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Biomedical subjects

R D Gelber

Publications and source records attributed to R D Gelber.

At least 127 records · Page 7Linked to original sources
PubMed1992

Allergic reactions to Erwinia asparaginase in children with acute lymphoblastic leukemia who had previous allergic reactions to Escherichia coli asparaginase.

BACKGROUND: Escherichia coli asparaginase is an active antileukemia agent in the treatment of childhood acute lymphoblastic leukemia. Allergic reactions occurred in 31 of 125 patients (24.8%) treated with weekly high-dose (25,000 IU/m2) intramuscular E. coli asparaginase and necessitated discontinuation of the drug. METHODS: The authors evaluated the toxic effects of Erwinia asparaginase in the 31 children who had allergic reactions to the E. coli preparation. RESULTS: Subsequent allergic reactions to Erwinia asparaginase occurred in 7 of the 31 children (22.6%). In contrast to previous reports with intravenous administration, most allergic reactions to both asparaginase preparations were characterized by mild urticaria that responded to use of diphenhydramine; none of the reactions was life-threatening. CONCLUSIONS: In summary, the authors found Erwinia asparaginase to be an acceptable substitute for E. coli asparaginase for most children who had allergic reactions. Through the use of both E. coli and Erwinia asparaginase, 94% of children could receive their intended asparaginase.

Adolescent↗
PubMed1992

Quality-of-life evaluation in a clinical trial of zidovudine therapy in patients with mildly symptomatic HIV infection. The AIDS Clinical Trials Group.

OBJECTIVE: To evaluate the effects of zidovudine therapy in patients with mildly symptomatic HIV infection using Q-TWiST (quality-adjusted: Time Without Symptoms and Toxicity). DESIGN: Analysis of a previously reported multicenter, randomized, placebo-controlled clinical trial. SETTING: Thirty-two AIDS Clinical Trial units. PATIENTS: A total of 351 patients with mildly symptomatic HIV infection were assigned to placebo, and 360 patients were assigned to zidovudine, 1200 mg/d. MEASUREMENTS: A modified Q-TWiST method for comparing treatments based on time spent without severe symptomatic adverse events and without disease progression. Zidovudine and placebo were compared in a threshold utility analysis considering reduction in quality of life associated with adverse events and disease progression. Adverse events defined by laboratory findings were distinguished from findings representing symptomatic events. RESULTS: The incidence of severe symptomatic adverse events was 22.8% for the zidovudine group and 15.1% for the placebo group (P = 0.01), but, as previously reported, zidovudine improved progression-free survival relative to placebo (at 18 months, 91% compared with 81%; P = 0.001). In an 18-month period, patients receiving zidovudine went an average of 14.5 months without disease progression or a severe symptomatic adverse event compared with 14.7 months for placebo. The zidovudine group gained 0.9 months without disease progression but lost 1.1 months due to adverse events. Within the 18-month observation period, treatment provided more Q-TWiST than placebo if the quality of life after HIV disease progression was assumed to be 10% to 20% worse than the quality of life after a severe symptomatic adverse event. CONCLUSIONS: The Q-TWiST analysis projects that quality-of-life reductions due to severe symptomatic adverse events might be balanced by the quality-of-life benefits of delayed HIV disease progression for patients who received zidovudine for mildly symptomatic HIV infection. At currently recommended doses (500 to 600 mg/d, half the dose used in this study) zidovudine therapy is likely to yield a more favorable result.

Double-Blind Method↗
PubMed1992

Behavioral effects of corticosteroids in children with acute lymphoblastic leukemia.

We evaluated the behavior of 38 children with standard-risk and high-risk acute lymphoblastic leukemia who received corticosteroids as part of their antileukemia chemotherapy. Each patient was assessed on two occasions: 16 weeks following remission and 1 year thereafter. Parent reports on emotional lability, attention span/hyperactivity, sleep disturbance, listlessness, peer relations, and depressed mood were obtained for 4 consecutive weeks: week before, week during, and 2 weeks after treatment administration. At the 16 week evaluation, standard-risk (N = 17) and high-risk (N = 21) treatment differed by steroid dose and systemic chemotherapy, while at the 1 year testing, treatment differed only by steroid dose (prednisone 40 mg/m2 vs. 120 mg/m2). Statistically significant changes in all measures were observed during treatment as compared with before and after treatment for both risk groups and assessment times. High-risk patients exhibited greater behavioral effects than standard-risk patients only for emotional lability, listlessness, and depressed mood at the 16 week testing, when both steroid dose and chemotherapy differed. Girls had slightly greater behavioral effects than boys, while no influence of age was observed. At the doses tested, steroid dose per se does not appear to be the primary variable affecting behavioral changes.

Age Factors↗
PubMed1992

Quality of life measures for patients receiving adjuvant therapy for breast cancer: an international trial. The International Breast Cancer Study Group.

Serial quality of life (QL) assessments are being obtained every 3 months for 2 years from patients with operable breast cancer in two ongoing International Breast Cancer Study Group (IBCSG) randomised clinical trials of adjuvant treatment. The QL-assessments include patient-derived perceived coping (PACIS, personal adjustment to chronic illness scale), well-being (Bf-S, Befindlichkeitsskala von Zerssen), mood, physical well-being and appetite (LASA, linear analogue self assessments). The first assessment within 6 weeks of surgery was performed by 70% of the patients. The analysis of serial assessments for 265 patients with each of the first four assessments completed showed that all measures improved with increasing time from study entry; that the degrees of improvement for the four major language groups were similar; and that measures were sensitive to treatment difference. In conclusion, measurement of QL related aspects in a multicultural clinical trial is feasible and possibly relevant for the evaluation of treatment results.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Meta-analysis: the fashion of summing-up evidence. Part II: Interpretations and uses.

In this commentary, we use evidence produced by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) ten-year update of a meta-analysis of trials of adjuvant therapies for early breast cancer which started prior to 1985 to illustrate aspects of interpretations and uses of meta-analysis results. The following issues are discussed: i) The meta-analysis provides an average summary for the effect of a treatment. Greater statistical power is obtained by increasing the number of events contributing to the analysis. However, summing up the results of various trials necessitates the loss of individual information concerning the magnitude of treatment effects which depend on tumor- and patient-related factors. Subgroup analyses within the meta-analysis process allow some recovery of such features; ii) The absolute benefit obtained from an effective treatment depends not only on the relative benefit of the treatment but also on the prognosis of the individual patients; iii) The results are more immediately applicable if less reliance is placed on the arithmetic construct inherent in the overview, using instead unconfounded information about the value of treatments actually administered. This avoids the need to extrapolate the effect for one component of the therapy by assuming a lack of interaction with its other components; iv) Although indirect comparisons between different meta-analyses are regularly made to pick the "winner" from among tested treatment modalities, it is unlikely that the optimal therapeutic regimen can be defined via such indirect comparisons, though such comparisons may raise interesting, testable hypotheses.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Sequential estrogen receptor determinations from primary breast cancer and at relapse: prognostic and therapeutic relevance. The International Breast Cancer Study Group (formerly Ludwig Group).

We retrospectively evaluated 401 selected patients who had estrogen receptor (ER) assays both at primary surgery and at relapse in an accessible site to determine the clinical relevance of the subsequent ER determination. The median time between ER assessments was 27 months (range: 2-122 months). The median follow-up time from diagnosis was 6 years (range: 2-12 years). For patients with ER+ tumors at primary diagnosis, 29% (76/261) had ER- tumors at relapse, while for ER- primaries, the conversion rate was 33% (46/140). Conversions from ER+ to ER- occurred more often when the time interval between assays was less than one year (p = 0.004), while conversions from ER- to ER+ tended to occur late (beyond three years; p = 0.0003). Treatments received between assays (usually adjuvant therapy) had only a slight influence on ER status conversion. Post-relapse survival was poor for patients who had the biopsy accessible recurrence within one year; an expression of the aggressive nature of the disease. Among patients whose accessible relapse was beyond one year, those with ER- primaries who converted to ER+ had a longer survival than those whose recurrence was classified again as ER- (p = 0.006). This group of patients with ER- primaries who recurred beyond one year with an ER+ tumor in an accessible site represented 29% (40/140) of all patients with ER- primaries and had an estimated overall survival rate of more than 60% at 6 years from the accessible relapse. ER determination upon relapse within one year has very little clinical relevance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Factors predicting treatment responsiveness and prognosis in node-negative breast cancer. The International (Ludwig) Breast Cancer Study Group.

PURPOSE: An international trial (formerly Ludwig Trial V) has been conducted in 1,275 subjects to ascertain if perioperative chemotherapy is beneficial for node-negative breast cancer patients and to identify subgroups of patients who benefit from this therapy. PATIENTS AND METHODS: Node-negative breast cancer patients were randomized to receive either one cycle of perioperative chemotherapy or no adjuvant treatment. A detailed pathology review was conducted in 1,203 of the 1,275 patients enrolled. Stepwise Cox regression analysis was used to search for factors either predicting chemotherapeutic responsiveness and/or influencing disease-free survival (DFS). RESULTS: As expected, primary tumor size, grade, and the presence of peritumoral vascular invasion are the most important prognostic factors. Perioperative chemotherapy provides a DFS advantage at 5 years of median follow-up and such treatment is more effective for estrogen receptor-negative than for estrogen receptor-positive tumors, for histologic grade 2 and 3 than for grade 1 tumors, and for patients in whom no axillary lymph node metastases were found even after serial sectioning and review by the Central Pathology Laboratory. CONCLUSION: Hormone receptor status and tumor grade are important factors for predicting responsiveness to perioperative chemotherapy in node-negative breast cancer.

Adult↗
PubMed1992

The relationship of sex and treatment modality to neuropsychologic outcome in childhood acute lymphoblastic leukemia.

PURPOSE: Long-term adverse neurobehavioral sequelae frequently are observed in pediatric patients treated for acute lymphoblastic leukemia (ALL). To clarify the relative contribution of cranial irradiation (CRT) therapy and drug therapy to these outcomes, we evaluated neuropsychologic outcomes associated with different doses of CRT and intravenous (IV) methotrexate (MTX) in long-term survivors. PATIENTS AND METHODS: Fifty-one patients treated for ALL on Dana-Farber Cancer Institute protocol 81-01 were evaluated by standardized cognitive and academic achievement tests. These children had been assigned at diagnosis to a standard-risk (SR) or high-risk (HR) group and received 1,800 cGy or 2,800 cGy CRT, respectively. A subgroup of these patients was randomized to receive MTX during remission induction, either as a single low dose (LD; 40 mg/m2) or a single high dose (HD; 4 g/m2) with leucovorin rescue. RESULTS: Sex and MTX randomization jointly predicted the intelligence quotient (IQ). Fifty percent of girls versus 14% of boys exhibited low IQ (less than 90; P = .01); 80% of girls who received HD MTX versus 25% of girls who received LD MTX exhibited low IQ (P = .03). In contrast, risk group better predicted performance on tasks sensitive to verbal memory and/or coding. CONCLUSIONS: We conclude that (1) significant neurotoxicity occurred principally in girls; (2) increased dose intensity of IV MTX was associated with lower IQ, but only in girls; and (3) increased dose of CRT may have been associated with impairment of verbal memory and coding.

Adolescent↗
PubMed1992

Prognostic importance of c-erbB-2 expression in breast cancer. International (Ludwig) Breast Cancer Study Group.

PURPOSE: To evaluate the prognostic importance of immunocytochemically determined c-erbB-2 overexpression in the primary tumors of patients with breast cancer. PATIENTS AND METHODS: Primary tumors from 1,506 breast cancer patients (760 node-negative and 746 node-positive) who were treated in the International (Ludwig) Breast Cancer Study Group Trial V were studied. Node-negative patients were allocated randomly to either a single cycle of perioperative chemotherapy (PeCT) or no adjuvant treatment, and node-positive patients received either a prolonged chemotherapy (with tamoxifen for postmenopausal patients) or a single perioperative cycle. RESULTS: Tumors from 16% of the node-negative patients and 19% of the node-positive patients were found to be c-erbB-2-positive. In both groups c-erbB-2 positivity correlated with negative progesterone receptors (PR), negative estrogen receptors (ER), and high tumor grade. Lobular carcinomas were all negative, and, thus support the view that such tumors represent a defined subtype of breast carcinoma. The expression of c-erbB-2 was prognostically significant for node-positive but not for node-negative patients. However, in both subgroups, the prognostic significance was greater for patients who had received more adjuvant therapy. For node-positive patients, the effect of prolonged-duration therapy on disease-free survival (DFS) was greater for patients without c-erbB-2 overexpression (hazards ratio [HR], = 0.57; 95% confidence interval [CI], 0.46 to 0.72) than for those with c-erbB-2 overexpression (HR, 0.77; 95% CI, 0.51 to 1.16). Similarly, for node-negative patients, the effect of PeCT on DFS was greater for those without c-erbB-2 overexpression (HR, 0.82; 95% CI, 0.61 to 1.09) than for those with c-erbB-2 overexpression (HR, 1.22; 95% CI, 0.66 to 2.25). CONCLUSION: We conclude that tumors with overexpression of the c-erbB-2 oncogene are less responsive to cyclophosphamide, methotrexate, and fluorouracil (CMF)-containing adjuvant therapy regimens than those with a normal amount of gene product.

Adult↗
PubMed1992

Intensive sequential chemotherapy for children with acute myelogenous leukemia: VAPA, 80-035, and HI-C-Daze.

Between 1976 and 1988 we treated 228 children age 18 years or less with AML on three consecutive protocols: Vapa, 80-035 and Hi-C Daze. All three protocols used intensive consolidation chemotherapy. VAPA and 80-035 used an anthracycline with standard dose cytosine arabinoside (ara-c) for remission induction followed by twelve to fourteen months of intensive sequential chemotherapy. Results were similar for these two treatment protocols. 90/125 (72%) of the patients achieved a complete remission with 45% projected disease free survival for the complete responders, and an event free survival of 31%. 8/26 (VAPA) and 3/21 (80-035) relapses were primary CNS. No factor significantly influenced the rate of complete remission, but M4 and M5 FAB subtypes and WBC greater than 100,000/ul predicted for shorter remission duration. 103 children received Hi-C DAZE. The protocol differed by utilizing high-dose ara-c during induction and consolidation and pairing VP-16 with azacytidine. Hi-C DAZE was modified after the first 33 patients (group 1) because of CNS toxicity; VP-16/azacytidine were substituted for high dose ara-c/daunorubicin as the second induction course for the next 70 patients (group 2). Twenty eight of 33 (85%) of group 1 and 54/70 (77%) of group 2 entered remission.

Adolescent↗
PubMed1992

Quality of life in clinical trials of adjuvant therapies. International Breast Cancer Study Group (formerly Ludwig Group).

Clinical trials of adjuvant therapies usually measure the effectiveness of treatments by comparing disease-free survival or overall survival. These take into consideration only indirectly the quality of life experienced by the patients. We present some approaches that were developed to assess the impact of adjuvant therapy on the quality of life of breast cancer patients, as well as new methods created to compare treatments based on time spent without symptoms and toxicity (TWiST). The integration of these two methods (measuring quality and comparing duration of time) will provide a new tool for evaluating benefits from treatments given in the adjuvant setting.

Antineoplastic Agents↗
PubMed1992

Reporting and interpreting adjuvant therapy clinical trials. International Breast Cancer Study Group (formerly Ludwig Group).

Identifying effective adjuvant treatments for patients with node-negative breast cancer is made difficult by the heterogeneity of the disease, the relatively low event rate and long follow-up time required, and the small magnitude of effects of current therapies. Several aspects of clinical trials that influence the appropriate reporting and interpretation of statistical results are discussed. We point out that the P value is a measure of the statistical uncertainty of an observed outcome and depends on the number of events available for analysis; it is not a measure of the magnitude of a treatment effect. We recommend that the relative reduction in the risk of an event and its 95% confidence interval be presented as an estimate of the treatment effect size, and that absolute improvements be used to judge whether treatment benefits outweigh the costs for the patient population. We suggest that subgroup analyses are important to define treatment effects within groups with different prognoses, and should be used with the understanding that multiple comparisons increase the chance of a false-positive result. Subgroup analysis should rely on the estimates of relative treatment effect and should avoid the use of the P value to declare incorrectly that "treatment is effective for one subgroup but not for another." We present the meta-analysis (overview) as a powerful method to demonstrate the statistical significance of a modest treatment effect by increasing the number of events available for analysis. The interpretation of overviews should consider the potential for treatment interactions and the validity of indirect comparisons that are not protected by a randomized design.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Neoplasms↗
PubMed1992

A single perioperative adjuvant chemotherapy course for node-negative breast cancer: five-year results of trial V. International Breast Cancer Study Group (formerly Ludwig Group).

Twelve hundred seventy-five patients who were defined as having node-negative breast cancer were evaluated in a randomized trial that compared a single cycle of combination chemotherapy started within 36 hours of surgery (848 patients) with no adjuvant treatment (427 patients). The chemotherapy consisted of intravenous cyclophosphamide, methotrexate, and fluorouracil given on days 1 and 8. Leucovorin (given on days 2 and 9) was added to the regimen to decrease severe toxic effects attributed to drug interaction between nitrous oxide used in anesthesia and methotrexate given in the immediate postoperative period. At a median follow-up of 60 months, the 5 year disease-free survival (DFS) percentages (+/- SE) were 74% +/- 2% for the treated group, and 68% +/- 2% for the no adjuvant therapy group. The estimated hazard ratio [95% confidence interval (CI)] was 0.78 (0.63 to 0.96); P = .02, representing a 22% +/- 9% relative reduction in the risk of relapse. The overall survival (OS) difference was not statistically significant with 5-year OS percentages of 88% +/- 1% for the treated group, and 85% +/- 2% for the control group [estimated hazard ratio (95% CI) = 0.85 (0.62 to 1.16); P = .31]. A subgroup analysis by menopausal status and by estrogen-receptor (ER) status revealed that the treatment effect was largest among the postmenopausal women with ER-negative tumors. The 5-year DFS percentages were 79% +/- 4% and 56% +/- 7%, and the OS percentages were 91% +/- 3% and 70% +/- 6%, for the treated and control groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Low-dose versus high-dose methotrexate during remission induction in childhood acute lymphoblastic leukemia (Protocol 81-01 update).

We evaluated event-free survival (EFS) and leukemia-free interval (LFI) of children treated for acute lymphoblastic leukemia (ALL). Patients were randomized to receive either a low dose or high dose of methotrexate (MTX) as a single agent at the time of diagnosis. Five days later, multidrug therapy was begun. We assessed the early antileukemic efficacy of the two doses of MTX, as well as toxicity and long-term efficacy. An increase in cell kill, as indicated by a larger decrease in the percentage of viable cells in the bone marrow between days 0 and 5, was observed for the high-dose MTX group when compared with the low-dose MTX group (P = .04). At 7.1 years of median follow-up, the 38 children randomized to receive high-dose MTX had a better EFS and LFI compared with the 39 patients randomized to receive low-dose MTX. The 7-year percentages (+/- SE) for EFS were 82% +/- 6% for high-dose MTX and 69% +/- 7% for low-dose MTX (P = .13). The 7-year percentages for LFI were 91% +/- 5% and 69% +/- 7%, respectively (P = .01). We recommend that high-dose MTX be considered as an effective addition to induction therapy in childhood ALL.

Antineoplastic Combined Chemotherapy Protocols↗