Staging & Surgical Management of Ovarian Cancer
WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).
Ovarian cancer remains the most lethal of gynecologic malignancies, and its mortality exceeds the combined mortality from both cervical and endometrial cancer in the United States. Ovarian malignancy is the fourth most common cause of cancer death in American women and accounts for 5% of all cancer deaths. In the United States about 1 in 70 women will develop ovarian cancer in her life-time, and 1 in 100 women will die of this disease. The grim realities of ovarian cancer result primarily from a failure to improve early diagnosis. At the time of diagnosis about 70%-75% of patients have advanced-stage disease and the 5-year survival of women with such disease remains only 25%-30%. The majority (85%-90%) of malignant ovarian tumors seen in the United States are epithelial.
The purpose of this document is to understand and evaluate advances in the surgical management of ovarian cancer, staging and prognostic factors. Important progress has been made in the management of ovarian malignancy in recent years. Insightful overview of the current understanding of the ovarian malignancy as well as the areas of continuing challenges are also discussed in this series of the articles exploring different aspects of ovarian cancer. While therapy for ovarian malignancy has undergone important progress, there is growing concern about the quality of life of these patients. The contributors to this symposium include many of the experts who have advanced the management of this disease, and their articles thoughtfully describe the progress and point to future areas of reproductive research (1).
Signs, Symptoms and Pre-Operative Evaluation:
Most women with ovarian cancer have no symptoms for long periods of time. When symptoms do develop, they are often vague and non-specific. A high index of suspicion is warranted in all women between the ages of 40 and 69 years who have persistent gastrointestinal symptoms that cannot be diagnosed. In advanced-stage disease, patients most often have symptoms related to the presence of ascites, omental metastases, or bowel metastases. The symptoms include abdominal tension, bloating, constipation, nausea, anorexia or in premenopausal patients there may be complaint of irregular or heavy menstrual cycle. The most important sign of epithelial ovarian cancer is the presence of pelvic mass on physical examination. Frequently encountered non-ovarian causes of apparent adnexal masses are diverticulitis, tubo-ovarian abscess, carcinoma of the cecum or sigmoid, pelvic kidney, and uterine or intraligamentous myomas.
Diagnosis: Serum CA 125 levels have been shown to be useful in distinguishing malignant from benign pelvic mass. For a postmenopausal patient with an adnexal mass and a very high serum CA 125 (>95 U/ml), there is a 96% positive predictive value for malignancy. For premenopausal patients, however, the specificity of the test is low because the CA 125 level tends to be elevated in common benign conditions (2). The size of lesion is important. If a cystic mass is >8 cm in diameter, the probability is high that the lesion is neoplastic, unless the patient has been taking clomiphene citrate or other agents to induce ovulation. Patients whose lesions are suggestive of malignancy (ie; predominantly solid, relatively fixed, or irregularly shaped) should undergo laparotomy, as should postmenopausal patients with adnexal masses. The diagnosis of an ovarian cancer requires an exploratory laparotomy.
Pre-operative evaluation: Before the planned exploration the patient should undergo routine hematologic and biochemical assessment. X-ray chest and an assessment of the urinary tract with intravenous pyelography are also useful. Abdominal and pelvic computed tomography (CT) or magnetic resonance imaging (MRI) are of no value for a patient with a definite mass. A CT and MRI should be performed for patients with ascites and no pelvic mass to look for liver or pancreatic tumors. If the hepatic enzyme values are normal, the likelihood of liver disease is low. Liver-spleen scans, bone scans, and brain scans are unnecessary unless symptoms or signs suggest metastases to these sites. The preoperative evaluation should exclude other primary cancers metastatic to the ovary. A barium enema or colonoscopy is indicated in some patients over 45 years of age to exclude a primary colonic lesion with ovarian metastasis. An upper gastrointestinal radiographic series or gastroscopy is indicated if symptoms indicate gastric involvement.
Bilateral mammography is indicated if there is any breast mass, because occasionally breast cancer metastatic to the ovaries can simulate primary ovarian cancer. Cervical cytologic study should be performed, although its value for the detection of ovarian cancer is very limited. Patients who have irregular menses or postmenopausal vaginal bleeding should have endometrial biopsy and endocervical curettage to exclude the presence of uterine or endocervical cancer metastatic to the ovary.
Ovarian epithelial cancers spread primarily by exfoliation of cells into the peritoneal cavity, lymphatic dissemination and by hematogenous route.
- Exfoliation in peritoneal cavity: This is the most common dissemination and cells tend to follow the circulatory path of the peritoneal fluid. Therefore, metastases are typically seen on the posterior cul-de-sac, paracolic gutters, right hemi-diaphragm, liver capsule, the peritoneal surfaces of the intestines and their mesenteries, and the omentum. The disease seldom invades the intestinal lumen but progressively agglutinates loops of bowels, leading to a functional intestinal obstruction. This condition is also known as carcinomatous ileus.
- Hematogenous route: Systemic metastases are seen more frequently in patients who have survived for some years. Spread to vital organ parenchyma, such as the lungs and liver, occurs in only about 2% to 3% of patients.
- Lymphatic dissemination: To pelvic and para-aortic lymph-nodes is common, particularly in advanced-stage disease. Burghardt et al reported that 78% of patients with stage III disease have metastases to the pelvic lymph-nodes. The rate of para-aortic lymph nodes positive for metastasis was 18% in stage I, 20% in stage II, 42% in stage III, and 67% in stage IV (3).
The morphology and histologic pattern, including the architecture and grade of the lesion, are important prognostic variables (4). Surgery accurately stages a patient and allows the evaluation of a series of variables that are often used to select post-operative therapy and prognosis. These factors are:
- Tumor Stage: the 5-year survival of patients with epithelial ovarian cancer is directly correlated with the tumor stage. While earlier studies reported 5-year survivals for patients with Stage I disease of approximately 60% to 80%, current studies utilizing a comprehensive staging laparotomy demonstrate the some subsets of patients with Stage I disease have a 90% 5-year survival. Stage II disease reported the range of 5-year survivals from 0% to 40%; Stage III disease have approximately survival of 15% to 20%, whereas patients with Stage IV disease have less than a 5% 5-year survival.
- Volume of Residual Disease: the volume of residual disease following cyto-reductive surgery is directly correlated with survival. Ovarian cancers that undergo intra-operative rupture or spillage do not worsen the prognosis, whereas tumors found to have already ruptured pre-operatively do have a poorer prognosis.
- Pathologic Factors: the morphology and histologic pattern, including the architecture and grade of lesion, are important prognostic variables. Clear cell carcinomas are associated with a prognosis worse than that of other histologic types. Cellular anaplasia and the proportion of undifferentiated cells, seems to be prognostic significance.
- Biologic Factors: more than 60 proto-oncogenes have been identified and studies have focused on the amplification or expression of these genetic loci and their relationship to the development and progression of ovarian cancer. An overall incidence of HER-2/neu expression has poorer prognosis, especially patients with more than 5 copies of the gene (5). The most commonly expressed tumor suppressor gene in ovarian cancer is p53. Indeed, as many as one-half of all epithelial ovarian cancers have evidence of mutated p53 in the tumor.
- CA 125 Levels: the prognostic significance of pre and postoperative CA 125 levels continues to be studied. Serum levels of CA 125 generally reflect volume of disease. High CA 125 levels may predict for unresectability and inferior survival. An elevated CA 125 has also been increasing used as an indicator of progression following completion of chemotherapy (6). However, unless regular CA 125 measurements are defined prospectively in a clinical trial, routine CA 125 levels should not be used to assess progression since bias could result if patients come off study early solely on the basis of an elevated CA 125.
The importance of thorough surgical staging cannot be overemphasized, because subsequent treatment will be determined by the stage of disease. Ovarian epithelial malignancies are staged according to the FIGO system:
Stage I: Growth limited to the ovaries
Stage Ia -- Growth limited to one ovary; no ascites containing malignant cells. No tumor on the external surface; capsule intact.
Stage Ib - Growth limited to both ovaries; no ascites containing malignant cells. No tumor on the external surfaces; capsule intact.
Stage Ic -- Tumor either stage Ia or Ib but with tumor on the surface of one or both ovaries; or with capsule ruptured; or with ascites present containing malignant cells or with positive peritoneal washings.
Stage II: Growth involving one or both ovaries with pelvic extension
Stage IIa -- Extension and/or metastases to the uterus and/or fallopian tubes
Stage IIb -- Extension to other pelvic tissues
Stage IIc -- Tumor either stage IIa or IIb but with tumor on the surface of one or both ovaries; or with capsule(s) ruptured; or with ascites present containing malignant cells or with positive peritoneal washings.
Stage III: Tumor involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal
or inguinal nodes. Superficial liver metastasis equals stage III. Tumor is limited to the true pelvis, but with
histologically proven malignant extension to small bowel or omentum.
Stage IIIa -- Tumor grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces.
Stage IIIb -- Tumor of one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, none Exceeding 2 cm in diameter. Nodes negative.
Stage IIIc -- Abdominal implants >2 cm in diameter or positive retroperitoneal or inguinal nodes or both.
Stage IV: Growth involving one or both ovaries with distant metastasis. If pleural effusion is present, there must be positive cytologic test results to allot a case to stage IV. Parenchymal liver metastasis equals stage IV.
Initial Surgery for Ovarian Cancer:
The ovarian tumor should be removed intact, if possible and a frozen histologic section should be obtained. For patients whose pre-operative evaluation suggests a probable malignancy, a midline or paramedian abdominal incision is recommended to allow adequate access to the upper abdomen. Staging involves following steps:
- Peritoneal cytologic examination. Any free fluid especially in pelvic cul-de-sac should be collected and submitted for cytological examination. If there is no fluid peritoneal washings should be performed by instilling and recovering 50-100 ml of saline from the pelvic cul-de-sac, each paracolic gutter, and beneath each hemidiaphragm.
- Determination of extent of disease by systemic exploration of intrabdominal viscera, pelvis, peritoneal surfaces, diaphragms, omentum and lymph-nodes (pelvic and para-aortic).
- Any suspicious areas or adhesions on the peritoneal surfaces should be sampled for biopsy. The diaphragm should be sampled either by biopsy or by scraping with a tongue depressor and obtaining a sample for cytologic assessment.
Borderline Malignant Epithelial Neoplasms -- the principal treatment of borderline ovarian tumors is surgical resection of the primary tumor. Extensive sectioning of the neoplasm is necessary to rule out truly invasive characteristics. Patients have a high survival rate and even lesions that behave in a malignant fashion usually have a typically indolent course. Conservative management and surgery should be considered when future fertility is desired.
Stage I Low-grade, Low-risk -- for patients who have undergone a thorough staging laparotomy and for whom there is no evidence of spread beyond the ovary, abdominal hysterectomy and bilateral salpingo-oopherectomy are appropriate therapy. The uterus and the contralateral ovary can be preserved in women with stage Ia, grade 1 or 2 disease who desire to preserve fertility. The conditions of the women should be monitored carefully with routine periodic pelvic examinations and determinations of serum CA 125 levels. Generally, the other ovary and the uterus are removed at the completion of childbearing.
Stage I High-grade, High-risk -- for patients whose disease is more poorly differentiated or in whom there are malignant cells either in ascetic fluid or in peritoneal washings, complete surgical staging must be performed. The surgery should include the performance of a hysterectomy and bilateral salpingo-oopherectomy in addition to the staging laparotomy.
Cytoreductive Surgery for Advanced-stage Disease -- the operation to remove the primary tumor as well as the associated metastatic disease is referred to as debulking surgery. The concept is simply to diminish the residual tumor burden to a point at which adjuvant therapy will be optimally effective. All forms of adjuvant therapy are most effective when a minimal tumor burden exists. Removal of large ovarian masses and omental involvement often reduces the tumor burden by 80%-90%. Benefits of lymphadenectomy in patients with bulk residual disease remains questionable (7). The GOG investigators evaluated the effect of the diameter of the largest residual disease on survival in patients with suboptimal cytoreduction. They demonstrated that cytoreduction, so that, the largest residual mass was <2 cm resulted in a significant survival benefit, but all residual diameters >2 cm had equivalent survival. Therefore, unless the mass can be cytoreduced to <2 cm, residual diameter did not influence survival. Resection of a portion of bowel should be considered only when such a resection will result in removal of all gross tumor.
Role of Interval Cytoreduction -- although aggressive surgical cytoreduction is the foundation of management in women with advanced ovarian carcinoma, not all patients will be candidates for upfront surgical debulking (ie, intra-parenchymal liver metastases), and optimal debulking may expose a patient to unacceptable morbidity. Likewise, even for those women who are medically fit to withstand surgery, a small percentage, despite maximum effort by a gynecologic oncologist, will not undergo optimal cytoreduction at the time of their initial surgery. It is this group of patients in whom interval cytoreduction may be beneficial (8). In an attempt to predict which patients will successfully undergo optimal cytoreduction, several authors have developed radiographic criteria or have used CA 125 levels to help direct the decision to operate first or treat with neoadjuvant chemotherapy.
Role of Second-Look Surgery -- currently, second-look surgery has a role only in assessing pathologic response to clinical trial therapy. Following standard chemotherapy, CA 125 physical examination and computed tomography can be used to assess clinical response (9). Gynecology Oncology Group (GOG) study of 158 addressed the issue of second-look surgery indirectly. At the time of treatment randomization, the decision to undergo second-look laparotomy or laparoscopy at the completion of chemotherapy was made by the treating clinician. Second-look surgery was mandatory and was not a statistical end point of the study. 50% of patients in the study underwent second-look surgery. The statement was made that there was no difference in relapse-free survival for patients registered for second-look surgery vs. no second-look surgery. Thus the conclusion was drawn that second-look surgery did not affect survival.
Role of Laparoscopy -- it can be used for second-look surgery, for staging of presumed "early" ovarian cancer, for placement of an intraperitoneal port for administration of intraperitoneal chemotherapy and for assessment of response to treatment (when more conventional measures of response are not useful). Laparoscopy is also appropriately used in assessment and removal of an adnexal mass. Laparoscopy has been reported to be useful in secondary cytoreduction. In some very special instances, laparoscopy in combination with mini-laparotomy has been useful in cytoreduction (10).
Recurrent Ovarian Cancer:
Patients with complete cytoreduction to microscopic disease are often cured with adjuvant chemotherapy. There is growing evidence that these patients with microscopic residual disease are excellent candidates for intraperitoneal chemotherapy, and this mode of chemotherapy delivery may be their best opportunity for cure. Patients with optimal cytoreduction also may benefit from intraperitoneal chemotherapy, but cure is less likely. For patients with suboptimal cytoreduction, intravenous chemotherapy with a combination of carboplatin and paclitaxel is the current standard therapy. Most of these patients will experience recurrence of cancer, with small chance of cure. An unfortunate reality of advanced ovarian cancer is that the majority will eventually suffer recurrence and will die of disease. The search for novel therapeutic in ovarian cancer continues. Unlike primary therapy, there is no established standard of treatment of recurrence. It is unclear if patients benefit from platinum-based re-challenge at first recurrence or at subsequent relapse. Also unclear is the best combination of agents to use. Most physicians initially retreat platinum-sensitive patients with carboplatin and paclitaxel. Other agents are considered for second recurrence insensitivity. Additional research is also focusing on immune-based therapy, including vaccines and monoclonal antibodies that specifically target tumor cells. The ultimate therapy may come in the form of individualized gene therapy, focusing on each patient's cancer-forming genetic aberrations. Until curative agents are identified, these patients must be treated with compassion and consideration for quality of life. "First do no harm" is especially pertinent in treating patients with primary and recurrent ovarian cancer (11).
For early ovarian cancer, appropriate surgical staging and adjuvant chemotherapy for selected cases will result in survival rates of 90-95%. For advanced ovarian cancer, survival depends primarily on the success of the initial surgical procedure. Salvage chemotherapy is important in ovarian cancer because many patients respond to several salvage regimens. Relative survival varies by age, women younger than 65 years are about twice likely to survive 5 years (56%) following diagnosis as women 65 years and older (28%). Overall, the 1- and 5-year relative survival of ovarian cancer patient is 76% and 45% respectively. If diagnosed at the localized stage, the 5 years survival rate is 93%, however, only about 19% of all cases are detected at this stage. For women with regional and distant disease, 5-year survival rates are 69% and 30% respectively. The 10 year relative survival rate of all stages combined is 38%. Apparent declines in survival rates from previous years are due to recent changes in the classification of malignant ovarian tumors rather than true reduction in survival (12). Because of high response rate of ovarian cancer, even after relapse, it is probably better to consider 10-year survival as the ideal end point. Finally, new biologic agents, in combination with traditional surgery and chemotherapy, may result in further improvement in survival for patients with ovarian cancer.
Advances in surgical techniques and approaches have contributed to the increase in survival for the patients of ovarian cancer. The surgeon makes a difference in survival. Access to specialist surgeons continues to be very important in the care of women with ovarian cancer to ensure adequate staging, optimal cytoreduction and application of secondary cytoreduction when appropriate. An optimal surgical approach should be carried out whenever possible. This is defined as the removal of all bulk tumor with the intent to leave minimal residual tumor (no individual mass >1-2 cm in diameter). It is not possible to advocate any one operation for all patients, and the clinician must make a judgment at the time of surgery. Unquestionably, patients with small residual tumor volumes have a better prognosis with any post-operative therapy. Even when optimal debulking is not possible, bilateral salpingo-oopherectomy, total abdominal hysterectomy, and omentectomy may afford significant palliation for the patient. Prognosis depends very much on stage, but other factors are also pertinent.
- Berkowitz RS, Seiden MV. Advances in the management of ovarian cancer -- a symposium. J Reprod Med. 2005;50:397-398.
- Jeyarajah AR, Ind TE, Skates S et al. Serum CA 125 elevation and risk of clinical detection of cancer in asymptomatic post-menopausal women. Cancer 1999;85:2068-2072.
- Burghardt E, Girardi F, LaHousen M et al. Patterns of pelvic and para-aortic lymph node involvement in ovarian cancer. Gynecol Oncol. 1991;40:103-110.
- Barnholtz-Sloan JS, Schwartz AG, Qureshi F, et al. Ovarian Cancer: Changes in patterns at diagnosis and relative survival over the last three decades. Am J Obstet Gynecol. 2003;189:1120-1127.
- Berchuck A et al. Over expression of HER-2neu is associated with poor survival in advanced epithelial ovarian cancer. Cancer 1990;50:4087.
- Latimer JA, Beng CG, Davy MLJ. For stage III epithelial ovarian cancer, the initial level of expression of CA 125 does not correlate with survival in women who respond to treatment. Int. J Gynecol Cancer. 1996;6:380-386.
- Guidozzi F, Ball JHS. Extensive primary Cytoreductive surgery for advanced epithelial ovarian cancer. Gynecol Oncol. 1994;53:326-334.
- Horowitz NS, Duska LR. Advances in the Surgical Management of Ovarian Cancer. Journal of Reproductive Medicine. 2005;50:454-466.
- Chu C, Rubin SC. Second-look laparotomy for epithelial ovarian cancer: A reappraisal. Curr Oncol Rep. 2001;3:11-18.
- Einat S, Amir S, Sivia M et al. Successful laparoscopic removal of a solitary adrenal metastasis from ovarian carcinoma: A case report. Gyncol Oncol. 2002;85:201-203.
- Bhoola S, Hoskins WJ. Diagnosis and management of epithelial ovarian cancer. Obstet Gynecol. 2006;107:1399-1410.
- American Cancer Society.: Cancer Facts and Figures 2007. Atlanta, Ga: American Cancer Society, 2007. Also available online (pdf). Last accessed August 6, 2007
Dedicated to Women's and Children's Well-being and Health Care Worldwide