Management of Early Ovarian Cancer

Ovarian cancer consistently ranks as the number 1 cause of death from gynecologic malignancies in the United States. In 2003, an estimated 25,400 new cases of ovarian cancer were diagnosed and approximately 14,300 women died from the disease.[1] The death total exceeds that of all other gynecologic cancers combined, due in large part to the advanced stage at which the majority of ovarian cancers are diagnosed. For purposes of this review, earlystage ovarian cancer can be classified as disease that has not spread beyond the true pelvis; ie, International Federation of Gynecology and Obstetrics (FIGO) stage I or II (Table 1). Earlystage ovarian cancer comprises approximately one-third of all cases of the disease and is associated with a 5-year survival rate ranging from 66% to 90%.[2] Early-stage ovarian cancer can be further subclassified based on the need for adjuvant therapy. The risk of recurrence is defined by certain prognostic factors, and although several clinicopathologic factors have consistently proven to place a patient at risk of relapse, there is disagreement about some factors. Controversy also continues as to what constitutes optimal treatment. This article focuses on epithelial ovarian cancers, which comprise the majority of ovarian cancers. Unfortunately, many studies of early-stage ovarian cancer are limited by inadequate staging and may overestimate the incidence of early disease while underestimating prognosis. In addition, the unrecognized inclusion of borderline tumors could potentially skew results. Development of Ovarian Cancer Epithelial ovarian cancer is believed to originate from the single layer of surface epithelium that covers the ovary. Disruption of this layer during ovulation may lead to invagination and result in cystic ovarian growths. Molecular genetic and morphologic techniques have provided evidence in support of this hypothesis. Examination of stage I ovarian carcinomas has demonstrated that they contain inclusion cysts with a morphologic continuum of normal epithelium, dysplastic epithelium, and invasive carcinoma.[3] Further evidence that epithelial inclusions may be the origin of ovarian carcinoma has also been demonstrated on the genetic level. Using laser capture microdissection and microarray technology, Leitao et al[4] showed that the gene expression profiles of ovarian cystic epithelium were significantly different from those of surface epithelial cells. They identified 126 genes that were differentially expressed in cysts compared to surface epithelium, with upregulation of cancer-specific antigens and putative oncogenic factors, downregulation of putative tumor suppressors, and altered expression of numerous genes associated with invasive disease. These data support the theory that epithelial inclusions represent a likely site of origin of ovarian cancer. Disease Spread
At a certain point, ovarian cancer cells will spread beyond the confines of the ovary. This is believed to occur by either direct extension, exfoliation of cells into the peritoneal cavity, lymphatic spread, or hematogenous dissemination. Ovarian cancer will eventually violate the ovarian capsule and spread directly to adjacent organs. In addition, once the capsule has been disrupted, exfoliated viable cells can be transported throughout the peritoneal cavity by normal peritoneal fluid and can implant on the parietal and visceral peritoneal surfaces, resulting in carcinomatosis. Lymphatic spread of ovarian cancer is believed to follow the vascular drainage of the ovary. In particular, the right ovarian vein drains directly into the inferior vena cava, and the left drains into the left renal vein. Lymphatic drainage from the ovary also occurs via the broad ligament and can lead to nodal disease in the pelvis. On occasion, spread via the round ligament can lead to involvement of the inguinal lymph nodes. Finally, hematogenous spread can result in liver, lung, central nervous system, or bone metastases. An understanding of the potential routes of spread is essential prior to undertaking a search for extraovarian spread of disease. Staging of Ovarian Cancer The importance of properly staging ovarian cancer cannot be overemphasized, given that adjuvant chemotherapy is recommended to treat all but the earliest stages of disease. The current FIGO staging system for ovarian cancer is based on a comprehensive surgical evaluation of the abdomen and pelvis and the spread pattern of the disease. Any surgeon who is confronted with an ovarian mass must be prepared to perform a staging procedure. The critical elements of the staging procedure are listed in Table 2. Inadequate Staging
Despite the importance of the primary surgical exploration, the procedure is performed in many women by a general obstetrician/gynecologist or general surgeon. McGowan et al demonstrated that nearly half of 291 patients who underwent surgical exploration for ovarian cancer had incomplete documentation of stage at initial laparotomy.[5] When the data were analyzed by specialty, only 35% of general surgeons and 52% of general obstetricians/gynecologists documented a complete staging procedure, compared to 97% of gynecologic oncologists. However, only 12% of patients had their initial surgery performed by a gynecologic oncologist. Trimbos et al also illustrated the problem of improper staging of early- stage ovarian cancer.[6] In this series from the Netherlands, 59 patients underwent their initial surgical procedure at a peripheral hospital, and only 9 (15%) had a comprehensive staging procedure. The majority of patients were operated on by a general gynecologist/obstetrician, and 2 (5%) of 43 were deemed as having undergone a complete staging procedure. When a general gynecologist performed the procedure with a vascular surgeon, 38% (5/13) had a complete procedure. Difficult, potentially morbid components of the staging procedure that were most commonly not performed were the diaphragmatic biopsies and sampling of the retroperitoneal lymph nodes. Surprisingly, simple, nonmorbid portions of the staging procedure, such as peritoneal biopsies, were also omitted. The authors concluded that a lack of surgical skill and a lack of knowledge about potential sites of spread were equally responsible for the incomplete staging in this series. Recent reports from the National Institutes of Health (NIH) indicate that only 9% of patients with early-stage ovarian cancer are treated appropriately.[ 7] The NIH has recommended that women with ovarian masses who have been identified preoperatively as having a significant risk of ovarian cancer be given the option of having their surgery performed by a gynecologic oncologist. In addition, the Society of Gynecologic Oncologists recently issued their guidelines for referral to or consultation with a gynecologic oncologist (Table 3).[8] Thorough surgical staging will reveal that a significant portion of patients with suspected early-stage disease actually have more advanced disease. Young et al demonstrated that as many as 31% of women with suspected early-stage disease will be upstaged after undergoing additional procedures.[9] The majority (77%) of patients in this series who were upstaged were found to have stage III disease. Of these, 66% had their disease detected by procedures other than second laparotomy. The use of alternative approaches to staging will be reviewed. Surgical Approaches Minimally Invasive Surgery
Despite the fact that laparotomy remains the standard approach to the management of most major gynecologic malignancies, over the past decade there has been a dramatic move toward incorporating minimally invasive surgery into the practice of gynecologic oncology. Better technology and improved operator skills have made many of the procedures that once required large abdominal incisions feasible with a minimally invasive approach. Decreased morbidity and hospital stay are some of the attractive features of minimally invasive surgery.

• Feasibility of Laparoscopy-The use of laparoscopy in the management of early ovarian cancer was first cited in a case report.[10] Unfortunately, a comprehensive staging procedure was not performed. Querleu and Leblanc first described the complete laparoscopic staging of ovarian cancer patients.[11] They described the procedure in nine patients who had initially undergone incomplete staging. Of these nine patients, seven were presumed to have stage IA disease and underwent surgery for staging purposes; two patients, who obviously had stage III disease at the time of initial surgery, were comprehensively staged during their secondlook procedure. In this report, laparoscopic staging comprised infrarenal para-aortic lymphadenectomy, peritoneal cytology, and multiple peritoneal biopsies.[11] Omentectomy, appendectomy, pelvic lymphadenectomy, contralateral salpingo- oophorectomy, salpingectomy, and/or laparoscopically assisted vaginal hysterectomy were performed, if they had not been done previously. The mean total operative time was 227 minutes (range: 130-360 minutes), and the mean time for the paraaortic node dissection was 111 minutes (range: 65-240 minutes). Mean para-aortic node count was 8.6 (range: 5-17), and only one patient was found to have microscopic disease on the right diaphragm. No major intraoperative complications occurred, and the mean hospital stay was 2.8 days (range: 1-5 days). These authors suggested that laparoscopy may be an acceptable alternative to a restaging laparotomy; however, they cautioned that this approach should only be undertaken by an accomplished surgeon trained in gynecologic oncology and laparoscopy. Childers et al reported on the laparoscopic staging of 14 patients with presumed stage I disease.[12] The staging consisted of pelvic and paraaortic lymphadenectomy, omentectomy, and washings. A hysterectomy was performed in five patients, and eight patients (57%) were upstaged based on operative findings-two to stage IC, three to stage II, and three to stage IIIC. Childers and his colleagues reported two perioperative complications, neither of which required conversion. The mean hospital stay was 1.6 days. The authors concluded that laparoscopic staging appeared to be an accurate technique that required further validation. Other groups have also demonstrated the feasibility of this staging procedure in patients with suspected early disease.[13] Recently, Leblanc et al updated their series in 28 patients with apparent stage I invasive ovarian cancer who underwent laparoscopic staging after an inadequate initial procedure (n = 25) or full laparoscopic management at initial surgery (n = 3).[14] The mean operative time was 230 minutes, and the mean hospital stay was 3.3 days. The median pelvic and para-aortic node counts were 13.7 and 19.7, respectively. One patient required conversion to laparotomy laparotomy secondary to adhesions, and one pelvic abscess developed after appendectomy. Of 28 patients, 6 were upstaged, and of the 22 pathologic stage IA patients, 1 (4.5%) recurred at 4 years.
• Laparoscopy vs Laparotomy- Although many of the technical aspects of the staging procedure have been shown to be feasible, the question remains as to whether laparoscopy can produce results similar to those of laparotomy. Critics of laparoscopic staging cite loss of the ability to palpate and inspect the entire abdominal cavity.[15] The Gynecologic Oncology Group (GOG) has completed a phase II study (protocol 9302) of the feasibility and adverse effects of laparoscopic staging of early-stage ovarian, tubal, or peritoneal cancer. Results are pending, but hopefully this will begin to clarify the role of laparoscopy in the management of early-stage ovarian cancers. Currently, laparotomy is considered the standard staging approach to early-stage disease, and patients should be so informed during their presurgical consultation.
• Hand-Assisted Laparoscopy-A new technique that has recently become available is called hand-assisted laparoscopic surgery (HALS). This technique employs a port that allows the surgeon to insert one hand into the abdominal cavity while maintaining the pneumoperitoneum. Although this requires a larger incision than traditional laparotomy, tactile sensation is restored. Krivak et al have reported on the use of this technique in ovarian cancer.[ 16] The authors studied 25 patients who were either staged or cytoreduced using HALS. Three patients with advanced-stage disease required conversion to traditional laparotomy to optimize cytoreduction. The procedure was also used to stage seven patients referred with unstaged disease. Procedures reported included hysterectomy, modified radical hysterectomy, bilateral salpingooophorectomy, omentectomy, pelvic and para-aortic node dissection, appendectomy, small bowel resection,partial colectomy, and low anterior resection. With a mean hospitalization of 1.8 days (range: 1-8 days), the authors concluded that this was a feasible alternative to laparotomy in carefully selected patients. The use of this technique warrants further investigation in the management of ovarian cancer.

Conservative Surgery
Although epithelial ovarian cancer is a disease of the postmenopausal population, it can occur in younger patients for whom the preservation of fertility is an issue. In fact, 7% to 8% of all malignant stage I epithelial cancers of the ovary occur in women less than 35 years old.[17] The standard surgical therapy for ovarian cancer would render these women infertile; thus, several studies have examined the role of conservative surgery in the management of early-stage ovarian cancer. Schilder et al reported the multiinstitutional experience in patients with stage IA and IC epithelial ovarian cancer who were treated with fertility-sparing surgery.[18] They identified 52 patients (42 stage IA, 10 stage IC) who had undergone unilateral oophorectomy and surgical staging; 20 patients also received adjuvant chemotherapy. With a median followup of 68 months, five recurrences were recorded, of which three developed in the remaining ovary. Two patients died of disease, and the 5-year survival rate was estimated to be 98%. Of the 24 patients who attempted conception, 17 were successful, with 26 full-term deliveries and 5 spontaneous abortions. The authors concluded that fertility-sparing surgery should be considered a treatment option for patients with stage I disease who wish to bear children. The survival of patients with early- stage epithelial ovarian cancer who have undergone fertility-sparing surgery has been compared to that of patients who have undergone hysterectomy and bilateral salpingooophorectomy in addition to staging. In a retrospective review, Brown et al identified 16 patients under age 40 with stage I epithelial ovarian cancer, who had undergone preservation of the contralateral ovary and hysterectomy at the time of surgical staging.[ 19] Of these women, 37% received adjuvant platinum-based chemotherapy due to high-risk features. At a median follow-up of 66 months (range: 1-174 months), 14 patients (88%) were alive and disease-free. Two of the 16 patients developed a recurrence in the retained ovary and died of their disease. Over the same time period, 92 patients with stage I disease underwent hysterectomy and bilateral salpingooophorectomy in addition to staging.[ 19] Of these 92 patients, 80 (87%) were alive without disease. There were eight successful pregnancies among five patients treated with fertility-sparing surgery. The authors concluded that fertility preservation in stage I patients is possible after comprehensive staging and does not appear to decrease survival. The subject of fertility preservation, however, remains controversial for this group of patients. These women should be counseled on the importance of comprehensive staging and the possibility of fertility preservation, and this conservative approach should be limited to patients who meet certain criteria (Table 4). Furthermore,controversy exists as to whether patients with grade 2 tumors should be managed with conservative therapy.[15,20] Second-Look Surgery
Second-look surgery is a systematic surgical exploration in an asymptomatic patient who has completed a planned course of chemotherapy for ovarian cancer. Its use has been evaluated in patients with early-stage disease. Walton et al reported on 112 patients with FIGO stage I/II ovarian carcinoma who underwent secondlook surgery after completion of adjuvant therapy in an Ovarian Cancer Study Group/GOG trial.[21] Of the 95 patients who were asymptomatic at 18 months, only 5% had positive findings compared to 53% of the 17 patients who were symptomatic (eg, bowel obstruction, abdominal or pelvic complaints, weight loss, or other symptoms suspicious for recurrent disease). In a smaller series, Rubin et al reported on 54 stage I patients who underwent second-look surgery following complete surgical staging and adjuvant chemotherapy.[22] They, like Walton et al, found that only 5.5% had disease.[22] None of the patients with grade 1 tumors had disease. Tumor grade was a significant predictor of recurrence following a negative second-look procedure, with grade 1/2 tumors associated with a 0% risk of recurrence compared to a 52% risk for grade 3 tumors. Substage, histologic type, and chemotherapy type or duration did not predict recurrence. Given the small positive yield of second-look surgery in early-stage patients who have been comprehensively staged initially, this strategy is not routinely recommended.