To determine the maximum-tolerated dose (MTD) and assess safety, pharmacokinetics, pharmacodynamics, and evidence of antitumor activity of RO4929097, a gamma secretase inhibitor of Notch signaling in ...patients with advanced solid malignancies.
Patients received escalating doses of RO4929097 orally on two schedules: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. To assess reversible CYP3A4 autoinduction, the expanded part of the study tested three dosing schedules: (B) as above; modified A, 3 consecutive d/wk for 3 weeks; and (C) continuous daily dosing. Positron emission tomography scans with (18)Ffluorodeoxyglucose (FDG-PET) were used to assess tumor metabolic effects.
Patients on schedule A (n = 58), B (n = 47), and C (n = 5; expanded cohort) received 302 cycles of RO4929097. Common grade 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. Transient grade 3 hypophosphatemia (dose-limiting toxicity, one patient) and grade 3 pruritus (two patients) were observed at 27 mg and 60 mg, respectively; transient grade 3 asthenia was observed on schedule A at 80 mg (one patient). Tumor responses included one partial response in a patient with colorectal adenocarcinoma with neuroendocrine features, one mixed response (stable disease) in a patient with sarcoma, and one nearly complete FDG-PET response in a patient with melanoma. Effect on CYP3A4 induction was observed.
RO4929097 was well tolerated at 270 mg on schedule A and at 135 mg on schedule B; the safety of schedule C has not been fully evaluated. Further studies are warranted on the basis of a favorable safety profile and preliminary evidence of clinical antitumor activity.
Preclinical studies performed in our laboratory have shown that high-dose selenium inhibits the development of carboplatin drug resistance in an ovarian cancer mouse xenograft model. Based on these ...data, as well as the potential serious toxicities of supranutritional doses of selenium, a phase I trial of a combination of selenium/carboplatin/paclitaxel was designed to determine the maximum tolerated dose, safety, and effects of selenium on carboplatin pharmacokinetics in the treatment of chemo-naive women with gynecologic cancers. Correlative studies were performed to identify gene targets of selenium.
Chemo-naïve patients with gynecologic malignancy received selenious acid IV on day 1 followed by carboplatin IV and paclitaxel IV on day 3. A standard 3 + 3 dose-escalating design was used for addition of selenium to standard dose chemotherapy. Concentrations of selenium in plasma and carboplatin in plasma ultrafiltrate were analyzed.
Forty-five patients were enrolled and 291 treatment cycles were administered. Selenium was administered as selenious acid to 9 cohorts of patients with selenium doses ranging from 50 μg to 5000 μg. Grade 3/4 toxicities included neutropenia (66.7%), febrile neutropenia (2.2%), pain (20.0%), infection (13.3%), neurologic (11.1%), and pulmonary adverse effects (11.1%). The maximum tolerated dose of selenium was not reached. Selenium had no effect on carboplatin pharmacokinetics. Correlative studies showed post-treatment downregulation of RAD51AP1, a protein involved in DNA repair, in both cancer cell lines and patient tumors.
Overall, the addition of selenium to carboplatin/paclitaxel chemotherapy is safe and well tolerated, and does not alter carboplatin pharmacokinetics. A 5000 μg dose of elemental selenium as selenious acid is suggested as the dose to be evaluated in a phase II trial.
•Selenious acid (5000 μg Se) can be safely combined with carboplatin/paclitaxel.•Pharmacokinetics of carboplatin on day 3 is not affected by selenious acid on day 1.•The average plasma half-life of Se administered as selenious acid is 25 h.•Selenious acid administered with carboplatin may downregulate RAD51AP1.
Purpose
The metabolism of pazopanib is primarily mediated by CYP3A4. The solubility of pazopanib is pH-dependent, and an elevated gastric pH may decrease its bioavailability. This study evaluated the ...effect of a potent CYP3A4 inhibitor, ketoconazole, and the proton pump inhibitor esomeprazole on the pharmacokinetics and safety of pazopanib and its metabolites.
Methods
In Arm A, patients received pazopanib 400 mg alone once daily for 7 days followed by pazopanib 400 mg plus ketoconazole 400 mg once daily for 5 days. In Arm B, patients received pazopanib 800 mg once daily for 7 days, followed by pazopanib 800 mg plus esomeprazole 40 mg once daily for 5 days, and then pazopanib alone on the last day.
Results
Arm A enrolled 21 patients. In the presence of ketoconazole, mean area under the plasma concentration–time curve 24 h post-dose (AUC
(0–24)
) and mean maximum observed concentration (
C
max
) of pazopanib increased by 66 and 45 %, respectively; mean AUC
(0–24)
and
C
max
for pazopanib metabolites were lower or remained unchanged. Arm B enrolled 13 patients. In the presence of esomeprazole, mean pazopanib AUC
(0–24)
and
C
max
decreased by 40 and 42 %, respectively; mean values of those parameters for metabolites of pazopanib also decreased.
Conclusions
Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided. If coadministration is necessary, pazopanib should be reduced to 400 mg. Concomitant use of pazopanib and proton pump inhibitors should also be avoided. Alternative dosing regimens that do not increase gastric pH at the time of pazopanib dosing should be considered.
Vascular blowout syndrome is a well-known, life-threatening condition complicating advanced-stage head and neck malignancies but has rarely been reported in the gynecologic oncology realm in ...association with the femoral circulation. A 50-year-old woman with metastatic vulvar squamous cell carcinoma presented with left threatened femoral arterial blowout, secondary to an exophytic neoplastic mass originating from the left inguinal lymph nodes.
Bland embolization of the tumor as well as 3 vessel covered stent revascularization was successfully performed with excellent tumor devascularization and reinstitution of arterial integrity.
Successful devascularization of the tumor, with no non-target embolization was achieved, with excellent apposition and deployment of 3 covered stents in the femoral artery bifurcation.
We present a unique case of threatened femoral artery blowout syndrome in the setting of metastatic vulvar carcinoma requiring various endovascular techniques for palliation. These endovascular techniques can be invaluable in minimally invasive palliation of advanced stage neoplasms abutting the iliofemoral circulation.
Highlights • Nonbacterial thrombotic endocarditis (NBTE) is a rare complication of cancer. • NBTE may precede the diagnosis of an occult gynecologic malignancy. • Malignancy - induced NBTE must be ...considered in patients with unprovoked venous thromboembolism. • The most effective treatment is anticoagulation and treatment of the underlying cancer.
Gestational trophoblastic neoplasia (GTN) with brain metastasis is usually seen in patients with advanced disease. Ten percent of metastatic gestational trophoblastic disease involves the brain and ...spinal cord, most often manifesting as an intracerebral mass or subdural hematoma, and are generally known to be a poor prognostic factor (Dadlani et al., 2010). Leptomeningeal metastases are tremendously rare and not well documented in the literature. A standardized treatment regimen for patients with brain metastases has not been established and is controversial due to a number of multimodal treatments that have been published in the literature without a prospective trial having been completed. We report a case of a patient with gestational trophoblastic disease that metastasized to the lung and leptomeninges, who after treatment with induction chemotherapy using etoposide (E) and cisplatin (P) followed by etoposide, methotrexate and dactinomycin (EMA) chemotherapy achieved a complete response without brain radiation (Han et al., 2012).
•EMA-EP, after induction with EP, can be utilized as first line chemotherapy in cases of high risk GTN.•Stage IV high risk GTN may present with relatively low β-HCG levels.•Intravenous chemotherapy alone is capable of curing most patients with high risk GTN.•Management of high risk GTN requires multidisciplinary individualized treatment.•Despite leptomeningeal spread of disease, a cure of GTN was able to be achieved with chemotherapy alone.
Pilomatrix carcinoma of the vulva Song, Mihae; Chekmareva, Marina; Bachmann, Gloria ...
Gynecologic oncology reports,
01/2016, Letnik:
15, Številka:
C
Journal Article
Recenzirano
Odprti dostop
Abstract Background Pilomatrix carcinomas are rare, frequently occurring in older male patients. We report a case of vulvar pilomatrix carcinoma in a 30-year-old woman, the second known reported case ...occurring on the external genitalia. Case A 30-year-old female originally presented at an outside institution for the management of an asymptomatic vulvar mass that was biopsied and read as invasive squamous cell carcinoma. Pathology review at our institution reclassified the vulvar mass as a low-grade pilomatrix carcinoma. The patient underwent radical hemivulvectomy without an inguinal–femoral groin node dissection. She has remained without evidence of disease recurrence for more than 5 years since her diagnosis. Conclusion Pilomatrix carcinoma can be confused for an invasive squamous cell carcinoma. Due to its low risk of metastases, a less radical surgical approach can be taken. Consideration of this unusual malignancy is important in the determination of appropriate management.
Overexpression of bcl-2 is a mechanism of drug resistance in cervical cancer. Agents that down-regulate bcl-2 may decrease tumor cell threshold and sensitize tumor cells to chemotherapy. The ...objective of this multi-institutional phase 2 trial was to evaluate the efficacy and toxicity of paclitaxel and bcl-2 modulators (13-cis retinoic acid and interferon alfa-2b) in patients with advanced-stage or recurrent cervical cancer.
Patients had biopsy-proven metastatic, first relapse, or persistent cervical cancer with no prior chemotherapy except for chemosensitizing agents. The treatment consisted of oral 13-cis retinoic acid, 1 mg/kg, and subcutaneous interferon alfa-2b, 6 mU/m, days 1 to 4, and intravenous paclitaxel, 175 mg/m, day 4 until disease progression or adverse events prohibited treatment. The primary endpoint was overall response rate.
Thirty-three patients were enrolled between March 2001 and June 2009. Thirty-one patients were eligible for evaluation of treatment response. Twenty-seven patients (82%) received prior concurrent chemoradiation or radiotherapy alone before study enrollment. The overall response rate was 30% (6 complete responses and 4 partial responses). Furthermore, 7 patients (21%) had stable disease. Grade 3 or 4 adverse events included neutropenia (n =16 48%), febrile neutropenia (n = 1 3%), and anemia (n = 1 3%). There were no treatment-related deaths. The median progression-free survival was 3.4 months (95% confidence interval, 2.0-7.4 months), and overall survival was 11.2 months (95% confidence interval, 7.5-26.2 months). Of 6 patients with complete responses, 5 patients survived more than 2 years.
Combination therapy with paclitaxel, 13-cis retinoic acid, and interferon alfa-2b is feasible and safe in treating patients with advanced and recurrent cervical cancer.
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