clinicians
should be aware that appropriate sampling of large pelvic masses
includes at least one pathologic section for every centimeter
of the mass. Of equal importance is the fact that the diagnosis
of a tumor of low malignant potential in the operating room by
frozen section does not confer the same accuracy as diagnosis
of an invasive tumor or a benign tumor by frozen section. It is
therefore of utmost importance to completely stage the patient
in a thorough fashion at the time of the initial surgery, as a
percentage of these cancers thought to be of borderline histology
intraoperatively will be documented as invasive on final pathologic
review.

Although the prognosis for patients with tumors of low malignant
potential is much better than for patients with invasive tumors,
approximately 10% of stage I tumors will ultimately recur. Because
these tumors are indolent, recurrences can present 10 to 15 years
after the initial diagnosis, making long-term follow-up necessary.
Surgical reexploration should be strongly considered in these
patients when recurrence is suspected, since long-term palliation
and even cure have been documented after secondary surgical resection
[11,12].

Laparoscopic Management of Adnexal Masses--Because of advances
in minimally invasive surgery, laparoscopic management of ovarian
masses has important considerations in the discussion of early
ovarian cancer. Older series [13,14] have documented an adverse
effect of tumor rupture in patients with stage I ovarian cancer,
although these findings have not been confirmed in more recent
series using more elaborate statistical methods [15]. It should
be noted that most patients in these studies received adjuvant
therapy after tumor rupture was documented, and this "adjuvant"
treatment may have negated, in part, the adverse prognostic effect
of tumor spill at the time of surgery. Despite the lack of convincing
data suggesting adverse outcomes in patients with tumor rupture,
adjuvant therapy is often given in cases of rupture, due to the
oncologist's bias or perhaps the bias written into protocols for
early ovarian carcinoma. All this considered, difficult dissections
performed laparoscopically are likely to result in tumor rupture.
In addition, laparoscopic surgery has a disadvantage in that the
surgeon loses the ability to carefully palpate and inspect all
of the peritoneal surfaces. Patients of any age group with an
elevated CA-125, or with suspicious findings on ultrasonic examination
(abnormalities within the cyst wall, septations, or any solid
component), should be managed with exploratory laparotomy, unless
they have consented to an investigational protocol for evaluating
pelvic masses laparoscopically. It should be apparent to any clinician
that loss of the ability to palpate and inspect the entire abdominal
cavity and retroperitoneum could significantly compromise the
accuracy of the surgical staging procedure and be detrimental
to the patient's prognosis.

Second-Look Laparotomy--Previously, operative reexploration
was an integral part of the management of advanced ovarian carcinoma.
Although this procedure helped physicians decide whether to discontinue
chemotherapy or to use additional therapeutic regimens, it has
not contributed to improvement in survival. Traditionally, second-look
laparotomy was considered for patients with advanced disease,
but several studies have now evaluated this procedure in patients
with early ovarian cancer [16,17]. Walton and coworkers [16] evaluated
the experience of the Gynecologic Oncology Group (GOG) in 112
patients who underwent initial surgical staging and had FIGO stage
I and II ovarian carcinomas documented histologically. Following
adjuvant therapy, these patients then underwent a restaging operation.
Of 95 patients who were asymptomatic prior to their second-look
laparotomy, only 5% had disease confirmed by second-look laparotomy,
as opposed to over half of 17 patients who were symptomatic prior
to their second-look laparotomy. These data suggest that for asymptomatic
patients with early-stage disease, in whom initial comprehensive
surgical staging was performed and followed by adjuvant therapy,
routine second-look surgery will yield positive results in only
a small percentage of patients. Therefore, routine use of second-look
laparotomy is not recommended.

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