Pooled safety analysis from phase III studies of trifluridine/tipiracil in patients with metastatic gastric or gastroesophageal junction cancer and metastatic colorectal cancer.

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) showed clinical benefit, including improved survival and manageable safety in previously treated patients with metastatic colorectal (mCRC) or gastric/gastroesophageal junction (mGC/GEJC) cancer in the phase III RECOURSE and TAGS trials, respectively. A pooled analysis was conducted to further characterize FTD/TPI safety, including management of haematologic toxicities and use in patients with renal or hepatic impairment. PATIENTS AND METHODS: Adults with ≥2 prior regimens for advanced mGC/GEJC or mCRC were randomized (2 : 1) to FTD/TPI [35 mg/m2 twice daily days 1-5 and 8-12 (28-day cycle); same dosage in both trials] or placebo plus best supportive care. Adverse events (AEs) were summarized in the safety population (patients who received ≥1 dose) and analysed by renal/hepatic function. RESULTS: TAGS and RECOURSE included 335 and 533 FTD/TPI-treated and 168 and 265 placebo-treated patients, respectively. Overall safety of FTD/TPI was similar in TAGS and RECOURSE. Haematologic (neutropenia, anaemia) and gastrointestinal (nausea, diarrhoea) AEs were most commonly observed. Laboratory-assessed grade 3-4 neutropenia occurred in 37% (TAGS)/38% (RECOURSE) of FTD/TPI-treated patients (median onset: 29 days/55 days), and 96% (TAGS)/97% (RECOURSE) of cases resolved regardless of renal/hepatic function. Supportive medications for neutropenia were received by 17% (TAGS) and 9% (RECOURSE); febrile neutropenia was reported in 2% and 4%, respectively. Overall grade ≥3 AEs were more frequent in patients with moderate renal impairment [81% (TAGS); 85% (RECOURSE)] versus normal renal function (74%; 67%); anaemia and neutropenia were more common in patients with renal impairment. FTD/TPI safety (including haematologic AEs) was consistent across patients with normal and mildly impaired hepatic function. CONCLUSIONS: These results support FTD/TPI as a well-tolerated treatment in patients with mGC/GEJC or mCRC, with a consistent safety profile. Safety was largely similar in patients with normal or mildly impaired renal/hepatic function; however, patients with renal impairment should be monitored for haematologic toxicities.

Neutropenia and survival outcomes in metastatic colorectal cancer patients treated with trifluridine/tipiracil in the RECOURSE and J003 trials.

BACKGROUND: The phase II J003 (N = 169) and phase III RECOURSE (N = 800) trials demonstrated a significant improvement in survival with trifluridine (FTD)/tipiracil (TPI) versus placebo in patients with refractory metastatic colorectal cancer. This post hoc analysis investigated pharmacokinetic data of FTD/TPI exposure and pharmacodynamic markers, such as chemotherapy-induced neutropenia (CIN) and clinical outcomes. PATIENTS AND METHODS: A total of 210 patients from RECOURSE were enrolled in this substudy. A limited sampling approach was used, with three pharmacokinetic samples drawn on day 12 of cycle 1. Patients were categorized as being above or below the median area under the plasma concentration-time curve (AUC) for FTD and TPI. We conducted a post hoc analysis using the entire RECOURSE population to determine the correlations between CIN and clinical outcome. We then carried out a similar analysis on the J003 trial to validate the results. RESULTS: In the RECOURSE subset, patients in the high FTD AUC group had a significantly increased CIN risk. Analyses of the entire population demonstrated that FTD/TPI-treated patients with CIN of any grade in cycles 1 and 2 had significantly longer median overall survival (OS) and progression-free survival (PFS) than patients who did not develop CIN and patients in the placebo group. Patients who required an FTD/TPI treatment delay had increased OS and PFS versus those in the placebo group and those who did not develop CIN. Similar results were obtained in the J003 cohort. CONCLUSIONS: In RECOURSE, patients with higher FTD drug exposure had an increased CIN risk. FTD/TPI-treated patients who developed CIN had improved OS and PFS versus those in the placebo group and those who did not develop CIN. Similar findings were reported in the J003 cohort, thus validating the RECOURSE results. The occurrence of CIN may be a useful predictor of treatment outcomes for FTD/TPI-treated patients. CLINICALTRIALS. GOV IDENTIFIER: NCT01607957 (RECOURSE). JAPAN PHARMACEUTICAL INFORMATION CENTER NUMBER: JapicCTI-090880 (J003).

A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer.

BACKGROUND: The effect of histology-based treatment regimen on diffuse gastric adenocarcinoma has not been evaluated in clinical trials. This international phase III trial evaluated the efficacy and safety of S-1 (a contemporary oral fluoropyrimidine)/cisplatin versus 5-fluorouracil (5-FU)/cisplatin in chemotherapy-naïve patients with diffuse-type adenocarcinoma involving the gastroesophageal junction or stomach. PATIENTS AND METHODS: Eligibility criteria included untreated, measurable, advanced diffuse adenocarcinoma confirmed by central pathology and performance status of 0-1. Patients were randomized (2 : 1) to receive S-1/cisplatin or 5-FU/cisplatin. Primary end point was overall survival (OS), and secondary end points were progression-free survival, time to treatment failure, overall response rate, and safety. A multivariable analysis was also carried out. RESULTS: Overall, 361 patients were randomized (S-1/cisplatin, n = 239; 5-FU/cisplatin, n = 122); half (51%) were men, and median age was 56.0 years. In each group, median number of treatment cycles per patient was 4 (range, S-1/cisplatin: 1-20; 5-FU/cisplatin: 1-30), and dose intensity was >95%. OS was not different in the two groups {median OS with S-1/cisplatin, 7.5 [95% confidence interval (CI): 6.7, 9.3]; 5-FU/cisplatin, 6.6 [95% CI: 5.7, 8.1] months; hazard ratio, 0.99 [95% CI: 0.76, 1.28]; P = 0.9312}. Overall response rate was significantly higher in the S-1/cisplatin than 5-FU/cisplatin group (34.7% versus 19.8%; P = 0.01), but progression-free survival and time to treatment failure were not different. Safety was similar between the 2 groups; however, fewer patients treated with S-1/cisplatin than 5-FU/cisplatin had ≥1 grade 3/4 treatment-emergent adverse event or ≥1 adverse event resulting in treatment discontinuation. One treatment-related death occurred in each group. Slow accrual led to early termination. CONCLUSIONS: These data suggest that S-1/cisplatin and 5-FU/cisplatin are similar in efficacy and safety in untreated patients with advanced diffuse adenocarcinoma of the gastroesophageal junction or stomach. The primary end point was not met. CLINICALTRIAL.GOV REGISTRATION NUMBER: NCT01285557.

Hippocrates: an integrated platform for telemedicine applications.

This paper describes 'Hippocrates', an integrated platform for telemedicine applications. Hippocrates allows computer supported co-operative work based on patient data folders consisting of selected diagnostic images, annotation text, patient history and other information. All data transferred is encrypted to ensure confidentiality and integrity. It operates on a local level over TCP/IP LAN environment and on a remote level over public ISDN lines.

Teleworks: a CSCW application for remote medical diagnosis support and teleconsultation.

The present paper describes methods for the design of both synchronous and asynchronous computer-supported cooperative work (CSCW) procedures suitable for the medical application area and specifically for the purpose of medical teleconsultation and remote diagnosis support. The experimental implementation of a CSCW system built upon a PC/Windows platform is detailed as an example of a low-cost system suitable for adoption in a wide range of medical teleconsultation applications.

Comparative effects of losartan and enalapril on exercise capacity and clinical status in patients with heart failure. The Losartan Pilot Exercise Study Investigators.

OBJECTIVES: This study was designed to determine 1) whether 12-week oral administration of losartan, an angiotensin II receptor antagonist, in patients with heart failure is well tolerated; and 2) whether functional capacity and clinical status of patients with heart failure in whom treatment with an angiotensin-converting enzyme (ACE) inhibitor is replaced with losartan for 12 weeks will remain similar to that noted in patients in whom treatment with an ACE inhibitor is continued. BACKGROUND: Losartan is a specific, nonpeptide angiotensin II receptor antagonist. Although specific receptor blockade with losartan has certain theoretic advantages over nonspecific ACE inhibition, definitive demonstration of comparable effects in patients with congestive heart failure is lacking. METHODS: A double-blind, multicenter, randomized, parallel, enalapril-controlled study was conducted in 116 patients with congestive heart failure (New York Heart Association functional classes II to IV) and left ventricular ejection fraction < or = 45% previously treated with stable doses of ACE inhibitors and diuretic agents, with or without concurrent digitalis and other vasodilators. After a baseline exercise period, open-label ACE inhibitors were discontinued, and patients were randomly assigned to 12 weeks of therapy with losartan, 25 mg/day (n = 38); losartan, 50 mg/day (n = 40); or enalapril, 20 mg/day (n = 38). Drug efficacy was evaluated by changes in maximal treadmill exercise time (using a modified Naughton protocol), 6-min walk test, left ventricular ejection fraction and dyspnea-fatigue index. Safety was measured by the incidence of clinical and laboratory adverse experiences. RESULTS: The treadmill exercise time and the 6-min walk test did not change significantly after replacement of ACE inhibitor therapy with losartan. Similarly, a significant change was not observed in either the dyspnea-fatigue index or left ventricular ejection fraction at the end of double-blind period relative to baseline. CONCLUSIONS: Losartan was generally well tolerated and comparable to enalapril in terms of exercise tolerance in this short-term (12-week) study of patients with heart failure. The clinical effects of long-term angiotensin II receptor blockade compared with ACE inhibition remain to be studied.

Design of CSCW applications for medical teleconsultation and remote diagnosis support.

Recent advances in telecommunication technology have permitted the implementation of tools for Computer Supported Cooperative Work (CSCW) based on real time transmission of different information types between two or more stations. The present paper describes methods for the design of both synchronous and asynchronous CSCW procedures suitable for the medical application area and specifically for the purpose of medical consultation and more generally, remote diagnosis support. The experimental implementation of such a CSCW system built upon a Personal Computer/Windows platform is detailed as an example of such a low-cost system suitable for adoption in a wide-range of medical teleconsultation applications.

Network and data security design for telemedicine applications.

The maturing of telecommunication technologies has ushered in a whole new era of applications and services in the health care environment. Teleworking, teleconsultation, mutlimedia conferencing and medical data distribution are rapidly becoming commonplace in clinical practice. As a result, a set of problems arises, concerning data confidentiality and integrity. Public computer networks, such as the emerging ISDN technology, are vulnerable to eavesdropping. Therefore it is important for telemedicine applications to employ end-to-end encryption mechanisms securing the data channel from unauthorized access of modification. We propose a network access and encryption system that is both economical and easily implemented for integration in developing or existing applications, using well-known and thoroughly tested encryption algorithms. Public-key cryptography is used for session-key exchange, while symmetric algorithms are used for bulk encryption. Mechanisms for session-key generation and exchange are also provided.

Antihypertensive efficacy and tolerability of once daily losartan potassium compared with captopril in patients with mild to moderate essential hypertension.

INTRODUCTION: Losartan potassium, an orally active, highly selective AT1 angiotensin II receptor inhibitor, effectively reduces blood pressure by direct receptor blockade, thereby lessening the likelihood of angiotensin converting enzyme (ACE) inhibitor-associated side effects such as dry cough or possibly angioedema. STUDY DESIGN: In this multinational, double-blind, randomized, parallel study, the efficacy and tolerability of once-daily losartan (50 mg) versus once-daily ACE inhibitor (captopril; 50 mg) was evaluated in 163 patients with mild to moderate hypertension. Non-responders after a 6-week treatment period had the dosage doubled for both study drugs until the end of study (week 12). RESULTS: Mean reductions in trough sitting diastolic blood pressure were significantly greater in the losartan group at week 6 (7.8 mmHg) and week 12 (9.1 mmHg) than in the captopril group (5.2 and 5.7 mmHg, respectively). Losartan and captopril were well tolerated. Headache was the most common adverse event reported in both groups. CONCLUSIONS: It was concluded that a once-daily administration of losartan was significantly more effective in this study in lowering sitting diastolic blood pressure than once-daily administration of captopril in patients with mild to moderate essential hypertension. Both losartan and captopril regimes were well tolerated.

Efficacy and tolerability of losartan potassium and atenolol in patients with mild to moderate essential hypertension.

The objective of this study was to compare the antihypertensive efficacy and tolerability of losartan potassium (losartan) and atenolol in patients with mild-to-moderate essential hypertension. This was a multinational, prospective, randomized, 12-week double-blind parallel study with a follow-up of 4 to 10 days posttreatment to assess any adverse effects of abrupt therapy withdrawal. Two hundred two patients were randomized (2:1) to treatment with losartan or atenolol, 50 mg once daily. Patients were titrated after 6 weeks to 100 mg once daily if their blood pressure was uncontrolled (sitting diastolic blood pressure > or = 90 mm Hg). Trough sitting diastolic blood pressure reductions at weeks 6 and 12 were similar in both the losartan (-9.2 mm Hg and -8.3 mm Hg) and atenolol (-10.8 mm Hg and -10.1 mm Hg) groups and a similar percentage of patients responded to each drug. Both agents were generally well tolerated, although eight patients (two patients taking losartan, and six taking atenolol) were withdrawn because of clinical adverse events (P < or = .05). Reduction in pulse rate from baseline averaged 10 beats/min in the atenolol group with no pulse rate reduction observed in the losartan group (P < .01). No evidence of rebound hypertension was observed in either group. In conclusion, losartan was as efficacious as atenolol in blood pressure reduction, and was at least as well tolerated.

Losartan in heart failure. Hemodynamic effects and tolerability. Losartan Hemodynamic Study Group.

BACKGROUND: The aim of the present study was to assess the short- and long-term effects of multiple doses of the angiotensin II receptor antagonist losartan in heart failure. METHODS AND RESULTS: A multicenter, placebo-controlled, oral, multidose (2.5, 10, 25, and 50 mg losartan once daily) double-blind comparison in patients with symptomatic heart failure and impaired left ventricular function (ejection fraction < 40%). Invasive 24-hour hemodynamic assessment was performed after the first dose and after 12 weeks of treatment. Clinical status and tolerability of treatment with losartan over the 12-week period were also evaluated. One hundred fifty-four patients were enrolled, of which 134 met the protocol criterion of baseline pulmonary capillary wedge pressure > or = 13 mm Hg. During short-term administration, systemic vascular resistance (SVR) (largest reduction against placebo of 197 dyne.s-1.cm-5 at 4 hours) and blood pressure fell significantly with 50 mg, lesser decreases were seen with 25 mg, and no discernible effects were seen with 2.5 and 10 mg. After 12 weeks of treatment, similar effects were seen on SVR and blood pressure (maximal fall in SVR against placebo, 318 dyne.s-1.cm-5 at 5 hours with 50 mg). In addition, pulmonary capillary wedge pressure fell with 2.5, 25, and 50 mg (largest reduction against placebo of 6.3 mm Hg at 6 hours with 50 mg), cardiac index rose with 25 and 50 mg, and heart rate was lower with all active treatment groups. Active treatment was well tolerated, and excess cough was not reported. CONCLUSIONS: This study showed that oral losartan administered to patients with symptomatic heart failure resulted in beneficial hemodynamic effects with short-term administration, with additional beneficial hemodynamic effects seen after 12 weeks of therapy. Clear effects were seen with both 25 and 50 mg, with the greatest effect seen with 50 mg.

First-dose effects of enalapril 2.5 mg and captopril 6.25 mg in patients with heart failure: a double-blind, randomized, multicenter study. The Enalapril-Captopril Investigators.

Significant decreases in blood pressure (BP) may occur when administration of angiotensin-converting enzyme (ACE) inhibitors is initiated for the treatment of heart failure. The purpose of this study was to compare the safety and tolerability of recommended initial doses of the longer-acting ACE inhibitor enalapril (ENAL) with those of the shorter-acting captopril (CAP) in patients with heart failure who were treated concomitantly with digitalis and diuretic agents. We evaluated BP, serum ACE activity, and clinical status when a low, first dose of ENAL (2.5 mg, n = 59) or CAP (6.25 mg, n = 58) was administered in a double-blind, randomized, and parallel fashion to 117 patients with mild to moderate heart failure. BP and serum ACE activity were measured at 30 min and hourly for 8 hours after drug administration. BP decreases were similar for both groups (mean supine BP -6.2/-4.8 mm Hg for ENAL vs -8.3/-6.4 mm Hg for CAP; mean standing BP -9.2/-5.6 mm Hg for ENAL vs -10.0/-4.7 mm Hg for CAP). Although the maximum mean decrease in BP occurred at hours 4 and 5 in the ENAL group and hours 1 and 2 in the CAP group, considerable between-group overlap was observed for individual patients. Decreases in mean serum ACE activity occurred earlier and were of shorter duration in the CAP group. ENAL significantly inhibited serum ACE activity to a greater extent than did CAP at all time points except the 1st hour. Administration of a first dose of ENAL, 2.5 mg or CAP, 6.25 mg to patients with heart failure was well tolerated.

Differences between nursing home admissions and residents.

The use of a cross-sectional sample of nursing home residents rather than a sample of admissions to estimate admission characteristics carries a potential bias. The purpose of this study was to fill this void by comparing abstracted records data for an admissions cohort (n = 1,118) and a residents cohort (n = 830) residing in the same nursing homes. Compared to residents, admissions were significantly more dependent in their ability to get around and to dress themselves, received more clinical services, and had a higher rate of medication use. Over a 12-month period, admissions had a fivefold greater likelihood of being discharged to community, but about the same mortality rate as residents. Within both groups, those discharged to the community as well as those who died had expenditures that were almost twice as high as those of their counterparts who remained alive in the nursing home.

Inadequate treatment of depressed nursing home elderly.

OBJECTIVE: To determine the prevalence of antidepressant drug treatment among nursing home elderly with major depression. DESIGN: Survey early and late in nursing home stay. SETTING: Sixty Medicaid/Medicare-certified skilled nursing homes. PARTICIPANTS: Admission cohort of 5,752 residents age 65 or older in 1976 through 1983. MEASURES: Chart review by nurse-abstractors of physicians' diagnoses, drug used, and alertness rating. Diagnosis of depression equivalent to DSM-III-R major depression. RESULTS: Of 868 persons with a diagnosis of depression in the medical record, only 10% were treated with antidepressant drugs. More received neuroleptics and benzodiazepines than received antidepressants, but most (52%) received no psychoactive drug at all. A subset of 258 depressed persons had positive notations in their records supporting a mental status rating of "alert and oriented." Of that subset, only 15% received antidepressants. When followed from admission to discharge or end of study the prevalence rate of antidepressant drug treatment increased by 4%. CONCLUSIONS: In the late 1970's and early 1980's, even when the primary care physician made and recorded a diagnosis of depression, most such nursing home residents remained untreated, incorrectly treated, or inadequately treated.

Longitudinal study of psychotropic drug use by elderly nursing home residents.

In this longitudinal study of patterns of use of psychotropic drugs by a cohort of elderly nursing home residents (N = 5,752), drug use was examined upon admission, 3 months later, and at discharge/end of study. At each time point, 17% of the cohort used neuroleptics. Half of the subjects discontinued neuroleptics at each time point; however, a similar number were initiated on the drug. Benzodiazepines were used by 21%, 15%, and 15% at each of the three time points, respectively. Twice as many people were taken off benzodiazepines as initiated on them following admission. The 5% rate of antidepressant use was constant across the three time periods, although only half of those who took antidepressants upon admission were also taking them upon discharge/end of study. The amount of change due to discontinuation of these drugs and adjustment in dosage levels challenges the stereotype of the "neglected psychotropic drug user" in nursing homes.

Evaluation of neuroleptic drug use by nursing home elderly under proposed Medicare and Medicaid regulations.

Federal regulations for use of neuroleptic drugs in Medicare- and Medicaid-certified nursing homes throughout the United States were implemented October 1, 1990. These regulations constitute the first time that prescription drugs are required, by law, to be justified by indications documented in the medical chart. This study used extant data to estimate ineligible neuroleptic use at the individual and nursing home levels had these regulations been in effect in 1976 through 1985. Subjects, randomly sampled admissions (N = 5752) and residents (N = 3191), were followed up for up to 24 months in 60 nursing homes. One half of neuroleptic use in each cohort could be considered ineligible under the regulations; all but one of the nursing homes had one or more individuals who were treated with the ineligible use of neuroleptics. Improvements in documentation and/or prescription of neuroleptic drugs for nursing home elderly will be needed to ensure compliance with these new regulations.

KIE: Guidelines developed by the federal Health Care Financing Administration (HCFA) for the administration of drugs in Medicare- and Medicaid-certified nursing homes were recently implemented, marking the first time that the use of prescription drugs must be justified on the patient's medical chart. This study applied the HCFA guidelines on the administration of neuroleptic drugs to an existing set of data about medication use in nursing homes to estimate the potential impact of the federal regulations. Subjects, both randomly sampled admissions and residents, were followed through nursing and medical records for up to 24 months in 60 nursing homes in eight Western states. Comparison of the study data with the HCFA criteria revealed that one half of the neuroleptic use in each cohort was ineligible by federal standards. The authors discuss the implications that the implementation of the HCFA guidelines has for the care of the elderly.