Faculty Bibliography

BACKGROUND:: The objective of the current study was to determine the prognostic significance of a pretreatment serum CA 125 level in patients with advanced epithelial ovarian carcinoma (EOC) who received treatment with a standard chemotherapy regimen. METHODS:: Patients with International Federation of Gynecology and Obstetrics stage III/IV ovarian carcinoma who were on 1 of 7 Gynecologic Oncology Group (GOG) phase 3 trials and received treatment with a standard regimen of intravenous cisplatin and paclitaxel were included. A Cox regression model was used to assess the impact of CA 125 levels drawn before the initiation of chemotherapy on progression-free survival (PFS) both overall and by subgroup, including surgical debulking status, disease stage, and histologic subtype. RESULTS:: In total, 1299 patients who were on the cisplatin/paclitaxel arms of the GOG trials were eligible. The median CA 125 level was 246 U/mL. Only 7.6% of patients had a normal CA 125 level (</=35 U/mL). The lowest median CA 125 level was observed in the group with mucinous tumors; however, 69% of women who had mucinous tumors had abnormal CA 125 levels. Shorter PFS was observed with increasing CA 125 and persisted in multivariate analysis. Overall and in the serous subgroup, a 1-fold increase in CA 125 level was associated with a 7% increase in the hazard of disease progression (P < .001). This association was even more pronounced in patients who had stage III disease that was debulked to microscopic disease (15%; P = .003) and in patients who had endometrioid tumors (17%; P = .001). CONCLUSIONS:: A normal CA 125 level in the setting of advanced EOC was rare even after surgical debulking. The pretreatment CA 125 level was an independent predictor of PFS in patients with advanced EOC who received a standard chemotherapy regimen, particularly in the setting of disease that was debulked to a microscopic residual and in the serous or endometrioid subtypes. Cancer 2009. (c) 2009 American Cancer Society

PURPOSE: Preclinical data suggested that bryostatin-1 (bryo) could potentiate the cytotoxicity of cisplatin when given prior to this drug. We designed a phase I study to achieve tolerable doses and schedules of bryo and cisplatin in combination and in this sequence. METHODS: Patients with non-hematologic malignancies received bryo followed by cisplatin in several schedules. Bryo was given as an 1 and a 24 h continuous infusion, while cisplatin was always given over 1 h at 50 and 75 mg/m(2); the combined regimen was repeated on an every 3-week and later on an every 2-week schedule. Bryo doses were escalated until recommended phase II doses were defined for each schedule. Patients were evaluated with computerized tomography every 2 cycles. RESULTS: Fifty-three patients were entered. In an every 2-week schedule, the 1-h infusion of bryo became limited by myalgia that was clearly cumulative. With cisplatin 50 mg/m(2) its recommended phase II dose was 30 mug/m(2). In the 3-week schedule, dose-limiting toxicities were mostly related to cisplatin effects while myalgias were tolerable. Pharmacokinetics unfortunately proved to be unreliable due to bryo's erratic extraction. Consistent inhibition of PKC isoform eta (eta) in peripheral blood mononuclear cells was observed following bryo. CONCLUSIONS: Bryo can be safely administered with cisplatin with minimal toxicity; however, only four patients achieved an objective response. Modulation of cisplatin cytotoxicity by bryo awaits further insight into the molecular pathways involved

BACKGROUND: We have previously established the recommended phase II dose (RPTD) of ixabepilone as 40 mg/m(2) administered over 1 h repeated every 3 weeks with neuropathy as a cumulative dose-limiting toxicity. We expanded the cohort at the RPTD to include detailed assessment of nerve damage in these patients. We report our findings on vibration perception threshold (VPT) and neuropathy. PATIENTS AND METHODS: Forty-four patients were treated with a median (range) of three (1-14) cycles of ixabepilone. The VPT (5-min duration) and nerve conduction test (NCT, 10-min duration) were carried out in the office, before ixabepilone dosing, and every two cycles thereafter. RESULTS: Neuropathy (grade 1 and grades 2-3) was observed in 17 (38.6%) and 11 (25%) patients, respectively. The mean increase in VPT as a function of grade 0-1 versus grades 2-3 neuropathy was 0.235 +/- 0.03 versus 0.869 +/- 0.09 (P = 0.049) vibration units. The F-wave frequency and distal motor latency, as assessed using the NCT, did not correlate with clinical neurotoxicity. CONCLUSION: The change in VPT is observed early and likely reflects early vibration perception change. Mean change in VPT correlates with the severity of clinical neuropathy. Whether VPT change predicts onset of severe neuropathy warrants prospective testing and validation.

BACKGROUND: Topotecan 14-day infusion combined with cisplatin was highly active in ovarian cancer, but too myelosuppressive. We therefore sought to evaluate the feasibility of substituting oxaliplatin for cisplatin to improve safety. METHODS: Ovarian and primary peritoneal cancer patients, pretreated with at least one prior platinum-containing regimen, performance status (PS) 0-1, without prior pelvic radiation were eligible. Topotecan was continuously infused days 1-15; oxaliplatin was given days 1 and 15; cycles were repeated every 28 days. Five dose levels were explored: topotecan (mg/m2/day)/oxaliplatin (mg/m2) doses: (1) 0.2/65; (2) 0.2/75; (3) 0.2/85; (4) 0.3/85; (5) 0.4/85. RESULTS: Twenty-three patients (20 ovarian, 1 tubal, and 2 peritoneal) were entered: median age 56 years (range, 37-77); PS: 0=12 and 1=11; histology: papillary serous 7, serous 4, adenocarcinoma 8, poorly differentiated 2. Median of 4 cycles were delivered. Grade 3 neutropenia occurred in 3 of 7 patients at level 5 (with fever at levels 4 and 5), without grade 4 neutropenia or thrombocytopenia. Other toxicities were mild and reversible (mainly gastrointestinal), except one grade 3 neuropathy and one oxaliplatin-related grade 3 hypersensitivity reaction. Six objective responses (five of them complete) were documented among 22 patients spanning several dose levels. CONCLUSION: Topotecan continuous infusion, combined with oxaliplatin, was associated with no grade 4 hematologic toxicity and evidence of activity. The recommended phase II dose is topotecan 0.4 mg/m2/day continuous infusion d1-15 with oxaliplatin 85 mg/m2 on days 1 and 15. A phase II evaluation as second-line treatment for both platinum-sensitive and -resistant ovarian cancer recurrences is ongoing

PURPOSE: To identify factors predictive of poor prognosis in a similarly treated population of women with stage IV epithelial ovarian cancer (EOC). PATIENTS AND METHODS: A retrospective review of 360 patients with International Federation of Gynecology and Obstetrics stage IV EOC who underwent primary surgery followed by six cycles of intravenous platinum/paclitaxel was performed. A proportional hazards model was used to assess the association of potential prognostic factors with progression-free survival (PFS) and overall survival (OS). RESULTS: The median PFS and OS for this group of stage IV ovarian cancer patients was 12 and 29 months, respectively. Multivariate regression analysis revealed that histology, malignant pleural effusion, intraparenchymal liver metastasis, and residual tumor size were significant prognostic variables. Whereas patients with microscopic residual disease had the best outcome, patients with 0.1 to 1.0 cm residual disease and patients with 1.1 to 5.0 cm residual disease had similar PFS and OS. Patients with a residual size more than 5 cm had a diminished PFS and OS when compared with all other groups. Median OS for microscopic, 0.1 to 5.0 cm, and more than 5.0 cm residual disease was 64, 30, and 19 months, respectively. CONCLUSION: Patients with more than 5 cm residual disease have the shortest PFS and OS, whereas patients with 0.1 to 1.0 and 1.1 to 5.0 cm have similar outcome. These findings suggest that ultraradical cytoreductive procedures might be targeted for selected patients in whom microscopic residual disease is achievable. Patients with less than 5.0 cm of disease initially and significant disease and/or comorbidities precluding microscopic cytoreduction may be considered for alternative therapeutic options other than primary cytoreduction

The co-existence of breast and ovarian cancers in the same individual should raise suspicion of a hereditary process. Patients with either BRCA1 or BRCA2 germ-line mutations have an average risk of 39% and 11% respectively of developing ovarian cancer by the age of 70; they have a risk of 35-85% of developing breast cancer in their lifetime. We report here unusual pathologic features in a BRCA2 germ-line mutation carrier recently diagnosed with synchronous breast and ovarian cancers, and summarize the findings in six other women who were diagnosed with ovarian cancer either simultaneously with the diagnosis of breast cancer or at varying times after the diagnosis. While in most instances this may be a coincidental occurrence in highly susceptible individuals, the patient we highlight raises the provocative hypothesis that at times breast cancer metastasizes to the ovaries of mutation carriers and stimulates the development of an ovarian cancer as well as other cancers. In addition, these ovarian cancers may have different mechanisms of metastases predisposing them to travel to unusual sites

Pegylated liposomal doxorubicin (PLD, Doxil, Caelyx) is widely used for the treatment of ovarian cancer. It is a stable formulation encapsulating doxorubicin in a 'Stealth' (i.e., pegylated) liposome with a half-life of about 72 hours. This drastically altered pharmacology confers on it a considerably lower risk of cardiotoxicity, no acute emesis, and near absence of alopecia or problems with extravasation necrosis. On the other hand, PLD's dose-limiting toxicity is cutaneous. Since the original phase I report, cutaneous toxicities reported with PLD fall into four common categories: the well known hand-foot syndrome (also called palmoplantar erythrodysesthesia, or PPE), a diffuse follicular rash, intertrigo-like eruption, and hyperpigmentation including melanotic macules