2023 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following high-emetic-risk antineoplastic agents.

PURPOSE: This systematic review updates the MASCC/ESMO recommendations for high-emetic-risk chemotherapy (HEC) published in 2016-2017. HEC still includes cisplatin, carmustine, dacarbazine, mechlorethamine, streptozocin, and cyclophosphamide in doses of > 1500 mg/m2 and the combination of cyclophosphamide and an anthracycline (AC) in women with breast cancer. METHODS: A systematic review report following the PRISMA guidelines of the literature from January 1, 2015, until February 1, 2023, was performed. PubMed (Ovid), Scopus (Google), and the Cochrane Database of Systematic Reviews were searched. The literature search was limited to randomized controlled trials, systematic reviews, and meta-analyses. RESULTS: Forty-six new references were determined to be relevant. The main topics identified were (1) steroid-sparing regimens, (2) olanzapine-containing regimens, and (3) other issues such as comparisons of antiemetics of the same drug class, intravenous NK1 receptor antagonists, and potentially new antiemetics. Five updated recommendations are presented. CONCLUSION: There is no need to prescribe steroids (dexamethasone) beyond day 1 after AC HEC, whereas a 4-day regimen is recommended in non-AC HEC. Olanzapine is now recommended as a fixed part of a four-drug prophylactic antiemetic regimen in both non-AC and AC HEC. No major differences between 5-HT3 receptor antagonists or between NK1 receptor antagonists were identified. No new antiemetic agents qualified for inclusion in the updated recommendations.

Phase III safety study of intravenous NEPA: a novel fixed antiemetic combination of fosnetupitant and palonosetron in patients receiving highly emetogenic chemotherapy.

Background: NEPA, an oral fixed combination of the NK1RA netupitant (300 mg) and clinically/pharmacologically distinct 5-HT3RA palonosetron (PALO, 0.50 mg), is the first fixed antiemetic combination to have been approved. A single oral NEPA capsule plus dexamethasone (DEX) given before anthracycline-cyclophosphamide (AC) and non-AC highly emetogenic chemotherapy (HEC) showed superior prevention of chemotherapy-induced nausea and vomiting (CINV) over PALO plus DEX for 5 days postchemotherapy. The safety of NEPA was well-established in the phase II/III clinical program in 1169 NEPA-treated patients. An intravenous (i.v.) formulation of the NEPA combination (fosnetupitant 235 mg plus PALO 0.25 mg) has been developed. Patients and methods: This randomized, multinational, double-blind, stratified (by sex and country) phase III study (NCT02517021) in chemotherapy-naïve patients with solid tumors assessed the safety of a single dose of i.v. NEPA infused over 30 min before initial and repeated cycles of HEC. Patients received either i.v. NEPA or oral NEPA, both with oral DEX on days 1-4. Safety was assessed primarily by treatment-emergent adverse events (AEs) and electrocardiograms. Results: A total of 404 patients completed 1312 cycles. The incidence and type of treatment-emergent AEs were similar for both treatment groups with the majority of AEs as mild/moderate in intensity. There was no increased incidence of AEs in subsequent cycles in either group. The incidence of treatment-related AEs was similar and relatively low in both groups (12.8% i.v. NEPA and 11.4% oral NEPA during the entire study), with constipation being the most common (6.4% i.v. NEPA, 6.0% oral NEPA). No serious treatment-related AEs occurred in either group. No infusion site or anaphylactic reactions related to i.v. NEPA occurred. No clinically relevant changes in QTc and no cardiac safety concerns were observed. Conclusions: Intravenous NEPA was well-tolerated with a similar safety profile to oral NEPA in patients with various solid tumors receiving HEC.

Rolapitant hydrochloride: prophylactic treatment for chemotherapy-induced nausea and vomiting.

Chemotherapy-induced nausea and vomiting (CINV) is a significant clinical issue which affects patients' quality of life as well as treatment decisions. Significant improvements in the control of CINV have occurred in the past 15 years with the introduction of new antiemetic agents: 5-HT3 receptor antagonists, tachykinin NK1 receptor antagonists and olanzapine. Aprepitant was the first NK1 receptor antagonist introduced (2003) for the prevention of CINV in combination with a 5-HT3 receptor antagonist and dexamethasone. Two additional NK1 receptor antagonists, netupitant and rolapitant, were approved by the FDA in 2014 and 2015, respectively. A description of rolapitant and its role in CINV will be presented, along with a comparison to the other NK1 receptor antagonists, aprepitant and netupitant.

Comparison of intermittent versus continuous infusion metoclopramide in control of acute nausea induced by cisplatin chemotherapy.

Sixty previously untreated patients with newly diagnosed advanced-stage lung cancer (21 small-cell, 39 non-small-cell) received chemotherapy with cisplatin and etoposide. Bleomycin was also used in the patients with non-small-cell lung cancer. During the first cycle of chemotherapy, 30 patients received antiemetic therapy with intermittent metoclopramide (regimen A), and the other 30 patients received continuous infusion metoclopramide (regimen B). During the second course of chemotherapy, patients were switched to the alternate regimen. Regimen A consisted of lorazepam, 1 mg, orally; dexamethasone, 10 mg, intravenously (IV) every four hours for three doses; diphenhydramine, 0.5 mg/kg, IV every four hours for three doses; metoclopramide, 1 mg/kg, IV bolus every two hours for six doses. Regimen B was identical to A except metoclopramide was administered as 1 mg/kg, IV bolus followed by 0.5 mg/kg/h for ten hours. Fifty-eight patients completed both antiemetic regimens. Thirty-nine of the 58 patients had total control of acute nausea and vomiting (0-1 episodes) with regimen A or B. Fourteen patients had poor control of acute nausea and vomiting (more than one episode) with regimen A but total control with regimen B. Five patients had poor control with either regimen. Dystonic reactions, akathisia, or diarrhea occurred in 20 of the 58 patients on regimen A, but in only eight of the 58 patients on regimen B. Compared with intermittent bolus, continuous infusion metoclopramide is more effective in total control of acute nausea and vomiting and has less toxicity.

Comparative clinical trial of granisetron and ondansetron in the prophylaxis of cisplatin-induced emesis. The Granisetron Study Group.

PURPOSE: To compare the efficacy and safety of granisetron and ondansetron, serotonin (5-HT3) receptor antagonists shown to be effective in the prevention of chemotherapy-induced emesis. PATIENTS AND METHODS: In a double-blind, randomized, stratified, parallel-group study, the efficacy and safety of granisetron and ondansetron were compared in 987 chemotherapy-naive patients who received cisplatin in doses > or = 60 mg/m2. Granisetron was administered as a single dose of 10 or 40 micrograms/kg before the start of chemotherapy. Ondansetron was administered in doses of 0.15 mg/kg before and 4 and 8 hours after the start of chemotherapy. The three treatment groups were well-matched with respect to demographic characteristics and the dose of cisplatin administered. RESULTS: For all evaluations, single doses of granisetron 10 or 40 micrograms/kg were as effective as three 0.15-mg/kg doses of ondansetron. Total control (no vomiting, no retching, no nausea, and no use of rescue) was attained by 38%, 41%, and 39% of all patients who received granisetron 10 microgram/kg, granisetron 40 micrograms/kg, and ondansetron, respectively. No vomiting or retching and no use of rescue antiemetics were reported in 47%, 48%, and 51% of patients who received granisetron 10 micrograms/kg, granisetron 40 micrograms/kg, and ondansetron, respectively; no nausea and no use of rescue antiemetics were reported in 39%, 42%, and 40% of patients, respectively. CONCLUSION: All three treatment regimens were well-tolerated. The results of this study indicate that a single dose of granisetron 10 or 40 micrograms/kg is as effective as three doses of ondansetron 0.15 mg/kg in the prevention of nausea and vomiting induced by cisplatin chemotherapy.

Efficacy and safety of granisetron, a selective 5-hydroxytryptamine-3 receptor antagonist, in the prevention of nausea and vomiting induced by high-dose cisplatin.

PURPOSE: To assess the antiemetic effects and safety profile of four different doses of granisetron (Kytril; SmithKline Beecham Pharmaceuticals, Philadelphia, PA) when administered as a single intravenous (IV) dose for prophylaxis of cisplatin-induced nausea and vomiting. PATIENTS AND METHODS: One hundred eighty-four chemotherapy-naive patients receiving high-dose cisplatin (81 to 120 mg/m2) were randomized to receive one of four granisetron doses (5, 10, 20, or 40 micrograms/kg) administered before chemotherapy. Patients were observed on an inpatient basis for 18 to 24 hours, and vital signs, nausea, vomiting, retching, and appetite were assessed. Safety analyses included incidence of adverse experiences and laboratory parameter changes. RESULTS: After granisetron doses of 5, 10, 20, and 40 micrograms/kg, a major response (< or = two vomiting or retching episodes, and no antiemetic rescue) was recorded in 23%, 57%, 58%, and 60% of patients, respectively, and a complete response (no vomiting or retching, and no antiemetic rescue) in 18%, 41%, 40%, and 47% of patients, respectively. There was a statistically longer time to first episode of nausea (P = .0015) and vomiting (P = .0001), and fewer patients were administered additional antiemetic medication in the 10-micrograms/kg dosing groups than in the 5-micrograms/kg dosing group. As granisetron dose increased, appetite return increased (P = .040). Headache was the most frequently reported adverse event (20%). CONCLUSION: A single 10-, 20-, or 40-micrograms/kg dose of granisetron was effective in controlling vomiting in 57% to 60% of patients who received cisplatin at doses greater than 81 mg/m2 and totally prevented vomiting in 40% to 47% of patients. There were no statistically significant differences in efficacy between the 10-micrograms/kg dose and the 20- and 40-micrograms/kg doses. Granisetron was well tolerated at all doses.

Oral ondansetron for the control of cisplatin-induced delayed emesis: a large, multicenter, double-blind, randomized comparative trial of ondansetron versus placebo.

PURPOSE: To investigate the efficacy and safety of oral ondansetron in the control of cisplatin-induced delayed emesis in patients who do not require rescue antiemetic therapy for acute emesis. PATIENTS AND METHODS: Five hundred thirty-eight chemotherapy-naive patients who received cisplatin chemotherapy (> or = 70 mg/m2), and who were not rescued for acute emesis, were eligible to be randomized to receive one of the three oral regimens to control delayed emesis. Group I received placebo on days 2 to 6; group II received ondansetron 8 mg twice daily on days 2 and 3 and placebo on days 4 to 6; group III received ondansetron 8 mg twice daily on days 2 to 6. All patients received intravenous ondansetron (0.15 mg/kg every 4 hours for three doses) for the control of acute emesis on day 1. The number of emetic episodes on days 2 and 3 combined (days 2/3, when incidence and severity of delayed emesis were expected to be greatest) was considered the primary measure of efficacy. RESULTS: Patients who received odansetron had significantly fewer emetic episodes on days 2/3, 4, and 5 than those who received placebo (P < or = .002 on each day). Additionally, significantly more patients who received ondansetron had a complete plus major response (C+MR; < or = two two emetic episodes) than those who received placebo on days 2/3 (56% v 37%, P = .001), 4 (94% v 85%, P = .005), and 5 (98% v 88%, P = .006). Patients who received ondansetron had significantly less nausea on day 2/3 when day-1 nausea was used as the baseline score (P = .025). Patients who received ondansetron also had significantly less nausea on day 4 (P = .042) and the results approached significance on day 5 (P = .066). CONCLUSION: Oral ondansetron had a significant effect in the control of cisplatin-induced delayed emesis and nausea in patients who had not required rescue antiemetics during the acute emesis period. The control of delayed nausea and vomiting was most notable in the immediate 2 days following cisplatin administration, with the clinical difference narrowing between the two treatment arms on subsequent days.

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.

Double-blind, randomized comparison of the antiemetic efficacy of intravenous dolasetron mesylate and intravenous ondansetron in the prevention of acute cisplatin-induced emesis in patients with cancer. Dolasetron Comparative Chemotherapy-induced Emesis Prevention Group.

PURPOSE: To assess the comparative antiemetic efficacy of single-dose intravenous (IV) dolasetron mesylate and ondansetron in preventing cisplatin-induced nausea and vomiting. PATIENTS AND METHODS: Cancer patients (n = 609) receiving first-course cisplatin chemotherapy were randomized to one of three treatments: 1.8 or 2.4 mg/kg dolasetron mesylate salt (equivalent to 1.3 and 1.8 mg/kg dolasetron base, respectively) or 32 mg ondansetron. Each treatment was infused over 15 minutes, 30 minutes before cisplatin administration. Patients were stratified to cisplatin doses of > or = 70 and less than 91 mg/m2 (n = 368) or > or = 91 mg/m2 (n = 241), administered over < or = 3 hours. Protocol-defined efficacy criteria included complete response (zero emetic episodes and no rescue medication), major response (1 to 2 emetic episodes and no rescue medication), and patients' report of nausea severity and satisfaction recorded on a 100-mm visual analog scale (VAS). RESULTS: The three treatments met protocol-specified criteria for equivalence. Complete response rates for dolasetron mesylate 1.8 mg/kg, 2.4 mg/kg, and ondansetron, respectively, were 49.2%, 45.6%, and 50.4% for patients in the lower cisplatin stratum (mean, 74.7 mg/m2) and 36.8%, 31.3%, and 31.8% in the higher cisplatin stratum (mean, 100.6 mg/m2). No significant differences were observed in the extent of nausea with either dolasetron dose compared with ondansetron. Less nausea was noted with 1.8 mg/kg dolasetron compared with the 2.4 mg/kg dose (P = .044) All three antiemetic treatments were well tolerated. Asymptomatic electrocardiogram changes were recorded with both dolasetron and ondansetron. CONCLUSION: A single IV dose of dolasetron mesylate (1.8 or 2.4 mg/kg) has comparable safety and efficacy to a single 32-mg IV dose of ondansetron in patients receiving cisplatin chemotherapy.

Stratified, randomized, double-blind comparison of intravenous ondansetron administered as a multiple-dose regimen versus two single-dose regimens in the prevention of cisplatin-induced nausea and vomiting.

PURPOSE: This study compares the efficacy and safety of two single-dose regimens with the approved three-dose regimen of ondansetron in the prevention of cisplatin-induced emesis. PATIENTS AND METHODS: This multicenter study was a stratified, randomized, double-blind, and parallel group design. Chemotherapy-naive inpatients were randomized to receive intravenous (IV) ondansetron (Zofran; Glaxo Inc, Research Triangle Park, NC) 0.15 mg/kg times three doses, every 4 hours or a single 8-mg or 32-mg dose followed by two saline doses that began 30 minutes before cisplatin administration. Cisplatin (high-dose > or = 100 mg/m2 or medium-dose 50 to 70 mg/m2) was given as a single infusion (< or = 3 hours). Patients were monitored for emetic episodes, adverse events, and laboratory safety parameters for 24 hours after cisplatin administration. RESULTS: A total of 699 patients (359 high-dose, 340 medium-dose) were enrolled. Of these, 618 were assessable for efficacy (15 ineligible, 66 protocol deviations). The 32-mg dose was superior to the 8-mg single dose with regard to total number of emetic episodes (high-dose, P = .015; medium-dose, P < .001), complete response (no emetic episodes: high-dose, 48% v 35%; P = .048; medium-dose, 73% v 50%; P = .001) and failure rate (> 5 emetic episodes, withdrawn or rescued: high-dose, 20% v 34%; P = .018; medium-dose, 9% v 23%; P = .005). The 32-mg single dose was also superior to the 0.15 mg/kg times three dose regimen with regard to total number of emetic episodes (medium-dose, P = .033) and failure rate (high-dose, 20% v 36%; P = .009; medium-dose, 9% v 22%; P = .011). Ondansetron was well tolerated. The most common adverse event was headache. An approximate 10-fold increase in the incidence of clinically significant transaminase elevations was observed in the high-dose versus medium-dose cisplatin strata (aspartate aminotransferase [AST], 6.5% v 0.7%; serum alanine aminotransferase [ALT], 5.0% v 0.3%). CONCLUSION: A 32-mg single dose of ondansetron is more effective than a single 8-mg dose and is at least as effective as the standard regimen of 0.15 mg/kg times three doses in the prevention of cisplatin-induced acute emesis.

Prevention of acute emesis in cancer patients following high-dose cisplatin with the combination of oral dolasetron and dexamethasone.

PURPOSE: Dolasetron is a 5-HT3 antagonist antiemetic with active oral and intravenous formulations. The effects of this class are enhanced when combined with dexamethasone. This study tested the ability of the combination of oral dolasetron 200 mg and oral dexamethasone 20 mg to prevent acute emesis in cancer patients receiving initial cisplatin at doses > or = 70 mg/m2. Additionally, patients were randomly assigned to receive a second dosage of the regimen 16 hours later to improve control of acute symptoms. PATIENTS AND METHODS: A total of 75 patients were entered, with 38 randomized to the two-dose regimen. Thirty-five percent were women and 77% had lung cancer. RESULTS: Overall, the regimen prevented acute vomiting in 76% (95% confidence interval, 65% to 85%), including 74% of 35 patients who received cisplatin at doses > or = 100 mg/m2. There was no observed difference in emesis prevention between the one-dose (76%) and two-dose (76%) regimens (95% confidence interval for the difference, -20% to 19%). The median time to the onset of emesis was 19 hours for the one-dose regimen and 17 hours for the two-dose regimen in those patients with emesis. Headache occurred in 11% who received one dose and 16% who received two doses. CONCLUSION: The combination of oral dolasetron 200 mg and dexamethasone 20 mg given only once prevented acute emesis in 76% of patients who received cisplatin > or = 70 mg/m2. Administration of a second dose of the regimen did not improve the observed prevention rate or delay the time to emesis. This one-dose oral regimen has comparable or better effectiveness than reported results of intravenous combination regimens in preventing cisplatin-induced vomiting and merits further study and use.

Phase III double-blind comparison of dolasetron mesylate and ondansetron and an evaluation of the additive role of dexamethasone in the prevention of acute and delayed nausea and vomiting due to moderately emetogenic chemotherapy.

PURPOSE: To compare the efficacy of dolasetron and ondansetron in controlling nausea and vomiting in the first 24 hours; to evaluate the efficacy when dexamethasone is added to either drug in the first 24 hours; and to extend these comparisons over 7 days in patients receiving moderately emetogenic chemotherapy. PATIENTS AND METHODS: This was a multicenter, double-blind, randomized study with six parallel arms that used a 2 x 2 factorial design in chemotherapy-naive patients. In arm 1, dolasetron (2.4 mg/kg) was given intravenously (I.V.) prechemotherapy, followed 24 hours later by oral dolasetron (200 mg once daily) for 6 days. Arms 2 and 3 consisted of dolasetron and dexamethasone 8 mg I.V., followed 24 hours later by oral dexamethasone (8 mg once daily) in one arm, and oral dexamethasone and dolasetron in the other, also for 6 days. In arms 4, 5, and 6, ondansetron (32 mg I.V. or 8 mg orally twice daily) was administered in a similar manner to arms 1, 2, and 3 before and 24 hours after chemotherapy. Mean nausea severity (MNS) was assessed on a visual analog scale (VAS) in a daily diary. RESULTS: Of 703 patients enrolled, 696 were eligible. There were 343 dolasetron- and 353 ondansetron-treated patients; 57% of dolasetron-treated patients had complete protection in the first 24 hours versus 67% of patients who received ondansetron (P = .013). MNS was also more pronounced on the dolasetron arm (P = .051). Sixty-seven percent of patients who received added dexamethasone in the first 24 hours had complete protection, compared with 55% without dexamethasone (P < .001). MNS was significantly reduced with the addition of dexamethasone (P < .001). At 7 days, dolasetron and ondansetron had equivalent complete protection rates (36% and 39%, respectively). With the addition of dexamethasone, 48% of patients compared with 28% had complete protection (P < .001). MNS was significantly improved with added dexamethasone (P < .001). CONCLUSION: At the doses used, dolasetron was significantly less effective than ondansetron at controlling nausea and vomiting in the first 24 hours in patients receiving moderately emetogenic chemotherapy, but there was no demonstrable difference between both drugs over 7 days. The addition of dexamethasone significantly improved the efficacy of both drugs in the first 24 hours and over 7 days.

Treatment of cancer-associated hypercalcemia. Double-blind comparison of rapid and slow intravenous infusion regimens of pamidronate disodium and saline alone.

BACKGROUND: We assessed the effects of 60-mg single doses of pamidronate disodium compared with saline alone in the treatment of cancer-associated hypercalcemia. METHODS: After pretreatment hydration, patients with corrected serum calcium concentrations of 3.0 mmol/L (12 mg/dL) or greater secondary to cancer were randomized to double-blind treatment with a single infusion of pamidronate disodium, 60 mg, over either 4 or 24 hours or continued infusions of 0.9% saline alone (n = 23 per group). Corrected serum calcium levels were measured daily for 7 days of inpatient evaluation. RESULTS: Response rates for both of the pamidronate regimens were significantly (P < .05) higher than that for saline alone. A complete response to treatment (corrected serum calcium concentration normalized) was observed for five (22%), 18 (78%), and 14 (61%) patients, respectively, who received saline alone, 4-hour infusion of pamidronate, and 24-hour infusion of pamidronate. There were no significant differences between the two pamidronate regimens. Median durations of complete response were 6, 6, and 11 days, respectively, and median times to relapse (includes complete plus partial responders and nonresponders) were 0, 7, and 7 days, respectively. Pamidronate was well tolerated as assessed by all clinical and laboratory measures, regardless of the time of infusion. CONCLUSIONS: A 4-hour infusion of pamidronate disodium, 60 mg, was as safe and effective as a 24-hour infusion, and both were superior to saline alone in lowering corrected serum calcium concentrations in patients with cancer-associated hypercalcemia.

Specificity of low dose fadrozole hydrochloride (CGS 16949A) as an aromatase inhibitor.

CGS 16949A (fadrozole hydrochloride), a potent cytochrome P450-mediated steroidogenesis inhibitor, blocks aromatase at low doses, but other biosynthetic steps at higher concentrations. Recent studies demonstrated inhibition of C11-hydroxylase, corticosterone methyloxidase-II, and deoxycorticosterone to corticosterone conversion with this agent at some-what higher concentrations than those required for blockade of aromatase. Based upon phase I studies, we postulated that relatively selective inhibition of aromatase might be possible if sufficiently low doses of CGS 16949A were used. A phase II study in 54 postmenopausal women with metastatic breast cancer examined the effects of low dose CGS 16949A on estrogen, mineralocorticoid, and glucocorticoid secretion. Two dose schedules and two dose levels were chosen based upon our prior dose escalation protocol study. Plasma estrone, estradiol, and estrone sulfate as well as urinary estrone and estradiol fell equally with 1.8-4 mg CGS 16949A given either on a twice daily or three times daily dose schedule. Isotopic kinetic studies demonstrated an 84% decrease in the rate of conversion of androstenedione to estrone to 0.40 +/- 0.07% (patients receiving 1.8-4 mg CGS 16949A daily). With these three regimens, basal levels of aldosterone and cortisol did not change significantly over a 12-week period of observation. Clinical examination, plasma electrolytes, and urinary sodium/potassium ratios suggested no biological evidence of mineralo-corticoid deficiency. ACTH-stimulated cortisol concentrations, however, were blunted at each dose level compared to pretreatment values. Nonetheless, peak responses exceeded 550 nmol/L, or a basal to peak difference of 190 nmol/L or greater, in 97% of instances. This probably reflected inhibition of C11-hydroxylase, since basal and ACTH-stimulated levels of 11-deoxycortisol were increased in response to CGS 16949A. Androstenedione and 17 alpha-hydroxyprogesterone also exhibited an upward trend in response to drug treatment. ACTH-stimulated aldosterone levels were blunted to a greater extent than those of cortisol, probably as a reflection of corticosterone methyloxidase type II blockade. Overall, the results suggest that CGS 16949A, at doses of 1.8-2 mg daily, blocks aromatase effectively and does not produce clinically important inhibition of cortisol or aldosterone biosynthesis. Thus, this agent can probably be used safely without glucocorticoid or mineralocorticoid supplementation.

Prophylaxis of infection in patients with aplastic anemia receiving allogeneic marrow transplants.

One hundred one patients with severe aplastic anemia underwent allogeneic marrow transplantation and received one of three forms of infection prophylaxis: oral nonabsorbable antibiotics and isolation and decontamination in a laminar airflow room (36 patients); prophylactic granulocyte transfusions from a single family member donor (33 patients); or conventional treatment in single rooms with hand-washing and mask precautions (31 patients). During the period of granulocytopenia, patients in the laminar airflow rooms acquired fewer infections than either of the other groups, but this difference was statistically significant only when compared with the group receiving conventional treatment. Patients in the laminar airflow rooms had significantly fewer infections after engraftment as compared with the other two groups. Incidence of interstitial pneumonia and graft rejection was not different among the three groups. Acute graft-versus-host disease occurred later (Day 47) in the group in the laminar airflow rooms as compared with the group receiving prophylactic granulocyte transfusions (Day 23) or the group receiving conventional treatment (Day 20). The incidence of grades II to IV acute graft-versus-host disease was less in the patients in the laminar airflow rooms but only reached borderline significance (p = 0.08) when compared with the conventionally treated patients. The survival at Day 100 was 92 percent for the group in the laminar airflow rooms, 79 percent for the group receiving prophylactic granulocyte transfusions, and 64 percent for the group receiving conventional treatment.

Mycobacterial infections in marrow transplant patients.

Bone marrow transplant recipients undergo ablation of host immune defenses with total-body irradiation or high dose chemotherapy, or both. Over a 5.6-year period, mycobacterial infections were observed in 7 of 682 patients with leukemia who received marrow grafts. Four patients had pulmonary and three extrapulmonary infection. Granulomas were observed in the lungs of three patients, in the liver of one patient, and in the skin of one patient. Cultures revealed Mycobacterium tuberculosis in two patients, Mycobacterium fortuitum in two patients, and Mycobacterium kansasii in one patient. In the six patients treated with antimycobacterial therapy in either the pretransplant or posttransplant period, complete resolution of the infection was achieved. Pretransplant chest radiograph abnormalities suggesting mycobacterial infections should be aggressively evaluated in these immunocompromised hosts. Prophylaxis should be considered in marrow graft recipients with a well-established history of inadequately treated tuberculosis, previous Bacille Calmette-Guerin immunotherapy, known family contacts, recent skin test conversion, or past skin test positivity.

A prisoner with chronic myeloid leukemia.

The health care received by prisoners in the area of tissue and organ transplantation is not well discussed or documented. We encountered a prisoner with newly diagnosed chronic myelogenous leukemia who was a candidate for allogeneic bone marrow transplantation and had two HLA-identical siblings who were willing to donate bone marrow. Based on humanitarian, constitutional, and ethical considerations, we suggest that the prisoner (patient) should receive the same health care as individuals who are not incarcerated and that the costs of care should play no greater role for prisoners than for other members of society.

Treatment of marrow graft recipients with thymopentin.

Four adult patients with acute non-lymphocytic leukemia were given marrow grafts from HLA-identical siblings following 120 mg/kg cyclophosphamide and 10-12 Gy total body irradiation. All received intermittent intravenous methotrexate as prophylaxis against graft-versus-disease (GVHD). In an attempt to accelerate immune recovery and prevent GVHD, each patient received thymopentin (TP5) for 100 days after grafting. No adverse effects were seen with TP5 administration. All four patients developed acute GVHD (one grade I, one grade II, and two grade III). Two patients died of late infections: one at 6 months from Pneumocystis carinii pneumonia and one at 11 months from disseminate Pseudomonas, Candida and cytomegalovirus infection. Two patients survive more than 3.9 years after transplantation with Karnofsky scores of 100%. One required treatment for chronic GVHD and recovered. Delayed-type hypersensitivity, antibody production to specific antigen in vivo, and results of in vitro immunologic studies were not altered by TP5 treatment. We conclude that while the administration of TP5 in these patients as described was not harmful, it did not prevent opportunistic infection, improve immunologic reconstitution or lower the incidences of acute or chronic GVHD from that of our previous experiences without thymopentin.

Protein turnover in advanced lung cancer patients.

Understanding the extent to which changes in whole-body protein kinetics contribute to the commonly observed weight loss and decrease in lean body mass (LBM) in patients with cancer is currently obscured by conflicting reports in the literature. While several studies have reported significant increases in whole-body protein turnover (WBPT), synthesis (WBPS), and catabolism (WBPC) in patients with cancer, others have failed to confirm these observations. We have measured whole-body protein kinetics using a primed constant infusion of 15N-glycine in a homogenous group of 32 newly diagnosed advanced lung cancer patients with comparable staging and before any antineoplastic treatment, and in 19 normal healthy volunteer controls. Urinary urea and ammonia 15N enrichment was determined in individually collected urine samples obtained during the 24-hour study period and averaged for the determination of protein kinetics. During the last 6 hours of urine collection, samples were obtained hourly for determination of 15N plateau enrichment. Twenty-four-hour urinary nitrogen and creatinine excretion was determined from 24-hour pooled urine samples. Resting metabolic expenditure (RME) was determined by indirect calorimetry and LBM was estimated from deuterium oxide dilution. Age body weight, LBM, RME, and 24-hour urinary nitrogen excretion did not differ between cancer and control subjects. WBPT, WBPC, and WBPS (g/kg/d) were significantly increased in lung cancer patients. However, when the same results were expressed either per kilogram LBM or per gram 24-hour urinary creatinine excretion, WBPT, WBPC, and WBPS rates were not statistically different from those of the controls.(ABSTRACT TRUNCATED AT 250 WORDS)