Sloan, Jeff A.

Purpose We determined the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLT) of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when infused on days 1, 8, and 15 of a 28-day cycle in advanced solid tumor patients. We also characterized the pharmacokinetics of 17-AAG, its effect on chaperone and client proteins, and whether cytochrome P450 (CYP) 3A5 and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphisms affected 17-AAG disposition or toxicity. Patients and Methods An accelerated titration design was used. Biomarkers were measured in peripheral-blood mononuclear cells (PBMCs) at baseline and on days 1 and 15, and pharmacokinetic analysis was performed on day 1 of cycle 1. CYP3A5*3 and NQO1*2 genotypes were determined and correlated with pharmacokinetics and toxicity. Results Twenty-one patients received 52 courses at 11 dose levels. DLTs at 431 mg/m2 were grade 3 bilirubin (n = 1), AST (n = 1), anemia (n = 1), nausea (n = 1), vomiting (n = 1), and myalgias (n = 1). No tumor responses were seen. 17-AAG consistently increased heat shock protein (Hsp) 70 levels in PBMCs. At the MTD, the clearance and half-life (t1/2) of 17-AAG were 11.6 L/h/m2 and 4.15 hours, respectively; whereas the active metabolite 17-aminogeldanamycin had a t1/2 of 7.63 hours. The CYP3A5*3 and NQO1*2 polymorphisms were not associated with 17-AAG toxicity. The CYP3A5*3 polymorphism was associated with higher 17-AAG clearance. Conclusion The MTD of weekly 17-AAG is 308 mg/m2. 17-AAG induced Hsp70 in PBMCs, indicating that Hsp90 has been affected. Further evaluation of 17-AAG is ongoing using a twice-weekly regimen, and this schedule of 17-AAG is being tested in combination with chemotherapy.

Purpose To describe the prevalence, clinical characteristics, and pattern of use of complementary and alternative medicine (CAM) in patients enrolled onto phase I trials. Patients and Methods Questionnaires were administered to 108 patients with advanced malignancies enrolled onto phase I chemotherapy trials at the Mayo Clinic Comprehensive Cancer Center (Rochester, MN). CAM was classified into two modalities, pharmacologic and nonpharmacologic. Clinical and demographic data, including age, sex, and prior cancer treatment, were subsequently obtained from patient charts and examined for any correlation with CAM use, using χ2 analysis. Results One hundred two survey forms were returned. Among respondents, 88.2% (90 of 102) had used at least one CAM modality; 93.3% (84 of 90) and 53.3% (48 of 90) had used pharmacologic and nonpharmacologic CAM, respectively; and 46.7% (42 of 90) used both modalities. Vitamin and mineral preparations constituted 89.3% (75 of 84) of all pharmacologic CAM used. Intake was highest for vitamins E (48.8% [41 of 84]) and C (38.1% [32 of 84]), and 71.4% (60 of 84) of respondents took nonvitamin/mineral agents. Green tea (29.8% [25 of 84]), echinacea (13.1% [11 of 84]), and essiac (9.5% [8 of 84]) were the most popular. Prayer and spiritual practices were the most commonly used nonpharmacologic CAM, accounting for 52.1% (25 of 48). Chiropractors, the most frequently visited nontraditional medicine practitioners, were consulted by only 10% (9 of 90) of those who practiced CAM. Both CAM modalities were used more frequently by women (53.5% [23 of 43]) than men (40.4% [19 of 47]). Conclusion CAM use is common among patients in phase I trials and should be ascertained by investigators, because some of the agents used may interact with investigational agents and affect adverse effects and/or efficacy.

Purpose To determine whether weekly epoetin alfa could improve hemoglobin (HgB) levels, reduce RBC transfusions, and improve quality of life (QOL) in patients with advanced cancer and with anemia after receiving myelosuppressive chemotherapy. Patients and Methods This double-blind, placebo-controlled study randomly assigned patients to placebo or epoetin alfa (Ortho Biotech, Bridgewater, NJ) 40,000 U subcutaneous weekly for 16 weeks. QOL, HgB, and RBC transfusions were measured pretreatment and monthly. Results The study accrued 344 patients; 330 were assessable for efficacy and 305 were assessable for QOL. Placebo-treated patients had a mean increase in HgB of 0.9 g/dL (range, −3.8 to +5.3) compared with 2.8 g/dL (range, −2.2 to +7.5) for epoetin-treated patients (P < .0001). During the study, 31.7% of placebo-treated patients achieved a ≥ 2 g/dL HgB increase compared with 72.7% of epoetin-treated patients (P < .0001). The incidence of RBC transfusion for placebo and epoetin treatment arms was 39.6% and 25.3% (P = .005), respectively. The placebo group received 256 units of RBCs compared with 127 units in the epoetin group (P < .0001). The incidence of toxicity in the groups was similar. Changes in the average QOL scores from baseline to the end of the study were similar in the two groups (P = not significant). The HgB responders (irrespective of treatment arm) had a mean change in Functional Assessment of Cancer Therapy (FACT) fatigue score from a baseline of +5.1 compared with −2.1 for the nonresponders (P = .006). Conclusion Epoetin alfa significantly improved HgB and reduced transfusions in this patient population. These results support the use of weekly epoetin alfa as an ameliorative agent for cancer-related anemia.

Purpose Studies suggest eicosapentaenoic acid (EPA), an omega-3 fatty acid, augments weight, appetite, and survival in cancer-associated wasting. This study determined whether an EPA supplement—administered alone or with megestrol acetate (MA)—was more effective than MA. Patients and Methods Four hundred twenty-one assessable patients with cancer-associated wasting were randomly assigned to an EPA supplement 1.09 g administered bid plus placebo; MA liquid suspension 600 mg/d plus an isocaloric, isonitrogenous supplement administered twice a day; or both. Eligible patients reported a 5-lb, 2-month weight loss and/or intake of less than 20 calories/kg/d. Results A smaller percentage taking the EPA supplement gained ≥ 10% of baseline weight compared with those taking MA: 6% v 18%, respectively (P = .004). Combination therapy resulted in weight gain of ≥ 10% in 11% of patients (P = .17 across all arms). The percentage of patients with appetite improvement (North Central Cancer Treatment Group Questionnaire) was not statistically different: 63%, 69%, and 66%, in EPA-, MA-, and combination-treated arms, respectively (P = .69). In contrast, 4-week Functional Assessment of Anorexia/Cachexia Therapy scores suggested MA-containing arms experienced superior appetite stimulation compared with the EPA arm, with scores of 40, 55, and 55 in EPA-, MA-, and combination-treated arms, respectively (P = .004). Survival was not significantly different among arms. Global quality of life was not significantly different among groups. With the exception of increased impotence in MA-treated patients, toxicity was comparable. Conclusion This EPA supplement, either alone or in combination with MA, does not improve weight or appetite better than MA alone.

Purpose Patients with incurable cancer are faced with difficult decisions regarding whether to take chemotherapy in an attempt to preserve the quality and/or prolong the quantity of their lives. The average prolongation in survival with chemotherapy compared with best supportive care has not been well described. Methods We performed a literature search using PUBMED combined with expert inquiry to identify trials comparing cytotoxic chemotherapy with best supportive care. Twenty-five randomized, controlled clinical trials comparing cytotoxic chemotherapy with best supportive care were identified. Sixteen trials (64%) were in patients with non–small-cell lung cancer (NSCLC). Data were extracted and analyzed. Results Sufficient data for statistical modeling were available for NSCLC trials. The mean sample size of the NSCLC trials was 175 patients. Response rates in the treatment arms for NSCLC ranged from 7% to 42%. A relationship between response rate and survival was observed for NSCLC. The estimated relationship for NSCLC suggested that each 3.3% increase in response rate correlated, on average, with a 1-week increase in median survival, and each 2% increase in response rate correlated, on average, with a 1% increase in 1-year survival. The mean increase in 1-year survival for trials of agents with at least a 20% response rate in NSCLC was 16%. Formulas are provided to help estimate how a given response rate may effect median and 1-year survival relative to best supportive care alone for NSCLC. Conclusion We found a relationship between response rate and both median and 1-year survival in NSCLC. This information may help oncologists estimate how an NSCLC chemotherapy regimen with a given response rate can, on average, impact survival relative to supportive care alone.

Purpose Few options are available for pain relief in patients with bone metastases who fail standard treatments. We sought to determine the benefit of radiofrequency ablation (RFA) in providing pain relief for patients with refractory pain secondary to metastases involving bone. Patients and Methods Thirty-one US and 12 European patients with painful osteolytic metastases involving bone were treated with image-guided RFA using a multitip needle. Treated patients had ≥ 4/10 pain and had either failed or were poor candidates for standard treatments such as radiation or opioid analgesics. Using the Brief Pain Inventory–Short Form, worst pain intensity was the primary end point, with a 2-unit drop considered clinically significant. Results Forty-three patients were treated (median follow-up, 16 weeks). Before RFA, the mean score for worst pain was 7.9 (range, 4/10 to 10/10). Four, 12, and 24 weeks following treatment, worst pain decreased to 4.5 (P < .0001), 3.0 (P < .0001), and 1.4 (P = .0005), respectively. Ninety-five percent (41 of 43 patients) experienced a decrease in pain that was considered clinically significant. Opioid usage significantly decreased at weeks 8 and 12. Adverse events were seen in 3 patients and included (1) a second-degree skin burn at the grounding pad site, (2) transient bowel and bladder incontinence following treatment of a metastasis involving the sacrum, and (3) a fracture of the acetabulum following RFA of an acetabular lesion. Conclusion RFA of painful osteolytic metastases provides significant pain relief for cancer patients who have failed standard treatments.

Purpose: A phase III, randomized, double-blind study was conducted by the North Central Cancer Treatment Group to determine the efficacy and toxicity of oral glutamine for the prevention of acute diarrhea in patients receiving pelvic radiation therapy (RT). Patients and Methods: All 129 patients enrolled from 14 institutions between February 1998 and October 1999 were eligible. Patients received 4 g of glutamine or placebo orally, twice a day, beginning with the first or second day of RT and continuing for 2 weeks after RT. During treatment, patients were assessed weekly for toxicity, and a bowel function questionnaire was administered. The primary measures of treatment efficacy were diarrhea levels measured by maximum grade of diarrhea, incidence of diarrhea, and average diarrhea score. After completion of RT, the bowel function questionnaire was administered weekly for 4 weeks and at 12 and 24 months. Toxicity was measured by National Cancer Institute common toxicity criteria. Results: The median age of patients was 69 years (range, 34 to 86 years). The two treatment arms were balanced with respect to all baseline factors. There were no significant differences in toxicity by treatment. Quality-of-life scores and the mean number of problems reported on the bowel function questionnaire were virtually identical for both treatment groups. The incidence of grade 3 or higher diarrhea was 20% for the glutamine arm and 19% for the placebo arm (P = .99). The maximum number of stools per day was 5.1 for the glutamine arm and 5.2 for the placebo arm (P = .99). Conclusion: There is no evidence of a beneficial effect of glutamine during pelvic RT.