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Russell J Schilder,
William E Brady,
Heather A Lankes,
James V Fiorica, Mark S Shahin,
Xun C Zhou,
Robert S Mannel,
Harsh B Pathak,
Wei Hu,
R Katherine Alpaugh,
Anil K Sood,
Andrew K Godwin
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ABSTRACT: Preclinical data suggest an important role for the sarcoma proto-oncogene tyrosine kinase (SRC) in the oncogenesis of epithelial ovarian cancer (EOC) or primary peritoneal carcinoma (PPC). The Gynecologic Oncology Group (GOG) conducted a Phase II trial to evaluate the efficacy and safety of dasatinib, an oral SRC-family inhibitor in EOC/PPC, and explored biomarkers for possible association with clinical outcome.
Eligible women had measurable, recurrent or persistent EOC/PPC and had received one or two prior regimens which must have contained a platinum and a taxane. Patients were treated with 100mg orally daily of dasatinib continuously until progression of disease or adverse effects prevented further treatment. Primary endpoints were progression-free survival (PFS)≥6months and response rate. Serial plasma samples were assayed for multiple biomarkers. Circulating free DNA was quantified as were circulating tumor and endothelial cells.
Thirty-five (35) patients were enrolled in a two-stage sequential design. Of the 34 eligible and evaluable patients, 20.6% (90% confidence interval: 10.1%, 35.2%) had a PFS≥6months; there were no objective responses. Grade 3-4 toxicities were gastrointestinal (mostly nausea and emesis; n=4), pulmonary (dyspnea and/or pleural effusion; n=4) and pain (n=5), and infrequent instances of anemia, malaise, insomnia, rash, and central nervous system hemorrhage. Lack of clinical activity limited any correlation of biomarkers with outcome.
Dasatinib has minimal activity as a single-agent in patients with recurrent EOC/PPC.
Gynecologic Oncology 06/2012; 127(1):70-4. · 3.89 Impact Factor
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ABSTRACT: Nab-paclitaxel is a novel Cremophor®-free nanoparticle of albumin-stabilized paclitaxel, which has favorable efficacy and toxicity characteristics relative to other solvent-based taxanes, such as paclitaxel and docetaxel.
Eligible patients had platinum- and taxane-resistant ovarian cancer, defined by persistent or progressive disease following primary chemotherapy (n = 5) or recurrence within 6 months of treatment completion (n = 42). All patients had measurable disease, no prior therapy for recurrent disease and Gynecologic Oncology Group performance status of ≤ 2. Treatment was nab-paclitaxel, 100 mg/m² days 1, 8, and 15 on a 28-day schedule. The primary endpoint was Response Evaluation Criteria in Solid Tumors v1.0 response rate, evaluated in a 2-stage design (with power of 0.90 for a RR of 25% and with alpha of 0.05 for RR of 10%).
Fifty-one patients were enrolled of which 47 were evaluable; median time from frontline therapy completion to registration was 21 days. Patient demographics include median age: 59 (34-78) years, serous histology: 72%, and high-grade: 81%. Efficacy: one complete and 10 partial responses were confirmed (23%); 17 patients (36%) had stable disease. The median progression-free survival was 4.5 months (95% CI: 2.2-6.7); overall survival was 17.4 months (95% CI: 13.2-20.8). Seventeen patients (36%) had PFS > 6 months. Toxicity: there were no grade 4 events; grade 3 events were neutropenia (6), anemia (3), GI (2), metabolic (2), pain (2), and leukopenia (1); neurosensory toxicity was observed as grade 2:5, grade 3:1.
Nab-paclitaxel has noteworthy single-agent activity and is tolerable in this cohort of refractory ovarian cancer patients previously treated with paclitaxel.
Gynecologic Oncology 07/2011; 122(1):111-5. · 3.89 Impact Factor
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ABSTRACT: This multicenter phase 2 trial was conducted by the Gynecologic Oncology Group to evaluate the activity and the safety of irofulven in patients with recurrent epithelial ovarian cancer. Eligible patients had documented recurrent ovarian cancer 6 to 12 months after receiving a front-line platinum-based regimen and no other chemotherapy. Patients were required to have measurable disease, performance status of 0 to 2, and adequate bone marrow, hepatic, and renal functions before study entry. The dose of irofulven was 0.45 mg/kg intravenously on days 1 and 8 every 21 days. Responses were defined by Response Evaluation Criteria in Solid Tumors. Fifty-five of 61 enrolled patients were evaluable for response and toxicity. There were 7 partial responses (12.7%), and 30 patients (54.6%) had stable disease. Median progression-free and overall survival were 6.4 months (1.3-37.5 months) and 22.1 months or more (2.8-57.8+ months), respectively. Patients received a median of 3 cycles (range, 1-21) of protocol therapy. Grade 4 hematologic toxicity was limited to reversible neutropenia and thrombocytopenia. Grade 4 nonhematologic toxicity was limited to one patient with anorexia and another with hypomagnesemia. Irofulven administered at this dose and schedule was well tolerated but had modest activity as a single agent.
International Journal of Gynecological Cancer 10/2010; 20(7):1137-41. · 1.65 Impact Factor
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ABSTRACT: The objective of this study was to estimate antitumor activity and toxicity of weekly docetaxel and gemcitabine as second-line chemotherapy for patients with recurrent uterine carcinosarcoma.
Patients with recurrent carcinosarcoma of the uterus who had failed one regimen of chemotherapy, had a Gynecologic Oncology Group (GOG) performance status of 0-2 and had measurable disease were included. Treatment consisted of gemcitabine 600 mg/m(2) and docetaxel 35 mg/m(2) intravenously on days 1, 8 and 15 of a 28-day cycle until disease progression or intolerable adverse effects. This study employed an optimal but flexible two-stage design with an early stopping rule. If more than 3 out of 22-24 or more than 4 out of 25-29 patients responded, accrual to the second stage was to be initiated.
Twenty-eight patients were enlisted. Three patients were not eligible after pathology review. One patient was never treated. Twenty-four patients were evaluable. Nine patients had previous radiation therapy. There were no complete responses. Partial responses were seen in two patients (8.3%), stable disease in eight (33.3%) and progressive disease in 12 patients (50%). Two patients were not evaluable (8.3%). The median progression-free survival was 1.8 months. The median survival was 4.9 months. The treatment caused myelosuppression, mainly neutropenia, but also thrombocytopenia and anemia. Dose modifications became necessary in the majority of patients. In five patients, treatment was discontinued due to toxicity.
This regimen of docetaxel and gemcitabine is not active in patients with recurrent carcinosarcoma of the uterus as second-line chemotherapy.
Gynecologic Oncology 05/2010; 118(2):139-44. · 3.89 Impact Factor
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ABSTRACT: To evaluate the effectiveness and toxicity of mifepristone in patients with ovarian, peritoneal and fallopian tube cancers.
Patients with confirmed epithelial ovarian, peritoneal and fallopian tube cancers which were persistent or recurred in less then 1 year after primary chemotherapy were entered into this study. Patients were given mifepristone 200 mg by mouth daily for a 28 day cycle. The medication was stopped for unacceptable toxicity or tumor progression.
Twenty-four patients were entered into the study. Twenty-two patients were evaluable for response. Only one patient had a partial response for a response rate of only 4.5% (90% confidence interval: 0.2%, 19.8%).
Mifepristone has not proven to be an effective agent in the treatment of patients with recurrent or persistent ovarian, peritoneal and fallopian tube cancers.
Gynecologic Oncology 11/2009; 116(3):332-4. · 3.89 Impact Factor
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ABSTRACT: The purpose is to investigate the safety and efficacy of i.p. topotecan and oral etoposide as salvage treatment for patients with platinum-resistant ovarian or primary peritoneal cancer.
Patients were treated with i.p. topotecan initial dose, 1 mg/m2 on days 1 to 5, followed by oral etoposide 100 mg on days 6 to 9 of a 28-day cycle for six cycles. Dose reduction of topotecan was used for severe bone marrow suppression. Peritoneal (topotecan) and plasma (topotecan and etoposide) levels were assessed at multiple time points using high-pressure liquid chromatography.
Twenty-two patients (mean age, 61 years) with a median of 1.5 prior treatments were enrolled. Etoposide peak plasma concentrations ranged from 1.9 to 6.9 microg/mL (mean, 3.6 microg/mL). Topotecan plasma levels rose with increasing peritoneal concentration and were detectable within 1 hour but tended to decrease rapidly to below detectable levels within 24 hours. The peak plasma concentration of topotecan was 12.82 +/- 8.55 microg/mL with a plasma half-life of 6.17 +/- 2.75 hours. A total of 104 cycles was administered; 14 patients (64%) completed all six planned cycles. All patients were evaluable for toxicity, and 21 patients were evaluable for response. The most common grade 4 toxicities were neutropenia and thrombocytopenia in eight and four patients (36 and 18%), respectively. There were no treatment-related deaths. The overall response rate was 38% [complete response, three (14%); partial response, five (24%)]. Seven patients had stable disease and six progressed while on treatment.
The combination of i.p. topotecan and oral etoposide is an active and well-tolerated regimen in platinum-resistant ovarian carcinoma. Additional studies investigating topotecan in combination with etoposide are warranted.
Clinical Cancer Research 10/2004; 10(18 Pt 1):6080-5. · 7.74 Impact Factor
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ABSTRACT: Although bowel symptoms and complaints are common after radical hysterectomy, the effects of operation on anorectal function are incompletely understood. In this prospective pilot study we evaluated the incidence of bowel symptoms, changes in anorectal physiology, and quality of life after radical hysterectomy.
Eleven women undergoing radical hysterectomy for early-stage cervical cancer completed bowel function symptom surveys and cancer-specific quality-of-life scales before operation and at 6 weeks and 6 months after operation. The bowel function symptom survey was also repeated at 18 months postoperation. Anorectal manometry, balloon defecation, and pudendal nerve latency tests were performed before the operation and 6 months postoperatively.
The mean age was 45.3 years (range 34 to 56 years), and four of the patients were postmenopausal. Resting and squeeze sphincter pressures, volume of saline infused at first leak, total volume retained, and threshold volume for maximum tolerable volume were all decreased significantly (p < 0.05) after operation. Pudendal nerve terminal motor latency increased (p < 0.05) bilaterally. There were no significant differences in sensory thresholds. At 18 months, two women reported constipation, six reported flatus incontinence, and two reported fecal incontinence. The total quality-of-life score declined at 6 weeks but then improved significantly by 6 months (p = 0.02).
Bowel dysfunction is common after radical hysterectomy. Many women exhibit manometric and subjective changes compatible with fecal incontinence.
Journal of the American College of Surgeons 10/2002; 195(4):513-9. · 4.55 Impact Factor
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ABSTRACT: We have previously reported the safety, efficient gene transfer, and favorable CA125 responses of individuals with recurrent ovarian cancer treated by p53 gene replacement with the adenoviral vector SCH 58500. The purpose of the present investigation was to evaluate the long-term follow-up of these heavily pretreated patients subsequent to SCH 58500 dosing.
Patients (n=36) were treated with either single-dose SCH 58500 in the phase I study or with multiple doses (MD) of SCH 58500 over multiple cycles in combination of platinum-based chemotherapy in the phase I/II portion of the study. Five patients were initially treated in the single-dose group and re-enrolled in the MD group. The MD group was evaluated both without the re-enrolled patients as MD1 (n=19), and as MD2 (n=24), which included them. Patients who were only treated on the single-dose arm were designated as SD (n=12). Most patients received additional chemotherapy at the discretion of their physicians on completion of the trial. The current analysis is a retrospective sequential cohort survival analysis.
The first patient was treated in March 1997 and the last patient completed SCH 58500 in September 1998. There was no difference in age at diagnosis, Karnofsky performance status, interval between diagnosis to SCH 58500, prior cycles or regimen of chemotherapy, platinum-free interval, percent platinum refractory patients, pretreatment CA125, or largest tumor volume between groups. Both MD groups had a slightly longer chemotherapy-free interval before SCH 58500 than the SD group. Median survival of individuals who received MD SCH 58500 with chemotherapy was 12-13.0 months, compared to only 5 months for those treated with SD SCH 58500. There are 10 long-term survivors more than 20 months after MD treatment for recurrent disease compared to only 2 long-term survivors after SD SCH 58500.
The 12- to 13.0-month median survival in a heavily pretreated population with recurrent ovarian cancer compares favorably to the 16-month median survival for individuals treated with paclitaxel at the time of initial recurrence of this disease and is more than double the 5-month survival seen with palliative radiotherapy or paclitaxel failure. These data suggest that further study of SCH58500 is clearly indicated.
Cancer Gene Therapy 08/2002; 9(7):567-72. · 2.80 Impact Factor
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ABSTRACT: Many factors modify ovarian cancer survival. There are conflicting reports regarding survival of individuals with hereditary BRCA1-related ovarian cancer. None have controlled for other mechanisms of BRCA1 silencing in the control cohort.
Fifty-nine cancers with presumed BRCA1 dysfunction because of mutation (24 germ-line and 16 somatic) or absent BRCA1 mRNA because of promoter hypermethylation (n = 19) were identified among 250 consecutively screened ovarian cancers. Controls were matched from the same population based on p53 mutation type, age at diagnosis, Fédération Internationale des Gynaecologistes et Obstetristes surgical stage and histological grade, residual disease, preoperative CA125, disease site, and the presence of BRCA1 mRNA translatable in an in vitro protein expression assay. BRCA1 promoter hypermethylation was determined by the methylation-specific PCR technique. The significance of promoter hypermethylation was confirmed by the absence of detectable BRCA1 mRNA.
The median survival for individuals with ovarian cancer BRCA1 dysfunction was 4.1 years versus 3.5 years in the case matched controls (P = 0.98). Grouped on the basis of the mechanism of BRCA1 dysfunction, median survival was 4.5, 2.8, and 2.3 years for germ-line, somatic, and BRCA1 promoter-silenced ovarian cancers. However, for the corresponding matched controls with wild-type BRCA1 sequence, the median survival was virtually identical: 4.6, 2.8, and 3.3 years, respectively. In a Cox proportional hazards analysis, only residual disease (P = 0.0001), age (P = 0.01), and Fédération Internationale des Gynaecologistes et Obstetristes stage (P = 0.011) entered the survival model.
In contrast with other published reports, we are unable to detect large survival differences between matched case-control cohorts of ovarian cancers with BRCA1 inactivation by any of three independent mechanisms.
Clinical Cancer Research 06/2002; 8(5):1196-202. · 7.74 Impact Factor
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ABSTRACT: The aim of this trial was to investigate the toxicity and efficacy of a 3-day topotecan administration schedule in combination with cyclophosphamide in the management of recurrent ovarian cancer.
Patients with recurrent measurable ovarian cancer who had up to two prior chemotherapy regimens for the management of their disease participating in this phase II trial were to receive topotecan at a dose of 1.25 mg/m(2)/day x 3 days in combination with cyclophosphamide at 600 mg/m(2) on Day 1 every 21 days. Dose escalation and reductions were permitted.
A total of 36 patients (median age = 65; range 37-84) were treated with this combination regimen. Seventeen were platinum-sensitive and 19 were platinum-resistant. A total of 169 cycles of chemotherapy was administered (median = 4; range 1-10). Major toxicity included grade 4 neutropenia (68.6%), neutropenic fever (7.1%), grade 3 thrombocytopenia (18.3%), and requirement for blood transfusion (19.5%). Dose escalation was possible in 3 (8.3%), and dose reduction was required in 14 (38.9%) patients. Overall response rate was 25 and 44.5% stable disease. Median progression-free interval and overall survival was 5.4 and 23.5 months, respectively, independent of platinum sensitivity.
The 3-day topotecan schedule in combination with cyclophosphamide appears to have good activity in recurrent ovarian cancer regardless of platinum sensitivity. Neutropenia was the only severe toxicity and was less prevalent than other reported trials of topotecan. This tolerable regimen offers patients more convenience and appears to have moderate activity.
Gynecologic Oncology 06/2002; 85(2):278-84. · 3.89 Impact Factor
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ABSTRACT: An ovarian mixed germ cell tumor in a 34-year-old woman contained a predominant component of polyembryoma as well as foci of choriocarcinoma, yolk sac tumor, and immature teratoma. No previous cases of identical composition have been found in the literature.
International Journal of Gynecological Pathology 02/2002; 21(1):78-81. · 1.45 Impact Factor
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ABSTRACT: Background. Ovarian cancer diagnosed during pregnancy is uncommon. Paclitaxel-based chemotherapy during pregnancy has not been reported previously.Case. A woman with ascites and an adnexal mass diagnosed during pregnancy at 27 weeks gestational age underwent a laparotomy with cytoreductive surgery and was diagnosed with stage IIIC papillary serous ovarian adenocarcinoma. She was treated with three cycles of paclitaxel and cisplatin during pregnancy. At 37 weeks, she underwent a cesarean section, abdominal hysterectomy, and cytoreduction. Three additional cycles of chemotherapy were given. She developed a recurrence within 6 weeks of completing chemotherapy. She received several cycles of chemotherapy, but died of recurrent cancer 29 months after diagnosis. The infant has normal growth and development at 30 months of age.Conclusion. This is the first reported case of paclitaxel use during pregnancy.
Gynecologic Oncology.
