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Chauncey T.R.,University of Washington | Chauncey T.R.,Fred Hutchinson Cancer Research Center | Gundacker H.,Southwest Oncology Group Statistical Center | Shadman M.,Southwest Oncology Group Statistical Center | And 9 more authors.
British Journal of Haematology

Attempts to overcome multi-drug resistance in acute myeloid leukaemia (AML) have been limited by toxicities. To investigate the effect of reducing peak drug levels, we performed sequential phase II studies using continuous infusion daunorubicin and cytarabine without (AD) and then with ciclosporin (ADC) in older patients with AML. Untreated patients (age 56+ years) received daunorubicin (45 mg/m2 per day for 3 d) and cytarabine (200 mg/m 2 per day for 7 d), both by continuous infusion, without (S0112, 60 patients) and then with (S0301, 50 patients) the addition of ciclosporin. Complete response (CR) rates were 38% on S0112 and 44% on S0301. Fatal induction toxicities occurred in 17% and 12% respectively, arising primarily from infection and haemorrhage. Median overall and relapse-free survival was 7 and 8 months for AD respectively, and 6 and 14 months for ADC. Patients with phenotypic or functional P-glycoprotein had somewhat higher CR rates with ADC than AD, although confidence intervals overlapped. In these sequential trials, continuous infusion AD produced CR rates comparable to those with bolus daunorubicin. The addition of ciclosporin did not cause undue toxicities, produced a similar CR rate, and possibly improved relapse-free survival. Further correlate analyses did not identify a subpopulation specifically benefitting from the addition of ciclosporin. © 2009 Blackwell Publishing Ltd. Source

Petrylak D.P.,Columbia University | Tangen C.M.,Southwest Oncology Group Statistical Center | Van Veldhuizen Jr. P.J.,Kansas City Medical Center | Goodwin J.W.,Ozarks Regional CCOP | And 6 more authors.
BJU International

Objective: To evaluate the epidermal growth factor receptor (EGFR)-targeted agent ZD1839 in patients who failed one previous chemotherapeutic regimen for metastatic transitional cell carcinoma (TCC), and to correlate patterns of response with the expression of EGFR. Patients and Methods: Thirty-one patients with metastatic TCC of the urothelial tract were treated with ZD1839 500 mg oral daily. Patients were required to have a pretreatment biopsy to assess EGF expression. Results: The median progression-free survival was 2 months, with only two patients (6.5%) surviving past 6 months with no disease progression. Thirty patients were evaluable for toxicity; there was grade 4 cerebrovascular ischaemia and an increase in creatinine level. All patients were evaluable for response, with one confirmed partial response (3%; 95% confidence interval, CI, 0-17%) in a patient with pulmonary metastases. All patients have died, and the estimated median (95% CI) survival is 3 (2-7) months. Conclusion:s: ZD1839 is ineffective as a second-line agent for urothelial carcinoma. © 2009 Southwest Oncology Group. Source

Alberts S.R.,Mayo Medical School | Kim G.P.,Mayo Clinic Florida | Morlan B.W.,Mayo Medical School | Dakhil S.R.,Wichita CCOP | And 2 more authors.
American Journal of Clinical Oncology: Cancer Clinical Trials

Objectives: Vascular endothelial growth factor has been shown to be overexpressed in several studies of hepatocellular carcinoma (HCC). Cediranib is a potent inhibitor of vascular endothelial growth factor signaling. We assessed the efficacy and toxicity of cediranib in patients with HCC. Methods: Twenty-eight patients with unresectable or metastatic HCC were enrolled in this study. Patients received 45 mg of cediranib orally, once daily, for 28-day cycles. The primary objective of this phase II study was to assess 6-month survival. Secondary objectives were to assess tumor response, time to progression, and toxicity. Results: All 28 patients were evaluable for efficacy outcomes. Twelve patients (42.9%) survived 6 months, 15 (53.6%) died within 6 months, and 1 (3.6%) was lost to follow-up before 6 months. The median overall survival was 5.8 months (95% confidence interval, 3.4-7.3 mo). No patients experienced confirmed response. The median time to progression was 2.8 months (95% confidence interval, 2.3-4.4 mo). Twenty-six patients (93%) experienced a grade 3+ adverse event with the most common adverse event s being fatigue (46%), anorexia (25%), hypertension (21%), and elevated alanine aminotransferase (18%). Conclusions: Owing to the toxicity, cediranib at this dose and schedule is not an effective treatment in patients with unresectable or metastatic HCC. Copyright © 2012 by Lippincott Williams & Wilkins. Source

Kirshner J.J.,Hematology Oncology Associates of Central New York | Heckler C.E.,University of Rochester | Janelsins M.C.,University of Rochester | Dakhil S.R.,Wichita CCOP | And 3 more authors.
Journal of Clinical Oncology

Purpose: Pegfilgrastim-induced bone pain is a significant clinical problem that may result in discontinuation of pegfilgrastim and lead to less effective chemotherapy dosing. Interventions for pegfilgrastim-induced bone pain are needed. Patients and Methods: The University of Rochester Cancer Center Clinical Community Oncology Program Research Base randomly assigned 510 patients at 17 sites to receive either naproxen (500 mg two times per day) or placebo on the day of pegfilgrastim administration, continuing for 5 to 8 days after pegfilgrastim. Patients recorded pain severity (using a scale of 0 to 10) and duration in daily diaries. The primary outcome measure was the area under the curve (AUC) for pain for days 1 through 5. Secondary outcome measures included the identification of risk factors for the development of pain and response to naproxen. Results Patients' mean age was 55.6 years and 86% were female. Sixty-eight percent of patients had breast cancer and 10% had lung cancer. Pain reached its peak at 3 days for both groups. The mean AUC for pain was 7.71 for the placebo group and 6.04 for the naproxen group (P = .037). Naproxen reduced maximum pain from 3.40 to 2.59 (P = .005). Naproxen also reduced overall pain incidence from 71.3% to 61.1% (P = .020) and duration from 2.40 to 1.92 days (P = .009). The reduction in severe pain (> 5 on a scale of 1 to 10) from 27.0% to 19.2% was also significant (P = .048). Risk factors could not be identified to predict incidence, severity, or ability to prevent pegfilgrastiminduced bone pain. Conclusion: Our phase III randomized placebo-controlled clinical trial demonstrated that naproxen at a dose of 500 mg twice per day is effective in reducing the incidence and severity of pegfilgrastim-induced bone pain. © 2012 by American Society of Clinical Oncology. Source

Roscoe J.A.,University of Rochester | Heckler C.E.,University of Rochester | Morrow G.R.,University of Rochester | Mohile S.G.,University of Rochester | And 3 more authors.
Journal of Clinical Oncology

Purpose: We conducted a double-blind randomized clinical trial of the following four regimens for controlling delayed nausea (DN): group 1: palonosetron + dexamethasone on day 1 with prochlorperazine on days 2 and 3; group 2: granisetron + dexamethasone on day 1 with prochlorperazine on days 2 and 3; group 3: aprepitant + palonosetron + dexamethasone on day 1 with aprepitant + dexamethasone on days 2 and 3; and group 4: palonosetron + dexamethasone on day 1 with prochlorperazine + dexamethasone on days 2 and 3. Patients and Methods: Chemotherapy-naive patients received doxorubicin, epirubicin, cisplatin, carboplatin, or oxaliplatin. The primary end point was average nausea assessed four times daily on days 2 and 3. Primary analyses were whether nausea control would be improved by using palonosetron versus granisetron on day 1 (group 1 v group 2); by adding dexamethasone on days 2 and 3 (group 1 v group 4); and by using aprepitant versus prochlorperazine (group 3 v group 4). Statistical significance was set at P = .017. Results: Two hundred thirty-four, 234, 241, and 235 evaluable patients were accrued to groups 1, 2, 3, and 4, respectively. Adjusted mean differences for the three planned analyses were as follows: palonosetron versus granisetron: -0.01 (95% CI, -0.23 to 0.20; P = .72); adding dexamethasone on days 2 and 3: 0.20 (95% CI, -0.02 to 0.41; P = .01); and using aprepitant versus prochlorperazine: -0.03 (95% CI, -0.24 to 0.19; P = .56). Conclusion: The addition of dexamethasone on days 2 and 3 reduced DN. Palonosetron and granisetron have similar effects on DN. The beneficial effect of adding aprepitant for control of DN was the same as adding prochlorperazine. © 2012 by American Society of Clinical Oncology. Source

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