Study Of Doses

[Ramya Bradbury]

In2019, after Kimberly completed her second round of radiation therapy for metastatic breast cancer, her oncologist put her on a daily dose of 125 mg of the targeted drug palbociclib (Ibrance), which was the recommended dose.

Undeterred, Kimberly continued insisting on a dose reduction, and eventually her oncologist relented, reducing the dose to 100 mg. Kimberly felt better almost immediately; her energy returned and the gastrointestinal issues subsided. She then pressed her oncologist to reduce the dose even further.

In a recent survey of 1,221 women with metastatic breast cancer, 86% reported having had at least one side effect related to their treatment. And 20% had such severe side effects that they had to go to the hospital or emergency room.

Several studies, for example, have shown that lower doses of palbociclib are still effective against tumors but cause fewer side effects, in particular reducing the drop in white blood cell counts (neutropenia) that can increase infection risk.

One study even found that patients who had their dose reduced because of side effects actually lived longer than those who stayed on the higher dose. An upcoming clinical trial will compare whether starting out on a reduced dose of palbociclib helps women with metastatic breast cancer stay on treatment longer.

The Food and Drug Administration (FDA) is also getting into the act. In 2021, the agency launched an initiative called Project Optimus to change how researchers select which dose of new drugs to test in cancer clinical trials.

In a related effort, FDA and the American Association for Cancer Research have held a series of workshops on cancer drug dose optimization. The most recent workshop, held in February 2024, focused on the use of computer modeling and simulation to better guide dose selection.

As long as that dose does not cause serious side effects, they gradually increase the dose in tests on additional groups of patients until they reach a dose where a certain percentage experiences serious side effects, known as dose-limiting toxicity. The next dose level down is then considered the maximum tolerated dose.

In particular, the models can help narrow the optimal dose range to test in humans, guide the doses that should be tested in different cancer types, and identify the best dose to use in combination with other drugs.

For example, researchers used data from a small clinical trial of the targeted therapy pralsetinib (Gavreto) in people with advanced lung cancer in a computer model to help identify the recommended dose to use in larger trials.

Over the last decade, for example, Dr. Ratain and his colleagues have focused much of their research on determining the most effective and safe doses of several cancer drugs that are already in wide use.

For example, they conducted a clinical trial testing two different doses of one of the most commonly used drugs to treat prostate cancer, abiraterone (Zytiga). In addition to dose, however, there was another difference: how the drug was taken.

Researchers are also exploring the possibility of using lower doses of immune checkpoint inhibitors, which have rapidly become standard treatments for many cancers. Other studies have analyzed if, under certain circumstances, giving these immunotherapies at their usual dose but less frequently is a viable treatment approach.

Dr. Ratain and his colleagues have been reviewing data on every FDA-approved cancer drug to determine which ones might be the most important to study in what are often called post-market optimization studies.

They are also developing a website to share potential dosing strategies for many approved cancer drugs, starting with the oral drugs and then moving to the intravenous drugs. By doing so, they hope to encourage researchers to perform dosing studies on these drugs to determine whether lower doses might be just as effective and potentially safer.

That survey found that 85% of oncologists did not believe that a higher dose of a cancer drug is always more effective than a lower dose, and 97% said they would be willing to discuss flexible dosing with their patients.

Individuals with opioid use disorder who were prescribed a lower buprenorphine dose were 20% more likely to discontinue treatment than those on a higher dose, according to a study of patients prescribed buprenorphine in Rhode Island from 2016 to 2020, as fentanyl became widely available. The study, published today in JAMA Network Open, was supported by the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health, and conducted by researchers at Brown University, Providence, Rhode Island; NIDA and the Rhode Island Department of Health.

Among patients newly initiating buprenorphine treatment for opioid use disorder, 59% of those prescribed the target daily dose of 16 milligrams recommended by the U.S. Food and Drug Administration and 53% of those prescribed the higher 24 mg daily dose discontinued treatment within 180 days. A statistical analysis that allowed for multivariable comparison of these two dose groups showed patients prescribed the recommended dose (16 mg) were significantly more likely to discontinue treatment over 180 days compared to those prescribed 24 mg.

Medications for opioid use disorder such as buprenorphine can safely and effectively support reduction in opioid use and overdose as well as recovery by decreasing opioid cravings and easing withdrawal symptoms. These findings build upon accumulating evidence of the safety and efficacy of higher doses of buprenorphine. Studies have shown that more than 16 mg of buprenorphine is safe and well tolerated in people with opioid use disorder in emergency department and outpatient treatment settings.

Patients prescribed a 24 mg dose of buprenorphine were retained in treatment for a longer period than those prescribed the recommended target maintenance dose of 16 mg. A statistical analysis showed the latter group was 20% more likely to discontinue treatment than those prescribed 24 mg.

To continue this research, scientists aim to conduct a prospective randomized clinical trial to assess the impact of daily buprenorphine doses up to 24 mg in improving treatment retention and reducing the risk of overdose and death. Within this trial, the researchers will also investigate the role of other factors that may be associated with treatment retention, including clinician prescribing practices, as well as patient socio-demographics and life circumstances. Findings from this trial could ultimately help inform updates to opioid use disorder treatment standards.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Vaccines that protect against human papillomavirus (HPV) infection can substantially reduce the risk of cervical cancer, and other cancers attributable to HPV. However, HPV vaccination rates are too low, especially in countries and regions with very high rates of cervical cancer and low resources. These vaccines are expensive and giving multiple doses can be difficult, especially in low-resource settings. Researchers from DCEG and Costa Rica are conducting the ESCUDDO study in order to determine if one dose of the HPV vaccines works as well as two doses in young women.

ESCUDDO is part of the Cancer Moonshot Initiative. Findings from the trial will provide the definitive evidence of the non-inferiority of one dose compared to two doses, which was the global gold standard in young girls until late 2022, when the WHO provided an alternative, off-label recommendation for providing two or one doses.

If one dose of an HPV vaccine were found to be sufficient to prevent HPV infections, which would reduce cervical precancer and cancer rates and burden, we would expect more widespread vaccine uptake. This could impact the United States and the world, with vaccination programs being able use existing resources to vaccinate more individuals.

There are two components to the study: (1) a controlled, randomized, double-blinded non-inferiority clinical trial to compare one-dose to two-dose vaccination; and (2) a concurrent epidemiologic survey for HPV infection status among unvaccinated women.

The epidemiologic HPV survey enrolls a group of unvaccinated women from the same geographic areas; they range in age from 16 to 22 years. These women attend three study visits six months apart to determine their HPV DNA status. They are offered HPV vaccination.

ESCUDDO will generate data that public health policy makers need to make evidence-based decisions related to large scale implementation of sustainable, cost-effective HPV vaccine programs. Evidence of strong protection from a single-dose of either HPV vaccine may enable nations to introduce HPV vaccination or to achieve extensive population coverage by vaccinating a much larger number of HPV-nave individuals, which, in combination with herd immunity, will result in decreased cervical cancer incidence and mortality over time. See the ESCUDDO trial Clinicaltrials.gov (NCT03180034).

The immune response to COVID-19 vaccines may wane over time. Booster shots are a safe and effective way to extend protection against variants of concern. Mixing vaccines may enhance the immune response, and it increases flexibility for when people need a booster dose but doses of the vaccine they first received are not available.

The National Institute of Allergy and Infectious Diseases (NIAID) is leading and funding a study in which adults who have been fully vaccinated against COVID-19 receive booster doses of different COVID-19 vaccines. The goal of this study is to determine whether receiving a booster dose of a different COVID-19 vaccine is safe and how the immune system responds to that dose.

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