Bercedis L. Peterson

Randomized Controlled Trial of Azacitidine in Patients With the Myelodysplastic Syndrome: A Study of the Cancer and Leukemia Group B

PURPOSE Patients with high-risk myelodysplastic syndrome (MDS) have high mortality from bone marrow failure or transformation to acute leukemia. Supportive care is standard therapy. We previously reported that azacitidine (Aza C) was active in patients with high-risk MDS. PATIENTS AND METHODS A randomized controlled trial was undertaken in 191 patients with MDS to compare Aza C (75 mg/m(2)/d subcutaneously for 7 days every 28 days) with supportive care. MDS was defined by French-American-British criteria. New rigorous response criteria were applied. Both arms received transfusions and antibiotics as required. Patients in the supportive care arm whose disease worsened were permitted to cross over to Aza C. RESULTS Responses occurred in 60% of patients on the Aza C arm (7% complete response, 16% partial response, 37% improved) compared with 5% (improved) receiving supportive care (P <.001). Median time to leukemic transformation or death was 21 months for Aza C versus 13 months for supportive care (P =.007). Transformation to acute myelogenous leukemia occurred as the first event in 15% of patients on the Aza C arm and in 38% receiving supportive care (P =.001). Eliminating the confounding effect of early cross-over to Aza C, a landmark analysis after 6 months showed median survival of an additional 18 months for Aza C and 11 months for supportive care (P =.03). Quality-of-life assessment found significant major advantages in physical function, symptoms, and psychological state for patients initially randomized to Aza C. CONCLUSION Aza C treatment results in significantly higher response rates, improved quality of life, reduced risk of leukemic transformation, and improved survival compared with supportive care. Aza C provides a new treatment option that is superior to supportive care for patients with the MDS subtypes and specific entry criteria treated in this study.

Fludarabine Compared with Chlorambucil as Primary Therapy for Chronic Lymphocytic Leukemia

BACKGROUND Fludarabine is an effective treatment for chronic lymphocytic leukemia that does not respond to initial treatment with chlorambucil. We compared the efficacy of fludarabine with that of chlorambucil in the primary treatment of chronic lymphocytic leukemia. METHODS Between 1990 and 1994, we randomly assigned 509 previously untreated patients with chronic lymphocytic leukemia to one of the following treatments: fludarabine (25 mg per square meter of body-surface area, administered intravenously daily for 5 days every 28 days), chlorambucil (40 mg per square meter, given orally every 28 days), or fludarabine (20 mg per square meter per day for 5 days every 28 days) plus chlorambucil (20 mg per square meter every 28 days). Patients with an additional response at each monthly evaluation continued to receive the assigned treatment for a maximum of 12 cycles. RESULTS Assignment of patients to the fludarabine-plus-chlorambucil group was stopped when a planned interim analysis revealed excessive toxicity and a response rate that was not better than the rate with fludarabine alone. Among the other two groups, the response rate was significantly higher for fludarabine alone than for chlorambucil alone. Among 170 patients treated with fludarabine, 20 percent had a complete remission, and 43 percent had a partial remission. The corresponding values for 181 patients treated with chlorambucil were 4 percent and 33 percent (P< 0.001 for both comparisons). The median duration of remission and the median progression-free survival in the fludarabine group were 25 months and 20 months, respectively, whereas both values were 14 months in the chlorambucil group (P<0.001 for both comparisons). The median overall survival among patients treated with fludarabine was 66 months, which was not significantly different from the overall survival in the other two groups (56 months with chlorambucil and 55 months with combined treatment). Severe infections and neutropenia were more frequent with fludarabine than with chlorambucil (P=0.08), although, overall, toxic effects were tolerable with the two single-drug regimens. CONCLUSIONS When used as the initial treatment for chronic lymphocytic leukemia, fludarabine yields higher response rates and a longer duration of remission and progression-free survival than chlorambucil.

The Cook-medley hostility scale: item content and ability to predict survival.

&NA; Previous studies have identified the MMPI‐based Cook and Medley hostility scale (Ho) as a predictor of health outcomes. To achieve a better understanding of the construct measured by this scale, Ho items were classified on an a priori basis. Six subsets were identified: Cynicism, Hostile Attributions, Hostile Affect, Aggressive Responding, Social Avoidance, and Other. Study 1 examined the correlations of these subsets with scales of the NEO Personality Inventory in two samples of undergraduates. Good convergent and discriminant validity were demonstrated, but there was some evidence that items in the Social Avoidance and Other categories reflect constructs other than hostility. Study 2 examined the ability of the Ho scale and the item subsets to predict the 1985 survival of 118 lawyers who had completed the MMPI in 1956 and 1957. As in previous studies, those with high scores had poorer survival (chi 2 = 6.37, p = 0.012). Unlike previous studies, the relation between Ho scores and survival was linear. Cynicism, Hostile Affect, and Aggressive Responding subsets were related to survival, whereas the other subsets were not. The sum of the three predictive subsets, with a chi 2 of 9.45 (p = 0.002), was a better predictor than the full Ho scale, suggesting that it may be possible to refine the scale and achieve an even more effective measure of those aspects of hostility that are deleterious to health.

Further Analysis of Trials With Azacitidine in Patients With Myelodysplastic Syndrome: Studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B

PURPOSE Within the last two decades, a new understanding of the biology of myelodysplastic syndrome (MDS) has developed. With this understanding, new classification systems, such as the WHO diagnostic criteria, and the International Prognostic Scoring System and response criteria guidelines reported by the International Working Group (IWG) have been developed. We report the combined results of three previously reported clinical trials (n = 309) with azacitidine using the WHO classification system for MDS and acute myeloid leukemia (AML) and IWG criteria for response. PATIENTS AND METHODS Data from three sequential Cancer and Leukemia Group B trials with azacitidine were recollected and reanalyzed as part of the New Drug Application process. The trials were conducted with either intravenous or subcutaneous azacitidine (75 mg/m2/d for 7 days every 28 days). RESULTS Complete remissions were seen in 10% to 17% of azacitidine-treated patients; partial remissions were rare; 23% to 36% of patients had hematologic improvement (HI). The median number of cycles to first response was three, and 90% of responses were seen by cycle 6. Using current WHO criteria, 103 patients had AML at baseline; 35% to 48% had HI or better responses. The median survival time for the 27 AML patients randomly assigned to azacitidine was 19.3 months compared with 12.9 months for the 25 patients assigned to observation. Furthermore, azacitidine did not increase the rate of infection or bleeding above the rate caused by underlying disease. CONCLUSION Azacitidine provides important clinical benefits for patients with high-risk MDS.

Changes in Weight, Body Composition, and Factors Influencing Energy Balance Among Premenopausal Breast Cancer Patients Receiving Adjuvant Chemotherapy

PURPOSE Weight gain is a common problem among breast cancer patients who receive adjuvant chemotherapy (CT). We undertook a study to determine the causes of this energy imbalance. PATIENTS AND METHODS Factors related to energy balance were assessed at baseline (within 3 weeks of diagnosis) and throughout 1 year postdiagnosis among 53 premenopausal women with operable breast carcinoma. Thirty-six patients received CT and 17 received only localized treatment (LT). Measures included body composition (dual energy x-ray absorptiometry), resting energy expenditure (REE; indirect calorimetry), dietary intake (2-day dietary recalls and food frequency questionnaires) and physical activity (physical activity records). RESULTS Mean weight gain in the LT patients was 1.0 kg versus 2.1 kg in the CT group (P =.02). No significant differences between groups in trend over time were observed for REE and energy intake; however, a significant difference was noted for physical activity (P =.01). Several differences between groups in 1-year change scores were detected. The mean change (+/- SE) in LT versus CT groups and P values for uncontrolled/controlled (age, race, radiation therapy, baseline body mass index, and end point under consideration) analysis are as follows: percentage of body fat (-0.1 +/- 0.4 v +2.2 +/- 0.6%; P =.001/0.04); fat mass (+0.1 +/- 0.3 v +2.3 +/- 0.7 kg; P =.002/0.04); lean body mass (+0.8 +/- 0.2 v -0.4 +/- 0.3 kg; P =.02/0.30); and leg lean mass (+0.5 +/- 0.1 v -0.2 +/- 0.1 kg; P =.01/0.11). CONCLUSION These data do not support overeating as a cause of weight gain among breast cancer patients who receive CT. The data suggest, however, that CT-induced weight gain is distinctive and indicative of sarcopenic obesity (weight gain in the presence of lean tissue loss or absence of lean tissue gain). The development of sarcopenic obesity with evidence of reduced physical activity supports the need for interventions focused on exercise, especially resistance training in the lower body, to prevent weight gain.

Effects of Home-Based Diet and Exercise on Functional Outcomes Among Older, Overweight Long-term Cancer Survivors: RENEW: A Randomized Controlled Trial

CONTEXT Five-year survival rates for early stage colorectal, breast, and prostate cancer currently exceed 90% and are increasing. Cancer survivors are at greater risk for second malignancies, other comorbidities, and accelerated functional decline. Lifestyle interventions may provide benefit, but it is unknown whether long-term cancer survivors can modify their lifestyle behaviors sufficiently to improve functional status. OBJECTIVE To determine whether a telephone counseling and mailed print material-based diet and exercise intervention is effective in reorienting functional decline in older, overweight cancer survivors. DESIGN, SETTING, AND PARTICIPANTS Randomized controlled trial of 641 overweight (body mass index > or = 25 and < 40), long-term (> or = 5 years) survivors (aged 65-91 years) of colorectal, breast, and prostate cancer, who were randomly assigned to an intervention group (n = 319) or delayed intervention (control) group (n = 322) in Canada, the United Kingdom, and 21 US states. Individuals were recruited for the Reach out to Enhance Wellness (RENEW) trial from July 1, 2005, through May 17, 2007. INTERVENTION A 12-month, home-based tailored program of telephone counseling and mailed materials promoting exercise, improved diet quality, and modest weight loss. The control group was wait-listed for 12 months. MAIN OUTCOME MEASURES Change in self-reported physical function on the Short-Form 36 physical function subscale (score range, 0-100; a high score indicates better functioning) from baseline to 12 months was the primary end point. Secondary outcomes included changes in function on the basic and advanced lower extremity function subscales of the Late Life Function and Disability Index (score range, 0-100), physical activity, body mass index, and overall health-related quality of life. RESULTS The mean baseline Short-Form 36 physical function score was 75.7. At the 12-month follow-up, the mean function scores declined less rapidly in the intervention group (-2.15; 95% confidence interval [CI], -0.36 to -3.93) compared with the control group (-4.84; 95% CI, -3.04 to -6.63) (P = .03). The mean baseline basic lower extremity function score was 78.2. The mean changes in basic lower extremity function were 0.34 (95% CI, -0.84 to 1.52) in the intervention group compared with -1.89 (95% CI, -0.70 to -3.09) in the control group (P = .005). Physical activity, dietary behaviors, and overall quality of life increased significantly in the intervention group compared with the control group, and weight loss also was greater (2.06 kg [95% CI, 1.69 to 2.43 kg] vs 0.92 kg [95% CI, 0.51 to 1.33 kg], respectively; P < .001). CONCLUSION Among older, long-term survivors of colorectal, breast, and prostate cancer, a diet and exercise intervention reduced the rate of self-reported functional decline compared with no intervention. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00303875.

Select High-Risk Genetic Features Predict Earlier Progression Following Chemoimmunotherapy With Fludarabine and Rituximab in Chronic Lymphocytic Leukemia: Justification for Risk-Adapted Therapy

PURPOSE Several new prognostic factors predicting rapid disease progression in chronic lymphocytic leukemia (CLL) have been identified, including unmutated Ig V(H) mutational status, del(11)(q23), del(17)(p13.1), and p53 mutations. To date, the impact of these same prognostic factors have not been examined relative to treatment outcome with chemoimmunotherapy. METHODS We examined the impact of these new prognostic factors on predicting treatment outcome in symptomatic, untreated CLL patients who received chemoimmunotherapy with fludarabine and rituximab as part of a completed, randomized phase II study, Cancer and Leukemia Group B (CALGB) 9712. RESULTS Eighty-eight patients treated as part of CALGB 9712 had detailed prognostic factor assessment performed. Using Ig V(H) mutational status to classify risk, there was no association between complete response rate with either unmutated Ig V(H) mutational status or high-risk interphase cytogenetics. However, the median progression-free survival (PFS; P = .048) and overall survival (OS; P = .01) were shorter among the Ig V(H) unmutated patients as compared with the Ig V(H) mutated patients. Using the hierarchical classification of Döhner, PFS (P = .005) and OS (P = .004) were significantly longer as the classification moved from high risk [del (11)(q22.3) or del (17)(p13.1)] to low risk. CONCLUSION These data demonstrate that high-risk CLL patients characterized by Ig V(H) unmutated (> or = 98%) or high-risk interphase cytogenetics, including either del(17p) or del(11q), appear to have a shorter PFS and OS with chemoimmunotherapy. Larger prospective studies will be required to determine the independent influence of Ig V(H) mutational status and interphase cytogenetics on treatment outcome.

Hostility patterns and health implications: correlates of Cook-Medley Hostility Scale scores in a national survey.

Correlated Cook-Medley Hostility Scale (Ho) scores with sociodemographic variables in a national survey of 2,536 adults. Multiple regression models revealed that Ho scores were associated with race (p less than .0001), years of education (p less than .001), sex (p less than .001), occupation (p = .0002), and income (p = .0025). Higher scores were found in non-Whites, men, and those of lower socioeconomic status. There was a Race x Income interaction (p less than .005), such that the greatest Ho score differences between the races occurred among those with the lowest incomes. Age was related to Ho scores in a curvilinear fashion: higher scores in the youngest and oldest age groups than in the middle-aged groups (p = .025). Marital status was unrelated to Ho scores. These patterns of hostility are similar to the patterns of health indicators in the population. Because hostility has been found to be associated with adverse health outcomes, hostility may account for some of the demographic variations in health status. However, it is argued that research must first establish the generality of the hostility-health relationship across subgroups of the population.

Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First- or Second-Line Therapy in Patients With Metastatic Renal Cell Cancer

PURPOSE We undertook this study to determine the activity and tolerability of sorafenib administered with interferon alfa-2b (IFN-alpha-2b) as first- or second-line therapy in metastatic renal cell cancer (RCC). PATIENTS AND METHODS Between November 2004 and October 2006, 40 patients at two sites were enrolled onto a phase II trial of sorafenib plus IFN-alpha-2b. Treatment consisted of 8-week cycles of sorafenib 400 mg orally bid plus IFN-alpha-2b 10 million U subcutaneously three times a week followed by a 2-week break. Patients were eligible to receive additional cycles of therapy until disease progression. Dose reduction of both drugs by 50% was permitted once for toxicity. RESULTS The response rate was 33% (95% CI, 19% to 49%; 13 of 40 patients), including 28% partial responses (n = 11) and 5% complete responses (n = 2). Responses were seen in treatment-naïve and interleukin-2 (IL-2) -treated patients within the first two cycles. The median duration of response was 12 months. With a median follow-up time of 14 months, median progression-free survival time was 10 months (95% CI, 8 to 18 months), and median overall survival time has not yet been reached. Fatigue, anorexia, anemia, diarrhea, hypophosphatemia, rash, nausea, and weight loss were the most common toxicities. Grade 3 toxicities were uncommon but included hypophosphatemia, neutropenia, rash, fatigue, and anemia. Dose reductions were required in 65% of patients. CONCLUSION The combination of sorafenib and IFN-alpha-2b has substantial activity in treatment-naïve and IL-2-treated patients with RCC. The toxicity exceeded that of either drug alone, but dose reductions and breaks between cycles allowed for chronic therapy. A larger, randomized trial would determine whether there is any advantage to this regimen compared with sorafenib alone.

Cerebral infarcts in patients with autopsy-proven Alzheimer's disease CERAD, part XVIII

Objective: To study the relation between cerebral infarction and clinical and neuropsychologic manifestations in patients with autopsy-proven Alzheimers disease (AD) enrolled in the Consortium to Establish a Registry for Alzheimers Disease (CERAD). Background: Prior studies report that subjects with neuropathologic evidence of AD and concomitant brain infarcts had poorer cognitive function and higher frequency of dementia than those with AD alone. Methods: Clinical and neuropsychologic manifestations of dementia were studied in 74 subjects with neuropathologic findings of AD alone and 32 with AD and concomitant cerebral infarcts or lacunar lesions. Results: The 32 patients with both AD and vascular lesions were significantly older at time of death (median age, 81 years) than the 74 patients with AD alone(76 years; p = 0.02). At the final follow-up visit, the severity of the dementia was greater in AD patients with vascular lesions(median Clinical Dementia Rating [CDR] = 3) than in those with AD alone (CDR= 2; p = 0.03). Patients with AD and vascular lesions performed significantly worse on verbal fluency, Boston Naming, and Mini-Mental State Examination (MMSE) tests. No differences between the groups were observed, however, in the semiquantitative measures of frequency of neuritic plaques or neurofibrillary tangles. Conclusions: The clinical-neuropathologic correlations in CERAD patients generally confirm those in prior studies, indicating that the presence of cerebral infarction in patients with AD is associated with greater overall severity of clinical dementia and poorer performance on specific tests of language and cognitive function.