A Systematic Evaluation of Cost-Saving Dosing Regimens for Therapeutic Antibodies and Antibody-Drug Conjugates for the Treatment of Lung Cancer.

BACKGROUND: Expensive novel anticancer drugs put a serious strain on healthcare budgets, and the associated drug expenses limit access to life-saving treatments worldwide. OBJECTIVE: We aimed to develop alternative dosing regimens to reduce drug expenses. METHODS: We developed alternative dosing regimens for the following monoclonal antibodies used for the treatment of lung cancer: amivantamab, atezolizumab, bevacizumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and ramucirumab; and for the antibody-drug conjugate trastuzumab deruxtecan. The alternative dosing regimens were developed by means of modeling and simulation based on the population pharmacokinetic models developed by the license holders. They were based on weight bands and the administration of complete vials to limit drug wastage. The resulting dosing regimens were developed to comply with criteria used by regulatory authorities for in silico dose development. RESULTS: We found that alternative dosing regimens could result in cost savings that range from 11 to 28%, and lead to equivalent pharmacokinetic exposure with no relevant increases in variability in exposure. CONCLUSIONS: Dosing regimens based on weight bands and the use of complete vials to reduce drug wastage result in less expenses while maintaining equivalent exposure. The level of evidence of our proposal is the same as accepted by regulatory authorities for the approval of alternative dosing regimens of other monoclonal antibodies in oncology. The proposed alternative dosing regimens can, therefore, be directly implemented in clinical practice.

The effect of rapid infusion of cisplatin on nephrotoxicity in patients with lung carcinoma.

WHAT IS KNOWN AND OBJECTIVE: The use of cisplatin in the treatment of lung carcinoma is limited by nephrotoxicity. The aim of this study was to determine whether the incidence of nephrotoxicity in patients with lung carcinoma is affected by the infusion rate of cisplatin (rapid infusion of cisplatin in 1 hour compared to regular infusion in 3 hours). METHODS: This observational, retrospective study was performed on patients diagnosed with non-small-cell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC) or mesothelioma receiving a cisplatin-containing chemotherapy regimen. Patients were divided into two cohorts (infusion of cisplatin in 1 hour vs 3 hours) based on the starting date of the chemotherapy regimen. The primary objectives were the difference in renal function after three cycles of chemotherapy and the incidence of nephrotoxicity. To assess nephrotoxicity, both the incidence of acute kidney injury (AKI) grade 1 and the maximum decrease in estimated glomerular filtration rate (eGFR) were determined. RESULTS: A total of 230 lung carcinoma patients with a cisplatin-containing chemotherapy regimen were included. Baseline characteristics were similar for the rapid and regular infusion cohorts, except for type of lung carcinoma, chemotherapy regimen and prevalence of hypertension. There was no significant difference in renal function between rapid infusion of cisplatin and regular infusion of cisplatin (eGFR 86.1 mL/min [71.0-96.3] vs 87.9 mL/min [71.6-97.3]; P = 0.938). The incidence of AKI grade 1 was not significantly different between rapid and regular infusion of cisplatin (29.3% vs 29.8%; P = 0.932). The maximum decrease in eGFR was 14.8 mL/min in the rapid infusion cohort and 17.7 mL/min in the regular infusion cohort (P = 0.364). WHAT IS NEW AND CONCLUSION: The incidence of nephrotoxicity after repeated infusion of cisplatin was not affected by the infusion rate of cisplatin. Therefore, a 1-hour infusion of cisplatin is a safe and feasible method, which may potentially shorten duration of hospital admittance and enable treating patients in the outpatient setting.

Trends in prescribing systemic treatment and overall survival for non-small cell lung cancer stage IIIB/IV in the Netherlands: 2008-2012.

BACKGROUND: The present study aims to give a detailed overview of day-to-day practice in the systemic treatment of NSCLC stage IIIB/IV and its clinical outcomes in six large teaching hospitals in the Netherlands in the period 2008-2012. METHODS: A retrospective observational cohort study was conducted in the Care for Outcome registry. Patients diagnosed with stage IIIB/IV NSCLC were included and drug data were collected. Outcomes included percentage of patients treated with systemic treatment, percentage of different first line treatment options, survival, and number and percentage of switches, dose reductions (<80% of the initial dose), and early discontinuation (<4 cycles). Descriptive analyses were conducted per hospital, year of diagnosis and several patient characteristics. Predictors for early discontinuation were explored in a logistic regression model. RESULTS: Overall, 47,9% of 2158 patients that were included received systemic treatment and 33,7% of those received second line treatment. Treatment frequencies were different between age categories, disease stage, PS and hospital (p<0.001). Half of the patients received <4 cycles and dose reductions were found for 20% of all patients. Interhospital differences were observed for early discontinuation and the number of switches. PS2-3 was associated with early discontinuation (OR 1.97 (p=0,007). Median survival was not different between hospitals and years of diagnosis. DISCUSSION: We provided detailed overview of day-to-day systemic treatment of NSCLC for six hospitals that (a) can fuel interhospital discussion to streamline treatment towards best practice and (b) can serve as reference data for follow-up of the adoption of novel systemic treatment options for advanced lung cancer.

[Are we on the verge of lung-cancer screening in the Netherlands?]. / Aan de vooravond van longkankerscreening.

Previous studies of low-dose computed tomography (CT) screening for lung cancer have shown a decrease in lung-cancer-related deaths. Data from the NELSON trial, using new thresholds for defining a positive test, resulted in less over-diagnosis without a decrease in test-specific sensitivity. However, in our opinion it is still too early to implement screening in the Netherlands. Further development of the optimal screening algorithm based on defined volumetric thresholds and stratified by personal characteristics such as age, smoking habits, gender and comorbidities, will probably result in a better balance between the harms and benefits of lung-cancer screening to individuals and society.

Long-term effects of carotid sinus denervation on arterial blood pressure in humans.

BACKGROUND: After experimental carotid sinus denervation in animals, blood pressure (BP) level and variability increase markedly but normalize to preoperative levels within 10 to 14 days. We investigated the course of arterial BP level and variability after bilateral denervation of the carotid sinus baroreceptors in humans. METHODS AND RESULTS: We studied 4 women (age 41 to 63 years) who were referred for evaluation of arterial baroreflex function because of clinical suspicion of carotid sinus denervation attributable to bilateral carotid body tumor resection. The course of BP level and variability was assessed from repeated office and 24-hour ambulatory measurements (Spacelabs/Portapres) during 1 to 10 years of (retrospective) follow-up. Rapid cardiovascular reflex adjustments to active standing and Valsalva's maneuver were assessed. Office BP level increased from 132/86 mm Hg (range, 118 to 148/80 to 92 mm Hg) before bilateral surgery to 160/105 mm Hg (range, 143 to 194/90 to 116 mm Hg) 1 to 10 years after surgery. During continuous 24-hour noninvasive BP recording (Portapres), a marked BP variability was apparent in all 4 patients. Initial symptomatic hypotension on change to the upright posture and abnormal responses to Valsalva's maneuver were observed. CONCLUSIONS: Acute carotid sinus denervation, as a result of bilateral carotid body tumor resection, has a long-term effect on the level, variability, and rapid reflex control of arterial BP. Therefore, in contrast to earlier experimental observations, the compensatory ability of the baroreceptor areas outside the carotid sinus seems to be of limited importance in the regulation of BP in humans.

Active and cognitive impairment-free life expectancies: results from the Melton Mowbray 75+ health checks.

OBJECTIVES: To estimate active and cognitive impairment-free life expectancy at older ages from longitudinal data collected during two consecutive rounds of health checks for patients aged > or =75 years. SETTING: A single, large general practice serving Melton Mowbray, Leicestershire, UK, and its surrounding area. OUTCOME MEASURES: active life expectancy was defined by independence in seven activities of daily living (mobility, transfer from bed, transfer from chair, bathing, feeding, dressing, using the toilet). Cognitive impairment was defined by a score of < or =7 on the information/orientation subtest of the Clifton Assessment Procedures of the Elderly. RESULTS: We assessed 1557 people aged > or =75 years at baseline. Active life expectancy at age 75 was 4.6 years for men and 3.1 years for women (50.5 and 29.2% of remaining life). Cognitive impairment-free life expectancy at age 75 was 8.4 years for men and 9.9 years for women (92.3 and 93.4% of remaining life). The proportion of active life decreased dramatically with age in both sexes: after the age of 87, almost all of remaining life was spent with some activity restriction. The proportion of life free from cognitive impairment, in comparison, decreased slowly in men and remained relatively constant in women at around 90%. CONCLUSIONS: The extra years lived by women over men appear to be spent with some form of activity restriction, although not all with cognitive impairment. Monitoring these trends over time will be important to ascertain whether we are exchanging longer life for poorer health.

Community surveys of late-life depression: who are the non-responders?

BACKGROUND: community surveys of depression among older people may be particularly prone to non-response. Information on non-responders is difficult to obtain and often limited to demographics. Therefore, the full extent of response bias is not always known. OBJECTIVE: to determine factors associated with non-response at each stage of a two-stage survey of late-life depression. SETTING: one large general practice (registered population >30000) serving the market town of Melton Mowbray, Leicestershire, UK. SUBJECTS: community residents (n=2633) aged 65-74 years registered with the practice. METHODS: a two-stage community survey of patients aged 65-74 years. The first stage was an interviewer-administered general health survey including a measure of depressive symptoms. We asked those who screened positive for possible depression to undergo a semi-structured psychiatric interview. We compared use of services and medication by non-responders and responders to both stages using primary-care records. We compared Townsend deprivation scores using data obtained from the 1991 census. RESULTS: responders to stage 1 were more likely to use both primary [odds ratio (OR) 1.65, 95% confidence interval (CI) 1.38-1.96] and secondary (OR 1.59, 95% CI 1.25-2.02) services and tended to live in more affluent areas (P=0.002). At stage 2, the only difference observed was a lower level of use of tranquillisers or hypnotics among responders (OR 0.27, 95% CI 0.11-0.67). CONCLUSIONS: older people with low levels of contact with health services may be under-represented in community surveys of depression. Investigators should look outside traditional health settings to promote the uptake of response in these studies.

Patterns of onset of disability in activities of daily living with age.

OBJECTIVES: To investigate the order in which activities of daily living (ADLs) are lost and whether the order is invariant between the sexes and age groups. DESIGN: Longitudinal data from the first five rounds of a routine health assessment by a nurse in participant's own home. SETTING: One large UK general practice with a list size of 32,500. PARTICIPANTS: Patients registered with the practice and age 75 and older. MEASUREMENTS: Disability was measured by self-report of performance in seven ADLs: mobility around the home, getting to and from the toilet, transfer from chair, transfer from bed, feeding, dressing, and bathing. Disability in each ADL was classified as being independent but having difficulty, using aids or help, or being unable to perform. Age at onset of disability in each ADL was calculated and analyzed using Kaplan-Meier plots and Cox regression models. Subjects who had died or remained independent by their last assessment were not included. RESULTS: The mean times between health assessments was approximately 20 months but with substantial variability both within and between individuals. A total of 1,344 people reported no difficulty in any ADL initially and 47.6% (640) subsequently reported disability. The order of activity restriction was bathing, mobility, toileting, dressing, transfers from bed and chair, and feeding. Women had a higher risk of disability in bathing (relative risk (RR) = 1.6, 95% confidence interval (CI) 1.3-1.9, P < .001) and toileting (RR = 1.7, 95% CI 1.2-2.5, P = .003), while for all ADLs there was a significant increase in the risk of disability with increasing age. The order of onset of disability for ADLs was invariant across sex and age groups. CONCLUSION: Lower-extremity strength (bathing, mobility, toileting) appears to be lost in older people before upper-extremity strength (dressing, feeding). Further work is now needed to develop prevention strategies to delay the onset of these disabilities.

The small intestine plays an important role in upregulating CGRP during sepsis.

Although studies have indicated that calcitonin gene-related peptide (CGRP), a potent vasodilatory peptide, is upregulated after endotoxic shock, it remains controversial whether this peptide increases during sepsis and, if so, whether the gut is a significant source of CGRP under such conditions. To study this, polymicrobial sepsis was induced by cecal ligation and puncture (CLP) followed by fluid resuscitation. Plasma levels of CGRP were measured at 2, 5, and 10 h after CLP (i.e., early, hyperdynamic sepsis) and at 20 h after CLP (late, hypodynamic sepsis). The results indicate that plasma CGRP did not increase at 2--5 h but increased by 177% at 10 h after CLP (P < 0.05). At 20 h after the onset of sepsis, however, the elevated plasma CGRP returned to the sham level. To determine the source of the increased plasma CGRP, the liver, spleen, small intestine, lungs, and heart were harvested, and tissue CGRP was assayed at 10 h after CLP in additional animals. Only the small intestine showed a significant increase in tissue levels of CGRP (by 129%, P < 0.05). Determination of portal vs. systemic levels of CGRP indicates that portal CGRP was 65.7 +/- 22.7% higher than the systemic level at 10 h after CLP, whereas portal CGRP in sham-operated rats was only 4.9 +/- 2.1% higher. Immunohistochemistry examination revealed that CGRP-positive stainings increased in the intestinal tissue but not in the liver at 10 h after the onset of sepsis. The distribution of CGRP stainings was associated with intestinal nerve fibers. These results, taken together, demonstrate that upregulation of CGRP occurs transiently during the progression of sepsis (at the late phase of the hyperdynamic sepsis), and the gut appears to be a major source of such an increase in circulating levels of this peptide.

A follow-up study of attempted railway suicides.

This paper reports the subsequent mortality of 94 persons who attempted suicide by jumping in front of London Underground trains between 1977 and 1979. The follow-up period was 10 yr. Despite the apparent seriousness of the method, completion of suicide was not found to be higher than in previous studies of attempted suicide by other methods. By the end of the follow-up period 18 persons had died, nine of natural causes. Coroners' inquests were held for the unnatural deaths. Seven verdicts of suicide and two of accidental death were recorded. Of the nine unnatural deaths four were from multiple injuries, three from drowning, one from asphyxia and one from acute narcotic poisoning. All four multiple injury deaths were women, three of these were from repeated incidents involving London Underground trains. The time interval between the index attempt and eventual death for the suicide/accident group ranged from 1 day to 43 months. For ethical reasons it was not possible to follow-up attempted suicides who were presumed to have remained alive.