Projected environmental and public health benefits of extended-interval dosing: an analysis of pembrolizumab use in a US national health system.

BACKGROUND: Health care is a major source of greenhouse gas emissions, leading to climate change and public health harms. Changes are needed to improve the environmental sustainability of health-care practices, but such changes should not sacrifice patient outcomes or financial sustainability. Alternative dosing strategies that reduce the frequency with which specialty drugs are administered, without sacrificing patient outcomes, are an attractive possibility for improving environmental sustainability. We sought to inform environmentally sustainable cancer care by estimating and comparing the environmental and financial effects of alternative, clinically equivalent strategies for pembrolizumab administration. METHODS: We conducted a retrospective analysis using a cohort of patients from the Veterans Health Administration (VHA) in the USA who received one or more pembrolizumab doses between May 1, 2020, and Sept 30, 2022. Using baseline, real-world administration of pembrolizumab, we generated simulated pembrolizumab use data under three near-equivalent counterfactual pembrolizumab administration strategies defined by combinations of weight-based dosing, pharmacy-level vial sharing and dose rounding, and extended-interval dosing (ie, every 6 weeks). For each counterfactual dosing strategy, we estimated greenhouse gas emissions related to pembrolizumab use across the VHA cohort using a deterministic environmental impact model that estimated greenhouse gas emissions due to patient travel, drug manufacture, and medical waste as the primary outcome measure. FINDINGS: We identified 7813 veterans who received at least one dose of pembrolizumab-containing therapy in the VHA during the study period. 59 140 pembrolizumab administrations occurred in the study period, of which 46 255 (78·2%) were dosed at 200 mg every 3 weeks, 12 885 (21·8%) at 400 mg every 6 weeks, and 14 955 (25·3%) were coadministered with infusional chemotherapies. Adoption of weight-based, extended-interval pembrolizumab dosing (4 mg/kg every 6 weeks) and pharmacy-level stewardship strategies (ie, dose rounding and vial sharing) for all pembrolizumab infusions would have resulted in 24·7% fewer administration events than baseline dosing (44 533 events vs 59 140 events) and an estimated 200 metric tons less CO2 emitted per year as a result of pembrolizumab use within the VHA (650 tons vs 850 tons of CO2, a relative reduction of 24%), largely due to reductions in distance travelled by patients to receive treatment. Similar results were observed when weight-based and extended-interval dosing were applied only to pembrolizumab monotherapy and pembrolizumab in combination with oral therapies. INTERPRETATION: Alternative pembrolizumab administration strategies might have environmental advantages over the current dosing and compounding paradigms. Specialty medication dosing can be optimised for health-care spending and environmental sustainability without sacrificing clinical outcomes. FUNDING: None.

Optimization of Free-Flap Limb Salvage and Maximizing Function and Quality of Life Following Oncologic Resection: 12-Year Experience.

INTRODUCTION: A knowledge gap exists regarding factors to optimize limb salvage and function following oncologic resection. METHODS: We conducted a retrospective review of all free flaps performed for upper extremity (UE) and lower extremity (LE) salvage from 2000 to 2012. RESULTS: Overall, 220 patients underwent free-flap reconstruction for limb salvage (UE: 64, and LE: 156). Flaps were classified as muscle-only (n = 77), myocutaneous (MC; n = 67), or fasciocutaneous (FC; n = 76). Smoking, diabetes, peripheral vascular disease, and prior chemotherapy or radiation had no impact on complications, while osteomyelitis significantly increased the risk of infection (odds ratio [OR] 19.5, confidence interval [95% CI] 3.77-100.64; p = 0.0004), wound healing complications (OR 7.51, 95% CI 2.21-25.49; p = 0.001), and amputation (OR 4.63, 95% CI 1.41-15.19; p = 0.01). Hardware increased the risk for flap loss (OR 4.92, 95% CI 1.33-18.23; p = 0.017). MC and FC flaps had increased risks for hematoma (p = 0.02) and reoperation for microvascular complications (p = 0.005) but were at lower risk for infection (OR 0.14, 95% CI 0.02-0.87; p = 0.03) compared with muscle-only flaps. There were a total of seven total flap losses (3.2%), with significantly increased risks for MC/FC flaps (OR 2.58, 95% CI 1.06-6.26; p = 0.03). For LE, 103 patients (66.3%) were fully ambulatory, while 23 (14.7%) were ambulatory with assistance (mean Musculoskeletal Tumor Society score (MSTS) 80.2, and Karnofsky score 84.0). For UE, 49 patients (76.6%) were able to perform their activities of daily living independently (mean MSTS 80.2, and Karnofsky score 86.0). Overall, 190 patients (86.4%) were successfully salvaged. CONCLUSIONS: Free flaps can be performed reliably for limb salvage following tumor extirpation. While MC/FC flaps demonstrated improved postoperative function, they were at significantly higher risk for take-backs and total flap loss.

Use of arsenic trioxide in a hemodialysis-dependent patient with relapsed acute promyelocytic leukemia.

Arsenic trioxide has been established for use in both relapsed and front-line treatment of acute promyelocytic leukemia. Dose adjustments are recommended to be considered in severe renal impairment although dosage reduction guidelines are not provided. In addition, toxicities of arsenic are significant. The use of arsenic trioxide has not been well studied in dialysis patients and there is a paucity of data in the literature to support the use in such a situation. We describe an 81-year-old relapsed acute promyelocytic leukemia hemodialysis-dependent patient with a pre-existing cardiac condition who was treated with 10 mg arsenic trioxide three times weekly after dialysis. These findings provide support along with the marginal amount of currently published data for an arsenic trioxide dosing regimen in hemodialysis patients.

SLC4A11 mediates ammonia import and promotes cancer stemness in hepatocellular carcinoma.

End stage liver disease is marked by portal hypertension, systemic elevations in ammonia, and development of hepatocellular carcinoma (HCC). While these clinical consequences of cirrhosis are well described, it remains poorly understood whether hepatic insufficiency and the accompanying elevations in ammonia contribute to HCC carcinogenesis. Using preclinical models, we discovered that ammonia entered the cell through the transporter SLC4A11 and served as a nitrogen source for amino acid and nucleotide biosynthesis. Elevated ammonia promoted cancer stem cell properties in vitro and tumor initiation in vivo. Enhancing ammonia clearance reduced HCC stemness and tumor growth. In patients, elevations in serum ammonia were associated with an increased incidence of HCC. Taken together, this study forms the foundation for clinical investigations using ammonia lowering agents as potential therapies to mitigate HCC incidence and aggressiveness.

Adopting Weight-Based Dosing With Pharmacy-Level Stewardship Strategies Could Reduce Cancer Drug Spending By Millions.

Immune checkpoint inhibitors, a class of drugs used in approximately forty unique cancer indications, are a sizable component of the economic burden of cancer care in the US. Instead of personalized weight-based dosing, immune checkpoint inhibitors are most commonly administered at "one-size-fits-all" flat doses that are higher than necessary for the vast majority of patients. We hypothesized that personalized weight-based dosing along with common stewardship efforts at the pharmacy level, such as dose rounding and vial sharing, would lead to reductions in immune checkpoint inhibitor use and lower spending. Using data from the Veterans Health Administration (VHA) and Medicare drug prices, we estimated reductions in immune checkpoint inhibitor use and spending that would be associated with pharmacy-level stewardship strategies, in a case-control simulation study of individual patient-level immune checkpoint inhibitor administration events. We identified baseline annual VHA spending for these drugs of approximately $537 million. Combining weight-based dosing, dose rounding, and pharmacy-level vial sharing would generate expected annual VHA health system savings of $74 million (13.7 percent). We conclude that adoption of pharmacologically justified immune checkpoint inhibitor stewardship measures would generate sizable reductions in spending for these drugs. Combining these operational innovations with value-based drug price negotiation enabled by recent policy changes may improve the long-term financial viability of cancer care in the US.

Nonoperative Treatment of Lymphedema.

Complex decongestive therapy is the mainstay of lymphedema (LE) therapy. It consists of two phases: an intensive volume reduction phase, principally involving low-stretch bandages and manual lymph drainage (MLD), followed by compression garment use to maintain the reduction achieved. Adjunctive treatments include the use of a sequential gradient pump, LE-specific exercises, skin and nail care, as well as risk-reduction precautions. Herein the techniques are described and the evidence for their effectiveness is reviewed.