Estimation of Percentage of Patients With Fibroblast Growth Factor Receptor Alterations Eligible for Off-label Use of Erdafitinib.

Importance: When a novel drug is granted accelerated approval, both its on-label and off-label uses must be taken into account. Objectives: To estimate the potential upper bound of off-label use of erdafitinib to treat advanced cancer with fibroblast growth factor receptor gene (FGFR) alterations, compare it to the upper bound of on-label use in urothelial cancer, and to review studies that may support off-label use. Design, Setting, and Participants: This cross-sectional study used frequency data on FGFR alterations by cancer type and the estimated number of deaths from all cancers for 2019 in the United States. Mortality statistics were used as surrogates for patients with advanced cancer. Analysis was conducted in May 2019. Exposure: Percentage of patients with an FGFR2 or FGFR3 alteration. Main Outcomes and Measures: Estimated number of patients with advanced cancer expressing an FGFR2 or FGFR3 alteration eligible for off-label use of erdafitinib by cancer type; number of studies investigating FGFR-targeting drugs for patients with cancer; and number of ongoing clinical trials on erdafitinib by cancer type. Results: A total of 15 cancer types had reported FGFR alterations. Of 455 440 estimated patients who died of cancer in 2019, 17 019 (3.7%) were estimated to have FGFR2 or FGFR3 alterations. Of these patients, 12 955 (76.1%) could be eligible for off-label treatment with erdafitinib. A total of 29 completed studies evaluated FGFR-targeting drugs in 11 cancer types, and 10 ongoing studies are studying erdafitinib for different oncological indications. Conclusions and Relevance: This study indicates that the potential for off-label use of FGFR inhibitors such as erdafitinib spans a number of cancer types and a large patient population. Systematic trials exploring off-label uses may be desirable for drugs that target clear, identifiable molecular alterations because this may be more efficient than off-label use in identifying clinical scenarios where the agent has activity.

Oral anticancer drugs: how limited dosing options and dose reductions may affect outcomes in comparative trials and efficacy in patients.

Historically, cancer medicine has avoided the problem of unequal dosing by comparing maximum-tolerated doses of intravenous regimens with proportionate dose reductions for toxicity. However, in recent years, with the development of numerous oral anticancer agents, dosing options are arbitrarily and increasingly limited by the size of pills. We contend that an underappreciated consequence of pill size is unequal dosing in comparative clinical trials and that this can have an impact on outcomes. We discuss how comparative effectiveness trials can be unbalanced and how the use of doses that are not sustainable might affect outcomes, especially marginal ones. We further argue that because of their poor tolerability and their limited dosing options, which often result in large dose adjustments in response to toxicity, the real-world clinical effectiveness of oral anticancer agents may be diminished and may not emulate results achieved in registration trials.

Selective therapeutic hypothermia: A review of invasive and noninvasive techniques / Hipotermia terapêutica seletiva: uma revisão de técnicas invasivas e não invasivas

OBJECTIVE: Therapeutic hypothermia is a promising treatment to prevent secondary neurologic injury. Clinical utility is limited by systemic complications of global hypothermia. Selective brain cooling remains a largely uninvestigated application. We review techniques of inducing selective brain cooling. METHOD: Literature review. RESULTS: Strategies of inducing selective brain cooling were divided between non-invasive and invasive techniques. Non-invasive techniques were surface cooling and cooling via the upper airway. Invasive cooling methods include transvascular and compartmental (epidural, subdural, subarachnoid and intraventricular) cooling methods to remove heat from the brain. CONCLUSION: Selective brain cooling may offer the best strategy for achieving hypothermic neuroprotection. Non-invasive strategies have proven disappointing in human trials. There is a paucity of human experiments using invasive methods of selective brain cooling. Further application of invasive cooling strategies is needed.

OBJETIVO: A hipotermia terapêutica é uma estratégia promissora para prevenção do dano neurológico secundário. Sua utilidade clínica é limitada por complicações sistêmicas da hipotermia global. Resfriamento cerebral seletivo (RCS), entretanto, permanece uma técnica pouco estudada. Revisamos aqui as diferentes técnicas de indução de RCS. MÉTODO: Revisão de literatura. RESULTADOS: As estratégias de indução de RCS foram divididas em invasivas e não-invasivas. Métodos de remoção de calor do cérebro não-invasivos incluem o resfriamento de superfície e o de vias aéreas superiores; as técnicas invasivas incluem resfriamento transvascular e compartimental (epidural, subdural, subaracnóideo e intraventricular). CONCLUSÃO: RCS pode oferecer a melhor estratégia para alcançar neuroproteção hipotérmica. Estratégias não-invasivas têm se mostrado ineficazes em estudos clínicos. Técnicas invasivas foram raramente estudadas em humanos e necessitam ser mais investigadas para tornarem-se úteis.

Selective therapeutic hypothermia: a review of invasive and noninvasive techniques.

OBJECTIVE: Therapeutic hypothermia is a promising treatment to prevent secondary neurologic injury. Clinical utility is limited by systemic complications of global hypothermia. Selective brain cooling remains a largely uninvestigated application. We review techniques of inducing selective brain cooling. METHOD: Literature review. RESULTS: Strategies of inducing selective brain cooling were divided between non-invasive and invasive techniques. Non-invasive techniques were surface cooling and cooling via the upper airway. Invasive cooling methods include transvascular and compartmental (epidural, subdural, subarachnoid and intraventricular) cooling methods to remove heat from the brain. CONCLUSION: Selective brain cooling may offer the best strategy for achieving hypothermic neuroprotection. Non-invasive strategies have proven disappointing in human trials. There is a paucity of human experiments using invasive methods of selective brain cooling. Further application of invasive cooling strategies is needed.