Margaret Davy

Randomized, Double-Blind, Placebo-Controlled Phase II Study of AMG 386 Combined With Weekly Paclitaxel in Patients With Recurrent Ovarian Cancer

PURPOSE To estimate the efficacy and toxicity of AMG 386, an investigational peptide-Fc fusion protein that neutralizes the interaction between the Tie2 receptor and angiopoietin-1/2, plus weekly paclitaxel in patients with recurrent ovarian cancer. PATIENTS AND METHODS Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned 1:1:1 to receive paclitaxel (80 mg/m(2) once weekly [QW], 3 weeks on/1 week off) plus intravenous AMG 386 10 mg/kg QW (arm A), AMG 386 3 mg/kg QW (arm B), or placebo QW (arm C). The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response, CA-125 response, safety, and pharmacokinetics. RESULTS One hundred sixty-one patients were randomly assigned. Median PFS was 7.2 months (95% CI, 5.3 to 8.1 months) in arm A, 5.7 months (95% CI, 4.6 to 8.0 months) in arm B, and 4.6 months (95% CI, 1.9 to 6.7 months) in arm C. The hazard ratio for arms A and B combined versus arm C was 0.76 (95% CI, 0.52 to 1.12; P = .165). Further analyses suggested an exploratory dose-response effect for PFS across arms (Tarones test, P = .037). Objective response rates for arms A, B, and C were 37%, 19%, and 27%, respectively. The incidence of grade ≥ 3 adverse events (AEs) in arms A, B, and C was 65%, 55%, and 64%, respectively. Frequent AEs included hypertension (8%, 6%, and 5% in arms A, B, and C, respectively), peripheral edema (71%, 51%, and 22% in arms A, B, and C, respectively), and hypokalemia (21%, 15%, and 5% in arms A, B, and C, respectively). AMG 386 exhibited linear pharmacokinetic properties at the tested doses. CONCLUSION AMG 386 combined with weekly paclitaxel was tolerable, with a manageable and distinct toxicity profile. The data suggest evidence of antitumor activity and a dose-response effect, warranting further studies in ovarian cancer.

Increased age and mortality associated with cervical carcinomas negative for human papillomavirus RNA

Attempts to relate presence and type of human papillomavirus in cervical carcinoma with prognosis have yielded conflicting results. To further investigate this relation, the association between survival of cervical cancer patients after diagnosis and the presence of human papillomavirus (HPV) RNA within the tumour was assessed retrospectively. Formalin-fixed biopsy specimens from 212 patients with cervical carcinoma who had been followed for up to 6 years were tested by in-situ hybridisation with 125I-labelled riboprobes. HPV-RNA-positive women were 11.9 years younger than HPV-negative women at diagnosis (p less than 0.001). Case-fatality rates from cervical cancer rose with absence of HPV RNA, age at diagnosis, or FIGO stage. Multivariate analysis confirmed that absence of detectable HPV RNA and advanced FIGO stage were independent risk factors. No differences in survival between HPV types 16, 18, 31, or 33 were seen. These observations suggest that cervical carcinoma patients fall into two groups--a younger, HPV-RNA-positive group, with a better prognosis, and an older, HPV-RNA-negative group with poorer prognosis. Treatment regimens for the two groups may need to differ.

Prognostic Importance of Preoperative CA-125 in International Federation of Gynecology and Obstetrics Stage I Epithelial Ovarian Cancer: An Australian Multicenter Study

PURPOSE To evaluate the prognostic significance of preoperative CA-125 levels on overall survival of patients with International Federation of Gynecology and Obstetrics (FIGO) stage I epithelial ovarian cancer (EOC). PATIENTS AND METHODS Data from 518 patients with FIGO stage I EOC treated in seven gynecologic oncology centers throughout Australia between 1990 and 2002 were analyzed. Patients with borderline tumors and nonepithelial ovarian carcinomas were excluded, as were women in whom CA-125 had not been determined preoperatively. Preoperative CA-125 levels were studied in surgically staged and incompletely staged patients and compared with prognostic factors, such as substage, grade, and histologic type. Multivariate Cox models were calculated. RESULTS CA-125 levels more than 30 U/mL were associated with higher grade, substage 1B and 1C, nonmucinous histologic type, and older age. In univariate analysis, higher histologic grade, the absence of surgical staging, and preoperative CA-125 levels more than 30 U/mL were associated with impaired survival. Multivariate analysis identified histologic grade, preoperative CA-125, and surgical staging as independent predictors for survival. In the subgroup of completely surgically staged patients, the 5-year overall survival rate was 82% (95% CI, 76% to 88%) for patients with CA-125 levels more than 30 U/mL and 95% (95% CI, 90% to 99%) for patients with CA-125 levels of 30 U/mL or less (P = .028). In the group of incompletely staged patients, the 5-year survival rates were similar for patients with elevated and normal serum CA-125 levels. CONCLUSION Complete surgical staging, histologic grade, and preoperative serum CA-125 levels are independent prognostic factors and should be included in the decision making for chemotherapy.

Cervical cancer: effect of glandular cell type on prognosis, treatment, and survival.

OBJECTIVE: To investigate survivals from cervical cancer, with special reference to effects of glandular histology and its influence on prognostic characteristics and management decisions. METHODS: Data on cervical cancers, diagnosed in 1984‐2000, were obtained from the gynecologic oncology registry of hospitals of the University of Adelaide. Comparisons were made of disease‐specific survival, age at diagnosis, diagnostic period, stage, grade, and primary course of treatment. RESULTS: The study included 544 squamous cell carcinomas, 43 adenosquamous carcinomas, five clear cell cancers, 136 other adenocarcinomas, and 19 cancers of “other” histological type. Overall survival was 72.2% at 5 years from diagnosis, decreasing to 67.5% at 15 years. Survival was lower for older ages, higher grades, and higher International Federation of Gynecology and Obstetrics stages, although equivalent for stages IIA and IIB. Unadjusted survivals varied by histological type (P = .001), with lower survivals suggested for adenosquamous and clear cell lesions and “other” histological types than for squamous cell carcinomas and other adenocarcinomas. After adjusting for age, stage, grade, and diagnostic period, adenocarcinomas had a higher case fatality than squamous cell lesions (relative risk 2.08,95% confidence limit 1.35, 3.21), whereas the elevation in relative risk was lower and not statistically significant for a combined adenosquamous and clear cell category at 1.25 (0.69, 2.24). For stage II, both adenocarcinomas and the adenosquamous and clear cell group had lower survivals than squamous cell cancers. CONCLUSION: Relative to squamous cell carcinomas, adenocarcinomas and potentially adenosquamous cancers are becoming more common. This has implications for screening, treatment, and prognosis. (Obstet Gynecol 2003; 101: 38‐45.

Influence of infusion time on unchanged cisplatin disposition in patients with ovarian cancer

SummaryThe disposition of unchanged cisplatin in ten patients with ovarian cancer receiving 2-h infusions of 100 mg/m2 was compared with that of ten patients receiving 6-h infusions. A high-performance liquid chromatographic assay specific for the unchanged drug was used and all collected samples were rapidly processed. Patients were catheterized for urine collections. Cisplatin renal clearance was significantly lower after 6-hour infusions (52.8±16.2 ml/min per m2) than after 2-h infusions (87.1±38.2 ml/min per m2) (P=0.026). Total clearance was also lower and less variable, although not significantly, in patients receiving the longer infusion. No differences in nonrenal clearance, volume of distribution, or half-life were observed between the two groups. There was only a poor relationship between cisplatin renal clearance and creatinine clearance after 2-h (r2=0.02; P=0.66) and 6-h infusions (r2=0.18; P=0.23). A single cisplatin plasma level obtained at the end of the infusion proved to be a good predictor of total cisplatin clearance after both 2-h (r2-0.70; P=0.0096) and 6-h infusions (r2=0.97; P=0.0001). This level was not significantly related to the relatively small changes in creatinine clearance that occurred after three courses of treatment.

Phenotypes of the ovarian follicular basal lamina predict developmental competence of oocytes

BACKGROUND The ovarian follicular basal lamina underlies the epithelial membrana granulosa and maintains the avascular intra-follicular compartment. Additional layers of basal lamina occur in a number of pathologies, including pili annulati and diabetes. We previously found additional layers of follicular basal lamina in a significant percentage of healthy bovine follicles. We wished to determine if this phenomenon existed in humans, and if it was related to oocyte function in the bovine. METHODS AND RESULTS We examined follicles from human ovaries (n = 18) by electron microscopy and found that many follicles had additional layers of basal lamina. Oocytes (n = 222) from bovine follicles with normal or unusual basal laminas were isolated and their ability to undergo in vitro maturation, fertilization and culture to blastocyst was compared. Healthy bovine follicles with a single layer of basal lamina had oocytes with significantly (P < 0.01) greater developmental competence than healthy follicles with additional layers of follicular basal lamina (65% versus 28%). CONCLUSIONS These findings provide direct evidence that the phenotype of the follicular basal lamina is related to oocyte competence.

Bilateral Juvenile Granulosa Cell Tumours Associated with Skeletal Enchondromas

Summary: Asynchronous bilateral granulosa cell tumours of the ovary occurred in a patient with enchondromas. The first tumour, presenting at age 15, was misdiagnosed initially as an androblastoma. The second tumour presented 7 years and 3 pregnancies later. The possible therapeutic and pathogenetic implications of these observations are discussed.

Cervical Cancer in South Australia: Trends in Incidence, Mortality and Case Survival

Summary: Approximately 90% of cervical cancers are considered preventable through regular screening and the treatment of precursor lesions, but fewer than 20% of South Australian women were found to have been screened in 1984.

Germ Cell Tumours in Younger Patients

Tumours of germ cell origin have an importance out of all proportion to their incidence. Although many are highly malignant some have proved remarkably susceptible to modern therapy. However, some of the principles which are widely recognized as applying to common epithelial ovarian malignancy cannot be transposed to tumours of germ cell origin. The use of tumour markers, notably chorionic gonadotrophin and alpha fetoprotein, has added great precision t o diagnosis and therapy. The age (figure 1) distribution differs from the common epithelial malignancy and the germ cell tumours are found in a significantly larger segment of the population of patients with ovarian malignancy under 40 years of age. The classification of germ cell tumours is difficult and has been bedevilled by changes in nomenclature. Extra gonadal tumours of germ cell origin are even more rare than those arising in the gonads and not always recognized as such(1). An understanding of the embryology of germ cells and their migration is helpful as extra gonadal turnours are found in ‘midline’ organs. Sometimes the primary cannot ever be detected (the atypical teratoma syndrome)(2). Extragonadal yolk sac tumours may arise at other sites in the female genital tract, and then in quite a different age group to similar tumours of the ovary and other types of ‘clear cell’ adenocarcinoma of the Mullerian tract (figure 2) .

A tale of two cancers : Collision presentation of ovarian carcinoma and lymphoma

Synchronous malignancies are rare diagnostic and treatment challenges. Here we present three cases of synchronous ovarian cancer and lymphoma. Both malignancies were recognised in the same histopathology sections. This report discusses diagnosis and management dilemmas with a brief literature review. The simultaneous presentation of ovarian cancer and lymphoma has not previously been reported.