Breast Cancer ICYMI

Key clinical point: Denosumab improves bone-related outcomes in women with high-risk early-stage breast cancer.

Major finding: Denosumab was associated with longer time to first bone metastasis in patients younger than 50 years (hazard ratio [HR], 0.70; P = .018) and in premenopausal women (HR, 0.74; P = .038). Denosumab also delayed the risk for first fracture (HR, 0.76; P = .004) and first skeletal-related event (HR, 0.52; P = .001).

Study details: An exploratory analysis of randomized, placebo-controlled phase 3 D-CARE trial of 4,509 patients with stage II/III breast cancer randomly assigned to receive adjuvant/neoadjuvant chemotherapy with either denosumab or placebo.

Disclosures: This study was funded by Amgen Inc. Dr. R Coleman received lecture funding, steering committee fees, and travel expenses from various sources and reported stock ownership in Inbiomotion. Dr. Y. Zhou, Dr. D. Jandial, and Dr. B. Cadieux were employees of and/or shareholders in Amgen. The other authors have no competing interest.

Source: Coleman R et al. Adv Ther. 2021 Jun 29. doi: 10.1007/s12325-021-01812-9.

Key clinical point: Denosumab improves bone-related outcomes in women with high-risk early-stage breast cancer.

Major finding: Denosumab was associated with longer time to first bone metastasis in patients younger than 50 years (hazard ratio [HR], 0.70; P = .018) and in premenopausal women (HR, 0.74; P = .038). Denosumab also delayed the risk for first fracture (HR, 0.76; P = .004) and first skeletal-related event (HR, 0.52; P = .001).

Study details: An exploratory analysis of randomized, placebo-controlled phase 3 D-CARE trial of 4,509 patients with stage II/III breast cancer randomly assigned to receive adjuvant/neoadjuvant chemotherapy with either denosumab or placebo.

Disclosures: This study was funded by Amgen Inc. Dr. R Coleman received lecture funding, steering committee fees, and travel expenses from various sources and reported stock ownership in Inbiomotion. Dr. Y. Zhou, Dr. D. Jandial, and Dr. B. Cadieux were employees of and/or shareholders in Amgen. The other authors have no competing interest.

Source: Coleman R et al. Adv Ther. 2021 Jun 29. doi: 10.1007/s12325-021-01812-9.

Key clinical point: Denosumab improves bone-related outcomes in women with high-risk early-stage breast cancer.

Major finding: Denosumab was associated with longer time to first bone metastasis in patients younger than 50 years (hazard ratio [HR], 0.70; P = .018) and in premenopausal women (HR, 0.74; P = .038). Denosumab also delayed the risk for first fracture (HR, 0.76; P = .004) and first skeletal-related event (HR, 0.52; P = .001).

Study details: An exploratory analysis of randomized, placebo-controlled phase 3 D-CARE trial of 4,509 patients with stage II/III breast cancer randomly assigned to receive adjuvant/neoadjuvant chemotherapy with either denosumab or placebo.

Disclosures: This study was funded by Amgen Inc. Dr. R Coleman received lecture funding, steering committee fees, and travel expenses from various sources and reported stock ownership in Inbiomotion. Dr. Y. Zhou, Dr. D. Jandial, and Dr. B. Cadieux were employees of and/or shareholders in Amgen. The other authors have no competing interest.

Source: Coleman R et al. Adv Ther. 2021 Jun 29. doi: 10.1007/s12325-021-01812-9.

Key clinical point: The clinical benefit of ribociclib is maintained in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer who required dose reduction to manage adverse events.

Major finding: Ribociclib dose reductions were reported in 45.8% of patients; most were attributed to adverse reactions. The median progression-free survival was 24.8, 24.9, and 29.6 months for patients who received 71% or less, 72%-96%, and 97%-100% ribociclib relative dose intensity, respectively. The clinical benefit ratio was 87.6%, 76.8%, and 73.6%, respectively.

Study details: A pooled analysis of MONALEESA-2, MONALEESA-3, and MONALEESA-7 trials evaluated the safety and impact of ribociclib dose reduction in 818 patients with HR-positive, HER2-negative advanced breast cancer.

Disclosures: The study was supported by Novartis Pharmaceuticals Corporation. The authors received grants, funding, and/or consulting/advisory/personal fees from various sources. Dr. JP Zarate, Dr. A Ridolfi, and Dr. KR Lorenc were employed by and owned stocks in Novartis.

Source: Burris HA et al. Br J Cancer. 2021 Jun 22. doi: 10.1038/s41416-021-01415-9.

Key clinical point: The clinical benefit of ribociclib is maintained in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer who required dose reduction to manage adverse events.

Major finding: Ribociclib dose reductions were reported in 45.8% of patients; most were attributed to adverse reactions. The median progression-free survival was 24.8, 24.9, and 29.6 months for patients who received 71% or less, 72%-96%, and 97%-100% ribociclib relative dose intensity, respectively. The clinical benefit ratio was 87.6%, 76.8%, and 73.6%, respectively.

Study details: A pooled analysis of MONALEESA-2, MONALEESA-3, and MONALEESA-7 trials evaluated the safety and impact of ribociclib dose reduction in 818 patients with HR-positive, HER2-negative advanced breast cancer.

Disclosures: The study was supported by Novartis Pharmaceuticals Corporation. The authors received grants, funding, and/or consulting/advisory/personal fees from various sources. Dr. JP Zarate, Dr. A Ridolfi, and Dr. KR Lorenc were employed by and owned stocks in Novartis.

Source: Burris HA et al. Br J Cancer. 2021 Jun 22. doi: 10.1038/s41416-021-01415-9.

Key clinical point: The clinical benefit of ribociclib is maintained in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer who required dose reduction to manage adverse events.

Major finding: Ribociclib dose reductions were reported in 45.8% of patients; most were attributed to adverse reactions. The median progression-free survival was 24.8, 24.9, and 29.6 months for patients who received 71% or less, 72%-96%, and 97%-100% ribociclib relative dose intensity, respectively. The clinical benefit ratio was 87.6%, 76.8%, and 73.6%, respectively.

Study details: A pooled analysis of MONALEESA-2, MONALEESA-3, and MONALEESA-7 trials evaluated the safety and impact of ribociclib dose reduction in 818 patients with HR-positive, HER2-negative advanced breast cancer.

Disclosures: The study was supported by Novartis Pharmaceuticals Corporation. The authors received grants, funding, and/or consulting/advisory/personal fees from various sources. Dr. JP Zarate, Dr. A Ridolfi, and Dr. KR Lorenc were employed by and owned stocks in Novartis.

Source: Burris HA et al. Br J Cancer. 2021 Jun 22. doi: 10.1038/s41416-021-01415-9.

Key clinical point: In patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer, CT-P6, a trastuzumab biosimilar shows 3-year survival comparable with trastuzumab.

Major finding: Median disease-free survival (DFS), overall survival (OS), and progression-free survival (PFS) were not reached in either group. In the CT-P6 vs trastuzumab group, the 3-year DFS, PFS, and OS rates were 83% vs 83%, 81% vs 87%, and 93% vs 94%, respectively.

Study details: A randomized, double-blind, active-controlled, phase 3 equivalence trial of 549 patients with HER2‑positive early breast cancer who received neoadjuvant treatment with CT-P6 or trastuzumab with chemotherapy, followed by surgery. Patients were followed up for 3 years (n=528) after receiving adjuvant CT-P6 or trastuzumab.

Disclosures: The study was funded by Celltrion, Inc. The authors received grants and consulting/advisory fees from various sources. Dr. SJ Lee and Dr. S Kim were employees of and/or stockholders in Celltrion.

Source: Stebbing J et al. Breast Cancer Res Treat. 2021 Jun 20. doi: 10.1007/s10549-021-06240-5.

Key clinical point: In patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer, CT-P6, a trastuzumab biosimilar shows 3-year survival comparable with trastuzumab.

Major finding: Median disease-free survival (DFS), overall survival (OS), and progression-free survival (PFS) were not reached in either group. In the CT-P6 vs trastuzumab group, the 3-year DFS, PFS, and OS rates were 83% vs 83%, 81% vs 87%, and 93% vs 94%, respectively.

Study details: A randomized, double-blind, active-controlled, phase 3 equivalence trial of 549 patients with HER2‑positive early breast cancer who received neoadjuvant treatment with CT-P6 or trastuzumab with chemotherapy, followed by surgery. Patients were followed up for 3 years (n=528) after receiving adjuvant CT-P6 or trastuzumab.

Disclosures: The study was funded by Celltrion, Inc. The authors received grants and consulting/advisory fees from various sources. Dr. SJ Lee and Dr. S Kim were employees of and/or stockholders in Celltrion.

Source: Stebbing J et al. Breast Cancer Res Treat. 2021 Jun 20. doi: 10.1007/s10549-021-06240-5.

Key clinical point: In patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer, CT-P6, a trastuzumab biosimilar shows 3-year survival comparable with trastuzumab.

Major finding: Median disease-free survival (DFS), overall survival (OS), and progression-free survival (PFS) were not reached in either group. In the CT-P6 vs trastuzumab group, the 3-year DFS, PFS, and OS rates were 83% vs 83%, 81% vs 87%, and 93% vs 94%, respectively.

Study details: A randomized, double-blind, active-controlled, phase 3 equivalence trial of 549 patients with HER2‑positive early breast cancer who received neoadjuvant treatment with CT-P6 or trastuzumab with chemotherapy, followed by surgery. Patients were followed up for 3 years (n=528) after receiving adjuvant CT-P6 or trastuzumab.

Disclosures: The study was funded by Celltrion, Inc. The authors received grants and consulting/advisory fees from various sources. Dr. SJ Lee and Dr. S Kim were employees of and/or stockholders in Celltrion.

Source: Stebbing J et al. Breast Cancer Res Treat. 2021 Jun 20. doi: 10.1007/s10549-021-06240-5.

Key clinical point: Bisphosphonate therapy for 5 vs 2 years in patients with high-risk early breast cancer yields no added survival benefit and leads to increased risk for adverse events.

Major finding: There were no significant differences in disease-free survival (hazard ratio [HR], 0.97; P = .81), overall survival (HR, 0.98; P = .90), and distant disease-free survival (HR, 0.87; P = .38) between 5- and 2-year bisphosphonate treatment groups. The rate of adverse events was 46.2% with 5-year therapy and 27.2% with 2-year treatment.

Study details: A randomized phase 3, open-label SUCCESS A trial of 2,987 patients with high-risk early breast cancer randomly assigned to receive bisphosphonate zoledronate for either 5 or 2 years.

Disclosures: The study was supported by AstraZeneca, Chugai, Menarini Silicon Biosystems (formerly Veridex), Lilly, Novartis, and Sanofi-Aventis. The authors received honoraria, personal fees, research support, consulting fees, and travel grants from various sources.

Source: Friedl TWP et al. JAMA Oncol. 2021 Jun 24. doi: 10.1001/jamaoncol.2021.1854.

Key clinical point: Bisphosphonate therapy for 5 vs 2 years in patients with high-risk early breast cancer yields no added survival benefit and leads to increased risk for adverse events.

Major finding: There were no significant differences in disease-free survival (hazard ratio [HR], 0.97; P = .81), overall survival (HR, 0.98; P = .90), and distant disease-free survival (HR, 0.87; P = .38) between 5- and 2-year bisphosphonate treatment groups. The rate of adverse events was 46.2% with 5-year therapy and 27.2% with 2-year treatment.

Study details: A randomized phase 3, open-label SUCCESS A trial of 2,987 patients with high-risk early breast cancer randomly assigned to receive bisphosphonate zoledronate for either 5 or 2 years.

Disclosures: The study was supported by AstraZeneca, Chugai, Menarini Silicon Biosystems (formerly Veridex), Lilly, Novartis, and Sanofi-Aventis. The authors received honoraria, personal fees, research support, consulting fees, and travel grants from various sources.

Source: Friedl TWP et al. JAMA Oncol. 2021 Jun 24. doi: 10.1001/jamaoncol.2021.1854.

Key clinical point: Bisphosphonate therapy for 5 vs 2 years in patients with high-risk early breast cancer yields no added survival benefit and leads to increased risk for adverse events.

Major finding: There were no significant differences in disease-free survival (hazard ratio [HR], 0.97; P = .81), overall survival (HR, 0.98; P = .90), and distant disease-free survival (HR, 0.87; P = .38) between 5- and 2-year bisphosphonate treatment groups. The rate of adverse events was 46.2% with 5-year therapy and 27.2% with 2-year treatment.

Study details: A randomized phase 3, open-label SUCCESS A trial of 2,987 patients with high-risk early breast cancer randomly assigned to receive bisphosphonate zoledronate for either 5 or 2 years.

Disclosures: The study was supported by AstraZeneca, Chugai, Menarini Silicon Biosystems (formerly Veridex), Lilly, Novartis, and Sanofi-Aventis. The authors received honoraria, personal fees, research support, consulting fees, and travel grants from various sources.

Source: Friedl TWP et al. JAMA Oncol. 2021 Jun 24. doi: 10.1001/jamaoncol.2021.1854.

Key clinical point: In patients with human epidermal growth factor receptor 2 (HER2)-positive locally recurrent or metastatic breast cancer, paclitaxel can be an alternative to docetaxel with first-line pertuzumab plus trastuzumab.

Major finding: The median follow-up was 68.7 months. The median progression-free survival was 19.4 (95% confidence interval [CI], 16.9-22.1) months in the docetaxel, 23.2 (95% CI,19.6-25.6) months in the paclitaxel, and 19.2 (95% CI, 11.7-37.1) months in the nab-paclitaxel group. Docetaxel was associated with higher rates of grade ≥3 neutropenia and febrile neutropenia.

Study details: A multicenter, open-label, single-arm phase 3b PERUSE study of 1,436 eligible patients with inoperable HER2-positive locally recurrent or metastatic breast cancer who received pertuzumab and trastuzumab with a taxane (docetaxel, paclitaxel, or nab-paclitaxel).

Disclosures: The study was supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland. The authors reported receiving research funding, personal fees, grants, honoraria, advisory/speaker/consulting fees, and travel/accommodation/expenses from various sources. Some authors were employed by and/or owned stocks in pharmaceutical companies.

Source: Miles D et al. Ann Oncol. 2021 Jul 1. doi: 10.1016/j.annonc.2021.06.024.

Key clinical point: In patients with human epidermal growth factor receptor 2 (HER2)-positive locally recurrent or metastatic breast cancer, paclitaxel can be an alternative to docetaxel with first-line pertuzumab plus trastuzumab.

Major finding: The median follow-up was 68.7 months. The median progression-free survival was 19.4 (95% confidence interval [CI], 16.9-22.1) months in the docetaxel, 23.2 (95% CI,19.6-25.6) months in the paclitaxel, and 19.2 (95% CI, 11.7-37.1) months in the nab-paclitaxel group. Docetaxel was associated with higher rates of grade ≥3 neutropenia and febrile neutropenia.

Study details: A multicenter, open-label, single-arm phase 3b PERUSE study of 1,436 eligible patients with inoperable HER2-positive locally recurrent or metastatic breast cancer who received pertuzumab and trastuzumab with a taxane (docetaxel, paclitaxel, or nab-paclitaxel).

Disclosures: The study was supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland. The authors reported receiving research funding, personal fees, grants, honoraria, advisory/speaker/consulting fees, and travel/accommodation/expenses from various sources. Some authors were employed by and/or owned stocks in pharmaceutical companies.

Source: Miles D et al. Ann Oncol. 2021 Jul 1. doi: 10.1016/j.annonc.2021.06.024.

Key clinical point: In patients with human epidermal growth factor receptor 2 (HER2)-positive locally recurrent or metastatic breast cancer, paclitaxel can be an alternative to docetaxel with first-line pertuzumab plus trastuzumab.

Major finding: The median follow-up was 68.7 months. The median progression-free survival was 19.4 (95% confidence interval [CI], 16.9-22.1) months in the docetaxel, 23.2 (95% CI,19.6-25.6) months in the paclitaxel, and 19.2 (95% CI, 11.7-37.1) months in the nab-paclitaxel group. Docetaxel was associated with higher rates of grade ≥3 neutropenia and febrile neutropenia.

Study details: A multicenter, open-label, single-arm phase 3b PERUSE study of 1,436 eligible patients with inoperable HER2-positive locally recurrent or metastatic breast cancer who received pertuzumab and trastuzumab with a taxane (docetaxel, paclitaxel, or nab-paclitaxel).

Disclosures: The study was supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland. The authors reported receiving research funding, personal fees, grants, honoraria, advisory/speaker/consulting fees, and travel/accommodation/expenses from various sources. Some authors were employed by and/or owned stocks in pharmaceutical companies.

Source: Miles D et al. Ann Oncol. 2021 Jul 1. doi: 10.1016/j.annonc.2021.06.024.

Key clinical point: Atezolizumab plus nab-paclitaxel shows no overall survival (OS) advantage in patients with advanced/metastatic triple-negative breast cancer (TNBC) overall, but improves OS in in a patient subgroup positive for programmed death-ligand 1 (PD-L1) expression in tumor-infiltrating immune cells.

Major finding: There was no difference in OS in the intent-to-treat population (P = .077). An exploratory analysis in the PD-L1 immune cell-positive population showed OS improvement with atezolizumab plus nab-paclitaxel (stratified hazard ratio, 0.67; 95% confidence interval, 0.53-0.86).

Study details: A randomized, double-blind, placebo-controlled phase 3 IMpassion130 trial of 902 patients with advanced/metastatic TNBC who received atezolizumab plus nab-paclitaxel (n=451) or placebo plus nab-paclitaxel (n=451).

Disclosures: This study was sponsored by F. Hoffmann-La Roche Ltd./Genentech, Inc. The authors received honoraria, travel support, research funding, consulting/advisory/steering committee fees, and grants from various sources. Some of the authors were employed by and/or owned stocks in Genentech/Roche.

Source: Emens LA et al. Ann Oncol. 2021 Jul 1. doi: 10.1016/j.annonc.2021.05.355.

Key clinical point: Atezolizumab plus nab-paclitaxel shows no overall survival (OS) advantage in patients with advanced/metastatic triple-negative breast cancer (TNBC) overall, but improves OS in in a patient subgroup positive for programmed death-ligand 1 (PD-L1) expression in tumor-infiltrating immune cells.

Major finding: There was no difference in OS in the intent-to-treat population (P = .077). An exploratory analysis in the PD-L1 immune cell-positive population showed OS improvement with atezolizumab plus nab-paclitaxel (stratified hazard ratio, 0.67; 95% confidence interval, 0.53-0.86).

Study details: A randomized, double-blind, placebo-controlled phase 3 IMpassion130 trial of 902 patients with advanced/metastatic TNBC who received atezolizumab plus nab-paclitaxel (n=451) or placebo plus nab-paclitaxel (n=451).

Disclosures: This study was sponsored by F. Hoffmann-La Roche Ltd./Genentech, Inc. The authors received honoraria, travel support, research funding, consulting/advisory/steering committee fees, and grants from various sources. Some of the authors were employed by and/or owned stocks in Genentech/Roche.

Source: Emens LA et al. Ann Oncol. 2021 Jul 1. doi: 10.1016/j.annonc.2021.05.355.

Key clinical point: Atezolizumab plus nab-paclitaxel shows no overall survival (OS) advantage in patients with advanced/metastatic triple-negative breast cancer (TNBC) overall, but improves OS in in a patient subgroup positive for programmed death-ligand 1 (PD-L1) expression in tumor-infiltrating immune cells.

Major finding: There was no difference in OS in the intent-to-treat population (P = .077). An exploratory analysis in the PD-L1 immune cell-positive population showed OS improvement with atezolizumab plus nab-paclitaxel (stratified hazard ratio, 0.67; 95% confidence interval, 0.53-0.86).

Study details: A randomized, double-blind, placebo-controlled phase 3 IMpassion130 trial of 902 patients with advanced/metastatic TNBC who received atezolizumab plus nab-paclitaxel (n=451) or placebo plus nab-paclitaxel (n=451).

Disclosures: This study was sponsored by F. Hoffmann-La Roche Ltd./Genentech, Inc. The authors received honoraria, travel support, research funding, consulting/advisory/steering committee fees, and grants from various sources. Some of the authors were employed by and/or owned stocks in Genentech/Roche.

Source: Emens LA et al. Ann Oncol. 2021 Jul 1. doi: 10.1016/j.annonc.2021.05.355.

Key clinical point: Atezolizumab in combination with paclitaxel does not improve survival in patients with unresectable locally advanced/metastatic triple-negative breast cancer (TNBC) vs paclitaxel plus placebo.

Major finding: The median follow-up was 14.2 months in the atezolizumab group and 14.5 months in the placebo group. Atezolizumab plus paclitaxel did not improve median overall survival vs paclitaxel plus placebo (hazard ratio, 1.11; 95% confidence interval, 0.76-1.64). Compared with placebo plus paclitaxel, atezolizumab plus paclitaxel was associated with a higher incidence of serious (25% vs 18%) and grade 3/4 adverse events (53% vs 46%).

Study details: A global randomized, double-blind, placebo-controlled phase 3 IMpassion131 trial of 651 patients with advanced/metastatic TNBC who were randomly assigned to atezolizumab plus paclitaxel or placebo plus paclitaxel.

Disclosures: The study was supported by F. Hoffmann-La Roche Ltd. The authors received honoraria, research grants, speaker/advisory/consulting fees, personal fees, and travel/accommodation/expenses from various sources. Some authors were employed by and/or owned stocks in pharmaceutical companies.

Source: Miles D et al. Ann Oncol. 2021 Jul 1. doi: 10.1016/j.annonc.2021.05.801.

Key clinical point: Atezolizumab in combination with paclitaxel does not improve survival in patients with unresectable locally advanced/metastatic triple-negative breast cancer (TNBC) vs paclitaxel plus placebo.

Major finding: The median follow-up was 14.2 months in the atezolizumab group and 14.5 months in the placebo group. Atezolizumab plus paclitaxel did not improve median overall survival vs paclitaxel plus placebo (hazard ratio, 1.11; 95% confidence interval, 0.76-1.64). Compared with placebo plus paclitaxel, atezolizumab plus paclitaxel was associated with a higher incidence of serious (25% vs 18%) and grade 3/4 adverse events (53% vs 46%).

Study details: A global randomized, double-blind, placebo-controlled phase 3 IMpassion131 trial of 651 patients with advanced/metastatic TNBC who were randomly assigned to atezolizumab plus paclitaxel or placebo plus paclitaxel.

Disclosures: The study was supported by F. Hoffmann-La Roche Ltd. The authors received honoraria, research grants, speaker/advisory/consulting fees, personal fees, and travel/accommodation/expenses from various sources. Some authors were employed by and/or owned stocks in pharmaceutical companies.

Source: Miles D et al. Ann Oncol. 2021 Jul 1. doi: 10.1016/j.annonc.2021.05.801.

Key clinical point: Atezolizumab in combination with paclitaxel does not improve survival in patients with unresectable locally advanced/metastatic triple-negative breast cancer (TNBC) vs paclitaxel plus placebo.

Major finding: The median follow-up was 14.2 months in the atezolizumab group and 14.5 months in the placebo group. Atezolizumab plus paclitaxel did not improve median overall survival vs paclitaxel plus placebo (hazard ratio, 1.11; 95% confidence interval, 0.76-1.64). Compared with placebo plus paclitaxel, atezolizumab plus paclitaxel was associated with a higher incidence of serious (25% vs 18%) and grade 3/4 adverse events (53% vs 46%).

Study details: A global randomized, double-blind, placebo-controlled phase 3 IMpassion131 trial of 651 patients with advanced/metastatic TNBC who were randomly assigned to atezolizumab plus paclitaxel or placebo plus paclitaxel.

Disclosures: The study was supported by F. Hoffmann-La Roche Ltd. The authors received honoraria, research grants, speaker/advisory/consulting fees, personal fees, and travel/accommodation/expenses from various sources. Some authors were employed by and/or owned stocks in pharmaceutical companies.

Source: Miles D et al. Ann Oncol. 2021 Jul 1. doi: 10.1016/j.annonc.2021.05.801.

A dietary supplement that mimics the effects of the high-fat, low-carbohydrate ketogenic diet is well tolerated and appears to reduce seizures in children and adults with treatment-resistant epilepsy, early research suggests. However, at least one expert has concerns.

In an open-label feasibility study, researchers assessed a liquid supplement known as K.Vita (Vitaflo International), which contains both decanoic acid and octanoic acid.

Although the study was small, the findings are promising, said coinvestigator Matthew Walker, MD, PhD, University College London Institute of Neurology, department of clinical and experimental epilepsy.

“The dietary supplement was reasonably well tolerated and while we weren’t specifically looking for efficacy here, we did see some patients had quite dramatic results in terms of reduced seizures,” Dr. Walker said.

Unlike the ketogenic diet, this dietary supplement is “very easy” to follow, involves only minor dietary modifications, and doesn’t require the intervention of a dietitian, he added.

The findings were published online July 23, 2021, in Brain Communications.
 

Key ingredients

In the ketogenic diet, the body uses body fat as its primary fuel source. The switch from carbohydrates to fat for body fuel results in built-up ketones.

Previous research shows the ketogenic diet is effective in reducing seizures in some patients with epilepsy. However, many patients find it difficult to tolerate, especially for extended periods. Dr. Walker also noted that ketones may have other long-term side effects, including osteoporosis.

He added that his team was keen to learn what elements of the ketogenic diet affect seizures. “Interestingly, we found that one of the fats used in the ketogenic diet, decanoic acid, has quite marked antiseizure effects,” Dr. Walker said.

Previous research has shown that decanoic acid, a medium-chain triglyceride–derived fatty acid, can cross the blood-brain barrier and decrease excitatory neurotransmission and network excitability in vitro.

Dr. Walker noted that ketones are necessary in order to reduce seizures.

“Rather than have a very high-fat, low-carbohydrate diet that causes ketones, we thought ‘why don’t we use a diet in which we just use mainly this fat, this decanoic acid, and avoid ketosis,’ ” he said.

The researchers then went to work developing the K.Vita dietary supplement, which mainly contains decanoic acid but also another fat, octanoic acid.
 

Assessing feasibility

The feasibility study included 61 patients (59% female) who began taking the supplement. Of these, 35 were children (aged 3-18 years) and 26 were adults. The children had Dravet syndrome or another genetically driven form of epilepsy, while most of the adults had a focal epilepsy.

All participants had failed multiple antiseizure medications – a median of 3 for children and 10 for adults who completed the trial. Of the 61 original participants, 20 (19 children and 1 adult) had tried the ketogenic diet but had stopped it for various reasons, including noncompliance and lack of efficacy.

The liquid supplement was introduced gradually. The amount administered was based on weight in the children and was a standard amount in adults, with the target being 240 mL.

Participants consumed the supplement in equal servings taken at regular intervals as part of a meal or snack. They could take it alone or mix it with yogurt or another food.

Patients with feeding tubes took the supplement immediately before or after or mixed into an enteral feed, with a water flush afterward.

Researchers provided patients and caregivers with guidance on excluding highly refined sugary foods and beverages. Starchy foods such as bread, pasta, rice, and potatoes were not restricted.

The study consisted of three visits: baseline, 5 weeks, and 12 weeks, in addition to regular phone and email contact. Participants were also asked to keep a seizure diary.
 

Highly acceptable to patients

Overall, the study withdrawal rate was 33%. After a protocol change involving a slower introduction of the supplement, there were fewer withdrawals, Dr. Walker reported. He noted that the proportion of participants who completed the study (41 of 61) is “much better than with most studies of adults following the ketogenic diet.”

The most frequently reported gastrointestinal symptoms with the supplement were bloating and constipation, but these were predominantly mild and tended to decrease over time. This, said Dr. Walker, contrasts to the ketogenic diet where side effects tend to persist.

There was no significant change in body weight or body mass index. “We did not see weight gain as a problem at all,” Dr. Walker said.

Of 15 caregivers and 19 adults who returned an acceptability questionnaire, 84% agreed or strongly agreed the supplement had a good flavor (strawberry); 88% liked the appearance and color; 77% liked the texture and consistency; and 88% agreed or strongly agreed it was easy to take.

About one-third of adults and two-thirds of caregivers said they believed the supplement reduced seizures.
 

50% seizure reduction

Only three children and one adult became ketotic. This is typically classified as a beta-hydroxybutyrate (BHB) greater than 1 mmol/L (10.4 mg/dL). The BHB levels detected were markedly lower than those observed in individuals following a ketogenic diet, the investigators note.

Of the 41 participants, 19 completed the diaries. There were also data from physician recordings, so researchers were able to retrieve seizure frequencies for 32 of the 41 (78%). Of these 32 patients, 14 (44%) had a 50% or greater reduction in seizures. Overall, children and adults “responded similarly,” Dr. Walker said.

He acknowledged the study numbers are small and emphasized that larger studies are needed to determine efficacy. He also hopes for a future randomized controlled trial comparing K.Vita with another supplement that contains different types of fats.

Interestingly, the product has already “passed” the regulatory approval process in the United Kingdom, so it can be labeled as a medicinal food and should be available for use at the beginning of 2022, Dr. Walker said.
 

Study concerns

Asked to comment on the findings, Daniel Goldenholz, MD, PhD, instructor in the department of neurology, Beth Israel Deaconess Medical Center, Boston, said the supplement may be helpful, but he has concerns about the study.

Many patients with epilepsy are “desperate” for therapies that will help treat their seizures, said Dr. Goldenholz, who was not involved with the research. “If there’s a dietary therapy that has the potential for being helpful, I’m loving that. I need that. My patients are begging for something that works.” It is “really exciting” that researchers are working on that goal, Dr. Goldenholz added.

However, he noted that it is too soon to start talking to patients about this new product. He also pointed out that a significant fraction of the study participants dropped out, many because they couldn’t tolerate the supplement. In addition, others didn’t produce a seizure diary.

Dr. Goldenholz and colleagues have published several studies showing that patients with no intervention at all can sometimes show a reduction in seizures compared with their baseline results.

“We found sizable 50% reductions attributable entirely to the natural fluctuations in seizure rates, rather than any therapy at all, he said.

Dr. Goldenholz added that he hopes to see future studies on this topic, and on similar therapies “with sufficient data and more reliable metrics for efficacy.”

The study was funded by Vitaflo International. Dr. Walker reports having received grants from Vitaflo International and personal fees from UCB Pharma, Eisai, and Sage. In addition, along with colleagues, he has a patent (Nutritional product) pending.

A version of this article first appeared on Medscape.com.

A dietary supplement that mimics the effects of the high-fat, low-carbohydrate ketogenic diet is well tolerated and appears to reduce seizures in children and adults with treatment-resistant epilepsy, early research suggests. However, at least one expert has concerns.

In an open-label feasibility study, researchers assessed a liquid supplement known as K.Vita (Vitaflo International), which contains both decanoic acid and octanoic acid.

Although the study was small, the findings are promising, said coinvestigator Matthew Walker, MD, PhD, University College London Institute of Neurology, department of clinical and experimental epilepsy.

“The dietary supplement was reasonably well tolerated and while we weren’t specifically looking for efficacy here, we did see some patients had quite dramatic results in terms of reduced seizures,” Dr. Walker said.

Unlike the ketogenic diet, this dietary supplement is “very easy” to follow, involves only minor dietary modifications, and doesn’t require the intervention of a dietitian, he added.

The findings were published online July 23, 2021, in Brain Communications.
 

Key ingredients

In the ketogenic diet, the body uses body fat as its primary fuel source. The switch from carbohydrates to fat for body fuel results in built-up ketones.

Previous research shows the ketogenic diet is effective in reducing seizures in some patients with epilepsy. However, many patients find it difficult to tolerate, especially for extended periods. Dr. Walker also noted that ketones may have other long-term side effects, including osteoporosis.

He added that his team was keen to learn what elements of the ketogenic diet affect seizures. “Interestingly, we found that one of the fats used in the ketogenic diet, decanoic acid, has quite marked antiseizure effects,” Dr. Walker said.

Previous research has shown that decanoic acid, a medium-chain triglyceride–derived fatty acid, can cross the blood-brain barrier and decrease excitatory neurotransmission and network excitability in vitro.

Dr. Walker noted that ketones are necessary in order to reduce seizures.

“Rather than have a very high-fat, low-carbohydrate diet that causes ketones, we thought ‘why don’t we use a diet in which we just use mainly this fat, this decanoic acid, and avoid ketosis,’ ” he said.

The researchers then went to work developing the K.Vita dietary supplement, which mainly contains decanoic acid but also another fat, octanoic acid.
 

Assessing feasibility

The feasibility study included 61 patients (59% female) who began taking the supplement. Of these, 35 were children (aged 3-18 years) and 26 were adults. The children had Dravet syndrome or another genetically driven form of epilepsy, while most of the adults had a focal epilepsy.

All participants had failed multiple antiseizure medications – a median of 3 for children and 10 for adults who completed the trial. Of the 61 original participants, 20 (19 children and 1 adult) had tried the ketogenic diet but had stopped it for various reasons, including noncompliance and lack of efficacy.

The liquid supplement was introduced gradually. The amount administered was based on weight in the children and was a standard amount in adults, with the target being 240 mL.

Participants consumed the supplement in equal servings taken at regular intervals as part of a meal or snack. They could take it alone or mix it with yogurt or another food.

Patients with feeding tubes took the supplement immediately before or after or mixed into an enteral feed, with a water flush afterward.

Researchers provided patients and caregivers with guidance on excluding highly refined sugary foods and beverages. Starchy foods such as bread, pasta, rice, and potatoes were not restricted.

The study consisted of three visits: baseline, 5 weeks, and 12 weeks, in addition to regular phone and email contact. Participants were also asked to keep a seizure diary.
 

Highly acceptable to patients

Overall, the study withdrawal rate was 33%. After a protocol change involving a slower introduction of the supplement, there were fewer withdrawals, Dr. Walker reported. He noted that the proportion of participants who completed the study (41 of 61) is “much better than with most studies of adults following the ketogenic diet.”

The most frequently reported gastrointestinal symptoms with the supplement were bloating and constipation, but these were predominantly mild and tended to decrease over time. This, said Dr. Walker, contrasts to the ketogenic diet where side effects tend to persist.

There was no significant change in body weight or body mass index. “We did not see weight gain as a problem at all,” Dr. Walker said.

Of 15 caregivers and 19 adults who returned an acceptability questionnaire, 84% agreed or strongly agreed the supplement had a good flavor (strawberry); 88% liked the appearance and color; 77% liked the texture and consistency; and 88% agreed or strongly agreed it was easy to take.

About one-third of adults and two-thirds of caregivers said they believed the supplement reduced seizures.
 

50% seizure reduction

Only three children and one adult became ketotic. This is typically classified as a beta-hydroxybutyrate (BHB) greater than 1 mmol/L (10.4 mg/dL). The BHB levels detected were markedly lower than those observed in individuals following a ketogenic diet, the investigators note.

Of the 41 participants, 19 completed the diaries. There were also data from physician recordings, so researchers were able to retrieve seizure frequencies for 32 of the 41 (78%). Of these 32 patients, 14 (44%) had a 50% or greater reduction in seizures. Overall, children and adults “responded similarly,” Dr. Walker said.

He acknowledged the study numbers are small and emphasized that larger studies are needed to determine efficacy. He also hopes for a future randomized controlled trial comparing K.Vita with another supplement that contains different types of fats.

Interestingly, the product has already “passed” the regulatory approval process in the United Kingdom, so it can be labeled as a medicinal food and should be available for use at the beginning of 2022, Dr. Walker said.
 

Study concerns

Asked to comment on the findings, Daniel Goldenholz, MD, PhD, instructor in the department of neurology, Beth Israel Deaconess Medical Center, Boston, said the supplement may be helpful, but he has concerns about the study.

Many patients with epilepsy are “desperate” for therapies that will help treat their seizures, said Dr. Goldenholz, who was not involved with the research. “If there’s a dietary therapy that has the potential for being helpful, I’m loving that. I need that. My patients are begging for something that works.” It is “really exciting” that researchers are working on that goal, Dr. Goldenholz added.

However, he noted that it is too soon to start talking to patients about this new product. He also pointed out that a significant fraction of the study participants dropped out, many because they couldn’t tolerate the supplement. In addition, others didn’t produce a seizure diary.

Dr. Goldenholz and colleagues have published several studies showing that patients with no intervention at all can sometimes show a reduction in seizures compared with their baseline results.

“We found sizable 50% reductions attributable entirely to the natural fluctuations in seizure rates, rather than any therapy at all, he said.

Dr. Goldenholz added that he hopes to see future studies on this topic, and on similar therapies “with sufficient data and more reliable metrics for efficacy.”

The study was funded by Vitaflo International. Dr. Walker reports having received grants from Vitaflo International and personal fees from UCB Pharma, Eisai, and Sage. In addition, along with colleagues, he has a patent (Nutritional product) pending.

A version of this article first appeared on Medscape.com.

A dietary supplement that mimics the effects of the high-fat, low-carbohydrate ketogenic diet is well tolerated and appears to reduce seizures in children and adults with treatment-resistant epilepsy, early research suggests. However, at least one expert has concerns.

In an open-label feasibility study, researchers assessed a liquid supplement known as K.Vita (Vitaflo International), which contains both decanoic acid and octanoic acid.

Although the study was small, the findings are promising, said coinvestigator Matthew Walker, MD, PhD, University College London Institute of Neurology, department of clinical and experimental epilepsy.

“The dietary supplement was reasonably well tolerated and while we weren’t specifically looking for efficacy here, we did see some patients had quite dramatic results in terms of reduced seizures,” Dr. Walker said.

Unlike the ketogenic diet, this dietary supplement is “very easy” to follow, involves only minor dietary modifications, and doesn’t require the intervention of a dietitian, he added.

The findings were published online July 23, 2021, in Brain Communications.
 

Key ingredients

In the ketogenic diet, the body uses body fat as its primary fuel source. The switch from carbohydrates to fat for body fuel results in built-up ketones.

Previous research shows the ketogenic diet is effective in reducing seizures in some patients with epilepsy. However, many patients find it difficult to tolerate, especially for extended periods. Dr. Walker also noted that ketones may have other long-term side effects, including osteoporosis.

He added that his team was keen to learn what elements of the ketogenic diet affect seizures. “Interestingly, we found that one of the fats used in the ketogenic diet, decanoic acid, has quite marked antiseizure effects,” Dr. Walker said.

Previous research has shown that decanoic acid, a medium-chain triglyceride–derived fatty acid, can cross the blood-brain barrier and decrease excitatory neurotransmission and network excitability in vitro.

Dr. Walker noted that ketones are necessary in order to reduce seizures.

“Rather than have a very high-fat, low-carbohydrate diet that causes ketones, we thought ‘why don’t we use a diet in which we just use mainly this fat, this decanoic acid, and avoid ketosis,’ ” he said.

The researchers then went to work developing the K.Vita dietary supplement, which mainly contains decanoic acid but also another fat, octanoic acid.
 

Assessing feasibility

The feasibility study included 61 patients (59% female) who began taking the supplement. Of these, 35 were children (aged 3-18 years) and 26 were adults. The children had Dravet syndrome or another genetically driven form of epilepsy, while most of the adults had a focal epilepsy.

All participants had failed multiple antiseizure medications – a median of 3 for children and 10 for adults who completed the trial. Of the 61 original participants, 20 (19 children and 1 adult) had tried the ketogenic diet but had stopped it for various reasons, including noncompliance and lack of efficacy.

The liquid supplement was introduced gradually. The amount administered was based on weight in the children and was a standard amount in adults, with the target being 240 mL.

Participants consumed the supplement in equal servings taken at regular intervals as part of a meal or snack. They could take it alone or mix it with yogurt or another food.

Patients with feeding tubes took the supplement immediately before or after or mixed into an enteral feed, with a water flush afterward.

Researchers provided patients and caregivers with guidance on excluding highly refined sugary foods and beverages. Starchy foods such as bread, pasta, rice, and potatoes were not restricted.

The study consisted of three visits: baseline, 5 weeks, and 12 weeks, in addition to regular phone and email contact. Participants were also asked to keep a seizure diary.
 

Highly acceptable to patients

Overall, the study withdrawal rate was 33%. After a protocol change involving a slower introduction of the supplement, there were fewer withdrawals, Dr. Walker reported. He noted that the proportion of participants who completed the study (41 of 61) is “much better than with most studies of adults following the ketogenic diet.”

The most frequently reported gastrointestinal symptoms with the supplement were bloating and constipation, but these were predominantly mild and tended to decrease over time. This, said Dr. Walker, contrasts to the ketogenic diet where side effects tend to persist.

There was no significant change in body weight or body mass index. “We did not see weight gain as a problem at all,” Dr. Walker said.

Of 15 caregivers and 19 adults who returned an acceptability questionnaire, 84% agreed or strongly agreed the supplement had a good flavor (strawberry); 88% liked the appearance and color; 77% liked the texture and consistency; and 88% agreed or strongly agreed it was easy to take.

About one-third of adults and two-thirds of caregivers said they believed the supplement reduced seizures.
 

50% seizure reduction

Only three children and one adult became ketotic. This is typically classified as a beta-hydroxybutyrate (BHB) greater than 1 mmol/L (10.4 mg/dL). The BHB levels detected were markedly lower than those observed in individuals following a ketogenic diet, the investigators note.

Of the 41 participants, 19 completed the diaries. There were also data from physician recordings, so researchers were able to retrieve seizure frequencies for 32 of the 41 (78%). Of these 32 patients, 14 (44%) had a 50% or greater reduction in seizures. Overall, children and adults “responded similarly,” Dr. Walker said.

He acknowledged the study numbers are small and emphasized that larger studies are needed to determine efficacy. He also hopes for a future randomized controlled trial comparing K.Vita with another supplement that contains different types of fats.

Interestingly, the product has already “passed” the regulatory approval process in the United Kingdom, so it can be labeled as a medicinal food and should be available for use at the beginning of 2022, Dr. Walker said.
 

Study concerns

Asked to comment on the findings, Daniel Goldenholz, MD, PhD, instructor in the department of neurology, Beth Israel Deaconess Medical Center, Boston, said the supplement may be helpful, but he has concerns about the study.

Many patients with epilepsy are “desperate” for therapies that will help treat their seizures, said Dr. Goldenholz, who was not involved with the research. “If there’s a dietary therapy that has the potential for being helpful, I’m loving that. I need that. My patients are begging for something that works.” It is “really exciting” that researchers are working on that goal, Dr. Goldenholz added.

However, he noted that it is too soon to start talking to patients about this new product. He also pointed out that a significant fraction of the study participants dropped out, many because they couldn’t tolerate the supplement. In addition, others didn’t produce a seizure diary.

Dr. Goldenholz and colleagues have published several studies showing that patients with no intervention at all can sometimes show a reduction in seizures compared with their baseline results.

“We found sizable 50% reductions attributable entirely to the natural fluctuations in seizure rates, rather than any therapy at all, he said.

Dr. Goldenholz added that he hopes to see future studies on this topic, and on similar therapies “with sufficient data and more reliable metrics for efficacy.”

The study was funded by Vitaflo International. Dr. Walker reports having received grants from Vitaflo International and personal fees from UCB Pharma, Eisai, and Sage. In addition, along with colleagues, he has a patent (Nutritional product) pending.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has issued a safety alert regarding an increased risk of death associated with Pepaxto (melphalan flufenamide) used in patients with multiple myeloma participating in the ongoing OCEAN clinical trial.

The drug was granted accelerated approval in February 2021 for use in combination with dexamethasone in the treatment of adults with relapsed or refractory multiple myeloma who had received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulator, and one CD38-directed monoclonal antibody.

As a condition of the accelerated approval, the manufacturer, Oncopeptides, was required to conduct a confirmatory clinical trial and launched the OCEAN trial.

Enrollment in OCEAN as well as other ongoing trials of the drug have now been halted, according to the FDA alert.

The warning comes in the wake of OCEAN trial findings showing worse survival among patients in the experimental group, who were receiving melphalan plus low-dose dexamethasone, compared with patients in the control group, who were receiving pomalidomide plus low-dose dexamethasone (hazard ratio for overall survival, 1.104). Median overall survival in the treatment and control groups was 19.7 and 25.0 months, respectively.

Health care professionals should “review patients’ progress on Pepaxto and discuss the risks of continued administration with each patient in the context of other treatments,” and patients currently receiving the drug should discuss the risks and benefits with their health care professional, the FDA advises. “Patients receiving clinical benefit from Pepaxto may continue treatment in the OCEAN trial provided they are informed of the risks and sign a revised written informed consent.”

The FDA also hinted at “a future public meeting to discuss the safety findings and explore the continued marketing of Pepaxto,” which has a price tag of $19,000 per treatment course.
 

Accelerated approval data

Melphalan flufenamide was initially evaluated in combination with low-dose dexamethasone in the multicenter, single-arm HORIZON trial of adults with relapsed or refractory multiple myeloma who received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulator, and one CD38-directed monoclonal antibody.

Patients received melphalan flufenamide at a dose of 40 mg intravenously on day 1 along with oral dexamethasone at a dose of 40 mg (or 20 mg for those over age 75 years) on days 1, 8, 15, and 22 of each 28-day cycle until disease progression or unacceptable toxicity.

The most common adverse reactions, occurring in at least 20% of patients, were fatigue, nausea, diarrhea, pyrexia, and respiratory tract infection. The most common laboratory abnormalities, occurring in at least 50% of patients, were decreased leukocytes, platelets, lymphocytes, neutrophils, and hemoglobin, and increased creatinine.

Accelerated approval was granted after the HORIZON trial showed an overall response rate of 23.7% and median duration of response of 4.2 months. The application by Oncopeptides received priority review and orphan drug status.
 

Confirmatory trial data

The confirmatory OCEAN trial compared melphalan flufenamide plus low-dose dexamethasone to pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma following 2-4 lines of therapy and in patients who were resistant to lenalidomide in the last line of therapy.

The FDA conducted an efficacy and safety evaluation of the OCEAN trial using a data cutoff date of February 3, 2021. At a median follow-up of 19.1 months, 117 of 246 patients (48%) in the melphalan flufenamide group had died, compared with 108 of 249 patients (43%) in the pomalidomide control group.

“Patient safety is paramount to Oncopeptides,” the company said in a press statement, which also notes that “dialogue with the FDA” is ongoing and that updated information will be provided as it becomes available.

The company plans to submit complete data from the OCEAN study to the International Myeloma Workshop meeting in Vienna being held September 8-11, 2021.

Health care professionals and patients should report adverse events or quality issues experienced with melphalan flufenamide or any other medication to the FDA MedWatch Adverse Event Reporting program, either online or by downloading and completing a reporting form and submitting via fax at 1-800-FDA-0178.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has issued a safety alert regarding an increased risk of death associated with Pepaxto (melphalan flufenamide) used in patients with multiple myeloma participating in the ongoing OCEAN clinical trial.

The drug was granted accelerated approval in February 2021 for use in combination with dexamethasone in the treatment of adults with relapsed or refractory multiple myeloma who had received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulator, and one CD38-directed monoclonal antibody.

As a condition of the accelerated approval, the manufacturer, Oncopeptides, was required to conduct a confirmatory clinical trial and launched the OCEAN trial.

Enrollment in OCEAN as well as other ongoing trials of the drug have now been halted, according to the FDA alert.

The warning comes in the wake of OCEAN trial findings showing worse survival among patients in the experimental group, who were receiving melphalan plus low-dose dexamethasone, compared with patients in the control group, who were receiving pomalidomide plus low-dose dexamethasone (hazard ratio for overall survival, 1.104). Median overall survival in the treatment and control groups was 19.7 and 25.0 months, respectively.

Health care professionals should “review patients’ progress on Pepaxto and discuss the risks of continued administration with each patient in the context of other treatments,” and patients currently receiving the drug should discuss the risks and benefits with their health care professional, the FDA advises. “Patients receiving clinical benefit from Pepaxto may continue treatment in the OCEAN trial provided they are informed of the risks and sign a revised written informed consent.”

The FDA also hinted at “a future public meeting to discuss the safety findings and explore the continued marketing of Pepaxto,” which has a price tag of $19,000 per treatment course.
 

Accelerated approval data

Melphalan flufenamide was initially evaluated in combination with low-dose dexamethasone in the multicenter, single-arm HORIZON trial of adults with relapsed or refractory multiple myeloma who received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulator, and one CD38-directed monoclonal antibody.

Patients received melphalan flufenamide at a dose of 40 mg intravenously on day 1 along with oral dexamethasone at a dose of 40 mg (or 20 mg for those over age 75 years) on days 1, 8, 15, and 22 of each 28-day cycle until disease progression or unacceptable toxicity.

The most common adverse reactions, occurring in at least 20% of patients, were fatigue, nausea, diarrhea, pyrexia, and respiratory tract infection. The most common laboratory abnormalities, occurring in at least 50% of patients, were decreased leukocytes, platelets, lymphocytes, neutrophils, and hemoglobin, and increased creatinine.

Accelerated approval was granted after the HORIZON trial showed an overall response rate of 23.7% and median duration of response of 4.2 months. The application by Oncopeptides received priority review and orphan drug status.
 

Confirmatory trial data

The confirmatory OCEAN trial compared melphalan flufenamide plus low-dose dexamethasone to pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma following 2-4 lines of therapy and in patients who were resistant to lenalidomide in the last line of therapy.

The FDA conducted an efficacy and safety evaluation of the OCEAN trial using a data cutoff date of February 3, 2021. At a median follow-up of 19.1 months, 117 of 246 patients (48%) in the melphalan flufenamide group had died, compared with 108 of 249 patients (43%) in the pomalidomide control group.

“Patient safety is paramount to Oncopeptides,” the company said in a press statement, which also notes that “dialogue with the FDA” is ongoing and that updated information will be provided as it becomes available.

The company plans to submit complete data from the OCEAN study to the International Myeloma Workshop meeting in Vienna being held September 8-11, 2021.

Health care professionals and patients should report adverse events or quality issues experienced with melphalan flufenamide or any other medication to the FDA MedWatch Adverse Event Reporting program, either online or by downloading and completing a reporting form and submitting via fax at 1-800-FDA-0178.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has issued a safety alert regarding an increased risk of death associated with Pepaxto (melphalan flufenamide) used in patients with multiple myeloma participating in the ongoing OCEAN clinical trial.

The drug was granted accelerated approval in February 2021 for use in combination with dexamethasone in the treatment of adults with relapsed or refractory multiple myeloma who had received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulator, and one CD38-directed monoclonal antibody.

As a condition of the accelerated approval, the manufacturer, Oncopeptides, was required to conduct a confirmatory clinical trial and launched the OCEAN trial.

Enrollment in OCEAN as well as other ongoing trials of the drug have now been halted, according to the FDA alert.

The warning comes in the wake of OCEAN trial findings showing worse survival among patients in the experimental group, who were receiving melphalan plus low-dose dexamethasone, compared with patients in the control group, who were receiving pomalidomide plus low-dose dexamethasone (hazard ratio for overall survival, 1.104). Median overall survival in the treatment and control groups was 19.7 and 25.0 months, respectively.

Health care professionals should “review patients’ progress on Pepaxto and discuss the risks of continued administration with each patient in the context of other treatments,” and patients currently receiving the drug should discuss the risks and benefits with their health care professional, the FDA advises. “Patients receiving clinical benefit from Pepaxto may continue treatment in the OCEAN trial provided they are informed of the risks and sign a revised written informed consent.”

The FDA also hinted at “a future public meeting to discuss the safety findings and explore the continued marketing of Pepaxto,” which has a price tag of $19,000 per treatment course.
 

Accelerated approval data

Melphalan flufenamide was initially evaluated in combination with low-dose dexamethasone in the multicenter, single-arm HORIZON trial of adults with relapsed or refractory multiple myeloma who received at least four prior lines of therapy and whose disease was refractory to at least one proteasome inhibitor, one immunomodulator, and one CD38-directed monoclonal antibody.

Patients received melphalan flufenamide at a dose of 40 mg intravenously on day 1 along with oral dexamethasone at a dose of 40 mg (or 20 mg for those over age 75 years) on days 1, 8, 15, and 22 of each 28-day cycle until disease progression or unacceptable toxicity.

The most common adverse reactions, occurring in at least 20% of patients, were fatigue, nausea, diarrhea, pyrexia, and respiratory tract infection. The most common laboratory abnormalities, occurring in at least 50% of patients, were decreased leukocytes, platelets, lymphocytes, neutrophils, and hemoglobin, and increased creatinine.

Accelerated approval was granted after the HORIZON trial showed an overall response rate of 23.7% and median duration of response of 4.2 months. The application by Oncopeptides received priority review and orphan drug status.
 

Confirmatory trial data

The confirmatory OCEAN trial compared melphalan flufenamide plus low-dose dexamethasone to pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma following 2-4 lines of therapy and in patients who were resistant to lenalidomide in the last line of therapy.

The FDA conducted an efficacy and safety evaluation of the OCEAN trial using a data cutoff date of February 3, 2021. At a median follow-up of 19.1 months, 117 of 246 patients (48%) in the melphalan flufenamide group had died, compared with 108 of 249 patients (43%) in the pomalidomide control group.

“Patient safety is paramount to Oncopeptides,” the company said in a press statement, which also notes that “dialogue with the FDA” is ongoing and that updated information will be provided as it becomes available.

The company plans to submit complete data from the OCEAN study to the International Myeloma Workshop meeting in Vienna being held September 8-11, 2021.

Health care professionals and patients should report adverse events or quality issues experienced with melphalan flufenamide or any other medication to the FDA MedWatch Adverse Event Reporting program, either online or by downloading and completing a reporting form and submitting via fax at 1-800-FDA-0178.

A version of this article first appeared on Medscape.com.

Drinking six or more cups of coffee per day is associated with smaller brain volume and a 53% increased risk for dementia compared with light coffee consumption (1-2 cups per day), according to the results of a large study.

amenic181/Getty Images

“With coffee intake, moderation is the key, and especially high levels of consumption may have adverse long-term effects on the brain,” said study investigator Elina Hypponen, PhD, professor of nutritional and genetic epidemiology and director of the Australian Center for Precision Health at the University of South Australia.

“These new data are concerning, and there is a need to conduct further carefully controlled studies to clarify the effects of coffee on the brain.”

The study was published online June 24 in Nutritional Neuroscience.
 

Potent stimulant

Coffee is a potent nervous system stimulant and is among the most popular nonalcoholic beverages. Some previous research suggests it benefits the brain, but the investigators noted that other research shows a negative or U-shaped relationship.

To investigate, the researchers examined data from the U.K. Biobank, a long-term prospective epidemiologic study of more than 500,000 participants aged 37-73 years who were recruited in 22 assessment centers in the United Kingdom between March 2006 and October 2010.

During the baseline assessment, information was gathered using touchscreen questionnaires, verbal interviews, and physical examinations that involved collection of blood, urine, and saliva samples. An imaging substudy was incorporated in 2014, the goal of which was to conduct brain, heart, and body MRI imaging for 100,000 participants.

The investigators conducted analyses on disease outcomes for 398,646 participants for whom information on habitual coffee consumption was available. Brain volume analyses were conducted in 17,702 participants for whom valid brain imaging data were available.

Participants reported coffee intake in cups per day. Researchers grouped coffee consumption into seven categories: nondrinkers, decaffeinated coffee drinkers, and caffeinated coffee drinkers who consumed less than 1 cup/d, 1-2 cups/d, 3-4 cups/d, 5-6 cups/d, and more than 6 cups/d.

The reference category was those who consumed 1-2 cups/d, rather than those who abstained from coffee, because persons who abstain are more likely to be at suboptimal health.

“Comparing the health of coffee drinkers to the health of those choosing to abstain from coffee will typically lead to an impression of a health benefit, even if there would not be one,” said Dr. Hypponen.

The researchers obtained total and regional brain volumes from the MRI imaging substudy starting 4-6 years after baseline assessment. They accessed information on incident dementia and stroke using primary care data, hospital admission electronic health records, national death registers, and self-reported medical conditions.

Covariates included socioeconomic, health, and other factors, such as smoking, alcohol and tea consumption, physical activity, stressful life events, and body mass index.

The investigators found that there was a linear inverse association between coffee consumption and total brain volume (fully adjusted beta per cup, –1.42; 95% confidence interval, –1.89 to –0.94), with consistent patterns for gray matter, white matter, and hippocampal volumes.

There was no evidence to support an association with white matter hyperintensity (WMH) volume (beta –0.01; 95% CI, –0.07 to 0.05).
 

Higher consumption, higher risk

The analysis also revealed a nonlinear association between coffee consumption and the odds of dementia (P nonlinearity = .0001), with slightly higher odds seen with non–coffee drinkers and decaffeinated-coffee drinkers and more notable increases for participants in the highest categories of coffee consumption compared with light coffee drinkers.

After adjustment for all covariates, the odds ratio of dementia among persons in the category of coffee intake was 1.53 (95% CI, 1.28-1.83). After full adjustments, the association with heavy coffee consumption and stroke was not significant, although “we can’t exclude a weak effect,” said Dr. Hypponen.

“For the highest coffee consumption group, the data support an association which may be anywhere from 0% to 37% higher odds of stroke after full adjustment,” she added.

People at risk for hypertension may develop “unpleasant sensations” and stop drinking coffee before a serious adverse event occurs, said Dr. Hypponen. In a previous study, she and her colleagues showed that those who have genetically higher blood pressure tend to drink less coffee than their counterparts without the condition.

“This type of effect might be expected to naturally limit the adverse effects of coffee on the risk of stroke,” said Dr. Hypponen.

The odds remained elevated for participants drinking more than 6 cups/d after the researchers accounted for sleep quality. There were no differences in risk between men and women or by age.

An examination of the consumption of tea, which often contains caffeine, did not show an association with brain volume or the odds of dementia or stroke.

“We don’t know whether the difference between associations seen for coffee and tea intake reflects the difference in related caffeine intake or some other explanation, such as dehydration or effects operating through blood cholesterol,” said Dr. Hypponen.

Although reverse causation is possible, there’s no reason to believe that it is relevant to the study results. Genetic evidence suggests a causal role of higher coffee intake on risk for Alzheimer’s disease. In addition, results of a clinical trial support the association between higher caffeine intake and smaller gray matter volume, said Dr. Hypponen.

The mechanisms linking coffee consumption to brain volumes and dementia are not well established. However, Dr. Hypponen noted that caffeine has been used to induce apoptosis in cancer studies using glial cells.

“Furthermore, adenosine receptors, which mediate many of the effects of caffeine in the brain, have been suggested to influence the release of growth factors, which in turn can have an influence on astrocyte proliferation and angiogenesis in the brain,” she said.

Some types of coffee contain cafestol, which increases blood cholesterol and can have adverse effects though related mechanisms, said Dr. Hypponen.

The mechanism may also involve dehydration, which may have a harmful effect on the brain. The study suggested a correlation between dehydration and high coffee intake. “Of course, if this is the case, it is good news, as then we can do something about it simply by drinking some water every time we have a cup of coffee,” she said.
 

Misleading conclusions

Coffee contains antioxidants, and although previous studies have suggested it might be beneficial, this hypothesis is “too simplistic,” said Dr. Hypponen. “While coffee is not going to be all ‘bad’ either, there are a lot of controversies and suggestions about beneficial effects of coffee which may not be true, or at least do not reflect the full story.”

If the drinking of coffee is at least partly determined by an individual’s health status, then that would often lead to misleading conclusions in observational studies, said Dr. Hypponen.

“When one uses as a comparison people who already have poor health and who do not drink coffee because of that, coffee intake will by default appear beneficial simply because there are more people with disease among those choosing abstinence,” she said.

Before now, there was “very little evidence about the association between coffee intake and brain morphology,” and the studies that were conducted were relatively small, said Dr. Hypponen.

One of these smaller studies included a group of women aged 13-30 years. It found that coffee consumption was not associated with total brain volumes, but the findings suggested a U-shaped association with hippocampal volume; higher values were seen both for nondrinkers and the groups with higher consumption.

A small study of elderly patients with diabetes showed no evidence of an association with white matter volume, but there was a possible age-dependent association with gray matter volume.

The largest of the earlier studies had results that were very similar to those of the current study, suggesting that increasing coffee intake is associated with smaller hippocampal volumes, said Dr. Hypponen.

One of the study’s limitations included the fact that full dietary information was available only for a subsample and that factors such as dehydration were measured at baseline rather than at the time of brain MRI.

Another possible study limitation was the use of self-reported data and the fact that lifestyle changes may have occurred between baseline and MRI or covariate measurement.

In addition, the study is subject to a healthy-volunteer bias, and its implications are restricted to White British persons. The association needs to be studied in other ethnic populations, the authors noted.
 

A reason to cut back?

Commenting on the findings, Walter Willett, MD, DrPH, professor of epidemiology and nutrition, Harvard T. H. Chan School of Public Health, Boston, said the study is large and quite well done.

“It does raise questions about an increase in risk of dementia with six or more cups of coffee per day,” said Dr. Willett. “At the same time, it provides reassurance about lack of adverse effects of coffee for those consuming three or four cups per day, and little increase in risk, if any, with five cups per day.”

It’s not entirely clear whether the increase in risk with six or more cups of coffee per day represents a “true effect” of coffee, inasmuch as the study did not seem to adjust fully for dietary factors, high consumption of alcohol, or past smoking, said Dr. Willett.

The findings don’t suggest that coffee lovers should give up their Java. “But six or more cups per day is a lot, and those who drink that much might consider cutting back a bit while research continues,” said Dr. Willett.

The study was supported by the National Health and Medical Research Council.

A version of this article first appeared on Medscape.com.

Drinking six or more cups of coffee per day is associated with smaller brain volume and a 53% increased risk for dementia compared with light coffee consumption (1-2 cups per day), according to the results of a large study.

amenic181/Getty Images

“With coffee intake, moderation is the key, and especially high levels of consumption may have adverse long-term effects on the brain,” said study investigator Elina Hypponen, PhD, professor of nutritional and genetic epidemiology and director of the Australian Center for Precision Health at the University of South Australia.

“These new data are concerning, and there is a need to conduct further carefully controlled studies to clarify the effects of coffee on the brain.”

The study was published online June 24 in Nutritional Neuroscience.
 

Potent stimulant

Coffee is a potent nervous system stimulant and is among the most popular nonalcoholic beverages. Some previous research suggests it benefits the brain, but the investigators noted that other research shows a negative or U-shaped relationship.

To investigate, the researchers examined data from the U.K. Biobank, a long-term prospective epidemiologic study of more than 500,000 participants aged 37-73 years who were recruited in 22 assessment centers in the United Kingdom between March 2006 and October 2010.

During the baseline assessment, information was gathered using touchscreen questionnaires, verbal interviews, and physical examinations that involved collection of blood, urine, and saliva samples. An imaging substudy was incorporated in 2014, the goal of which was to conduct brain, heart, and body MRI imaging for 100,000 participants.

The investigators conducted analyses on disease outcomes for 398,646 participants for whom information on habitual coffee consumption was available. Brain volume analyses were conducted in 17,702 participants for whom valid brain imaging data were available.

Participants reported coffee intake in cups per day. Researchers grouped coffee consumption into seven categories: nondrinkers, decaffeinated coffee drinkers, and caffeinated coffee drinkers who consumed less than 1 cup/d, 1-2 cups/d, 3-4 cups/d, 5-6 cups/d, and more than 6 cups/d.

The reference category was those who consumed 1-2 cups/d, rather than those who abstained from coffee, because persons who abstain are more likely to be at suboptimal health.

“Comparing the health of coffee drinkers to the health of those choosing to abstain from coffee will typically lead to an impression of a health benefit, even if there would not be one,” said Dr. Hypponen.

The researchers obtained total and regional brain volumes from the MRI imaging substudy starting 4-6 years after baseline assessment. They accessed information on incident dementia and stroke using primary care data, hospital admission electronic health records, national death registers, and self-reported medical conditions.

Covariates included socioeconomic, health, and other factors, such as smoking, alcohol and tea consumption, physical activity, stressful life events, and body mass index.

The investigators found that there was a linear inverse association between coffee consumption and total brain volume (fully adjusted beta per cup, –1.42; 95% confidence interval, –1.89 to –0.94), with consistent patterns for gray matter, white matter, and hippocampal volumes.

There was no evidence to support an association with white matter hyperintensity (WMH) volume (beta –0.01; 95% CI, –0.07 to 0.05).
 

Higher consumption, higher risk

The analysis also revealed a nonlinear association between coffee consumption and the odds of dementia (P nonlinearity = .0001), with slightly higher odds seen with non–coffee drinkers and decaffeinated-coffee drinkers and more notable increases for participants in the highest categories of coffee consumption compared with light coffee drinkers.

After adjustment for all covariates, the odds ratio of dementia among persons in the category of coffee intake was 1.53 (95% CI, 1.28-1.83). After full adjustments, the association with heavy coffee consumption and stroke was not significant, although “we can’t exclude a weak effect,” said Dr. Hypponen.

“For the highest coffee consumption group, the data support an association which may be anywhere from 0% to 37% higher odds of stroke after full adjustment,” she added.

People at risk for hypertension may develop “unpleasant sensations” and stop drinking coffee before a serious adverse event occurs, said Dr. Hypponen. In a previous study, she and her colleagues showed that those who have genetically higher blood pressure tend to drink less coffee than their counterparts without the condition.

“This type of effect might be expected to naturally limit the adverse effects of coffee on the risk of stroke,” said Dr. Hypponen.

The odds remained elevated for participants drinking more than 6 cups/d after the researchers accounted for sleep quality. There were no differences in risk between men and women or by age.

An examination of the consumption of tea, which often contains caffeine, did not show an association with brain volume or the odds of dementia or stroke.

“We don’t know whether the difference between associations seen for coffee and tea intake reflects the difference in related caffeine intake or some other explanation, such as dehydration or effects operating through blood cholesterol,” said Dr. Hypponen.

Although reverse causation is possible, there’s no reason to believe that it is relevant to the study results. Genetic evidence suggests a causal role of higher coffee intake on risk for Alzheimer’s disease. In addition, results of a clinical trial support the association between higher caffeine intake and smaller gray matter volume, said Dr. Hypponen.

The mechanisms linking coffee consumption to brain volumes and dementia are not well established. However, Dr. Hypponen noted that caffeine has been used to induce apoptosis in cancer studies using glial cells.

“Furthermore, adenosine receptors, which mediate many of the effects of caffeine in the brain, have been suggested to influence the release of growth factors, which in turn can have an influence on astrocyte proliferation and angiogenesis in the brain,” she said.

Some types of coffee contain cafestol, which increases blood cholesterol and can have adverse effects though related mechanisms, said Dr. Hypponen.

The mechanism may also involve dehydration, which may have a harmful effect on the brain. The study suggested a correlation between dehydration and high coffee intake. “Of course, if this is the case, it is good news, as then we can do something about it simply by drinking some water every time we have a cup of coffee,” she said.
 

Misleading conclusions

Coffee contains antioxidants, and although previous studies have suggested it might be beneficial, this hypothesis is “too simplistic,” said Dr. Hypponen. “While coffee is not going to be all ‘bad’ either, there are a lot of controversies and suggestions about beneficial effects of coffee which may not be true, or at least do not reflect the full story.”

If the drinking of coffee is at least partly determined by an individual’s health status, then that would often lead to misleading conclusions in observational studies, said Dr. Hypponen.

“When one uses as a comparison people who already have poor health and who do not drink coffee because of that, coffee intake will by default appear beneficial simply because there are more people with disease among those choosing abstinence,” she said.

Before now, there was “very little evidence about the association between coffee intake and brain morphology,” and the studies that were conducted were relatively small, said Dr. Hypponen.

One of these smaller studies included a group of women aged 13-30 years. It found that coffee consumption was not associated with total brain volumes, but the findings suggested a U-shaped association with hippocampal volume; higher values were seen both for nondrinkers and the groups with higher consumption.

A small study of elderly patients with diabetes showed no evidence of an association with white matter volume, but there was a possible age-dependent association with gray matter volume.

The largest of the earlier studies had results that were very similar to those of the current study, suggesting that increasing coffee intake is associated with smaller hippocampal volumes, said Dr. Hypponen.

One of the study’s limitations included the fact that full dietary information was available only for a subsample and that factors such as dehydration were measured at baseline rather than at the time of brain MRI.

Another possible study limitation was the use of self-reported data and the fact that lifestyle changes may have occurred between baseline and MRI or covariate measurement.

In addition, the study is subject to a healthy-volunteer bias, and its implications are restricted to White British persons. The association needs to be studied in other ethnic populations, the authors noted.
 

A reason to cut back?

Commenting on the findings, Walter Willett, MD, DrPH, professor of epidemiology and nutrition, Harvard T. H. Chan School of Public Health, Boston, said the study is large and quite well done.

“It does raise questions about an increase in risk of dementia with six or more cups of coffee per day,” said Dr. Willett. “At the same time, it provides reassurance about lack of adverse effects of coffee for those consuming three or four cups per day, and little increase in risk, if any, with five cups per day.”

It’s not entirely clear whether the increase in risk with six or more cups of coffee per day represents a “true effect” of coffee, inasmuch as the study did not seem to adjust fully for dietary factors, high consumption of alcohol, or past smoking, said Dr. Willett.

The findings don’t suggest that coffee lovers should give up their Java. “But six or more cups per day is a lot, and those who drink that much might consider cutting back a bit while research continues,” said Dr. Willett.

The study was supported by the National Health and Medical Research Council.

A version of this article first appeared on Medscape.com.

Drinking six or more cups of coffee per day is associated with smaller brain volume and a 53% increased risk for dementia compared with light coffee consumption (1-2 cups per day), according to the results of a large study.

amenic181/Getty Images

“With coffee intake, moderation is the key, and especially high levels of consumption may have adverse long-term effects on the brain,” said study investigator Elina Hypponen, PhD, professor of nutritional and genetic epidemiology and director of the Australian Center for Precision Health at the University of South Australia.

“These new data are concerning, and there is a need to conduct further carefully controlled studies to clarify the effects of coffee on the brain.”

The study was published online June 24 in Nutritional Neuroscience.
 

Potent stimulant

Coffee is a potent nervous system stimulant and is among the most popular nonalcoholic beverages. Some previous research suggests it benefits the brain, but the investigators noted that other research shows a negative or U-shaped relationship.

To investigate, the researchers examined data from the U.K. Biobank, a long-term prospective epidemiologic study of more than 500,000 participants aged 37-73 years who were recruited in 22 assessment centers in the United Kingdom between March 2006 and October 2010.

During the baseline assessment, information was gathered using touchscreen questionnaires, verbal interviews, and physical examinations that involved collection of blood, urine, and saliva samples. An imaging substudy was incorporated in 2014, the goal of which was to conduct brain, heart, and body MRI imaging for 100,000 participants.

The investigators conducted analyses on disease outcomes for 398,646 participants for whom information on habitual coffee consumption was available. Brain volume analyses were conducted in 17,702 participants for whom valid brain imaging data were available.

Participants reported coffee intake in cups per day. Researchers grouped coffee consumption into seven categories: nondrinkers, decaffeinated coffee drinkers, and caffeinated coffee drinkers who consumed less than 1 cup/d, 1-2 cups/d, 3-4 cups/d, 5-6 cups/d, and more than 6 cups/d.

The reference category was those who consumed 1-2 cups/d, rather than those who abstained from coffee, because persons who abstain are more likely to be at suboptimal health.

“Comparing the health of coffee drinkers to the health of those choosing to abstain from coffee will typically lead to an impression of a health benefit, even if there would not be one,” said Dr. Hypponen.

The researchers obtained total and regional brain volumes from the MRI imaging substudy starting 4-6 years after baseline assessment. They accessed information on incident dementia and stroke using primary care data, hospital admission electronic health records, national death registers, and self-reported medical conditions.

Covariates included socioeconomic, health, and other factors, such as smoking, alcohol and tea consumption, physical activity, stressful life events, and body mass index.

The investigators found that there was a linear inverse association between coffee consumption and total brain volume (fully adjusted beta per cup, –1.42; 95% confidence interval, –1.89 to –0.94), with consistent patterns for gray matter, white matter, and hippocampal volumes.

There was no evidence to support an association with white matter hyperintensity (WMH) volume (beta –0.01; 95% CI, –0.07 to 0.05).
 

Higher consumption, higher risk

The analysis also revealed a nonlinear association between coffee consumption and the odds of dementia (P nonlinearity = .0001), with slightly higher odds seen with non–coffee drinkers and decaffeinated-coffee drinkers and more notable increases for participants in the highest categories of coffee consumption compared with light coffee drinkers.

After adjustment for all covariates, the odds ratio of dementia among persons in the category of coffee intake was 1.53 (95% CI, 1.28-1.83). After full adjustments, the association with heavy coffee consumption and stroke was not significant, although “we can’t exclude a weak effect,” said Dr. Hypponen.

“For the highest coffee consumption group, the data support an association which may be anywhere from 0% to 37% higher odds of stroke after full adjustment,” she added.

People at risk for hypertension may develop “unpleasant sensations” and stop drinking coffee before a serious adverse event occurs, said Dr. Hypponen. In a previous study, she and her colleagues showed that those who have genetically higher blood pressure tend to drink less coffee than their counterparts without the condition.

“This type of effect might be expected to naturally limit the adverse effects of coffee on the risk of stroke,” said Dr. Hypponen.

The odds remained elevated for participants drinking more than 6 cups/d after the researchers accounted for sleep quality. There were no differences in risk between men and women or by age.

An examination of the consumption of tea, which often contains caffeine, did not show an association with brain volume or the odds of dementia or stroke.

“We don’t know whether the difference between associations seen for coffee and tea intake reflects the difference in related caffeine intake or some other explanation, such as dehydration or effects operating through blood cholesterol,” said Dr. Hypponen.

Although reverse causation is possible, there’s no reason to believe that it is relevant to the study results. Genetic evidence suggests a causal role of higher coffee intake on risk for Alzheimer’s disease. In addition, results of a clinical trial support the association between higher caffeine intake and smaller gray matter volume, said Dr. Hypponen.

The mechanisms linking coffee consumption to brain volumes and dementia are not well established. However, Dr. Hypponen noted that caffeine has been used to induce apoptosis in cancer studies using glial cells.

“Furthermore, adenosine receptors, which mediate many of the effects of caffeine in the brain, have been suggested to influence the release of growth factors, which in turn can have an influence on astrocyte proliferation and angiogenesis in the brain,” she said.

Some types of coffee contain cafestol, which increases blood cholesterol and can have adverse effects though related mechanisms, said Dr. Hypponen.

The mechanism may also involve dehydration, which may have a harmful effect on the brain. The study suggested a correlation between dehydration and high coffee intake. “Of course, if this is the case, it is good news, as then we can do something about it simply by drinking some water every time we have a cup of coffee,” she said.
 

Misleading conclusions

Coffee contains antioxidants, and although previous studies have suggested it might be beneficial, this hypothesis is “too simplistic,” said Dr. Hypponen. “While coffee is not going to be all ‘bad’ either, there are a lot of controversies and suggestions about beneficial effects of coffee which may not be true, or at least do not reflect the full story.”

If the drinking of coffee is at least partly determined by an individual’s health status, then that would often lead to misleading conclusions in observational studies, said Dr. Hypponen.

“When one uses as a comparison people who already have poor health and who do not drink coffee because of that, coffee intake will by default appear beneficial simply because there are more people with disease among those choosing abstinence,” she said.

Before now, there was “very little evidence about the association between coffee intake and brain morphology,” and the studies that were conducted were relatively small, said Dr. Hypponen.

One of these smaller studies included a group of women aged 13-30 years. It found that coffee consumption was not associated with total brain volumes, but the findings suggested a U-shaped association with hippocampal volume; higher values were seen both for nondrinkers and the groups with higher consumption.

A small study of elderly patients with diabetes showed no evidence of an association with white matter volume, but there was a possible age-dependent association with gray matter volume.

The largest of the earlier studies had results that were very similar to those of the current study, suggesting that increasing coffee intake is associated with smaller hippocampal volumes, said Dr. Hypponen.

One of the study’s limitations included the fact that full dietary information was available only for a subsample and that factors such as dehydration were measured at baseline rather than at the time of brain MRI.

Another possible study limitation was the use of self-reported data and the fact that lifestyle changes may have occurred between baseline and MRI or covariate measurement.

In addition, the study is subject to a healthy-volunteer bias, and its implications are restricted to White British persons. The association needs to be studied in other ethnic populations, the authors noted.
 

A reason to cut back?

Commenting on the findings, Walter Willett, MD, DrPH, professor of epidemiology and nutrition, Harvard T. H. Chan School of Public Health, Boston, said the study is large and quite well done.

“It does raise questions about an increase in risk of dementia with six or more cups of coffee per day,” said Dr. Willett. “At the same time, it provides reassurance about lack of adverse effects of coffee for those consuming three or four cups per day, and little increase in risk, if any, with five cups per day.”

It’s not entirely clear whether the increase in risk with six or more cups of coffee per day represents a “true effect” of coffee, inasmuch as the study did not seem to adjust fully for dietary factors, high consumption of alcohol, or past smoking, said Dr. Willett.

The findings don’t suggest that coffee lovers should give up their Java. “But six or more cups per day is a lot, and those who drink that much might consider cutting back a bit while research continues,” said Dr. Willett.

The study was supported by the National Health and Medical Research Council.

A version of this article first appeared on Medscape.com.