Jonathan S. Berek

Rethinking ovarian cancer: recommendations for improving outcomes.

There have been major advances in our understanding of the cellular and molecular biology of the human malignancies that are collectively referred to as ovarian cancer. At a recent Helene Harris Memorial Trust meeting, an international group of researchers considered actions that should be taken to improve the outcome for women with ovarian cancer. Nine major recommendations are outlined in this Opinion article.

The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma.

OBJECTIVE The Gynecologic Oncology Group has divided patients with advanced epithelial ovarian cancer into those with optimal residual cancer, in which the maximum diameter of residual is < or = 1 cm, and suboptimal residual cancer, in which the residual disease is > 1 cm. Within the optimal group of patients there is a survival difference between patients with microscopic residual disease and those with any macroscopic disease < or = 1 cm. No analysis of the effect of various residual disease diameters in patients with residual disease > or = 1 cm has been performed. This study evaluates the effect of residual disease diameter in patients with suboptimal disease entered on a randomized trial of intense versus standard chemotherapy. STUDY DESIGN Gynecologic Oncology Group protocol 97 compared cisplatin 50 mg/m2 and cyclophosphamide 500 mg/m2 for eight courses with the same drugs at 100 mg/m2 and 1000 mg/m2 for four courses, respectively. There was no difference in progression-free interval or survival between the two arms. Of the 458 stage III (with residual disease > 1 cm) and stage IV patients entered in this study, 294 stage III patients comprise the current analysis. Surgical reporting forms, operation reports, and pathology reports were reviewed to determine initial greatest tumor diameter and residual tumor diameter. Patients were grouped by residual diameter. Multivariate analysis considered residual diameter of disease, age, histologic characteristics, performance status, and ascites. An adjusted relative hazard of dying of ovarian cancer was calculated for each residual disease group. RESULTS Patients ranged in age from 20 to 80 years, with a median of 60 years. All patients were Gynecologic Oncology Group performance status 0 to 2. Fifty-two percent had grade 3 tumors, and 39% and 9%, respectively, had grade 2 or 1 tumors. All patients had stage III disease. Ninety percent had serous, endometrioid, or mixed epithelial cell type tumors. Multivariate analysis revealed a relative risk of dying as follows: residual disease < 2 cm, relative risk 1.00; 2 to 2.9 cm, relative risk 1.90; 3 to 3.9 cm, relative risk 1.91; 4 to 5.9 cm, relative risk 1.74; 6 to 7.9 cm, relative risk 1.85; 8 to 9.9 cm, relative risk 2.16; > or = 10 cm, relative risk 1.82. The difference in survival between those with < 2 cm residual disease and those with > or = 2 cm residual disease was significant (p < 0.01). There is no significant difference in the risk of dying between groups with residual disease > or = 2 cm. CONCLUSIONS Among patients with suboptimal (> 1 cm residual disease) epithelial ovarian cancer, those who have small diameter residual disease (< 2 cm) tend to survive longer than those who have larger residual disease. Among those with larger residual disease, size does not affect prognosis appreciably.

Ovarian cancer: epidemiology, biology, and prognostic factors.

Ovarian cancer varies widely in frequency among different geographic regions and ethnic groups, with a high incidence in Northern Europe and the United States, and a low incidence in Japan. The majority of cases are sporadic, and only 5% to 10% of ovarian cancers are familial. The etiology of ovarian cancer is poorly understood. Models of ovarian carcinogenesis include the theory of incessant ovulation, in which a persons age at ovulation, i.e., lifetime number of ovulatory cycles, is an index of her ovarian cancer risk. Excessive gonadotropin and androgen stimulation of the ovary have been postulated as contributing factors. Exposure of the ovaries to pelvic contaminants and carcinogens may play a role in the pathogenesis of ovarian cancer. Epidemiologic and molecular-genetic studies identify numerous risk and protective factors. The most significant risk factor is a family history of the disease. Recent advances in molecular genetics have found mutations in the BRCA1 and BRCA2 tumor suppressor genes responsible for the majority of hereditary ovarian cancer. Additional risk factors include nulliparity and refractory infertility. Protective factors include multiparity, oral contraceptives, and tubal ligation or hysterectomy. With five years of oral contraceptive use, women can cut their risk of ovarian cancer approximately in half; this also holds true for individuals with a family history. Stage at diagnosis, maximum residual disease following cytoreductive surgery, and performance status are the three major prognostic factors. Using a multimodality approach to treatment, including aggressive cytoreductive surgery and combination chemotherapy, five-year survival rates are as follows: Stage I (93%), Stage II (70%), Stage III (37%), and Stage IV (25%).

Ovarian Conservation at the Time of Hysterectomy and Long-Term Health Outcomes in the Nurses' Health Study

OBJECTIVE: To report long-term health outcomes and mortality after oophorectomy or ovarian conservation. METHODS: We conducted a prospective, observational study of 29,380 women participants of the Nurses’ Health Study who had a hysterectomy for benign disease; 16,345 (55.6%) had hysterectomy with bilateral oophorectomy, and 13,035 (44.4%) had hysterectomy with ovarian conservation. We evaluated incident events or death due to coronary heart disease (CHD), stroke, breast cancer, ovarian cancer, lung cancer, colorectal cancer, total cancers, hip fracture, pulmonary embolus, and death from all causes. RESULTS: Over 24 years of follow-up, for women with hysterectomy and bilateral oophorectomy compared with ovarian conservation, the multivariable hazard ratios (HRs) were 1.12 (95% confidence interval [CI] 1.03–1.21) for total mortality, 1.17 (95% CI 1.02–1.35) for fatal plus nonfatal CHD, and 1.14 (95% CI 0.98–1.33) for stroke. Although the risks of breast (HR 0.75, 95% CI 0.68–0.84), ovarian (HR 0.04, 95% CI 0.01–0.09, number needed to treat=220), and total cancers (HR 0.90, 95% CI 0.84–0.96) decreased after oophorectomy, lung cancer incidence (HR=1.26, 95% CI 1.02–1.56, number needed to harm=190), and total cancer mortality (HR=1.17, 95% CI 1.04–1.32) increased. For those never having used estrogen therapy, bilateral oophorectomy before age 50 years was associated with an increased risk of all-cause mortality, CHD, and stroke. With an approximate 35-year life span after surgery, one additional death would be expected for every nine oophorectomies performed. CONCLUSION: Compared with ovarian conservation, bilateral oophorectomy at the time of hysterectomy for benign disease is associated with a decreased risk of breast and ovarian cancer but an increased risk of all-cause mortality, fatal and nonfatal coronary heart disease, and lung cancer. In no analysis or age group was oophorectomy associated with increased survival. LEVEL OF EVIDENCE: II

Randomized trial of cyclophosphamide plus cisplatin with or without doxorubicin in ovarian carcinoma: a Gynecologic Oncology Group Study.

A randomized clinical trial was conducted in women with stage III ovarian carcinoma (less than or equal to 1 cm residual lesions), using cyclophosphamide plus cisplatin (CP) with or without doxorubicin. There were 349 evaluable patients, of whom 176 received CP while 173 patients received CP plus doxorubicin (CAP). Hematologic toxicity was almost identical. There was no significant difference in progression-free interval (PFI) (median, 22.7 months and 24.6 months), frequency of negative second-look laparotomy (30.2% and 32.8%), or survival (median, 31.2 months and 38.9 months) between CP and CAP, respectively. Thus, doxorubicin in the dose schedule employed does not improve combination chemotherapy of optimal stage III ovarian carcinoma. Several other findings, independent of treatment arm, were of interest. There was a significant difference in PFI and survival by residual disease category (yes v no) and by grade of differentiation (1 v 2 + 3). In multivariate analysis, age, residual disease at entry, cell type (clear cell carcinoma), and time from surgery to initiation of chemotherapy were significant predictors of survival. There was no difference in outcome comparing those who refused second-look with those who had a second-look.

Surgical-pathologic variables predictive of local recurrence in squamous cell carcinoma of the vulva☆

One hundred and thirty-five patients with squamous carcinoma of the vulva were treated at UCLA and City of Hope Medical Centers between 1957 and 1985. Sixty-two cases were stage I, 48 stage II, 18 stage III, and 7 stage IV. Twenty-one patients developed a local vulvar recurrence after primary radical resection. Ninety-one patients had a surgical tumor-free margin greater than or equal to 8 mm on tissue section and none had a local vulvar recurrence. Forty-four patients had a margin less than 8 mm; 21 had a local recurrence and 23 did not (P less than 0.0001). Of the 23 patients with a margin less than 8 mm who did not recur locally, 14 remained free of disease, and 9 had either advanced disease, declining health, or short follow-up. Depth of invasion is associated with local recurrence, with a 9.1-mm reference value correctly predicting outcome in 81.5% of cases. Increasing tumor thickness is associated with local recurrence, with a 10-mm reference value predictive of 90% non-recurrence and 33% recurrences. A pushing border pattern is less likely to recur than an infiltrative growth pattern. Lymph-vascular space invasion has a combined predictive accuracy of 81.5%. Increasing keratin and greater than 10 mitoses per 10 high-power fields correlate with local recurrence. Neither clinical tumor size nor coexisting benign vulvar pathology correlates with local recurrence. Fourteen of twenty-one patients with vulvar recurrence died of metastatic disease, four died of intercurrent disease, and three were alive at 32, 68, and 157 months, with 16 recurring in less than 1 year. Surgical margin is the most powerful predictor of local vulvar recurrence. Combining factors in a stepwise logistical regression does not significantly improve this predictive value. Accounting for specimen preparation and fixation, a 1-cm tumor-free surgical margin on the vulva results in a high rate of local control, whereas a margin less than 8 mm is associated with a 50% chance of recurrence.

Assessment of current International Federation of Gynecology and Obstetrics staging of vulvar carcinoma relative to prognostic factors for survival (a Gynecologic Oncology Group study).

Analysis of 588 patients with vulvar carcinoma delineated four risk groups by the proportional hazards model. Groin node status (laterality and number positive) and lesion diameter were the only two important independent prognostic factors. The 5-year relative survival rates were 98%, 87%, 75%, and 29% for the risk group categories of minimal (negative groin nodes and lesion diameter less than or equal to 2 cm), low (one positive groin node and lesion diameter less than or equal to 2 cm or negative groin nodes and fewer than two lesions less than or equal to 8 cm diameter), intermediate (negative groin nodes and lesion diameter greater than 8 cm diameter, one positive groin node and lesion diameter greater than 2 cm, or two unilaterally positive groin nodes and lesion diameter less than or equal to 8 cm), and high (three or more positive groin nodes or two bilaterally positive groin nodes), respectively. Applying the International Federation of Gynecology and Obstetrics staging (1988) to these data discriminated risk of death (caused by recurrent vulvar cancer); the 5-year rates were 98%, 85%, 74%, and 31% for stages I, II, III, and IV, respectively. However, within International Federation of Gynecology and Obstetrics stage III there were 47 low-, 95 intermediate-, and 28 high-risk patients with relative survivals of 95%, 74%, and 34%, respectively. Overall, this assessment validates current International Federation of Gynecology and Obstetrics vulvar carcinoma staging, but further refinements are warranted in stage III.

Ovarian conservation at the time of hysterectomy for benign disease

Objective: Prophylactic oophorectomy is often recommended concurrent with hysterectomy for benign disease. The optimal age for this recommendation in women at average risk for ovarian cancer has not been determined. Methods: Using published age-specific data for absolute and relative risk, both with and without oophorectomy, for ovarian cancer, coronary heart disease, hip fracture, breast cancer, and stroke, a Markov decision analysis model was used to estimate the optimal strategy for maximizing survival for women at average risk of ovarian cancer. For each 5-year age group from 40 to 80 years, 4 strategies were compared: ovarian conservation or oophorectomy, and use of estrogen therapy or nonuse. Outcomes, as proportion of women alive at age 80 years, were measured. Sensitivity analyses were performed, varying both relative and absolute risk estimates across the range of reported values. Results: Ovarian conservation until age 65 benefits long-term survival for women undergoing hysterectomy for benign disease. Women with oophorectomy before age 55 have 8.58% excess mortality by age 80, and those with oophorectomy before age 59 have 3.92% excess mortality. There is sustained, but decreasing, benefit until the age of 75, when excess mortality for oophorectomy is less than 1%. These results were unchanged following multiple sensitivity analyses and were most sensitive to the risk of coronary heart disease. Conclusion: Ovarian conservation until at least age 65 benefits long-term survival for women at average risk of ovarian cancer when undergoing hysterectomy for benign disease.

Preoperative evaluation of serum CA 125 levels in premenopausal and postmenopausal patients with pelvic masses. Discrimination of benign from malignant disease

CA 125 levels were measured in 158 patients with palpable pelvic masses who were about to undergo diagnostic laparotomy. When the 68 patients found to have cancer were compared with the 90 patients with benign disease, those with malignancies were significantly older, were more frequently postmenopausal, and had significantly higher values of serum CA 125. Patients with benign pelvic masses had CA 125 levels greater than 65 U/ml in 8% of cases, whereas those with malignancies had CA 125 levels greater than 65 U/ml in 75% of cases. If only those patients who had frankly malignant, primary, nonmucinous epithelial ovarian carcinomas were considered, CA 125 levels greater than 65 U/ml predicted malignancy with a sensitivity of 91% for all patients. Greater sensitivity and specificity were observed in the postmenopausal subgroup than in the premenopausal subgroup. In the postmenopausal group with a 63% prevalence of ovarian cancer the predictive positive value was 98% and the predictive value negative was 72%. In a premenopausal population with a 15% prevalence of ovarian cancer the predictive value for a positive test was 49%, while the predictive value for a negative test was 93%.

Distant metastases in epithelial ovarian carcinoma.

A review of 255 patients with epithelial ovarian carcinoma revealed that metastases consistent with Stage IV disease developed in 97 patients (38.0%) at some time during the natural history of their disease. Malignant pleural effusions developed in 63 patients (24.7%), and their median survival (from the time of diagnosis of the effusion) was 6 months. Parenchymal liver metastases developed in 24 patients (9.4%; median survival, 5 months); parenchymal lung metastases in 18 patients (7.1%; median survival, 8 months); distant lymph node metastases in 18 patients (7.1%; median survival, 9 months); subcutaneous nodules in nine patients (3.5%; median survival, 12 months); a malignant pericardial effusion in six patients (2.4%; median survival, 2.3 months); central nervous system metastases in five patients (2%; median survival, 1.3 months); and bone metastases in four patients (1.6%; median survival, 4 months). Patients with Stage IV disease at the time of diagnosis had a median survival of 9.1 months, while patients with a delayed occurrence of distant metastases had a median survival of only 4 months from the time of diagnosis of the distant metastases. Significant risk factors for distant metastases were malignant ascites, peritoneal carcinomatosis, large metastatic disease within the abdomen, and retroperitoneal lymph node involvement at the time of the initial surgery. The significance of positive retroperitoneal nodes and bulky upper abdominal disease has important therapeutic implications.