Ovarian Cancer Surgical Practice Guidelines

Scope and Format of Guidelines

The Society of Surgical Oncology surgical practice guidelines focuson the signs and symptoms of primary cancer, timely evaluation of the symptomaticpatient, appropriate preoperative evaluation for extent of disease, androle of the surgeon in diagnosis and treatment. Separate sections on adjuvanttherapy, follow-up programs, or management of recurrent cancer have beenintentionally omitted. Where appropriate, perioperative adjuvant combined-modalitytherapy is discussed under surgical management. Each guideline is presentedin minimal outline form as a delineation of therapeutic options.

Since the development of treatment protocols was not the specific aimof the Society, the extensive development cycle necessary to produce evidence-basedpractice guidelines did not apply. We used the broad clinical experienceresiding in the membership of the Society, under the direction of AlfredM. Cohen, md, Chief, Colorectal Service, Memorial Sloan-Kettering CancerCenter, to produce guidelines that were not likely to result in significantcontroversy.

Following each guideline is a brief narrative highlighting and expandingon selected sections of the guideline document, with a few relevant references.The current staging system for the site and approximate 5-year survivaldata are also included.

The Society does not suggest that these guidelines replace good medicaljudgment. That always comes first. We do believe that the family physician,as well as the health maintenance organization director, will appreciatethe provision of these guidelines as a reference for better patient care.

Society of Surgical Oncology Practice Guidelines:Ovarian Cancer

Symptoms and Signs Early-stage disease

• Symptoms:
• Abdominal swelling (self-palpation of mass)
• Abdominal pain
• Urinary symptoms
• Abnormal vaginal bleeding
• Fatigue
• Signs:
• Palpation of a mass on pelvic examination (Risk of malignancy increasesif mass is solid, irregular, fixed, or bilateral.)
• Identification of an ovarian mass on ultrasound, CT scan, or MRI (Riskof cancer increases with increasing size of mass, with a complex mass,and with increasing age of patient.)
• Elevation of CA-125 above 35 units (CA-125 may be less than 35 unitsin up to 50% of stage I cancers.)

Advanced-stage disease

• Symptoms:
• Abdominal swelling (secondary to masses or ascites)
• Abdominal pain
• Urinary symptoms
• Gastrointestinal symptoms
• Abnormal vaginal bleeding
• Fatigue
• Respiratory distress
• Signs:
• Abdominal distension
• Palpation of masses on pelvic or abdominal eamination
• Ultrasound, CT scan, or MRI evidence of ascites and/or complex pelvicand/or abdominal masses
• X-ray evidence of pleural effusion

Evaluation of the Symptomatic PatientEarly-stage disease

• Complete history and physical examination
• Serum CA-125 level
• Serum beta hCG, AFP, and LDH in women less than 30 years old
• Chest x-ray
• Pelvic ultrasound (Morphology index and color flow Doppler may be helpfulbut are of unproven benefit.)
• CT scan and MRI usually add little to the evaluation of early diseaseand should not be considered routine.
• Uterine curettage or biopsy if patient has abnormal vaginal bleeding
• In women over age 45, stool guaiac should be performed. Consider colonevaluation (barium enema and sigmoidoscopy or colonoscopy) if symptomswarrant. Consider upper gastrointestinal x-ray studies or endoscopy ifsymptoms warrant.
• Mammography screening as appropriate for age

Advanced-stage disease

• Complete history and physical examination
• Serum CA-125 level
• Serum beta hCG, AFP, and LDH in women less than 30 years old
• Chest x-ray
• CT scan (or MRI) of the abdomen and pelvis
• Uterine curettage or biopsy if patient has abnormal vaginal bleeding
• Stool guaiac for women over age 45. Consider colon evaluation (bariumenema and sigmoidoscopy or colonoscopy) if symptoms warrant. Consider uppergastrointestinal x-rays or endoscopy if symptoms warrant.
• Mammography screening as appropriate for age

Appropriate timeliness of surgical referral

• Evaluation with due diligence for the above symptoms or signs

Preoperative Evaluation for Extent of DiseaseTests indicated for all patients

• Chest x-ray
• CBC, urinalysis, serum screening profile to include liver functionand renal function tests
• CT scan (or MRI) of the abdomen and pelvis

Tests indicated by symptoms

• Barium enema and sigmoidoscopy or colonoscopy
• Upper gastrointestinal x-rays or endoscopy
• Cystoscopy

Role of the Surgeon in Initial Management Evaluation of the symptomatic patient

• Since patients may be referred to the surgeon after some part of theabove evaluation, the role of the surgeon is to assess the evaluation todate and complete the necessary studies as outlined above.

Diagnostic procedures

• The diagnostic procedures outlined above should be completed basedon those studies required for all patients and those necessary becauseof symptoms.

Surgical considerations

• The role of the surgeon is critical in the management of ovarian cancerand consists of: (1) establishment of the diagnosis and appropriate surgicalstaging and (2) cytoreduction of patients with advanced disease. Ovariancancers are responsive to chemotherapy in about 80% of cases, and the successof chemotherapy is directly related to the volume of disease that remainsafter cytoreductive surgery.
• Preparation for surgery:
• Assessment of apparent disease status with preoperative diagnosticevaluation as indicated
• Treatment of any medical problems that may influence surgical therapy
• Mechanical and antibiotic bowel preparation
• Establishment of the diagnosis and surgical staging:
  In patients with advanced disease, the proper surgical stage is usuallyapparent when the abdomen is opened. However, in apparent early-stage disease,a full surgical staging procedure (based on known patterns of disease spread)is very important. Studies have shown that one-third of patients thoughtto have early-stage disease will be upstaged by an appropriate surgicalstaging procedure. The appropriate surgical staging procedure is outlinedbelow.
  
• Removal of the uterus, both fallopian tubes and ovaries. (In selectedcases in young women with tumors confined to one ovary, a unilateral salpingo-oophorectomywith preservation of childbearing potential may be appropriate.)
• Biopsies from the cul-de-sac, rectosigmoid serosa, bladder peritoneum,peritoneum of both pelvic sidewalls, peritoneum of both pelvic gutters,and peritoneal covering of both diaphragms
• Infracolic omentectomy
• Sampling of bilateral pelvic and para-aortic lymph nodes
• Saline lavage of the abdomen and pelvis for cytology
• Cytoreduction of advanced disease:

Many studies in the literature have documented improved survival inpatients with advanced ovarian cancer when "optimal" cytoreductionis accomplished. This usually refers to leaving no tumor nodule more than2 cm in diameter. While every effort should be made to achieve optimalcytoreduction, only about 35% to 45% of patients with advanced ovariancancer can achieve an optimal disease status with initial surgery. Thesurgeon must evaluate the patient based on his or her training and expertiseand use his or her surgical judgment to perform appropriate surgery withoutexcessive morbidity. The essentials of the operation are listed below.

• Total abdominal hysterectomy and bilateral salpingooophorectomy
• Omentectomy (either infracolic or total, depending on the extent oftumor involvement)
• Tumor debulking or cytoreduction. This may involve bowel resectionor resection of part of the urinary tract if such a procedure will resultin optimal cytoreduction. There appears to be little benefit to such proceduresunless optimal cytoreduction is achieved
• Pelvic and para-aortic lymphadenectomy may be indicated if there areenlarged lymph nodes and the cancer is otherwise optimally cytoreduced.

These guidelines are copyrighted by the Society of Surgical Oncology(SSO). All rights reserved. These guidelines may not be reproduced in anyform without the express written permission of SSO. Requests for reprintsshould be sent to: James R. Slawny, Executive Director, Society of SurgicalOncology, 85 W Algonquin Road, Arlington Heights, IL 60005

Ovarian cancer is the leading cause of death from gynecologic malignanciesin the United States. In 1996, approximately 26,700 new cases of ovariancancer were diagnosed, and approximately 14,800 women died of this disease.

Several investigators have postulated a causal relationship betweencertain environmental and genetic factors and this malignancy. Lactoseconsumption has been reported to be a dietary risk factor, especially whencombined with an inherited decrease in the levels of galactose-1-phosphateuridyl transferase. Consumption of significant amounts of animal fat mayalso be a risk factor.

Other investigators have established a causal relationship between exogenouschemicals, such as asbestos and talc, and the development of ovarian carcinoma.Pelvic irradiation, viruses (particularly mumps), nulliparity, and nonuseof oral contraceptives are also associated with an increased risk of ovarianmalignancy, presumably because of sustained elevations of gonadotropins.A 1983 summary article on oral contraceptives and ovarian carcinoma founda relative risk of 0.64 (95% confidence interval, 0.57 to 0.73) associatedwith use of oral contraceptives.

The majority of epithelial ovarian cancer cases occur sporadically.In a population-based case-control study, Schildkraut and Thompson foundthat the odds ratios for ovarian cancer in first- and second-degree relativesof patients with the disease were 3.6 (95% confidence interval, 1.8 to7.1) and 2.9 (95% confidence interval, 1.6 to 5.3), respectively, whencompared to women with no family history of the disease.

Increasing evidence indicates that there are a small number of familiesat particularly high risk for developing epithelial ovarian carcinoma,Three hereditary syndromes associated with the occurrence of familial ovariancancer have been described; all three syndromes have an autosomal dominantpattern of transmission with variable penetrance. These include the ovariancancer syndrome, the hereditary breast-ovarian cancer syndrome, and theLynch II syndrome, which includes a predisposition to ovarian, endometrial,and colon cancer.

Diagnosis

Ovarian cancer is an insidious disease that produces few or no specificsymptoms, even when advanced. Patients who develop pelvic masses of significantsize, which can occur with both early and advanced disease, may complainof abdominal swelling or symptoms related to pressure on the bladder orrectum. In advanced-stage patients with massive ascites or pleural effusions,respiratory distress may occur.

Signs of ovarian cancer may include pelvic masses or ascites detectableon physical examination and imaging techniques. It is important to recognizethat a significant proportion of patients with advanced ovarian cancer,perhaps 20%, may have essentially normal-sized ovaries, despite the presenceof ascites and extensive upper abdominal tumor.

Evaluation of patients with suspected ovarian cancer should includea complete history and physical examination, with particular attentiongiven to a family history of cancer. Routine testing appropriate for patientsundergoing major abdominal surgery should be performed. Selected tumormarker determinations and imaging studies are indicated. Multiple extensiveimaging studies are usually not required.

The poor survival associated with ovarian cancer is related to the difficultyof making an early diagnosis. The cure rates for patients with diseaselimited to the ovary are 85% to 95%, while survival of patients with tumorspread into the abdomen is 20% to 40%.

Screening

It is obvious that significant improvement in overall survival wouldbe achieved by the early diagnosis of ovarian cancer. Unfortunately, noscreening test for ovarian cancer has proven to be of benefit. Serum CA-125testing is not sensitive enough, with almost 50% of women with stage Iovarian cancer having serum levels within the normal range. Pelvic or transvaginalultrasound is not specific enough for routine screening, in that reportedseries to date have resulted in about 10 to 13 negative operations forevery case of ovarian cancer diagnosed. The April 1994 NIH Consensus Statementstated that there were no proven effective methods of screening for ovariancancer.

Staging

Invasive epithelial ovarian carcinoma can spread by local extension,lymphatic invasion, intraperitoneal implantation, or hematogenous dissemination,all of which have implications for staging. The TNM staging system forovarian cancer is shown in Table 1, alongwith approximate 5-year survival rates according to stage. Staging accuracydepends on how aggressively the surgeon looks for disease. Approximately75% of patients with invasive epithelial ovarian carcinoma have higherthan stage I disease. In patients with early-stage epithelial ovarian carcinoma,meticulous surgical staging is imperative to ascertain the need for adjuvanttherapy.

As mentioned above, stage is undoubtedly one of the strongest predictorsof survival. Histologic grade and histologic subtype have also been identifiedas independent prognosticators. Other predictors include initial tumorvolume, lymph node involvement, and residual tumor volume at the completionof surgery (optimal cytoreduction).

Treatment

The surgeon plays a critical role in the management of suspected ovariancancer. This includes establishment of the diagnosis and comprehensivesurgical staging, as well as tumor debulking in patients found to haveadvanced disease. Ovarian cancers are highly responsive to chemotherapy,and both the selection of appropriate postoperative chemotherapy and theefficacy of the therapy depend on appropriate surgical staging and cytoreduction.Surgeons undertaking operations for possible ovarian cancer should haveboth the necessary technical expertise and a thorough understanding ofthe management of the disease itself.

In patients with apparent early-stage ovarian cancer, comprehensivesurgical staging is of paramount importance, since about one-third of patientswill have occult metastatic disease not apparent on gross inspection. Theuterus and contralateral ovary may be preserved in selected cases in youngwomen who wish to preserve childbearing potential.

In patients with advanced-stage disease, optimal cytoreduction (removalof all tumor masses more than 1 to 2 cm in largest diameter) can be accomplishedin about 35% to 45% of patients, and will result in improved response tochemotherapy, median survival, and long-term survival. Aggressive operations,including resection of portions of the intestinal and urinary tracts, aregenerally indicated if they will allow for optimal debulking.

The management of patients with ovarian cancer serves as a prominentexample of the importance of multimodality oncologic therapy. Optimal treatmentof this disease requires the skillful and appropriate integration of cancersurgery and chemotherapy, and is best carried out in centers in which anexperienced and coordinated multidisciplinary team is available.

Follow-up

Follow-up for patients with ovarian cancer who have completed primarychemotherapy depends on the initial stage of disease. Although properlystaged patients with early-stage disease (stage I and stage II withoutresidual disease) rarely benefit from second-look laparotomy, many expertsrecommend second-look operations for patients with advanced disease. Otherexperts do not recommend second-look operations for any patients. If additionaltherapy is available in the event of residual disease, second-look operationshould be considered.

For patients who have a negative second-look laparotomy and for thosewho have a complete clinical response and do not undergo second-look laparotomy,follow-up consists of physical examination with pelvic examination at 3-monthintervals for 2 years and thereafter at 6-month intervals for an additional3 years. Serum CA-125 levels are measured at each visit and Pap smearsare obtained at yearly intervals.

Although some physicians obtain periodic CT scans of the abdomen andpelvis and chest x-rays, the value of such routine testing is not established,and many physicians obtain such tests only if symptoms or findings on examinationare suspicious. Diagnostic imaging is indicated in patients with an elevatedCA-125 level.

References:

Centers for Disease Control: Cancer and steroid hormone study: Oralcontraceptives and the risk of ovarian cancer. JAMA 248(12):1596-1599,1983.

Cramer DW, et al: Ovarian cancer and talc: A case controlled study.Cancer 50:372-376, 1982.

Curtin JP: Diagnosis and staging of epithelial ovarian cancer, in MarkmanM, Hoskins WJ (eds): Cancer of the Ovary, pp 153-162. New York, Raven Press,1993.

Hoskins WJ: Primary cytoreduction, in Markman M, Hoskins WJ (eds): Cancerof the Ovary, pp 163-173. New York, Raven Press, 1993.

Hoskins WJ: Primary surgical management of advanced epithelial cancer,in Rubin SC, Sutton G (eds): Ovarian Cancer, pp 241-254. New York, McGraw-Hill, 1993.

Hoskins WJ, Rubin SC: Surgery and the treatment of patients with advancedovarian cancer. Semin Oncol 18:213-221, 1991.

Lynch HT: Genetic risk and ovarian cancer. Gynecol Oncol 46(1):1-3,1982.

Moore D: Primary surgical management of early epithelial ovarian carcinoma,in Rubin S, Sutton G (eds): Ovarian Cancer, pp 219-239. New York, McGraw-Hill,1993.

National Institutes of Health Consensus Development Conference Statement:Ovarian cancer: Screening, treatment and follow-up. Gynecol Oncol 55:54,1994.

Redman JR, Petroni GR, Saigo PE, et al: Prognostic factors in advancedovarian cancer. J Clin Oncol 4:515, 1986.

Rubin S, Lewis JL Jr: Surgery cancer of the ovary, in Nichols D (ed):Gynecologic and Obstetric Surgery, pp 664-680. St. Louis, Mosby, 1993.

Schildkraut JM, Thompson WD: Familial ovarian cancer: A population basedcase controlled study. Am J Epidemiol 128:456-466, 1988.

Smith EM, Anderson B: The effects of symptoms and delay in seeking diagnosison stage of disease at diagnosis among women with cancers of the ovary.Cancer 56(11):2727-2732, 1985.

Sorbe B, Frankendal B, Veress B: Importance of histologic grading andthe prognosis of epithelial ovarian carcinoma. Obstet Gynecol 59(5):576-582,1982.

Wingo PA, Tong T, Bolden S: Cancer statistics, 1995. CA Cancer J Clin45:8-30, 1995.