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ABSTRACT: 2-Methoxyestradiol (Panzem, 2ME2) is an endogenous metabolite of estradiol that destabilizes microtubules and exerts anti-angiogenic properties. This study was conducted to determine the activity and safety of 2ME2 administered as a NanoCrystal dispersion (NCD) formulation in patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC).
Eligible patients had relapsed, platinum-resistant or refractory EOC with measurable or detectable disease. There was no limit on the number of prior treatment regimens. 2ME2 NCD 1000 mg orally four times daily (q.i.d.) was administered continuously during 4 week cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints were assessment of toxicity, rate of clinical benefit defined as the number of patients experiencing an objective response, a CA125 response or stable disease (SD) >3 months, mean change in CA-125, progression-free survival (PFS), and pharmacokinetic analyses of 2ME2.
Eighteen patients were enrolled. Median age was 65.5 (range 40-73). Patients had received a median of five prior treatments. The most common adverse events were fatigue (78%), nausea (78%), diarrhea (39%), neuropathy (50%), edema (39%), and dyspnea (44%), the majority being grade 1-2. There were no objective responses, but seven patients had SD as best response. Of those, two patients had SD for greater than 12 months. The rate of clinical benefit was 31.3%. Fairly stable plasma levels of 2ME2 ranging within the predicted therapeutic window were observed.
The NCD formulation of 2ME2 is well tolerated in patients with heavily pretreated EOC. Few of these heavily pretreated patients had sustained stable disease.
Gynecologic Oncology 08/2009; 115(1):90-6. · 3.89 Impact Factor
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ABSTRACT: Many insects jump by storing and releasing energy in elastic structures within their bodies. This allows them to release large amounts of energy in a very short time to jump at very high speeds. The fastest of the insect jumpers, the froghopper, uses a catapult-like elastic mechanism to achieve their jumping prowess in which energy, generated by the slow contraction of muscles, is released suddenly to power rapid and synchronous movements of the hind legs. How is this energy stored?
The hind coxae of the froghopper are linked to the hinges of the ipsilateral hind wings by pleural arches, complex bow-shaped internal skeletal structures. They are built of chitinous cuticle and the rubber-like protein, resilin, which fluoresces bright blue when illuminated with ultra-violet light. The ventral and posterior end of this fluorescent region forms the thoracic part of the pivot with a hind coxa. No other structures in the thorax or hind legs show this blue fluorescence and it is not found in larvae which do not jump. Stimulating one trochanteral depressor muscle in a pattern that simulates its normal action, results in a distortion and forward movement of the posterior part of a pleural arch by 40 microm, but in natural jumping, the movement is at least 100 microm.
Calculations showed that the resilin itself could only store 1% to 2% of the energy required for jumping. The stiffer cuticular parts of the pleural arches could, however, easily meet all the energy storage needs. The composite structure therefore, combines the stiffness of the chitinous cuticle with the elasticity of resilin. Muscle contractions bend the chitinous cuticle with little deformation and therefore, store the energy needed for jumping, while the resilin rapidly returns its stored energy and thus restores the body to its original shape after a jump and allows repeated jumping.
BMC Biology 10/2008; 6:41. · 5.75 Impact Factor
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Daniela Matei,
Robert E Emerson,
Jeanne Schilder,
Nancy Menning,
Lee Ann Baldridge,
Cynthia S Johnson,
Tim Breen,
John McClean,
Doyle Stephens,
Charles Whalen, Gregory Sutton
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ABSTRACT: Ovarian tumors frequently express c-Kit and/or platelet-derived growth factor receptors (PDGFRs). Imatinib mesylate blocks the growth of ovarian cancer cells in vitro and may enhance the activity of chemotherapy. This study was conducted to determine the activity of imatinib in combination with docetaxel in patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC).
Eligible patients had recurrent, platinum-resistant, or refractory EOC that expressed PDGFRalpha or c-kit, as determined by immunohistochemistry. Imatinib mesylate at a dose of 600 mg orally once daily was administered continuously with docetaxel at a dose of 30 mg/m(2) given intravenously once weekly in Weeks 1 through 4 of every 6-week cycle. The primary endpoint was objective response rate (ORR) as assessed by the Response Evaluation Criteria in Solid Tumors (RECIST).
Thirty-four patients were screened for PDGFRalpha and c-kit expression to enroll 23 patients between December 2003 and October 2005. Four patients had c-kit-positive/PDGFR-negative tumors, 11 patients had PDGFR-positive/c-kit-negative tumors, and 8 patients had c-kit-positive/PDGFR-positive tumors. The median patient age was 56 years (range, 33-76 years). Patients had received a median of 3 prior treatments. The ORR was 21.7% and included 1 complete and 4 partial responses. An additional 3 patients had stable disease for more than 4 months. Expression of PDGFR, c-kit, phosphatase and tensin homolog (PTEN), and phosphorylated protein kinase B (Akt) did not predict response to therapy. The most common adverse events encountered were fatigue (83%), nausea (74%), diarrhea (61%), anorexia (52%), and edema (65%), and the majority of those events were graded as grade 1 or 2.
The combination imatinib and docetaxel was tolerated in patients with heavily pretreated EOC that expressed c-kit or PDGFRalpha. Few patients had sustained responses or stable disease.
Cancer 08/2008; 113(4):723-32. · 4.77 Impact Factor
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ABSTRACT: To evaluate outcome in patients with clinical stage I/II papillary serous (PS) or clear cell (CC) endometrial carcinoma treated with whole abdominal radiotherapy.
After total abdominal hysterectomy with bilateral salpingo-oophorectomy, pelvic/para-aortic lymph node sampling, and peritoneal washings, eligible patients received radiotherapy (RT) to the abdomen (3000 cGy at 150 cGy/day) with a pelvic boost (1980 cGy at 180 cGy/day).
Among 21 PS patients (median age: 68 years), one refused therapy, and another received a non-protocol vaginal boost. In total, eight patients died of disease (DOD) between 9.6 and 35.2 months. Five others died due to protocol treatment (1), toxicity from subsequent chemotherapy (1), intercurrent disease (1), and unknown cause (2). Five-year progression-free survival (PFS) was 38%. Among treated patients who DOD, sites of recurrence included lung (2), lung/vagina (1), abdomen/pelvis (1), vagina (1), and abdomen (2). Among 13 CC patients (median age: 63 years), one received pelvic RT only and died with intercurrent disease. Five others died due to DOD (3), intercurrent disease (1), and unknown cause (1). Five-year PFS was 54%. Among patients who DOD, sites of recurrence included lung (1), vagina (1), and unknown (1). Grade 3/4 toxicities for both histologic groups included gastrointestinal (three grade 4; three grade 3), hematologic (one grade 4), and cutaneous (one grade 3).
Over half of the treatment failures were within the radiation field. Systemic chemotherapy, radiosensitizing chemotherapy, or sequential radiation and chemotherapy should be considered in future adjuvant trials for these patients.
Gynecologic Oncology 03/2006; 100(2):349-54. · 3.89 Impact Factor
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ABSTRACT: To evaluate toxicity, survival, and recurrence-free interval in women with loco-regionally advanced endometrial carcinoma treated with postoperative whole abdominal radiation therapy.
Whole abdominal irradiation with pelvic plus or minus para-aortic boost was initiated within 8 weeks of total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic washings, and selective pelvic and para-aortic node sampling in eligible, consenting patients.
Of 180 evaluable patients entered on the study with surgically staged III and IV endometrial carcinoma maximally debulked to less than 2 cm, 77 had typical endometrial adenocarcinoma and 103 had high-risk histology, either papillary serous or clear cell carcinoma. Patients with typical endometrial adenocarcinoma were significantly younger and had significantly fewer poorly differentiated cancers. Proportionally, there were twice as many non-Whites with high-risk histologies as non-Whites with typical endometrial adenocarcinoma. Forty-five percent of patients with typical endometrial adenocarcinomas had positive pelvic nodes compared to 51% of those with high-risk histologies. Both histologic groups had similar distribution for performance status, para-aortic node positivity, site and extent of disease, and International Federation of Gynecology and Obstetrics (FIGO) stage. The frequency of severe or life-threatening adverse effects among 174 patients evaluable for radiation toxicity included 12.6% with bone marrow depression, 15% GI, and 2.2% hepatic toxicity. The recurrence-free survival rates were 29% and 27% (at 3 years) for the typical endometrial adenocarcinoma and high-risk histologies, respectively. The survival rates were 31% and 35%, respectively. No patient with gross residual disease survived.
Whole abdominal irradiation in maximally resected advanced endometrial carcinoma has tolerable toxicity, and it is suggested that the outcome may be improved by this adjunctive treatment in patients with completely resected disease.
Gynecologic Oncology 07/2005; 97(3):755-63. · 3.89 Impact Factor
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ABSTRACT: To determine progression-free survival (PFS) and overall survival (OS) in women with completely resected stage I or II carcinosarcoma of the uterus treated with adjuvant ifosfamide and cisplatin, and to assess the toxicity of this regimen.
Eligible patients had histologically confirmed carcinosarcoma (mixed mesodermal tumor) and no postoperative radiotherapy following complete resection for clinical stage I or II disease. They were to have adequate renal, hepatic, and hematologic functions and performance status of 2 or less. Study entry was to be within 8 weeks of hysterectomy. Patients with previous chemotherapy, or other noncutaneous malignancies, were ineligible. Ifosfamide was administered 1.5 g/m2 intravenously (IV) over 1 h and cisplatin was given 20 mg/m(2) over 15 min followed by mesna 120 mg/m2 IV bolus, then 1.5 g/m2/24 h as a continuous infusion. Initial doses (daily x 5 every 21 days x 3 cycles) were reduced by 20% (to 4 days) for myelotoxicity.
Nine of seventy-six patients enrolled were deemed ineligible and another two who did not receive protocol treatment were inevaluable. Of the 65 evaluable patients, median age was 65 years; 50 patients (77%) were stage I and 15 (23%) were stage II. PFS and OS, respectively, were 69% and 82% at 24 months, and 54% and 52% at 84 months. Overall 5-year survival was 62%. Leukopenia was the most commonly reported, but manageable, toxicity.
Adjuvant ifosfamide and cisplatin after primary surgery for stage I or II carcinosarcoma of the uterus is tolerable. In the absence of concurrent controls, the impact on PFS and OS is unclear. Pelvic relapse remains problematic.
Gynecologic Oncology 04/2005; 96(3):630-4. · 3.89 Impact Factor
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ABSTRACT: This is a phase II group-wide study of liposomal doxorubicin chemotherapy in patients with advanced or recurrent uterine leiomyosarcomas. The aim was to evaluate clinical response and toxicity.
Patients with histologically confirmed persistent or recurrent leiomyosarcomas of the uterus with documented disease progression after appropriate local therapy were invited to participate in this study. Bidimensionally measurable disease, GOG performance status of 0, 1, or 2 (Karnofsky 80-100) was required; all patients must have failed local therapeutic measures and be considered incurable. Other eligibility criteria included adequate hepatic, renal, and hematologic function. Patients were ineligible if they had received previous chemotherapy or had other noncutaneous malignancies. Patients received liposomal doxorubicin 50 mg/m2 IV over 1 h. Courses were repeated every 4 weeks until disease progression or adverse side effects supervened.
Thirty-five patients were entered into this study between May 2000 and June 2001. Three patients were determined ineligible because of wrong pathological cell type or inadequate pathology information and one was inevaluable for lack of data. Median age was 52 years (range 36-78 years). GOG performance status was 2 in 1 instance, 1 in 15 cases, and 0 in 15 others. Eleven patients (35.5%) had received radiotherapy. A median of 2.0 courses was given (range 1-8). Five patients (16.1%) experienced grade 3 or 4 neutropenia, and seven (22.6%) had grade 3 or 4 anemia. Two patients developed grade 3 and one patient developed grade 4 cardiovascular adverse events, not necessarily drug related. There were seven cases of grade 3 or 4 gastrointestinal toxicity and two patients developed grade 3 dermatologic toxicity. One complete (3.2%) and four partial (12.9%) responses were reported. Ten patients (32.3%) had stable disease, 15 (48.4%) had increasing disease, and response could not be assessed in 1 (3.2%).
The dose and schedule of liposomal doxorubicin employed in this trial showed no advantage over historical results with doxorubicin in the treatment of uterine leiomyosarcoma.
Gynecologic Oncology 04/2005; 96(3):749-52. · 3.89 Impact Factor
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ABSTRACT: Forty-nine evaluable patients with advanced or recurrent endometrial carcinoma who were no longer controllable with surgery, radiotherapy, and hormonal therapy and who had not received prior chemotherapy were treated with cisplatin 50 mg/m2 intravenously every 3 weeks. Two complete responses (4%) and eight partial responses (16%) were observed among the 49 patients. Twenty-two (45%) exhibited stable disease for at least 2 months, while 17 patients (35%) progressed less than 2 months after initiating chemotherapy. Adverse effects included mild leukopenia (31%), nausea and vomiting (72%), and mild azotemia (51%). Only 2 patients experienced life-threatening toxicity; one related to renal failure and the other to sepsis and shock. Cisplatin thus has definite activity when given at the dose and schedule tested to patients with endometrial carcinoma who have not received prior Chemotherapy.
Gynecologic Oncology.
