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R J Gralla

Publications and source records attributed to R J Gralla.

At least 19 recordsLinked to original sources
PubMed2006

Combined data from two phase III trials of the NK1 antagonist aprepitant plus a 5HT 3 antagonist and a corticosteroid for prevention of chemotherapy-induced nausea and vomiting: effect of gender on treatment response.

GOALS OF WORK: Prevention of chemotherapy-induced nausea and vomiting (CINV) with standard antiemetics has been more difficult to achieve in female patients. Data from two phase III trials of the NK1 antagonist aprepitant were assessed for potential effect of gender on treatment response. PATIENTS AND METHODS: 1,044 patients receiving cisplatin (> or = 70 mg/m2) were randomly assigned to control regimen [ondansetron (O) 32 mg i.v. and dexamethasone (D) 20 mg p.o. on day 1; D 8 mg twice daily on days 2-4] or aprepitant (A) regimen (A 125 mg p.o. plus O 32 mg and D 12 mg on day 1; A 80 mg and D 8 mg once daily on days 2-3; and D 8 mg on day 4). The primary endpoint was overall complete response (no emesis and no rescue therapy over days 1-5). Data were analyzed by a modified intent-to-treat approach. Between-treatment comparisons for each gender were made using logistic regression. MAIN RESULTS: Women comprised 42 and 43% of the aprepitant and control groups, respectively. In the control group, 41% of women had overall complete response compared with 53% of men. In the aprepitant group, 66% of women had overall complete response compared with 69% of men. CONCLUSION: The addition of aprepitant may negate the adverse prognostic effect of female gender on the prevention of CINV in patients receiving highly emetogenic chemotherapy.

Adrenal Cortex Hormones↗
PubMed2005

A comparison of visual analogue and numerical rating scale formats for the Lung Cancer Symptom Scale (LCSS): does format affect patient ratings of symptoms and quality of life?

PROBLEM AND PURPOSE: The Lung Cancer Symptom Scale (LCSS), a site-specific health-related quality of life measure for patients with lung cancer, was originally developed using a Visual Analogue Scale (VAS) format. However, the VAS format is not readily compatible with data management and software programs using scanning. The primary aim of this study was to evaluate the convergence of ratings obtained with a Numerical Rating Scale (NRS), with an 11-pt response category format, to those obtained with a VAS format. The intent was to determine the degree of agreement between two formats to generalize the existing psychometric properties for the original measure to the new presentation. DESIGN/SETTING: This methodological study evaluated the feasibility, reliability, and validity of a NRS format for the LCSS. The study was conducted at two cancer centers in New York City. PATIENTS/PROCEDURES: Sixty-eight patients with non-small cell lung cancer (NSCLC) completed both versions of the LCSS along with demographic and feasibility questions on a single occasion. The VAS form was administered first, followed by the NRS form to prevent bias. The intraclass correlation coefficient (ICC), Lin's concordance correlation coefficient (CCC), and Bland-Altman plots were used to evaluate agreement and to characterize bias. RESULTS: Cronbach's alpha for the NRS format total score was 0.89 for the 68 patients with NSCLC. Agreement was excellent, with both the ICC and CCC > or = 0.90 for the two summary scores (total score and average symptom burden index) for the LCSS. Only five of the nine individual items showed this level of strict agreement. An agreement criterion of > or = 0.80 (representing excellent) was observed for seven of the nine individual items (all but appetite loss and hemoptysis). Mean differences tended to be slightly lower for the VAS format compared to the NRS format (more so for the appetite and hemoptysis items), with evidence of scale shift for the same two items. The summary measures showed good concordance as measured by the ICC and CCC, but did display mean differences (VAS - NRS) of -2.7 and -3.1, respectively. CONCLUSIONS: Overall, the NRS format for the LCSS suitable for scanning has good feasibility, reliability (internal consistency), and convergent validity. The complete set of concordance evaluation measures supports the reproducibility of VAS scores by NRS scores, particularly for the two summary scores.

Adult↗
PubMed2001

Multi-institutional phase I/II trial of oral bexarotene in combination with cisplatin and vinorelbine in previously untreated patients with advanced non-small-cell lung cancer.

PURPOSE: Bexarotene (Targretin; Ligand Pharmaceuticals, Inc, San Diego, CA) is a retinoid-X-receptor (RXR)-selective retinoid with preclinical antitumor activity in squamous cell cancers. In this phase I/II trial, we combined bexarotene with cisplatin and vinorelbine in the treatment of patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-three patients who had stage IIIB NSCLC with pleural effusion or stage IV NSCLC and had received no prior therapy received bexarotene in combination with cisplatin (100 mg/m2) and vinorelbine (alternating doses of 30 mg/m2 and 15 mg/m2). In the phase I portion, the daily dose of bexarotene was escalated in cohorts of three patients from 150 mg/m2 to 600 mg/m2, beginning 1 week before the start of the cisplatin-vinorelbine regimen. Once the maximum-tolerated dose (MTD) of bexarotene was determined, the study entered the phase II portion. Response rate was the primary end point; median survival time and 1-year survival rate were secondary end points. RESULTS: In the phase I portion, the daily MTD of bexarotene was determined to be 400 mg/m2. Eight of 43 patients exhibited major responses. Seven (25%) of the 28 patients in the phase II portion responded to treatment. The median survival time in the phase II portion was 14 months; nine (32%) of the 28 patients were still alive at a minimum follow-up of 2 years. One-year and projected 3-year survival rates were 61% and 30%, respectively. The most common grade 3 and 4 adverse events were hyperlipemia, leukopenia, nausea, vomiting, pneumonia, dyspnea, anemia, and asthenia. Grade 3 and 4 laboratory abnormalities with incidences greater than 5% were decreased hemoglobin levels and WBC, absolute neutrophil, and absolute lymphocyte counts and increased prothrombin time and creatinine and amylase levels. Of the two cases of pancreatitis, one required hospitalization and both were associated with increased triglyceride levels. There was one death secondary to renal insufficiency unrelated to bexarotene treatment. CONCLUSION: In patients with advanced NSCLC, bexarotene with cisplatin and vinorelbine yielded acceptable phase II response rates (25%) and was associated with better-than-expected survival (14-month median survival time; 61% 1-year, 32% 2-year, and 30% projected 3-year survival rates). The regimen should be studied in larger clinical trials.

Administration, Oral↗
PubMed1999

Reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist. L-754,030 Antiemetic Trials Group.

BACKGROUND: The localization of substance P in brain-stem regions associated with vomiting, and the results of studies in ferrets, led us to postulate that a neurokinin-1-receptor antagonist would be an antiemetic in patients receiving anticancer chemotherapy. METHODS: In a multicenter, double-blind, placebo-controlled trial involving 159 patients who had not previously received cisplatin, we evaluated the prevention of acute emesis (occurring within 24 hours) and delayed emesis (on days 2 to 5) after a single dose of cisplatin therapy (70 mg or more per square meter of body-surface area). Before receiving cisplatin, all the patients received granisetron (10 microg per kilogram of body weight intravenously) and dexamethasone (20 mg orally). The patients were randomly assigned to one of three treatments in addition to granisetron and dexamethasone: 400 mg of an oral trisubstituted morpholine acetal (also known as L-754,030) before cisplatin and 300 mg on days 2 to 5 (group 1), 400 mg of L-754,030 before cisplatin and placebo on days 2 to 5 (group 2), or placebo before cisplatin and placebo on days 2 to 5 (group 3). Additional medication was available at any time to treat occurrences of vomiting or nausea. RESULTS: In the acute-emesis phase, 93 percent of the patients in groups 1 and 2 combined and 67 percent of those in group 3 had no vomiting (P<0.001). In the delayed-emesis phase, 82 percent of the patients in group 1, 78 percent of those in group 2, and 33 percent of those in group 3 had no vomiting (P<0.001 for the comparison between group 1 or 2 and group 3). The median nausea score in the delayed-emesis phase was significantly lower in group 1 than in group 3 (P=0.003). No serious adverse events were attributed to L-754,030. CONCLUSIONS: The neurokinin-1-receptor antagonist L-754,030 prevents delayed emesis after treatment with cisplatin. Moreover, combining L-754,030 with granisetron plus dexamethasone improves the prevention of acute emesis.

Acetals↗
PubMed1999

Normative data and trends in quality of life from the Lung Cancer Symptom Scale (LCSS).

Normative data and trends for a disease- and site-specific quality of life (QL) instrument for individuals with lung cancer, the Lung Cancer Symptom Scale (LCSS), are presented to facilitate the user's interpretation of test scores. Data for patients enrolled in two large, identical, randomized trials of a new combination chemotherapy regimen for patients with stages III and IV non-small-cell lung cancer (NSCLC) were combined into one dataset (n = 673). For these patients with a Karnofsky performance status (KPS) of 60-100%, QL had been prospectively measured at baseline, day 29 and every 6 weeks thereafter. Descriptive statistics for the LCSS are presented for three time points (baseline, day 29 and day 71) and for specific demographic and disease-related characteristics (age, gender, race, performance status and stage of disease) to provide expected values and their variability during chemotherapy. Data from a small dataset of 63 NSCLC inpatients with KPS scores of 20-50% are also presented for a comparison sample of supportive care for inpatients and hospice patients. For the 673 NSCLC patients at baseline there were no significant differences in QL by age, gender, or race. Major presenting lung cancer symptoms at baseline for this combined sample were dyspnea 87%, cough 86%, pain 81%, loss of appetite 75%, and hemoptysis 41%. Of these patients, 81% had three or more presenting symptoms at baseline (2% had no symptoms; 5%, one symptom; 12%, two symptoms; 18%, three symptoms; 27%, four symptoms; and 36%, five symptoms). The mean LCSS baseline score (best = 0; worst = 100) was 26.56 (SD 16.10). The mean scores for day 29 and day 71 were 25.46 (SD 16.52) and 25.30 (SD 16.93), respectively, but follow-up assessments on progressers were not obtained. Stage III patients had a mean LCSS score of 23.7 (SD 15.1), whereas stage IV patients reported a mean LCSS score of 27.3 (SD 16.3). The mean LCSS score for the group with KPS 60-70% was 34.8 (SD 15.5), and that for the group with KPS 80-100% was 23.3 (SD 15.1). The mean LCSS score for the lower performance group, with KPS scores of 20-50% at baseline, was 46.85 (SD 17.65).

Adult↗
PubMed1999

Guidelines for anti-emetic therapy: acute emesis.

Anti-emetic therapy has become integral to the management of patients with cancer. Goals related to complete emesis control include providing treatment that reduces hospitalisation and time in the ambulatory setting, care that is convenient for the patient and therapy that enhances patients' quality of life. A panel of clinical, health economic and basic scientists with expertise in various oncology disciplines reviewed published literature to develop evidence-based consensus guidelines for the prevention and treatment of chemotherapy-induced emesis. Currently, serotonin receptor antagonists and corticosteroids are the two categories of anti-emetics that are most effective, have the fewest side-effects and are convenient to use. These agents are recommended in combination for highly emetogenic chemotherapy regimens and as single agents or in combination for moderately to highly emetogenic chemotherapy. When possible, these agents may be given orally in single doses; current evidence does not support dose escalation for either category of anti-emetics. In special situations, such as the use of high-dose chemotherapy combination regimens, the most emetogenic component of the regimen should dictate the choice of anti-emetic. Appropriate anti-emetic use described in these guidelines represents both good medical practice and a sensible economic approach to care.

Acute Disease↗
PubMed1999

Randomized phase II study of the neurokinin 1 receptor antagonist CJ-11,974 in the control of cisplatin-induced emesis.

PURPOSE: To determine the efficacy and safety of the neurokinin type 1 receptor antagonist CJ-11,974 for the control of high-dose cisplatin-induced emesis. PATIENTS AND METHODS: A double-blind, randomized, phase II design with a group sequential stopping rule was used in this study. Sixty-one patients with cancer who were receiving cisplatin at a dose of at least 100 mg/m2 for the first time were enrolled. All patients received granisetron 10 microg/kg and dexamethasone 20 mg intravenously 30 minutes before they were given cisplatin. Patients were randomly assigned to two groups: group 1 received CJ-11,974 100 mg, and group 2 received placebo orally 30 minutes before and 12 hours after cisplatin and then twice daily on days 2 through 5 after cisplatin. The primary end point was the percentage of patients who developed delayed emesis (emesis on the second to fifth days after cisplatin). RESULTS: Thirty patients were enrolled in group 1, and 31 patients were enrolled in group 2. Fifty-eight patients were assessable for efficacy. Complete control of emesis (expressed as the percentage of patients who had no emesis) was as follows: day 1, 85.7% (group 1) and 66.7% (group 2) (P = .090); days 2 through 5, 67.8% (group 1) and 36.6% (group 2) (P = .0425, adjusted); days 1 through 5, 64.3% (group 1) and 30% (group 2) (P = .009). Patients in group 1 experienced significantly less nausea than patients in group 2 on day 1 (P = .024). Treatment was well tolerated in both groups. CONCLUSION: We conclude from this exploratory phase II trial that CJ-11,974 is superior to placebo in controlling cisplatin-induced delayed emesis and may provide additive benefit in acute emesis and nausea control when combined with a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone. Additional larger trials are indicated to confirm the clinical value of CJ-11,974.

Adult↗
PubMed1998

Methodology of antiemetic trials: response assessment, evaluation of new agents and definition of chemotherapy emetogenicity.

Establishing appropriate and practical methodology is a key to progress in the investigation of chemotherapy-induced nausea and vomiting. Critical issues include patient response assessment, proper trial design for evaluating new agents, and the definition of chemotherapy emetogenicity. In assessing antiemetic response, the primary end-point should be complete control of emesis and nausea. Emesis and nausea should be independently assessed with the period of observation defined (acute, delayed, anticipatory). Emesis can be evaluated by measuring the number of emetic episodes either by direct observation or by patient self-report using patient-completed diaries. Nausea should be measured by patient self-report with the standard parameters, including frequency and intensity. New antiemetic drug development should proceed in an orderly progression from open-label phase I-II trials defining tolerance and minimally fully effective dose to phase III comparative trials. A randomized, parallel, double-blind study is the preferred design for the latter, and the comparator arm should always include the current best available treatment. Antiemetic placebos are no longer acceptable with chemotherapy regimens known to produce emesis in a majority of patients. None of the emetogenic classifications proposed to date adequately accounts for all known important patient- and treatment-related prognostic variables. A modification of a recently reported schema is proposed for use in making antiemetic treatment recommendations and defining the emetogenic challenge in clinical trials.

Antiemetics↗
PubMed1998

Consensus proposal for 5HT3 antagonists in the prevention of acute emesis related to highly emetogenic chemotherapy. Dose, schedule, and route of administration.

Selective antagonists to the Type 3 serotonin receptor (5HT3) in combination with corticosteroids are now considered the standard of care for the prevention of emesis from moderately to highly emetogenic chemotherapy. Here we address issues of optimal dose, schedule and route of administration of four currently available selectable 5HT3 antagonists. This paper utilizes an evidence based medicine approach to the literature regarding this class of drugs, emphasizing the results large, randomized, controlled trials to make formal recommendations concerning optimal use of this important new class of anti-emetic agents. We conclude that for each drug there is a plateau in therapeutic efficacy at a definable dose level above which further dose escalation does not improve outcome. Furthermore, a single dose is as effective as multiple doses or continuous infusion, and finally, emerging data demonstrate that the oral route is equally efficacious as the intravenous route of administration, even with highly emetogenic chemotherapy.

Antiemetics↗
PubMed1998

Single-dose oral granisetron has equivalent antiemetic efficacy to intravenous ondansetron for highly emetogenic cisplatin-based chemotherapy.

PURPOSE: To compare the antiemetic efficacy of a single dose of an oral antiemetic (granisetron 2 mg) with a single dose of an intravenous (i.v.) antiemetic (ondansetron 32 mg) given before cisplatin-based chemotherapy. PATIENTS AND METHODS: This was a multicenter, randomized, double-blind, parallel-group study. Patients (N = 1,054) scheduled to receive cisplatin (> or = 60 mg/m2)-based chemotherapy were randomized to receive either 2 mg of oral granisetron tablets 1 hour before chemotherapy (n = 534) or i.v. ondansetron (32 mg) 30 minutes before chemotherapy (n = 520). The primary efficacy end point was total control (no emesis, no nausea, and no use of antiemetic rescue medication) over the initial 24 hours after the start of chemotherapy. Dexamethasone or methylprednisolone were permitted, but not required, as concomitant prophylactic antiemetics. RESULTS: Total control was equivalent 24 hours after cisplatin chemotherapy for single-dose oral granisetron (54.7%) and i.v. ondansetron (58.3%) (95% confidence interval [CI], -9.6 to 2.4). Similar proportions of patients remained nausea-free in the granisetron group (55.4%) and the ondansetron group (59%) (95% CI, -9.6 to 2.4). The rate of complete control of emesis was 61.2% in the granisetron group and 67.1% in the ondansetron group (95% CI, -11.7 to -0.1). Both treatment regimens were well tolerated, with similar patterns of adverse reactions, generally of a mild degree. The most common side effects included constipation (14%), headache (15%), and diarrhea (10%). CONCLUSION: Oral granisetron, administered as a single 2-mg dose, provided equivalent total antiemetic control when compared with i.v. ondansetron (32 mg) in patients who received highly emetogenic, cisplatin-based chemotherapy.

Administration, Oral↗
PubMed1998

Efficacy of intravenous granisetron to control nausea and vomiting during multiple cycles of cisplatin-based chemotherapy.

The safety and efficacy of granisetron (10 micrograms/kg and 40 micrograms/kg) were evaluated during a second (n = 393) and third (n = 200) cycle of chemotherapy in this multicenter, double-blind, randomized, parallel-group study. Granisetron was administered as a single intravenous dose before the start of cisplatin chemotherapy (> or = 60 mg/m2). Total control (no vomiting, no retching, no nausea, and no use of antiemetic rescue medication) after the first 24 hr following chemotherapy was achieved in 40% and 49% of patients in Cycles 2 and 3, respectively, for the 10 micrograms/kg group, and in 42% and 38% of patients in Cycles 2 and 3, respectively, for the 40 micrograms/kg group. Both dose levels of granisetron were well tolerated. The results demonstrate comparable efficacy between the 10 micrograms/kg and 40 micrograms/kg doses of granisetron in preventing nausea and vomiting during repeat cycles of high-dose cisplatin-based chemotherapy. The results of this study show that granisetron 10 micrograms/kg is safe and well tolerated, and remains effective with repeat cycle use.

Adult↗
PubMed1997

Randomized, double blind, dose-response trial across four oral doses of dolasetron for the prevention of acute emesis after moderately emetogenic chemotherapy. Oral Dolasetron Dose-Response Study Group.

BACKGROUND: This double blind parallel group study assessed the acute antiemetic efficacy of four oral doses of dolasetron mesylate in cancer patients receiving their first course of intravenous chemotherapy with doxorubicin and/or cyclophosphamide. METHODS: Patients were randomized to receive 25, 50, 100, or 200 mg of dolasetron mesylate 30 minutes prior to chemotherapy and were monitored for nausea and emetic episodes for the next 24 hours. RESULTS: Three hundred and nineteen cancer patients at 32 sites completed the study. Most patients were female (81%); of this group, 69% had breast carcinoma. A highly statistically significant linear trend demonstrating improved response with higher doses was detected for complete response (no emetic episodes and no rescue medication) (P < 0.001), for complete plus major response (0-2 emetic episodes and no rescue medication) (P < 0.001), and for patient visual analog scale assessments of nausea (P = 0.001) and general satisfaction with antiemetic therapy (P = 0.001). No serious adverse events were noted. The most frequent adverse event was mild, self-limiting headache, which has been reported with other drugs in this class. CONCLUSIONS: Single oral doses of dolasetron mesylate were found to be effective in preventing acute emesis in cancer patients receiving moderately emetogenic chemotherapy.

Administration, Oral↗
PubMed1997

Efficacy and safety of different doses of granisetron for the prophylaxis of cisplatin-induced emesis.

The purpose of this study was to evaluate the efficacy and safety of four different doses of granisetron when administered as a single intravenous (i.v.) dose for prophylaxis of cisplatin-induced emesis in a multicenter, randomized, parallel-group, double-blind investigation. A total of 353 chemotherapy-naive patients were enrolled, stratified according to cisplatin dose (moderate dose: 50-80 mg/m2, n = 169; high dose: 81-120 mg/m2, n = 184) and randomized to one of four granisetron doses: 5, 10, 20, or 40 micrograms/kg. Control of emesis was evaluated by the percentages of patients attaining complete response (no vomiting or retching, and no rescue medication) and major response (< or = 2 episodes of vomiting or retching, and no rescue medication). Patients were assessed on an inpatient basis for 18-24 h. Safety analyses consisted of adverse events and laboratory parameter changes. Complete response rates over 24 h after chemotherapy were 23%, 48%, 48%, and 44% for granisetron doses of 5, 10, 20, and 40 micrograms/kg, respectively, in the combined patient population (P = 0.011 for linear trend); 29%, 56%, 58%, and 41%, respectively, in the moderate-dose cisplatin stratum (P = 0.278 for linear trend); and 18%, 41%, 40%, and 47%, respectively, in the high-dose cisplatin stratum (P = 0.011 for linear trend). Transient headache was the most frequently reported adverse event (19%). There was no evidence of association between increased dose and headache. A single 10-, 20- or 40-micrograms/kg dose of granisetron is comparably effective in controlling nausea and vomiting associated with moderate or high-dose cisplatin chemotherapy. Granisetron was safe and well tolerated at all doses.

Adult↗
PubMed1997

Clinical and methodological issues in antiemetic therapy: a worldwide survey of experts' opinions. Multinational Association of Supportive Care in Cancer.

During the 1995 Multinational Association of Supportive Care in Cancer (MASCC) Congress, a consensus conference was planned by the Subcommittee for Antiemetics. To define the topics to be discussed, a questionnaire containing both clinical and methodological issues was sent to 118 experts in 31 countries. The questionnaire contained 33 items on clinical and 19 items on methodological issues, and each response was rated on a 4-level categorical scale. The clinical issues were evaluated for interest, that is clinical importance, and feasibility, that is availability of sufficient data to make them suitable topics for the consensus conference. About 60% of questionnaires were returned, with a small number of missing responses. The responses to the items of clinical interest showed that about two-thirds of the issues identified by the Subcommittee were found by the experts to be of at least high interest, but often the availability of data was found to be insufficient for their discussion. Prevention of acute emesis induced by cisplatin and by moderately emetogenic chemotherapy and the optimal intravenous dose and schedule of the 5-HT3 receptor antagonists were the items with the highest interest and feasibility. The issues in the methodological section were also mostly found to be of at least high interest. The distinction between acute and delayed emesis, the evaluation of the persistence of antiemetic efficacy in subsequent cycles of chemotherapy and the statistical analysis of delayed emesis were the methodological issues in which the highest interest was recorded. Data collected will be used to define the main topics to be discussed during the planned consensus conference.

Antiemetics↗
PubMed1997

A dilemma in analysis: issues in the serial measurement of quality of life in patients with advanced lung cancer.

Despite the availability of several instruments to evaluate quality of life (QL) over time in patients with lung cancer, barriers in measurement remain. This methodological study used LCSS data (Lung Cancer Symptom Scale, a disease- and site-specific QL measure) to examine analysis methods to quantify QL where data needed for serial evaluation may be missing. Data from two large randomized trials, conducted at 30 centers, of a new combination chemotherapy regimen incorporating a new agent for patients (n = 673) with Stage III and IV non-small cell lung cancer were obtained for this study. QL had been prospectively measured at baseline, day 29, and every six weeks thereafter using the LCSS. For the slope analysis (SA) and area under the curve (AUC) analyses, an adjustment score of zero was used to indicate QL on the day of death (mortality adjustment) and each subsequent day until the end of the assessment period. Significant differences in QL, symptom scores and known prognostic factors at baseline were found in the attrition group. SA and AUC analysis allowed inclusion of 581 patients, giving an adequacy rate of 86%. By using a mortality adjustment, an additional 45 patients were included, increasing the inclusion rate to 93%. With the use of the mortality adjustment, QL was shown to decline over the interval, as opposed to rise if the adjustment had not been performed. The conclusions of the study were: (1) analysis for serial data using SA and AUC provides useful, but differing information; (2) when attrition (caused by death) is a factor, a mortality adjustment presented a more accurate assessment of QL as an endpoint; (3) more frequent evaluations of QL will capture rapid changes in patient status and reduce the attrition bias; (4) all patients should be followed until they die; and (5) QL should be given full consideration as a primary endpoint separate from survival.

Aged↗