The Management of Early Ovarian Cancer
The Management of Early Ovarian Cancer
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.
In the past year, ovarian cancer ranked as the fifth most common cause of malignancy among women in the United States . 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% . 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).
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 .
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  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 . 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 . 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%) .
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 . 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%) . These studies are flawed by nonrandomized small numbers of patients, many of whom did not have comprehensive surgical staging. In contrast, Williams and coworkers  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 . 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 . 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  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.