Benjamin E. Greer

Phase III Trial of Carboplatin and Paclitaxel Compared With Cisplatin and Paclitaxel in Patients With Optimally Resected Stage III Ovarian Cancer: A Gynecologic Oncology Group Study

PURPOSE In randomized trials the combination of cisplatin and paclitaxel was superior to cisplatin and cyclophosphamide in advanced-stage epithelial ovarian cancer. Although in nonrandomized trials, carboplatin and paclitaxel was a less toxic and highly active combination regimen, there remained concern regarding its efficacy in patients with small-volume, resected, stage III disease. Thus, we conducted a noninferiority trial of cisplatin and paclitaxel versus carboplatin and paclitaxel in this population. PATIENTS AND METHODS Patients with advanced ovarian cancer and no residual mass greater than 1.0 cm after surgery were randomly assigned to receive cisplatin 75 mg/m2 plus a 24-hour infusion of paclitaxel 135 mg/m2 (arm I), or carboplatin area under the curve 7.5 intravenously plus paclitaxel 175 mg/m2 over 3 hours (arm II). RESULTS Seven hundred ninety-two eligible patients were enrolled onto the study. Prognostic factors were similar in the two treatment groups. Gastrointestinal, renal, and metabolic toxicity, as well as grade 4 leukopenia, were significantly more frequent in arm I. Grade 2 or greater thrombocytopenia was more common in arm II. Neurologic toxicity was similar in both regimens. Median progression-free survival and overall survival were 19.4 and 48.7 months, respectively, for arm I compared with 20.7 and 57.4 months, respectively, for arm II. The relative risk (RR) of progression for the carboplatin plus paclitaxel group was 0.88 (95% confidence interval [CI], 0.75 to 1.03) and the RR of death was 0.84 (95% CI, 0.70 to 1.02). CONCLUSION In patients with advanced ovarian cancer, a chemotherapy regimen consisting of carboplatin plus paclitaxel results in less toxicity, is easier to administer, and is not inferior, when compared with cisplatin plus paclitaxel.

Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study.

PURPOSE Vascular endothelial growth factor (VEGF) seems to be a promoter of tumor progression for epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC). We conducted a phase II trial to assess the efficacy and tolerability of single-agent bevacizumab, an anti-VEGF monoclonal antibody. PATIENTS AND METHODS Eligible patients had persistent or recurrent EOC/PPC after one to two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group performance status of at least 2. Treatment consisted of bevacizumab 15 mg/kg intravenously every 21 days until disease progression or prohibitive toxicity. Primary end points were progression-free survival (PFS) at 6 months and clinical response. RESULTS The study consisted of 62 eligible and assessable patients, median age 57 years, 41 (66.1%) having received two prior regimens and 36 (58.1%) [CORRECTED] considered platinum resistant. Grade 3 adverse events at least possibly related to bevacizumab were hematologic (1), GI (3), hypertension (6), thromboembolism (1), allergy (2), hepatic (1), pain (3), coagulation (1), constitutional (1), and dyspnea (1). Grade 4 adverse events included pulmonary embolus (1), vomiting and constipation (1), and proteinuria (1). Thirteen patients (21.0%) experienced clinical responses (two complete, 11 partial; median response duration, 10 months), and 25 (40.3%) survived progression free for at least 6 months. Median PFS and overall survival were 4.7 and 17 months, respectively. There was no significant association of prior platinum sensitivity, age, number of prior chemotherapeutic regimens, or performance status with the hazard of progression or death. CONCLUSION Bevacizumab seems to be well tolerated and active in the second- and third-line treatment of patients with EOC/PPC and merits phase III investigation.

Acute nonlymphocytic leukemia after therapy with alkylating agents for ovarian cancer: a study of five randomized clinical trials.

We evaluated the occurrence of acute nonlymphocytic leukemia (ANL) among 1399 women with ovarian cancer who were treated in five randomized clinical trials. Of the 1399 women, 998 had been treated with alkylating agents, and among these, 12 cases of ANL were observed; the expected number was 0.11. Ten patients with ANL had received melphalan, and two chlorambucil. ANL was not observed in 401 women who had been treated with surgery or radiation or both, without alkylating agents. The excess risk of ANL that was associated with alkylating-agent therapy was 5.8 cases per 1000 women per year, and the cumulative seven-year risk of ANL among patients who were treated with chemotherapy alone was indistinguishable from that observed in patients receiving both radiation and chemotherapy. A positive correlation between initial drug dose and the risk of ANL was suggested. These data underscore the need to assess other cytotoxic agents and regimens of drug administration to identify those that do not have harmful late effects.

The effect of body mass index on clinical/pathologic features, surgical morbidity, and outcome in patients with endometrial cancer.

OBJECTIVE To evaluate the effect of body mass index (BMI) on clinical/pathologic features, surgical morbidity, and outcome in patients with endometrial cancer. METHODS All women with surgically treated endometrial cancer at the University of Washington in Seattle, Washington, between 1 January 1990 and 1 January 2000 were eligible; 439 patients were identified and 43 were excluded due to incomplete medical records; 396 patients underwent retrospective chart review. Statistical analysis was performed by SPSS. Median follow-up time was 27 months (range, 1 to 120 mo). RESULTS Mean BMI was 34 (range, 15 to 69). BMI was <30 in 40.7% of patients, 30 to 40 in 32.3%, and >40 in 27.0%. Clinically, patients with a BMI of >40 were more likely to have hypertension, diabetes, and pulmonary disease. Those patients with a BMI of >40 had statistically longer operating times (209 vs. 159 min) and more blood loss (604 vs. 324 ml) than patients with a BMI of <30. However, there was no difference between the three groups in number of lymph nodes removed, units of blood transfused, length of hospital stay, number of intensive care unit (ICU) days, or intraoperative complications. Postoperatively, patients with a BMI of >40 were more likely to have a wound separation than thinner patients. Pathologically, patients with a BMI of >40 were more likely to have endometrioid histology, lower stage disease, and lower grade tumors than women with a BMI of <30. However, 11.3% of patients with lymph node sampling and a BMI of >40 had positive lymph nodes and 23% were stage II or higher. Forty-two patients (10.6%) recurred. There were no postoperative deaths, and there was no difference in survival between the three groups. CONCLUSIONS Patients with a BMI of >40 frequently have favorable stage I endometrial cancers. However, approximately a quarter of these patients have evidence of cervical or extrauterine disease. This study confirms that surgical staging can be performed adequately and safely in morbidly obese patients with no difference in length of hospital stay, number of ICU days, intraoperative or postoperative complications.

GYNECOLOGIC MALIGNANCIES IN IMMUNOSUPPRESSED ORGAN HOMO-GRAFT RECIPIENTS

Immunosuppressed organ homograft recipients have a 5 to 69% incidence of de novo malignancies at some time after transplantation. Gynecologic cancers were encountered in 21 of 224 patients (9%) with these tumors. The predominant lesion was carcinoma of the cervix (18 cases), of which 16 were intraepithelial and 2 were invasive. Gynecologic malignancies have also been encountered in non-transplant patients who were treated with immunosuppressive agents or cancer chemotherapy. All such individuals require gynecologic examination before commencement of treatment and at regular intervals thereafter so that malignancies may be diagnosed at an early stage and treated effectively. Most neoplasms respond well to conventional cancer therapy, but high-grade malignancies may necessitate reduction or cessation of immunosuppressive therapy as well.

Advanced stage mucinous adenocarcinoma of the ovary is both rare and highly lethal: a Gynecologic Oncology Group study.

Primary mucinous adenocarcinomas of the ovary are uncommon, and their biological behavior is uncertain. Retrospective studies have suggested that many mucinous carcinomas initially diagnosed as primary to the ovary have in fact metastasized from another site. A prospective randomized trial provided an opportunity to estimate the frequency of mucinous tumors, diagnostic reproducibility, and clinical outcomes.

Fetal and maternal considerations in the management of stage I-B cervical cancer during pregnancy.

Abstract The timing of treatment for stage I-B cervical carcinoma diagnosed during pregnancy is complicated by conflicting concerns for fetal survival and control of malignancy. There were 11 pregnant women with stage I-B cervical carcinoma diagnosed prior to fetal viability since 1969. Six patients were managed with termination of pregnancy and radical hysterectomy with pelvic lymphadenectomy. In 5 patients, treatment was delayed for 6 to 17 weeks and then delivery was accomplished by cesarean section followed directly by radical hysterectomy and pelvic lymphadenectomy. Two of the infants experienced complicated neonatal courses and would have benefited from additional delay. Benefits that could be achieved by delaying delivery for the fetus were calculated from a review of 600 inborn infants without congenital anomalies admitted to the neonatal intensive care (NICU) during 1984 and 1985. Neonatal mortality decreased from 32.8% at 26–27 weeks to 2.7% at 34–35 weeks gestation. Similar improvements in neonatal morbidity were demonstrated. Although adverse maternal outcomes were not associated with delay, an evaluation of risk cannot be derived from this series. Significant fetal benefit can accrue from relatively short delays in planned delivery dates. When stage I-B cervical carcinoma is diagnosed during pregnancy and when fetal survival is desired, delivery should be delayed to achieve fetal maturity, rather than only potential viability.

Combined Weekly Topotecan and Biweekly Bevacizumab in Women With Platinum- Resistant Ovarian, Peritoneal, or Fallopian Tube Cancer

A phase 2 trial was conducted to determine the toxicity and efficacy of combined weekly topotecan and biweekly bevacizumab in patients with primary or secondary platinum‐resistant ovarian, peritoneal, or fallopian tube cancer (OC).

PREDICTIVE AND PROGNOSTIC ANGIOGENIC MARKERS IN A GYNECOLOGIC ONCOLOGY GROUP PHASE II TRIAL OF BEVACIZUMAB IN RECURRENT AND PERSISTENT OVARIAN OR PERITONEAL CANCER

OBJECTIVE Potential predictive/prognostic angiogenic markers were prospectively examined in a phase II trial of bevacizumab in epithelial ovarian cancer (EOC)/primary peritoneal cancer (PPC). METHODS Recurrent/persistent EOC/PPC patients were treated with bevacizumab (15 mg/kg IV q21days) until disease progression. Validated-immunohistochemistry (IHC) assays were performed on pre-cycle 1/4 tumor biopsies for CD31-microvessel density (MVD), VEGF-histoscore (HS), p53-HS, and TSP1 image analysis score (IA). Pre-cycle 1/4 serum and plasma VEGF were quantified using a validated-ELISA. RESULTS CD31-MVD and serum VEGF, evaluated pre-cycle 1 in 41/61 and 51/61 eligible patients, respectively, did not appear to be correlated. High CD31-MVD, categorized at the median, appeared to be associated with tumor response, a 13-month shorter median survival, and an increased risk of death (unadjusted hazard ratio [HR] = 2.2, 95% confidence interval [CI] = 1.067-4.467). In addition, each standard deviation (SD) increase in CD31-MVD appeared to be associated with worse survival in unadjusted and adjusted analyses. IHC and plasma biomarkers did not change with bevacizumab treatment except for serum VEGF, which appeared to decrease during bevacizumab treatment. This decrease was not associated with response. High pre-cycle 1 serum VEGF, categorized at the median, was associated with 22-month shorter median survival and an increased risk of death (unadjusted HR = 2.7, 95% CI = 1.369-5.191). Categorized p53 appeared to be associated with unadjusted survival and each SD increase in TSP1-IA appeared to be associated with a decreased risk of progression in unadjusted and adjusted analyses. CONCLUSIONS Despite the limitations in sample size and exploratory nature of the study, angiogenic markers in tumor and serum may provide prognostic value in recurrent/persistent EOC/PPC, and are being prospectively evaluated in the GOG phase III trial of carboplatin, paclitaxel and bevacizumab/placebo in previously untreated EOC/PPC.

Cryocoagulation of the endometrium at the uterine cornua

A cryoprobe that will produce coagulation necrosis and subsequent scar formation of the cornual areas of the uterus has been tested. A discussion is made of the developmental program, including the design of the instrument, efficacy and safety testing in baboons, and preliminary investigations of the safety of this procedure in man.