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Biomedical subjects

Christopher W Ryan

Publications and source records attributed to Christopher W Ryan.

At least 19 recordsLinked to original sources
PubMed2006

A phase II trial of O6-benzylguanine and carmustine in patients with advanced soft tissue sarcoma.

PURPOSE: Tumor resistance to alkylating agents such as carmustine (BCNU) has been found to be associated with intracellular expression of O6-methylguanine-DNA methyltransferase (MGMT). Administration of O6-benzylguanine (O6-BG), a substrate that inactivates MGMT, may help overcome chemotherapy resistance. We performed a phase II study to explore the activity of O6-BG in combination with BCNU in patients with advanced soft tissue sarcoma. EXPERIMENTAL DESIGN: Informed consent was obtained from patients with metastatic soft tissue sarcoma naïve to systemic chemotherapy (adjuvant chemotherapy allowed). Patients received O6-BG 120 mg/m2 I.V. followed by BCNU 40 mg/m2 I.V. Treatment was repeated every 6 weeks until disease progression or development of unacceptable toxicity. RESULTS: No objective responses were observed in 12 enrolled patients. Four patients exhibited stable disease lasting 11-25+ weeks. The median overall survival was 16.9 months (95% CI, 2.9-NR). The most common grade 3-4 toxicities were neutropenia, thrombocytopenia, and anemia. Depletion of MGMT activity was demonstrated in peripheral blood mononuclear cells. Immunohistochemical estimation of MGMT expression from archival tissue ranged from 20 to 99% positive staining cells. CONCLUSIONS: Observed toxicities were consistent with previous studies of O6-BG plus BCNU. The degree of MGMT expression was variable in this small sample of heterogeneous sarcomas. Further development of this regimen and dose for the treatment of soft tissue sarcoma is not warranted due to the lack of objective responses.

Adult↗
PubMed2006

Testosterone loss and estradiol administration modify memory in men.

PURPOSE: Little is known about the effect of androgen deprivation therapy on the brain despite the fact that sex steroid receptors are abundant in cortical brain regions that mediate memory and other cognitive functions. We characterized the impact of androgen deprivation and of subsequent estradiol therapy on the long-term and working memory of patients with prostate cancer. MATERIALS AND METHODS: Long-term memory (immediate and delayed paragraph recall tests), working memory (SOP and Trails tests) and Profile of Mood States were assessed at baseline and 4 weeks later in 18 patients with androgen independent prostate cancer beginning second line hormonal therapy with transdermal estradiol 0.6 mg/24 hours. The same assessments were performed in 2 age matched control groups of 18 patients with prostate cancer undergoing androgen deprivation continuing on hormonal therapy and 17 community dwelling healthy men. RESULTS: Immediate and delayed verbal memory were significantly worse in patients with prostate cancer on androgen deprivation than in age matched healthy controls. In addition, men with prostate cancer took more time to complete the Trails A task, indicating slower processing speed, but did not differ significantly from healthy controls in working memory tasks. In individual repeated measures analyses, verbal memory performance improved with estradiol therapy but did not change in the 2 control groups. CONCLUSIONS: Sex steroid loss and replacement have effects on specific cognitive processes in older men. Furthermore, estrogen has the potential to reverse the neurotoxic effects on memory performance caused by androgen deprivation.

Affect↗
PubMed2005

Effects of transdermal estrogen on levels of lipids, lipase activity, and inflammatory markers in men with prostate cancer.

Androgen deprivation therapy (ADT) for prostate cancer is now used in earlier disease stages and as adjuvant treatment. Recognizing and reducing the toxicity of this therapy, including worsened lipid levels and cardiovascular disease (CVD) risks, has become an important clinical concern. Oral estrogen therapy induces hypogonadism and mitigates many side effects of ADT, but has a high thrombosis risk. Transdermal estrogen therapy (TDE) has a lower thrombosis risk than oral estrogen and may improve CVD risk compared with ADT. This prospective pilot study of 18 men with androgen-independent prostate cancer receiving ADT measured effects of TDE on lipid and inflammatory CVD risk factors before and after 8 weeks of TDE (estradiol 0.6 mg/day). During treatment, estradiol levels rose 17-fold; total cholesterol, LDL cholesterol, and apolipoprotein B levels decreased. HDL2 cholesterol increased, with no changes in triglyceride or VLDL cholesterol levels. Dense LDL cholesterol decreased and LDL buoyancy increased in association with a decrease in HL activity. Highly sensitive C-reactive protein levels and other inflammatory markers did not worsen. Compared with ADT, short-term TDE therapy of prostate cancer improves lipid levels without deterioration of CVD-associated inflammatory markers and may, on longer-term follow-up, improve CVD and mortality rates.

Administration, Cutaneous↗
PubMed2005

Phase II study of transdermal estradiol in androgen-independent prostate carcinoma.

BACKGROUND: Oral estrogen therapy has activity in patients with hormone-naive and androgen-independent prostate carcinoma (AIPC), but its utility is limited by the associated risk of thromboembolic toxicity. Parenteral administration may be safer as it avoids "first pass" liver exposure to estrogen. The authors tested the safety and efficacy of transdermal estradiol (TDE), as well as the effect of therapy on hot flashes, sex hormones, the procoagulant cascade, and bone turnover in patients with AIPC. METHODS: Patients with prostate carcinoma progressing after primary hormonal therapy received TDE 0.6 mg per 24 hours (administered as six 0.1 mg per 24-hour patches replaced every 7 days). Serum prostate-specific antigen (PSA) and hormone levels, coagulation factors, markers of bone turnover, bone density measurements, and a hot flash diary were collected at regular intervals. RESULTS: Three of 24 patients (12.5%; 95% confidence interval [CI], 0-26%) had a confirmed PSA reduction >50%. The Kaplan-Meier estimate of median time to disease progression was 12 weeks (95% CI, 4.6-19.4 weeks). Toxicity was modest and no thromboembolic complications occurred. The mean (+/-95% CI) serum estradiol level increased from 17.2 pg.mL (range, 14.8-19.6 pg/mL) to 460.7 pg/mL (range, 334.6-586.7 pg/mL). The total testosterone level remained stable in the anorchid range during treatment, but the free testosterone level decreased as a result of increased sex hormone binding globulin. No change in factor VIII activity, F 1.2, or resistance to activated protein C was observed, whereas a modest decrease in the protein S level was observed. CONCLUSIONS: In patients with APIC, TDE was well tolerated and produced a modest response rate, but was not associated with thromboembolic complications or clinically important changes in several coagulation factors.

Administration, Cutaneous↗
PubMed2005

A phase II trial of UFT and leucovorin in women 65 years and older with advanced breast cancer.

The incidence of breast cancer increases with age. This trial evaluated the efficacy and safety of oral UFT (ftorafur plus uracil) plus leucovorin in elderly patients with advanced breast cancer. Eligibility criteria included age > or =65 years, locally advanced or metastatic breast cancer, < or =1 prior chemotherapy regimens in the setting of metastatic disease, performance status 0-2, and adequate end-organ function. UFT at 300 mg/m2 per day as 2 divided doses and 30 mg leucovorin with each dose were administered orally daily for 21 days, followed by a 7-day rest period. Ten patients were accrued. Six patients received treatment in their first relapse and 3 in their second. One patient was chemotherapy-naive. The dose-limiting toxicity was diarrhea with grade 3 or 4 diarrhea occurring more often in the oldest patients (1 of 6 patients between 65 and 69 vs. 3 of 4 patients > or =70 years old). Protocol treatment was discontinued in 2 patients (ages 78 and 83) secondary to severe gastrointestinal toxicity. One patient achieved a partial response. Although UFT/leucovorin had efficacy in 1 patient, toxicity in the patients over 70 years of age was increased. Careful evaluation of anticancer drug toxicity in very elderly patients is important as our population ages.

Aged↗
PubMed2005

High dose pulse calcitriol, docetaxel and estramustine for androgen independent prostate cancer: a phase I/II study.

PURPOSE: We determined the safety and preliminary efficacy of the combination of high dose pulse calcitriol (1,25-dihydroxycholecalciferol) with a standard regimen of docetaxel plus estramustine in patients with metastatic androgen independent prostate cancer. MATERIALS AND METHODS: Patients were treated with 60 microg calcitriol orally on day 1, 280 mg estramustine orally 3 times daily on days 1 to 5 and 60 mg/m docetaxel on day 2 (70 mg/m after cycle 1) every 21 days for up to 12 cycles. Patients also received 325 mg aspirin and 1 or 2 mg warfarin orally daily. Regimen safety was assessed in the first 6 patients and a dose de-escalation scheme for calcitriol was planned if dose limiting toxicities were noted during treatment cycle 1 in greater than a third of patients. RESULTS: A total of 24 patients, including 11 who were chemotherapy naïve and 13 who had previously been treated with docetaxel, were evaluable for toxicity and 22 for prostate specific antigen decrease data. The regimen was generally well tolerated. Treatment related grades 3 or greater toxicity seen in more than 1 patient included hypophosphatemia in 16.7% and neutropenia in 12.5%. Four patients had thromboembolic complications. Asymptomatic hypercalcemia was seen in 4 patients, including grades 2 and 1 in 1 and 3, respectively. Six of 11 evaluable, chemotherapy naïve patients (55%) met prostate specific antigen response criteria. One of 11 patients (9%) treated with prior docetaxel met these criteria. CONCLUSIONS: High dose calcitriol may be safely added to docetaxel and estramustine administered on a 21-day schedule.

Administration, Oral↗
PubMed2005

A phase I/II dose-escalation study of exisulind and docetaxel in patients with hormone-refractory prostate cancer.

OBJECTIVE: To determine the safety and efficacy, in a dose-escalation study, of exisulind (an oral sulphone metabolite of sulindac thought to induce apoptosis in malignant cells by inhibiting cGMP-phosphodiesterase) combined with docetaxel in men with hormone-refractory prostate cancer (HRPC), as pre-clinical studies suggested activity against prostate cancer and synergy with cytotoxic agents. PATIENTS AND METHODS: Thirty-four patients with HRPC were treated with oral exisulind twice daily for 21-day cycles and intravenous docetaxel given for 1 h on the first day of each cycle. Three dose levels were assessed, combining exisulind 150 and 250 mg twice daily with docetaxel at 60 or 75 mg/m2. Toxicity was then evaluated using standard criteria. RESULTS: The recommended phase II dose was determined to be exisulind 250 mg and docetaxel 60 mg/m2, with escalation to 75 mg/m2 after cycle 1, as tolerated. The most common grade 3-4 toxicities among all patients were neutropenia (56%), infection (24%) and hyperglycaemia (18%). Twelve of 32 evaluable patients (38%, 95% confidence interval, CI, 23-55%) had a decline in PSA by at least half. Only four of 17 evaluable patients (95% CI, 1-47%) treated at the phase II dose level had such a decline in PSA. The median (95% CI) overall survival of all patients was 16 (12.9-19.7) months and median progression-free survival 4.7 (2.7-5.2) months. CONCLUSION: The combination of exisulind and docetaxel was tolerable in patients with HRPC. The PSA response rates do not suggest an improvement over historical data with single-agent docetaxel in this population.

Administration, Oral↗
PubMed2005

A phase II study of nilutamide in men with prostate cancer after the failure of flutamide or bicalutamide therapy.

OBJECTIVE: To determine the prostate-specific antigen (PSA) response and time to PSA or radiographic progression in men with prostate cancer refractory to bicalutamide and/or flutamide therapy. PATIENTS AND METHODS: Men with histologically confirmed prostate cancer not amenable to curative surgery or radiation therapy were eligible for the study if they had radiographic or PSA progression on at least one antiandrogen (not nilutamide) despite continued androgen suppression and standard antiandrogen withdrawal periods. All men received nilutamide 150 mg/day orally for > or = 8 weeks unless there was unacceptable toxicity or disease progression. All men were evaluated for response, safety and toxicity. Baseline PSA levels, chest X-ray, bone scan and abdominopelvic computed tomography studies were obtained; the re-evaluation included PSA levels every 4 weeks and repeated imaging every 8 weeks in those with baseline abnormalities. The chest X-ray was repeated if there were pulmonary symptoms. Nineteen men were consented and 16 were evaluable for response. RESULTS: The median (range) Gleason score was 7 (6-9) and the median number of previous second-line therapies was 2 (1-4). Bicalutamide therapy had failed in all patients. At baseline, 13 (of 16 men) had radiographically evident disease, nine with diffuse osseous and four with radiographically measurable metastases. There was no grade 3/4 toxicity; the commonest grade 1/2 toxicities were constipation (three), sensory neuropathy (four), fatigue (six), and visual changes (two) involving transiently altered colour vision and sensitivity to light, respectively. Responses included three partial and 13 with progressive disease. CONCLUSIONS: The study was discontinued after a planned interim analysis because nilutamide had no apparent activity. Although well tolerated, nilutamide offers benefit to few men with prostate cancer in whom bicalutamide has failed.

Adult↗
PubMed2004

Dose-ranging study of the safety and pharmacokinetics of atrasentan in patients with refractory malignancies.

PURPOSE: Atrasentan is an orally bioavailable selective antagonist of the endothelin receptor ET(A). Due to the potential activity of this agent against prostate cancer, the majority of subjects enrolled in prior studies had been male. This Phase I study sought to determine the toxicity and pharmacokinetics of daily atrasentan in a population of both female and male subjects with advanced malignancies. EXPERIMENTAL DESIGN: Patients with refractory malignancies received atrasentan once daily at doses ranging from 5 mg to 75 mg. At least 3 subjects were treated at each dose level before enrollment began at the next higher dose level. Enrollment for specific dose levels was expanded if any subject experienced serious drug-related toxicity. Plasma concentration profiles for atrasentan were determined after dosing on days 1 and 28. RESULTS: Thirty-five patients received atrasentan at doses from 5 mg to 75 mg. The most frequent drug-related adverse events were headache (60%), rhinitis (49%), and peripheral edema (31%). These toxicities were mild to moderate in severity and reversible on cessation of treatment. Dose escalation was stopped at the 75-mg dose level due to the occurrence of three severe adverse events (2 hyponatremia and 1 hypotension). Atrasentan was rapidly absorbed after oral administration; mean time to maximum observed concentration ranged from 0.3 to 1.7 h. Terminal elimination half-life averaged 26 h. No significant difference between sexes was found in any atrasentan pharmacokinetic parameter tested, including maximum observed plasma concentration, time to maximum observed concentration, minimum observed plasma concentration, area under the plasma concentration-time curve, and elimination rate constant. CONCLUSIONS: Atrasentan is well tolerated in both female and male cancer patients at doses of up to 60 mg/day with dose-limiting toxicity observed at 75 mg/day. The most frequently observed toxicities were headache, rhinitis, and edema. There was no statistically significant difference in atrasentan pharmacokinetics between sexes.

Administration, Oral↗
PubMed2004

A randomized Phase II trial of the antiangiogenic agent SU5416 in hormone-refractory prostate cancer.

PURPOSE: To assess the activity of the antiangiogenic agent and VEGFR2 inhibitor SU5416 in hormone-refractory prostate cancer. PATIENTS AND METHODS: Thirty-six chemotherapy naïve patients were randomized to treatment with SU5416 (145 mg/m(2)) and dexamethasone premedication or dexamethasone alone. Patients in the control arm could cross over to experimental therapy after progression. Prostate-specific antigen (PSA) was measured every 2 weeks, and radiological evaluation was performed every 8 weeks. In vitro assessment of SU5416 on PSA secretion was assessed in the LNCaP cell line. Baseline serum basic fibroblast growth factor and plasma vascular endothelial growth factor (VEGF) were explored as prognostic factors. RESULTS: VEGF receptor-2 expression is detectable in prostate cancer cell lines, and SU5416 inhibited in vitro PSA secretion. No effect of SU5416 on PSA secretion or time to progression is detectable in patients. VEGF and basic fibroblast growth factor were not prognostic. Headache and fatigue were the most common SU5416 toxicities, but hyperglycemia, hyponatremia, lymphopenia, infection, and adrenal suppression, all attributable to steroids and the required central line, were common. CONCLUSION: No disease modifying effects of SU5416 were detectable in this small study. Modest toxicity, an inconvenient administration schedule, and availability of other VEGFR-targeted agents support the decision to halt further evaluation of SU5416 in prostate cancer.

Aged↗
PubMed2004

Phase II trial of PS-341 in patients with renal cell cancer: a University of Chicago phase II consortium study.

PURPOSE: Determine response rate, time to disease progression, and toxicity of the proteasome inhibitor PS-341 in patients with stage IV renal cell cancer. PATIENTS AND METHODS: PS-341 1.5 mg/m(2) was administered intravenously twice weekly for 2 weeks every 21 days. Dose escalation to 1.7 mg/m(2) ensued in the absence of grade 3 to 4 toxicities. Re-evaluation took place after three cycles. To assess proteasome inhibition, patients were randomly assigned to tumor core biopsy either before the first dose or after the third cycle of PS-341. Additionally, whole blood was collected at the same time intervals. RESULTS: Twenty-three patients were enrolled; 21 were assessable for response. Two patients were never treated (one patient refused treatment and one had insufficient tumor for biopsy). Eighteen patients completed at least three cycles of therapy; three patients experienced disease progression after two cycles. Grade 4 toxicities were arthralgia, diarrhea, and vomiting. Grade 3 toxicities included thrombocytopenia with one hemorrhage, anemia, febrile neutropenia, gastrointestinal toxicity, pain, fatigue, neuropathy (one sensory, one mixed sensorimotor), and electrolyte disturbances. Grade 1 to 2 neuropathy occurred in seven patients. One case of thrombosis and one case of pleural effusion occurred. Only one objective response was seen. Proteasome activity was measured by specific chymotryptic activity (SpA) and chymotryptic/tryptic activity (ChT:T). After PS-341, there was a decrease in mean whole blood SpA and ChT:T (P =.07 and.11, respectively). CONCLUSION: Evidence is lacking for clinically significant activity of PS-341 in metastatic renal cell cancer. Insufficient biopsy and whole blood sample numbers preclude conclusions regarding proteasome inhibition within tumor. Further evaluation in this disease setting is not recommended.

Adult↗
PubMed2003

Surgical treatment of gastrointestinal stromal tumors in the imatinib (STI-571) era.

BACKGROUND: Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors that are characterized by constitutive overexpression of the tyrosine kinase receptor KIT (CD117). Imatinib mesylate is a selective inhibitor of tyrosine kinase-mediated activity. This study reports a single-institution experience of surgical resection and the use of imatinib in the treatment of GIST. METHODS: A retrospective review from 1995 to 2002 identified 57 patients (M:F, 29:28; median age, 61 years) with GIST who were treated at the University of Chicago. Twenty-eight patients underwent exploratory surgery with curative intent; 29 patients were referred for treatment of metastatic disease after surgery at outside institutions. Twenty-nine patients were treated with oral imatinib for either metastatic disease (n=26 patients) or in the adjuvant setting after complete resection (n=3 patients). RESULTS: Resections were performed in 53 patients, and metastatic disease was identified in 17 patients at the time of exploratory surgery. Immunohistochemical staining for CD117 was positive in 96% of patients. A size larger than 5 cm, a mitotic rate larger than 1/10 high-power field, and tumor necrosis predicted recurrence in patients after resection. The median follow-up period was 18 months (range, 4-81 months). Twenty-three patients (40%) are alive without disease; 22 patients (39%) are alive with disease; 7 patients died, and 5 patients are lost to follow-up. Among the 26 patients with metastatic disease who were treated with imatinib, 5 deaths have occurred, and disease stabilization or tumor regression was observed initially in 22 patients, with a median duration of response of 19 months. CONCLUSIONS: Complete surgical extirpation remains the only curative treatment of GIST. Imatinib-targeted therapy of metastatic disease yields encouraging clinical responses. The true efficacy of imatinib in this setting, as induction therapy or as an adjuvant treatment in patients with GIST, is unknown pending the completion of ongoing prospective trials.

Antineoplastic Agents↗
PubMed2003

Prognostic factors for survival with gemcitabine plus 5-fluorouracil based regimens for metastatic renal cancer.

PURPOSE: Combination gemcitabine and 5-fluorouracil (5-FU) may have activity in metastatic renal cell cancer. To identify patient subgroups most likely to benefit and compare survival to that in previously described patient series long-term survival as a function of known and suspected prognostic variables was determined. MATERIALS AND METHODS: The survival status of 153 patients with metastatic renal cell cancer treated on 1 phase I and 4 phase II trials of gemcitabine/5-FU based regimens was updated. Univariate and multivariate Cox proportional hazards models were constructed using multiple imputation for missing values. RESULTS: Performance status, prior nephrectomy, number of metastatic sites, decreased albumin and elevated alkaline phosphatase were highly prognostic for survival. Sarcomatoid differentiation and hypercalcemia had borderline prognostic significance. Using a previous described prognostic model that divided patients into 3 risk groups survival in those treated with gemcitabine/5-FU in this series was consistently better than survival in similar patients treated in the Motzer series. CONCLUSIONS: Previously described prognostic factors for survival in metastatic renal cancer were confirmed. There is no clearly identifiable group that is most likely to benefit from a gemcitabine/5-FU regimen but there is a continued suggestion that this regimen provides a modest improvement over historical chemotherapy approaches.

Antimetabolites, Antineoplastic↗
PubMed2003

Angiosarcoma masquerading as embryonal carcinoma in the metastasis from a mature testicular teratoma.

Sarcoma can arise within a germ cell tumor (GCT) from a malignant transformation of teratomatous elements or as late sequelae to radiation therapy. Angiosarcoma as a malignant component in testicular GCTs has rarely been reported and is often misdiagnosed as embryonal carcinoma. We report the case of a 23-year-old man with mature teratoma of the testis and retroperitoneal metastasis exhibiting components of mature teratoma intermingled with high-grade angiosarcoma. It is important to recognize the presence of a high-grade sarcomatous component within a GCT because of its aggressive clinical behavior and different response to therapy.

Adult↗
PubMed2002

A phase II trial of intravenous gemcitabine and 5-fluorouracil with subcutaneous interleukin-2 and interferon-alpha in patients with metastatic renal cell carcinoma.

BACKGROUND: The objective of this study was to determine the response rate and toxicity of gemcitabine and continuous-infusion 5-fluorouracil (5-FU) in combination with subcutaneous interleukin-2 (IL2) and interferon-alpha (IFNA) in patients with metastatic renal cell carcinoma. METHODS: Forty-one patients were treated with gemcitabine 600 mg/m2 on Days 1, 8, and 15 and continuous-infusion 5-FU on Days 1-21. The dose of 5-FU was 200 mg/m2 per day for the initial 8 patients but was reduced to 150 mg/m2 per day for all remaining patients due to toxicity. Starting on Day 15, IL2 and IFNA were administered for 4 weeks. IL2 was administered at a dose of 11 x 10(6) IU subcutaneously (s.c.) 4 days per week and IFNA was administered at a dose of 10.0 x 10(6) IU s.c. 2 days per week. RESULTS: Of 41 patients enrolled in the study, there was 1 complete response (CR), and there were 5 partial responses (PR), for an overall response rate of 14.6% (90% confidence interval [90%CI], 6.6-26.9%). The median time to disease progression was 6.6 months (90%CI, 3.9-7.5 months), and the median overall survival was 20.6 months (90%CI, 9.6-23.3 months). Toxicity was moderate to severe, with fatigue, fever, anorexia, or nausea experienced by 75-90% of patients. Mucositis and neutropenia, likely due to the gemcitabine and 5-FU, were experienced by a majority of patients. CONCLUSIONS: The addition of gemcitabine and 5-FU to subcutaneous IL2 and IFNA results in a similar response rate to what was observed in previous studies of IL2-based therapy. The toxicity of this four-drug combination is significant, and the regimen is not recommended for further development.

Adult↗