Pharmacology

In a phase 2 cohort study, the KRAS (G12C) inhibitor adagrasib induced an objective response in about one out of three patients with KRAS (G12C)–mutated non–small cell lung cancer (NSCLC) who had previously been treated with platinum-based chemotherapy and immune therapy.

Adagrasib targets KRAS (G12C), which had long been thought undruggable until research published in 2013 revealed a new binding pocket that did not compete directly against the protein’s natural binding partner. The new trial further validates the approach. “It supports that clinically effective targeted therapies can be developed for patients with KRAS (G12C)–mutant NSCLC,” said Pasi Jänne, MD, PhD, who is the lead author of the study describing the new results published online in the New England Journal of Medicine.

KRAS is the most frequently mutated oncogene in human cancers. A mutated form is found in about 25% of NSCLCs. KRAS plays a key role in cell signaling governing growth, maturation, and cell death. The mutated form is linked to cancer growth and spread. Patients with mutated KRAS have few effective treatment options.

Adagrasib is currently under study and not yet approved by the Food and Drug Administration. However, sotorasib (Lumakras, Amgen), which also inhibits KRAS (G12C), was approved in May 2021 by the FDA for KRAS (G12C)–mutated NSCLC. There are some key differences between the drugs. Adagrasib has a half-life of 23 hours versus 5 hours for sotorasib, and the newer drug has the potential to penetrate the central nervous system. That could be an important consideration in NSCLC since it often metastasizes to the brain. “Having pharmacological approaches to treat brain metastases is a wonderful new therapeutic option for lung cancer patients,” said Dr. Jänne, who is director of the Lowe Center for Thoracic Oncology at Dana Farber Cancer Institute, Boston.

Adagrasib is being investigated as part of the KRYSTAL-1 study, alone and as part of combinations in various solid tumors. Previously treated NSCLC KRAS (G12C) patients are also being enrolled in a phase 3 study of adagrasib combined with docetaxel, as well as another phase 2 study of adagrasib combined with pembrolizumab as first-line therapy for NSCLC KRAS (G12C).

Adagrasib is likely to remain a second-line therapy following chemotherapy and immunotherapy. “The activity by itself at the moment is not sufficient to be a first-line treatment. That may change in the future in combination with a standard of care agent or in a subset of patients with KRAS (G12C)–mutant NSCLC, although no subset with higher efficacy has been identified to date. Identification of predictive biomarkers for patients likely to benefit from single agent or an adagrasib combination treatment remains a high priority,” Dr. Jänne said.

The study included 116 patients who had previously been treated with platinum-based chemotherapy and anti–programmed death 1 or programmed death–ligand 1 therapy. They received 600 mg oral adagrasib twice per day over a median follow-up period of 12.9 months. About 42.9% (95% confidence interval, 33.5%-52.6%) experienced a confirmed objective response with a median duration of 8.5 months (95% CI, 6.2-13.8 months). The median progression-free survival was 6.5 months (95% CI, 4.7-8.4 months). After a median follow-up of 15.6 months, the median overall survival was 12.6 months (95% CI, 9.2-19.2 months). The estimated overall survival at 1 year was 50.8% (95% CI, 40.9%-60.0%).

33 patients had stable central nervous system metastases that had been previously treated. About 33.3% had an intracranial confirmed objective response (95% CI, 18.0-51.8%) with a median duration of response of 11.2 months (95% CI, 2.99 months to not available).

Adverse events are similar to what is seen with other targeted therapies, according to Dr. Jänne. 97.4% of patient reported a treatment-related adverse event; 52.6% had grade 1-2 adverse events, and 44.8% had grade 3 adverse events. 6.9% discontinued the drug as a result.

Dr. Jänne has consulted for Mirati Therapeutics and is a member of its scientific advisory board. The study was funded by Mirati Therapeutics.

In a phase 2 cohort study, the KRAS (G12C) inhibitor adagrasib induced an objective response in about one out of three patients with KRAS (G12C)–mutated non–small cell lung cancer (NSCLC) who had previously been treated with platinum-based chemotherapy and immune therapy.

Adagrasib targets KRAS (G12C), which had long been thought undruggable until research published in 2013 revealed a new binding pocket that did not compete directly against the protein’s natural binding partner. The new trial further validates the approach. “It supports that clinically effective targeted therapies can be developed for patients with KRAS (G12C)–mutant NSCLC,” said Pasi Jänne, MD, PhD, who is the lead author of the study describing the new results published online in the New England Journal of Medicine.

KRAS is the most frequently mutated oncogene in human cancers. A mutated form is found in about 25% of NSCLCs. KRAS plays a key role in cell signaling governing growth, maturation, and cell death. The mutated form is linked to cancer growth and spread. Patients with mutated KRAS have few effective treatment options.

Adagrasib is currently under study and not yet approved by the Food and Drug Administration. However, sotorasib (Lumakras, Amgen), which also inhibits KRAS (G12C), was approved in May 2021 by the FDA for KRAS (G12C)–mutated NSCLC. There are some key differences between the drugs. Adagrasib has a half-life of 23 hours versus 5 hours for sotorasib, and the newer drug has the potential to penetrate the central nervous system. That could be an important consideration in NSCLC since it often metastasizes to the brain. “Having pharmacological approaches to treat brain metastases is a wonderful new therapeutic option for lung cancer patients,” said Dr. Jänne, who is director of the Lowe Center for Thoracic Oncology at Dana Farber Cancer Institute, Boston.

Adagrasib is being investigated as part of the KRYSTAL-1 study, alone and as part of combinations in various solid tumors. Previously treated NSCLC KRAS (G12C) patients are also being enrolled in a phase 3 study of adagrasib combined with docetaxel, as well as another phase 2 study of adagrasib combined with pembrolizumab as first-line therapy for NSCLC KRAS (G12C).

Adagrasib is likely to remain a second-line therapy following chemotherapy and immunotherapy. “The activity by itself at the moment is not sufficient to be a first-line treatment. That may change in the future in combination with a standard of care agent or in a subset of patients with KRAS (G12C)–mutant NSCLC, although no subset with higher efficacy has been identified to date. Identification of predictive biomarkers for patients likely to benefit from single agent or an adagrasib combination treatment remains a high priority,” Dr. Jänne said.

The study included 116 patients who had previously been treated with platinum-based chemotherapy and anti–programmed death 1 or programmed death–ligand 1 therapy. They received 600 mg oral adagrasib twice per day over a median follow-up period of 12.9 months. About 42.9% (95% confidence interval, 33.5%-52.6%) experienced a confirmed objective response with a median duration of 8.5 months (95% CI, 6.2-13.8 months). The median progression-free survival was 6.5 months (95% CI, 4.7-8.4 months). After a median follow-up of 15.6 months, the median overall survival was 12.6 months (95% CI, 9.2-19.2 months). The estimated overall survival at 1 year was 50.8% (95% CI, 40.9%-60.0%).

33 patients had stable central nervous system metastases that had been previously treated. About 33.3% had an intracranial confirmed objective response (95% CI, 18.0-51.8%) with a median duration of response of 11.2 months (95% CI, 2.99 months to not available).

Adverse events are similar to what is seen with other targeted therapies, according to Dr. Jänne. 97.4% of patient reported a treatment-related adverse event; 52.6% had grade 1-2 adverse events, and 44.8% had grade 3 adverse events. 6.9% discontinued the drug as a result.

Dr. Jänne has consulted for Mirati Therapeutics and is a member of its scientific advisory board. The study was funded by Mirati Therapeutics.

In a phase 2 cohort study, the KRAS (G12C) inhibitor adagrasib induced an objective response in about one out of three patients with KRAS (G12C)–mutated non–small cell lung cancer (NSCLC) who had previously been treated with platinum-based chemotherapy and immune therapy.

Adagrasib targets KRAS (G12C), which had long been thought undruggable until research published in 2013 revealed a new binding pocket that did not compete directly against the protein’s natural binding partner. The new trial further validates the approach. “It supports that clinically effective targeted therapies can be developed for patients with KRAS (G12C)–mutant NSCLC,” said Pasi Jänne, MD, PhD, who is the lead author of the study describing the new results published online in the New England Journal of Medicine.

KRAS is the most frequently mutated oncogene in human cancers. A mutated form is found in about 25% of NSCLCs. KRAS plays a key role in cell signaling governing growth, maturation, and cell death. The mutated form is linked to cancer growth and spread. Patients with mutated KRAS have few effective treatment options.

Adagrasib is currently under study and not yet approved by the Food and Drug Administration. However, sotorasib (Lumakras, Amgen), which also inhibits KRAS (G12C), was approved in May 2021 by the FDA for KRAS (G12C)–mutated NSCLC. There are some key differences between the drugs. Adagrasib has a half-life of 23 hours versus 5 hours for sotorasib, and the newer drug has the potential to penetrate the central nervous system. That could be an important consideration in NSCLC since it often metastasizes to the brain. “Having pharmacological approaches to treat brain metastases is a wonderful new therapeutic option for lung cancer patients,” said Dr. Jänne, who is director of the Lowe Center for Thoracic Oncology at Dana Farber Cancer Institute, Boston.

Adagrasib is being investigated as part of the KRYSTAL-1 study, alone and as part of combinations in various solid tumors. Previously treated NSCLC KRAS (G12C) patients are also being enrolled in a phase 3 study of adagrasib combined with docetaxel, as well as another phase 2 study of adagrasib combined with pembrolizumab as first-line therapy for NSCLC KRAS (G12C).

Adagrasib is likely to remain a second-line therapy following chemotherapy and immunotherapy. “The activity by itself at the moment is not sufficient to be a first-line treatment. That may change in the future in combination with a standard of care agent or in a subset of patients with KRAS (G12C)–mutant NSCLC, although no subset with higher efficacy has been identified to date. Identification of predictive biomarkers for patients likely to benefit from single agent or an adagrasib combination treatment remains a high priority,” Dr. Jänne said.

The study included 116 patients who had previously been treated with platinum-based chemotherapy and anti–programmed death 1 or programmed death–ligand 1 therapy. They received 600 mg oral adagrasib twice per day over a median follow-up period of 12.9 months. About 42.9% (95% confidence interval, 33.5%-52.6%) experienced a confirmed objective response with a median duration of 8.5 months (95% CI, 6.2-13.8 months). The median progression-free survival was 6.5 months (95% CI, 4.7-8.4 months). After a median follow-up of 15.6 months, the median overall survival was 12.6 months (95% CI, 9.2-19.2 months). The estimated overall survival at 1 year was 50.8% (95% CI, 40.9%-60.0%).

33 patients had stable central nervous system metastases that had been previously treated. About 33.3% had an intracranial confirmed objective response (95% CI, 18.0-51.8%) with a median duration of response of 11.2 months (95% CI, 2.99 months to not available).

Adverse events are similar to what is seen with other targeted therapies, according to Dr. Jänne. 97.4% of patient reported a treatment-related adverse event; 52.6% had grade 1-2 adverse events, and 44.8% had grade 3 adverse events. 6.9% discontinued the drug as a result.

Dr. Jänne has consulted for Mirati Therapeutics and is a member of its scientific advisory board. The study was funded by Mirati Therapeutics.

The Food and Drug Administration has approved concomitant use of the biologic pegloticase (Krystexxa) and methotrexate to lower serum uric acid levels (sUA) in patients with chronic gout.

Olivier Le Moal/Getty Images

Pegloticase, which has been available for 12 years, is a pegylated uric acid specific enzyme that lowers sUA by converting it to allantoin.

Though pegloticase is effective in treating chronic gout in patients refractory to conventional treatment, approximately 92% of patients develop antibodies against the drug, resulting in reduced efficacy.

Based on the immunomodulatory effects of methotrexate, researchers of the randomized, placebo-controlled MIRROR trial sought to determine whether combination treatment of pegloticase with methotrexate (multiple brands) would prevent the development of anti-drug antibodies.

Findings from the phase 4 trial found that co-administration of pegloticase and methotrexate reduced the formation of new anti-PEG antibodies. In the group receiving methotrexate and pegloticase, 23.2% (22 out of 95) of patients had an increase in anti-PEG antibodies, compared with 50% (24 of 48) in the pegloticase plus placebo group, according to a recent company press release.

Nearly three-quarters (71%) of participants in the group pretreated with methotrexate, followed by combination pegloticase-methotrexate, had sUA levels that dopped to below 6 mg/dL during the 52-week study. By comparison, 38.5% of participants in the pegloticase and placebo group reached the endpoint. Though gout flare occurred in both groups, methotrexate did not appear to increase the risk for adverse events or gout flare.

The study, led by John Botson, MD, RPh, CCD, a rheumatologist in Anchorage, Alaska, concluded that these measurements demonstrated a significant improvement from traditional pegloticase-only treatment of gout. “This trial confirms not only improved efficacy but improved safety in patients treated with pegloticase in combination with methotrexate 15 mg orally once weekly,” Dr. Botson said last month in an interview with this news organization.

The study was funded by Horizon. Dr. Botson reports receiving research support from Horizon and Radius Health and speaker fees from AbbVie, Amgen, Aurinia, ChemoCentryx, Horizon, Eli Lilly, and Novartis.

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

The Food and Drug Administration has approved concomitant use of the biologic pegloticase (Krystexxa) and methotrexate to lower serum uric acid levels (sUA) in patients with chronic gout.

Olivier Le Moal/Getty Images

Pegloticase, which has been available for 12 years, is a pegylated uric acid specific enzyme that lowers sUA by converting it to allantoin.

Though pegloticase is effective in treating chronic gout in patients refractory to conventional treatment, approximately 92% of patients develop antibodies against the drug, resulting in reduced efficacy.

Based on the immunomodulatory effects of methotrexate, researchers of the randomized, placebo-controlled MIRROR trial sought to determine whether combination treatment of pegloticase with methotrexate (multiple brands) would prevent the development of anti-drug antibodies.

Findings from the phase 4 trial found that co-administration of pegloticase and methotrexate reduced the formation of new anti-PEG antibodies. In the group receiving methotrexate and pegloticase, 23.2% (22 out of 95) of patients had an increase in anti-PEG antibodies, compared with 50% (24 of 48) in the pegloticase plus placebo group, according to a recent company press release.

Nearly three-quarters (71%) of participants in the group pretreated with methotrexate, followed by combination pegloticase-methotrexate, had sUA levels that dopped to below 6 mg/dL during the 52-week study. By comparison, 38.5% of participants in the pegloticase and placebo group reached the endpoint. Though gout flare occurred in both groups, methotrexate did not appear to increase the risk for adverse events or gout flare.

The study, led by John Botson, MD, RPh, CCD, a rheumatologist in Anchorage, Alaska, concluded that these measurements demonstrated a significant improvement from traditional pegloticase-only treatment of gout. “This trial confirms not only improved efficacy but improved safety in patients treated with pegloticase in combination with methotrexate 15 mg orally once weekly,” Dr. Botson said last month in an interview with this news organization.

The study was funded by Horizon. Dr. Botson reports receiving research support from Horizon and Radius Health and speaker fees from AbbVie, Amgen, Aurinia, ChemoCentryx, Horizon, Eli Lilly, and Novartis.

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

The Food and Drug Administration has approved concomitant use of the biologic pegloticase (Krystexxa) and methotrexate to lower serum uric acid levels (sUA) in patients with chronic gout.

Olivier Le Moal/Getty Images

Pegloticase, which has been available for 12 years, is a pegylated uric acid specific enzyme that lowers sUA by converting it to allantoin.

Though pegloticase is effective in treating chronic gout in patients refractory to conventional treatment, approximately 92% of patients develop antibodies against the drug, resulting in reduced efficacy.

Based on the immunomodulatory effects of methotrexate, researchers of the randomized, placebo-controlled MIRROR trial sought to determine whether combination treatment of pegloticase with methotrexate (multiple brands) would prevent the development of anti-drug antibodies.

Findings from the phase 4 trial found that co-administration of pegloticase and methotrexate reduced the formation of new anti-PEG antibodies. In the group receiving methotrexate and pegloticase, 23.2% (22 out of 95) of patients had an increase in anti-PEG antibodies, compared with 50% (24 of 48) in the pegloticase plus placebo group, according to a recent company press release.

Nearly three-quarters (71%) of participants in the group pretreated with methotrexate, followed by combination pegloticase-methotrexate, had sUA levels that dopped to below 6 mg/dL during the 52-week study. By comparison, 38.5% of participants in the pegloticase and placebo group reached the endpoint. Though gout flare occurred in both groups, methotrexate did not appear to increase the risk for adverse events or gout flare.

The study, led by John Botson, MD, RPh, CCD, a rheumatologist in Anchorage, Alaska, concluded that these measurements demonstrated a significant improvement from traditional pegloticase-only treatment of gout. “This trial confirms not only improved efficacy but improved safety in patients treated with pegloticase in combination with methotrexate 15 mg orally once weekly,” Dr. Botson said last month in an interview with this news organization.

The study was funded by Horizon. Dr. Botson reports receiving research support from Horizon and Radius Health and speaker fees from AbbVie, Amgen, Aurinia, ChemoCentryx, Horizon, Eli Lilly, and Novartis.

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

Long thought to be untreatable, KRAS is one of the most difficult to treat oncogenic drivers responsible for approximately 25% of all tumors, including 68% of pancreatic tumors and 20% of all non–small cell lung cancers (NSCLC).

We now have a treatment – sotorasib – for patients with locally advanced or metastatic NSCLC that is driven by a KRAS mutation (G12C). And, now, there is a second treatment – adagrasib – under study, which, according to a presentation recently made at the annual meeting of the American Society of Clinical Oncology, looks promising.

Ras is a membrane-bound regulatory protein (G protein) belonging to the family of guanosine triphosphatases (GTPases). Ras functions as a guanosine diphosphate/triphosphate binary switch by cycling between the active GTP-bound and the inactive GDP-bound states in response to extracellular stimuli. The KRAS (G12C) mutation affects the active form of KRAS and results in abnormally high concentrations of GTP-bound KRAS leading to hyperactivation of downstream oncogenic pathways and uncontrolled cell growth, specifically of ERK and MEK signaling pathways.

At the ASCO annual meeting in June, Spira and colleagues reported the results of cohort A of the KRYSTAL-1 study evaluating adagrasib as second-line therapy patients with advanced solid tumors harboring a KRAS (G12C) mutation. Like sotorasib, adagrasib is a KRAS (G12C) inhibitor that irreversibly and selectively binds KRAS (G12C), locking it in its inactive state. In this study, patients had to have failed first-line chemotherapy and immunotherapy with 43% of lung cancer patients responding. The 12-month overall survival (OS) was 51%, median overall survival was 12.6 and median progression-free survival (PFS) was 6.5 months. Twenty-five patients with KRAS (G12C)–mutant NSCLC and active, untreated central nervous system metastases received adagrasib in a phase 1b cohort. The intracranial overall response rate was 31.6% and median intracranial PFS was 4.2 months. Systemic ORR was 35.0% (7/20), the disease control rate was 80.0% (16/20) and median duration of response was 9.6 months. Based on these data, a phase 3 trial evaluating adagrasib monotherapy versus docetaxel in previously treated patients with KRAS (G12C) mutant NSCLC is ongoing.

The Food and Drug Administration approval of sotorasib in 2021 was, in part, based on the results of a single-arm, phase 2, second-line study of patients who had previously received platinum-based chemotherapy and/or immunotherapy. An ORR rate of 37.1% was reported with a median PFS of 6.8 months and median OS of 12.5 months leading to the FDA approval. Responses were observed across the range of baseline PD-L1 expression levels: 48% of PD-L1 negative, 39% with PD-L1 between 1%-49%, and 22% of patients with a PD-L1 of greater than 50% having a response.

The major toxicities observed in these studies were gastrointestinal (diarrhea, nausea, vomiting) and hepatic (elevated liver enzymes). About 97% of patients on adagrasib experienced any treatment-related adverse events, and 43% experienced a grade 3 or 4 treatment-related adverse event leading to dose reduction in 52% of patients, a dose interruption in 61% of patients, and a 7% discontinuation rate. About 70% of patients treated with sotorasib had a treatment-related adverse event of any grade, and 21% reported grade 3 or 4 treatment-related adverse events.

A subgroup in the KRYSTAL-1 trial reported an intracranial ORR of 32% in patients with active, untreated CNS metastases. Median overall survival has not yet reached concordance between systemic and intracranial disease control was 88%. In addition, preliminary data from two patients with untreated CNS metastases from a phase 1b cohort found cerebrospinal fluid concentrations of adagrasib with a mean ratio of unbound brain-to-plasma concentration of 0.47, which is comparable or exceeds values for known CNS-penetrant tyrosine kinase inhibitors.

Unfortunately, KRAS (G12C) is not the only KRAS mutation out there. There are a myriad of others, such as G12V and G12D. Hopefully, we will be seeing more drugs aimed at this set of important mutations. Another question, of course, is when and if these drugs will move to the first-line setting.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Long thought to be untreatable, KRAS is one of the most difficult to treat oncogenic drivers responsible for approximately 25% of all tumors, including 68% of pancreatic tumors and 20% of all non–small cell lung cancers (NSCLC).

We now have a treatment – sotorasib – for patients with locally advanced or metastatic NSCLC that is driven by a KRAS mutation (G12C). And, now, there is a second treatment – adagrasib – under study, which, according to a presentation recently made at the annual meeting of the American Society of Clinical Oncology, looks promising.

Ras is a membrane-bound regulatory protein (G protein) belonging to the family of guanosine triphosphatases (GTPases). Ras functions as a guanosine diphosphate/triphosphate binary switch by cycling between the active GTP-bound and the inactive GDP-bound states in response to extracellular stimuli. The KRAS (G12C) mutation affects the active form of KRAS and results in abnormally high concentrations of GTP-bound KRAS leading to hyperactivation of downstream oncogenic pathways and uncontrolled cell growth, specifically of ERK and MEK signaling pathways.

At the ASCO annual meeting in June, Spira and colleagues reported the results of cohort A of the KRYSTAL-1 study evaluating adagrasib as second-line therapy patients with advanced solid tumors harboring a KRAS (G12C) mutation. Like sotorasib, adagrasib is a KRAS (G12C) inhibitor that irreversibly and selectively binds KRAS (G12C), locking it in its inactive state. In this study, patients had to have failed first-line chemotherapy and immunotherapy with 43% of lung cancer patients responding. The 12-month overall survival (OS) was 51%, median overall survival was 12.6 and median progression-free survival (PFS) was 6.5 months. Twenty-five patients with KRAS (G12C)–mutant NSCLC and active, untreated central nervous system metastases received adagrasib in a phase 1b cohort. The intracranial overall response rate was 31.6% and median intracranial PFS was 4.2 months. Systemic ORR was 35.0% (7/20), the disease control rate was 80.0% (16/20) and median duration of response was 9.6 months. Based on these data, a phase 3 trial evaluating adagrasib monotherapy versus docetaxel in previously treated patients with KRAS (G12C) mutant NSCLC is ongoing.

The Food and Drug Administration approval of sotorasib in 2021 was, in part, based on the results of a single-arm, phase 2, second-line study of patients who had previously received platinum-based chemotherapy and/or immunotherapy. An ORR rate of 37.1% was reported with a median PFS of 6.8 months and median OS of 12.5 months leading to the FDA approval. Responses were observed across the range of baseline PD-L1 expression levels: 48% of PD-L1 negative, 39% with PD-L1 between 1%-49%, and 22% of patients with a PD-L1 of greater than 50% having a response.

The major toxicities observed in these studies were gastrointestinal (diarrhea, nausea, vomiting) and hepatic (elevated liver enzymes). About 97% of patients on adagrasib experienced any treatment-related adverse events, and 43% experienced a grade 3 or 4 treatment-related adverse event leading to dose reduction in 52% of patients, a dose interruption in 61% of patients, and a 7% discontinuation rate. About 70% of patients treated with sotorasib had a treatment-related adverse event of any grade, and 21% reported grade 3 or 4 treatment-related adverse events.

A subgroup in the KRYSTAL-1 trial reported an intracranial ORR of 32% in patients with active, untreated CNS metastases. Median overall survival has not yet reached concordance between systemic and intracranial disease control was 88%. In addition, preliminary data from two patients with untreated CNS metastases from a phase 1b cohort found cerebrospinal fluid concentrations of adagrasib with a mean ratio of unbound brain-to-plasma concentration of 0.47, which is comparable or exceeds values for known CNS-penetrant tyrosine kinase inhibitors.

Unfortunately, KRAS (G12C) is not the only KRAS mutation out there. There are a myriad of others, such as G12V and G12D. Hopefully, we will be seeing more drugs aimed at this set of important mutations. Another question, of course, is when and if these drugs will move to the first-line setting.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Long thought to be untreatable, KRAS is one of the most difficult to treat oncogenic drivers responsible for approximately 25% of all tumors, including 68% of pancreatic tumors and 20% of all non–small cell lung cancers (NSCLC).

We now have a treatment – sotorasib – for patients with locally advanced or metastatic NSCLC that is driven by a KRAS mutation (G12C). And, now, there is a second treatment – adagrasib – under study, which, according to a presentation recently made at the annual meeting of the American Society of Clinical Oncology, looks promising.

Ras is a membrane-bound regulatory protein (G protein) belonging to the family of guanosine triphosphatases (GTPases). Ras functions as a guanosine diphosphate/triphosphate binary switch by cycling between the active GTP-bound and the inactive GDP-bound states in response to extracellular stimuli. The KRAS (G12C) mutation affects the active form of KRAS and results in abnormally high concentrations of GTP-bound KRAS leading to hyperactivation of downstream oncogenic pathways and uncontrolled cell growth, specifically of ERK and MEK signaling pathways.

At the ASCO annual meeting in June, Spira and colleagues reported the results of cohort A of the KRYSTAL-1 study evaluating adagrasib as second-line therapy patients with advanced solid tumors harboring a KRAS (G12C) mutation. Like sotorasib, adagrasib is a KRAS (G12C) inhibitor that irreversibly and selectively binds KRAS (G12C), locking it in its inactive state. In this study, patients had to have failed first-line chemotherapy and immunotherapy with 43% of lung cancer patients responding. The 12-month overall survival (OS) was 51%, median overall survival was 12.6 and median progression-free survival (PFS) was 6.5 months. Twenty-five patients with KRAS (G12C)–mutant NSCLC and active, untreated central nervous system metastases received adagrasib in a phase 1b cohort. The intracranial overall response rate was 31.6% and median intracranial PFS was 4.2 months. Systemic ORR was 35.0% (7/20), the disease control rate was 80.0% (16/20) and median duration of response was 9.6 months. Based on these data, a phase 3 trial evaluating adagrasib monotherapy versus docetaxel in previously treated patients with KRAS (G12C) mutant NSCLC is ongoing.

The Food and Drug Administration approval of sotorasib in 2021 was, in part, based on the results of a single-arm, phase 2, second-line study of patients who had previously received platinum-based chemotherapy and/or immunotherapy. An ORR rate of 37.1% was reported with a median PFS of 6.8 months and median OS of 12.5 months leading to the FDA approval. Responses were observed across the range of baseline PD-L1 expression levels: 48% of PD-L1 negative, 39% with PD-L1 between 1%-49%, and 22% of patients with a PD-L1 of greater than 50% having a response.

The major toxicities observed in these studies were gastrointestinal (diarrhea, nausea, vomiting) and hepatic (elevated liver enzymes). About 97% of patients on adagrasib experienced any treatment-related adverse events, and 43% experienced a grade 3 or 4 treatment-related adverse event leading to dose reduction in 52% of patients, a dose interruption in 61% of patients, and a 7% discontinuation rate. About 70% of patients treated with sotorasib had a treatment-related adverse event of any grade, and 21% reported grade 3 or 4 treatment-related adverse events.

A subgroup in the KRYSTAL-1 trial reported an intracranial ORR of 32% in patients with active, untreated CNS metastases. Median overall survival has not yet reached concordance between systemic and intracranial disease control was 88%. In addition, preliminary data from two patients with untreated CNS metastases from a phase 1b cohort found cerebrospinal fluid concentrations of adagrasib with a mean ratio of unbound brain-to-plasma concentration of 0.47, which is comparable or exceeds values for known CNS-penetrant tyrosine kinase inhibitors.

Unfortunately, KRAS (G12C) is not the only KRAS mutation out there. There are a myriad of others, such as G12V and G12D. Hopefully, we will be seeing more drugs aimed at this set of important mutations. Another question, of course, is when and if these drugs will move to the first-line setting.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Pharmacists can now prescribe Paxlovid, Pfizer’s COVID-19 antiviral pill, directly to patients.

The Food and Drug Administration revised the drug’s emergency use authorization on July 6, letting state-licensed pharmacists screen patients and determine if they are eligible for Paxlovid, according to The Associated Press.

Previously, only doctors could prescribe the antiviral drug, the AP reported. With some limits, pharmacists can now prescribe the medication for patients who face high risks for severe COVID-19.

“The FDA recognizes the important role pharmacists have played and continue to play in combating this pandemic,” Patrizia Cavazzoni, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a statement.

“Since Paxlovid must be taken within 5 days after symptoms begin, authorizing state-licensed pharmacists to prescribe Paxlovid could expand access to timely treatment for some patients who are eligible to receive this drug for the treatment of COVID-19,” she said.

Tom Kraus, the vice president of government relations at the American Society of Health-System Pharmacists, said in a statement that the organization was “pleased to see the FDA remove this barrier to patients’ access to this critical treatment.”

“Pharmacists have played a vital role in our pandemic response efforts and are well-positioned to help patients, particularly those in rural and underserved communities, benefit from this medication,” he said.

But some doctor’s groups questioned the FDA’s move. Jack Resneck Jr., MD, the president of the American Medical Association, said in a statement that prescribing Paxlovid “requires knowledge of a patient’s medical history, as well as clinical monitoring for side effects and follow-up care to determine whether a patient is improving” – requirements that are “far beyond a pharmacist’s scope and training.”

“In the fight against a virus that has killed more than a million people in the United States and is still extremely present and transmissible, patients will get the best, most comprehensive care from physician-led teams – teams that include pharmacists. But, whenever possible, prescribing decisions should be made by a physician with knowledge of a patient’s medical history and the ability to follow up. To ensure the best possible care for COVID-19 patients, we urge people who test positive to discuss treatment options with their physician, if they have one,” he said.

After testing positive for COVID-19, patients should first consider seeking care from their regular health care provider or locating a Test-to-Treat site in their area, the FDA said. Although the latest update allows pharmacists to prescribe Paxlovid, community pharmacies that don’t yet take part in the Test-to-Treat program can decide if they will offer the prescription service to patients.

Paxlovid is authorized to treat mild to moderate COVID-19 in adults and in kids ages 12 and older who weigh at least 88 pounds. Patients who report a positive at-home test are eligible for Paxlovid under the FDA authorization.

If patients want to seek a prescription directly from a pharmacist, they should bring electronic or printed health records from the past year, including their most recent reports of blood work, so the pharmacist can review for kidney or liver problems. Pharmacists can also get this information from the patient’s health care provider.

In addition, patients should bring a list of all medications they are taking, including over-the-counter medications, so the pharmacist can screen for drugs that can have serious interactions with Paxlovid.

Under the limits in the updated FDA authorization, pharmacists should refer patients for more screening if Paxlovid isn’t a good option or if there’s not enough information to find out how well their kidneys or liver works, as well as potential drug interactions.

Paxlovid is intended for people with COVID-19 who face the highest risks for serious disease, the AP reported, including older adults and those with health conditions such as heart disease, obesity, cancer, or diabetes. It isn’t recommended for people with severe kidney or liver problems. A course of treatment requires three pills twice a day for 5 days.

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

Pharmacists can now prescribe Paxlovid, Pfizer’s COVID-19 antiviral pill, directly to patients.

The Food and Drug Administration revised the drug’s emergency use authorization on July 6, letting state-licensed pharmacists screen patients and determine if they are eligible for Paxlovid, according to The Associated Press.

Previously, only doctors could prescribe the antiviral drug, the AP reported. With some limits, pharmacists can now prescribe the medication for patients who face high risks for severe COVID-19.

“The FDA recognizes the important role pharmacists have played and continue to play in combating this pandemic,” Patrizia Cavazzoni, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a statement.

“Since Paxlovid must be taken within 5 days after symptoms begin, authorizing state-licensed pharmacists to prescribe Paxlovid could expand access to timely treatment for some patients who are eligible to receive this drug for the treatment of COVID-19,” she said.

Tom Kraus, the vice president of government relations at the American Society of Health-System Pharmacists, said in a statement that the organization was “pleased to see the FDA remove this barrier to patients’ access to this critical treatment.”

“Pharmacists have played a vital role in our pandemic response efforts and are well-positioned to help patients, particularly those in rural and underserved communities, benefit from this medication,” he said.

But some doctor’s groups questioned the FDA’s move. Jack Resneck Jr., MD, the president of the American Medical Association, said in a statement that prescribing Paxlovid “requires knowledge of a patient’s medical history, as well as clinical monitoring for side effects and follow-up care to determine whether a patient is improving” – requirements that are “far beyond a pharmacist’s scope and training.”

“In the fight against a virus that has killed more than a million people in the United States and is still extremely present and transmissible, patients will get the best, most comprehensive care from physician-led teams – teams that include pharmacists. But, whenever possible, prescribing decisions should be made by a physician with knowledge of a patient’s medical history and the ability to follow up. To ensure the best possible care for COVID-19 patients, we urge people who test positive to discuss treatment options with their physician, if they have one,” he said.

After testing positive for COVID-19, patients should first consider seeking care from their regular health care provider or locating a Test-to-Treat site in their area, the FDA said. Although the latest update allows pharmacists to prescribe Paxlovid, community pharmacies that don’t yet take part in the Test-to-Treat program can decide if they will offer the prescription service to patients.

Paxlovid is authorized to treat mild to moderate COVID-19 in adults and in kids ages 12 and older who weigh at least 88 pounds. Patients who report a positive at-home test are eligible for Paxlovid under the FDA authorization.

If patients want to seek a prescription directly from a pharmacist, they should bring electronic or printed health records from the past year, including their most recent reports of blood work, so the pharmacist can review for kidney or liver problems. Pharmacists can also get this information from the patient’s health care provider.

In addition, patients should bring a list of all medications they are taking, including over-the-counter medications, so the pharmacist can screen for drugs that can have serious interactions with Paxlovid.

Under the limits in the updated FDA authorization, pharmacists should refer patients for more screening if Paxlovid isn’t a good option or if there’s not enough information to find out how well their kidneys or liver works, as well as potential drug interactions.

Paxlovid is intended for people with COVID-19 who face the highest risks for serious disease, the AP reported, including older adults and those with health conditions such as heart disease, obesity, cancer, or diabetes. It isn’t recommended for people with severe kidney or liver problems. A course of treatment requires three pills twice a day for 5 days.

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

Pharmacists can now prescribe Paxlovid, Pfizer’s COVID-19 antiviral pill, directly to patients.

The Food and Drug Administration revised the drug’s emergency use authorization on July 6, letting state-licensed pharmacists screen patients and determine if they are eligible for Paxlovid, according to The Associated Press.

Previously, only doctors could prescribe the antiviral drug, the AP reported. With some limits, pharmacists can now prescribe the medication for patients who face high risks for severe COVID-19.

“The FDA recognizes the important role pharmacists have played and continue to play in combating this pandemic,” Patrizia Cavazzoni, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a statement.

“Since Paxlovid must be taken within 5 days after symptoms begin, authorizing state-licensed pharmacists to prescribe Paxlovid could expand access to timely treatment for some patients who are eligible to receive this drug for the treatment of COVID-19,” she said.

Tom Kraus, the vice president of government relations at the American Society of Health-System Pharmacists, said in a statement that the organization was “pleased to see the FDA remove this barrier to patients’ access to this critical treatment.”

“Pharmacists have played a vital role in our pandemic response efforts and are well-positioned to help patients, particularly those in rural and underserved communities, benefit from this medication,” he said.

But some doctor’s groups questioned the FDA’s move. Jack Resneck Jr., MD, the president of the American Medical Association, said in a statement that prescribing Paxlovid “requires knowledge of a patient’s medical history, as well as clinical monitoring for side effects and follow-up care to determine whether a patient is improving” – requirements that are “far beyond a pharmacist’s scope and training.”

“In the fight against a virus that has killed more than a million people in the United States and is still extremely present and transmissible, patients will get the best, most comprehensive care from physician-led teams – teams that include pharmacists. But, whenever possible, prescribing decisions should be made by a physician with knowledge of a patient’s medical history and the ability to follow up. To ensure the best possible care for COVID-19 patients, we urge people who test positive to discuss treatment options with their physician, if they have one,” he said.

After testing positive for COVID-19, patients should first consider seeking care from their regular health care provider or locating a Test-to-Treat site in their area, the FDA said. Although the latest update allows pharmacists to prescribe Paxlovid, community pharmacies that don’t yet take part in the Test-to-Treat program can decide if they will offer the prescription service to patients.

Paxlovid is authorized to treat mild to moderate COVID-19 in adults and in kids ages 12 and older who weigh at least 88 pounds. Patients who report a positive at-home test are eligible for Paxlovid under the FDA authorization.

If patients want to seek a prescription directly from a pharmacist, they should bring electronic or printed health records from the past year, including their most recent reports of blood work, so the pharmacist can review for kidney or liver problems. Pharmacists can also get this information from the patient’s health care provider.

In addition, patients should bring a list of all medications they are taking, including over-the-counter medications, so the pharmacist can screen for drugs that can have serious interactions with Paxlovid.

Under the limits in the updated FDA authorization, pharmacists should refer patients for more screening if Paxlovid isn’t a good option or if there’s not enough information to find out how well their kidneys or liver works, as well as potential drug interactions.

Paxlovid is intended for people with COVID-19 who face the highest risks for serious disease, the AP reported, including older adults and those with health conditions such as heart disease, obesity, cancer, or diabetes. It isn’t recommended for people with severe kidney or liver problems. A course of treatment requires three pills twice a day for 5 days.

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

Ann Marco, 73, who was diagnosed with ovarian cancer in late 2018, credits her oncology team for saving her life. They treated her with chemotherapy, debulking surgery, and more chemotherapy. But it is her second and current care team that helped restore Ms. Marco’s quality of life, directing her toward such resources as palliative care, physical therapy and counseling for her and her husband.

“I can’t say enough about my palliative care doctor. She helped me manage pain, and the fatigue associated with chemotherapy. When she noticed that my leg was swollen she suspected a blood clot and sent me for an ultrasound,” Ms. Marco said.

The ultrasound revealed that she did indeed have a blood clot, for which she received, and continues to receive, medication. “Because with ovarian cancer, you always have blood clots. So little things like that, though they’re not that little, have really helped me in my journey with this cancer,” Ms. Marco said.

That journey has had its ups and downs. One chemotherapy regimen was so intolerable she decided to discontinue it, with full support of her oncologist. I told her, I just want to live my life, whether that’s only 6 more months or 3 years, but I don’t want to live it like this. And she said, ‘Ann, we’re going to do what you want to do.’”

Nine months later, when her cancer started growing again, Ms. Marco returned to chemotherapy. But this regimen has been much more tolerable, and it also appears to be doing its job. A recent CT scan showed that the tumors are shrinking.

“They’ll never go away. I have metastatic cancer. But they’re smaller, and I was really thrilled about that. It’s the best news I’ve had in more than 3 years,” Ms. Marco said.
 

End-of-life aggressive care still common

Despite clinical guidelines advising against intensive or invasive end-of-life care, more than half of women with terminal ovarian cancer receive at least one aggressive intervention, shows a study published in JCO Oncology Practice.

“We have good evidence that the types of aggressive end-of-life care we looked at in this paper are generally related to a lower quality of life for patients, poorer bereavement outcomes for their families, and even shorter duration survivals,” said lead author Megan A. Mullins, PhD, MPH, a postdoctoral research fellow at the University of Michigan in Ann Arbor. “This suggests there’s a disconnect between what people think aggressive care might do and what it’s doing.”

In their evaluation of variation in end-of-life care, Dr. Mullins and her colleagues analyzed SEER-Medicare data on 6,288 women with ovarian cancer who died between 2016 and 2020. They found that 51% of those women received some form of aggressive cancer care. The most common forms were not being admitted to hospice (28.9%), receiving an invasive procedure (20.7%) and being admitted to an intensive care unit (18.6%).

Dr. Mullins noted that since palliative care was officially recognized as a specialty in 2006, there has been increasing guidance for earlier integration of palliative care and reducing the aggressiveness of end-of-life care; both ASCO and the National Quality Form have standards advising against aggressive end-of-life care.

“But there are a lot of complicated factors that I think make it hard to move the needle in this area,” she said. “For one thing, particularly with ovarian cancer, women tend to have recurrences. I’ve spoken with physicians who got their patients through a difficult patch; they rebounded and they did fine. You don’t know for sure if that’s going to happen again if you try something else. Prognostication is not an exact science.”

Also, end-of-life discussions can be challenging conversations. “Nobody wants to take hope away from their patients. But there’s evidence to show that these conversations don’t actually reduce patients’ hopes – that’s a misconception,” Dr. Mullins said.

“It’s challenging. In the United States, we don’t like to talk about death and dying. But I think having these conversations earlier and more often can help make them a more regular part of care,” she said.

Brittany A. Davidson, MD, a gynecologic oncologist with Duke Health in Durham, N.C., who wrote an accompanying editorial, acknowledges that end-of-life can be fraught with fear, anxiety, and a lot of emotion. But she finds helping patients and their families navigate the ups and downs of their cancer one of the most rewarding aspects of her career as a physician.

“We want to help patients and their family members make these transitions as smoothly as possible,” she said.

A proponent of communications skills training for physicians in general, Dr. Brittany said doctors can learn to identify cues that patients are ready to have conversations about their end-of-life care.

“Those cues will help us facilitate conversations sooner rather than later so we’re not waiting until the very end,” she said.

What these conversations consist of varies depending on where the patient is in her cancer trajectory. In a patient with recurrent ovarian or recurrent uterine cancer, this might start with making sure the patient understands that while their cancer is treatable, it is very unlikely to be curable.

“I have often had patients who have been treated for cancer for several years and didn’t know their cancer wasn’t curable. How many missed opportunities have we overlooked?” Dr. Davidson said.

Then the conversation can turn to the goals of treatment. What’s important to the patient? “Are there events they want to be around for? Symptoms they want to avoid? Some patients really want to know what it’s going to be like to die. I try to take the lead from the patient. Ask what kind of information is helpful to them. Is it numbers? Is it symptoms? It’s really different for everybody,” Dr. Davidson said.

Although Dr. Mullins’s research and Dr. Davidson’s editorial suggest there’s room for improvement toward achieving goal-concordant care in gynecological cancers, Dr. Davidson suspects these patients might be faring a bit better than patients with other types of cancer based on her own anecdotal observations.

“One of the unique things about gynecologic oncology is that we have an amazing longitudinal relationship with our patients – we are not only their surgeons, we’re their oncologists. In other solid tumors, care is fractionated.

“That’s one of the reasons I love gynecologic oncology. I have the opportunity to know my patients through all the stages they experience as part of their cancer. I’d like to think that allows me a better opportunity to get to know them and help them recognize the value of palliative care,” Dr. Mullins said.

Ann Marco, 73, who was diagnosed with ovarian cancer in late 2018, credits her oncology team for saving her life. They treated her with chemotherapy, debulking surgery, and more chemotherapy. But it is her second and current care team that helped restore Ms. Marco’s quality of life, directing her toward such resources as palliative care, physical therapy and counseling for her and her husband.

“I can’t say enough about my palliative care doctor. She helped me manage pain, and the fatigue associated with chemotherapy. When she noticed that my leg was swollen she suspected a blood clot and sent me for an ultrasound,” Ms. Marco said.

The ultrasound revealed that she did indeed have a blood clot, for which she received, and continues to receive, medication. “Because with ovarian cancer, you always have blood clots. So little things like that, though they’re not that little, have really helped me in my journey with this cancer,” Ms. Marco said.

That journey has had its ups and downs. One chemotherapy regimen was so intolerable she decided to discontinue it, with full support of her oncologist. I told her, I just want to live my life, whether that’s only 6 more months or 3 years, but I don’t want to live it like this. And she said, ‘Ann, we’re going to do what you want to do.’”

Nine months later, when her cancer started growing again, Ms. Marco returned to chemotherapy. But this regimen has been much more tolerable, and it also appears to be doing its job. A recent CT scan showed that the tumors are shrinking.

“They’ll never go away. I have metastatic cancer. But they’re smaller, and I was really thrilled about that. It’s the best news I’ve had in more than 3 years,” Ms. Marco said.
 

End-of-life aggressive care still common

Despite clinical guidelines advising against intensive or invasive end-of-life care, more than half of women with terminal ovarian cancer receive at least one aggressive intervention, shows a study published in JCO Oncology Practice.

“We have good evidence that the types of aggressive end-of-life care we looked at in this paper are generally related to a lower quality of life for patients, poorer bereavement outcomes for their families, and even shorter duration survivals,” said lead author Megan A. Mullins, PhD, MPH, a postdoctoral research fellow at the University of Michigan in Ann Arbor. “This suggests there’s a disconnect between what people think aggressive care might do and what it’s doing.”

In their evaluation of variation in end-of-life care, Dr. Mullins and her colleagues analyzed SEER-Medicare data on 6,288 women with ovarian cancer who died between 2016 and 2020. They found that 51% of those women received some form of aggressive cancer care. The most common forms were not being admitted to hospice (28.9%), receiving an invasive procedure (20.7%) and being admitted to an intensive care unit (18.6%).

Dr. Mullins noted that since palliative care was officially recognized as a specialty in 2006, there has been increasing guidance for earlier integration of palliative care and reducing the aggressiveness of end-of-life care; both ASCO and the National Quality Form have standards advising against aggressive end-of-life care.

“But there are a lot of complicated factors that I think make it hard to move the needle in this area,” she said. “For one thing, particularly with ovarian cancer, women tend to have recurrences. I’ve spoken with physicians who got their patients through a difficult patch; they rebounded and they did fine. You don’t know for sure if that’s going to happen again if you try something else. Prognostication is not an exact science.”

Also, end-of-life discussions can be challenging conversations. “Nobody wants to take hope away from their patients. But there’s evidence to show that these conversations don’t actually reduce patients’ hopes – that’s a misconception,” Dr. Mullins said.

“It’s challenging. In the United States, we don’t like to talk about death and dying. But I think having these conversations earlier and more often can help make them a more regular part of care,” she said.

Brittany A. Davidson, MD, a gynecologic oncologist with Duke Health in Durham, N.C., who wrote an accompanying editorial, acknowledges that end-of-life can be fraught with fear, anxiety, and a lot of emotion. But she finds helping patients and their families navigate the ups and downs of their cancer one of the most rewarding aspects of her career as a physician.

“We want to help patients and their family members make these transitions as smoothly as possible,” she said.

A proponent of communications skills training for physicians in general, Dr. Brittany said doctors can learn to identify cues that patients are ready to have conversations about their end-of-life care.

“Those cues will help us facilitate conversations sooner rather than later so we’re not waiting until the very end,” she said.

What these conversations consist of varies depending on where the patient is in her cancer trajectory. In a patient with recurrent ovarian or recurrent uterine cancer, this might start with making sure the patient understands that while their cancer is treatable, it is very unlikely to be curable.

“I have often had patients who have been treated for cancer for several years and didn’t know their cancer wasn’t curable. How many missed opportunities have we overlooked?” Dr. Davidson said.

Then the conversation can turn to the goals of treatment. What’s important to the patient? “Are there events they want to be around for? Symptoms they want to avoid? Some patients really want to know what it’s going to be like to die. I try to take the lead from the patient. Ask what kind of information is helpful to them. Is it numbers? Is it symptoms? It’s really different for everybody,” Dr. Davidson said.

Although Dr. Mullins’s research and Dr. Davidson’s editorial suggest there’s room for improvement toward achieving goal-concordant care in gynecological cancers, Dr. Davidson suspects these patients might be faring a bit better than patients with other types of cancer based on her own anecdotal observations.

“One of the unique things about gynecologic oncology is that we have an amazing longitudinal relationship with our patients – we are not only their surgeons, we’re their oncologists. In other solid tumors, care is fractionated.

“That’s one of the reasons I love gynecologic oncology. I have the opportunity to know my patients through all the stages they experience as part of their cancer. I’d like to think that allows me a better opportunity to get to know them and help them recognize the value of palliative care,” Dr. Mullins said.

Ann Marco, 73, who was diagnosed with ovarian cancer in late 2018, credits her oncology team for saving her life. They treated her with chemotherapy, debulking surgery, and more chemotherapy. But it is her second and current care team that helped restore Ms. Marco’s quality of life, directing her toward such resources as palliative care, physical therapy and counseling for her and her husband.

“I can’t say enough about my palliative care doctor. She helped me manage pain, and the fatigue associated with chemotherapy. When she noticed that my leg was swollen she suspected a blood clot and sent me for an ultrasound,” Ms. Marco said.

The ultrasound revealed that she did indeed have a blood clot, for which she received, and continues to receive, medication. “Because with ovarian cancer, you always have blood clots. So little things like that, though they’re not that little, have really helped me in my journey with this cancer,” Ms. Marco said.

That journey has had its ups and downs. One chemotherapy regimen was so intolerable she decided to discontinue it, with full support of her oncologist. I told her, I just want to live my life, whether that’s only 6 more months or 3 years, but I don’t want to live it like this. And she said, ‘Ann, we’re going to do what you want to do.’”

Nine months later, when her cancer started growing again, Ms. Marco returned to chemotherapy. But this regimen has been much more tolerable, and it also appears to be doing its job. A recent CT scan showed that the tumors are shrinking.

“They’ll never go away. I have metastatic cancer. But they’re smaller, and I was really thrilled about that. It’s the best news I’ve had in more than 3 years,” Ms. Marco said.
 

End-of-life aggressive care still common

Despite clinical guidelines advising against intensive or invasive end-of-life care, more than half of women with terminal ovarian cancer receive at least one aggressive intervention, shows a study published in JCO Oncology Practice.

“We have good evidence that the types of aggressive end-of-life care we looked at in this paper are generally related to a lower quality of life for patients, poorer bereavement outcomes for their families, and even shorter duration survivals,” said lead author Megan A. Mullins, PhD, MPH, a postdoctoral research fellow at the University of Michigan in Ann Arbor. “This suggests there’s a disconnect between what people think aggressive care might do and what it’s doing.”

In their evaluation of variation in end-of-life care, Dr. Mullins and her colleagues analyzed SEER-Medicare data on 6,288 women with ovarian cancer who died between 2016 and 2020. They found that 51% of those women received some form of aggressive cancer care. The most common forms were not being admitted to hospice (28.9%), receiving an invasive procedure (20.7%) and being admitted to an intensive care unit (18.6%).

Dr. Mullins noted that since palliative care was officially recognized as a specialty in 2006, there has been increasing guidance for earlier integration of palliative care and reducing the aggressiveness of end-of-life care; both ASCO and the National Quality Form have standards advising against aggressive end-of-life care.

“But there are a lot of complicated factors that I think make it hard to move the needle in this area,” she said. “For one thing, particularly with ovarian cancer, women tend to have recurrences. I’ve spoken with physicians who got their patients through a difficult patch; they rebounded and they did fine. You don’t know for sure if that’s going to happen again if you try something else. Prognostication is not an exact science.”

Also, end-of-life discussions can be challenging conversations. “Nobody wants to take hope away from their patients. But there’s evidence to show that these conversations don’t actually reduce patients’ hopes – that’s a misconception,” Dr. Mullins said.

“It’s challenging. In the United States, we don’t like to talk about death and dying. But I think having these conversations earlier and more often can help make them a more regular part of care,” she said.

Brittany A. Davidson, MD, a gynecologic oncologist with Duke Health in Durham, N.C., who wrote an accompanying editorial, acknowledges that end-of-life can be fraught with fear, anxiety, and a lot of emotion. But she finds helping patients and their families navigate the ups and downs of their cancer one of the most rewarding aspects of her career as a physician.

“We want to help patients and their family members make these transitions as smoothly as possible,” she said.

A proponent of communications skills training for physicians in general, Dr. Brittany said doctors can learn to identify cues that patients are ready to have conversations about their end-of-life care.

“Those cues will help us facilitate conversations sooner rather than later so we’re not waiting until the very end,” she said.

What these conversations consist of varies depending on where the patient is in her cancer trajectory. In a patient with recurrent ovarian or recurrent uterine cancer, this might start with making sure the patient understands that while their cancer is treatable, it is very unlikely to be curable.

“I have often had patients who have been treated for cancer for several years and didn’t know their cancer wasn’t curable. How many missed opportunities have we overlooked?” Dr. Davidson said.

Then the conversation can turn to the goals of treatment. What’s important to the patient? “Are there events they want to be around for? Symptoms they want to avoid? Some patients really want to know what it’s going to be like to die. I try to take the lead from the patient. Ask what kind of information is helpful to them. Is it numbers? Is it symptoms? It’s really different for everybody,” Dr. Davidson said.

Although Dr. Mullins’s research and Dr. Davidson’s editorial suggest there’s room for improvement toward achieving goal-concordant care in gynecological cancers, Dr. Davidson suspects these patients might be faring a bit better than patients with other types of cancer based on her own anecdotal observations.

“One of the unique things about gynecologic oncology is that we have an amazing longitudinal relationship with our patients – we are not only their surgeons, we’re their oncologists. In other solid tumors, care is fractionated.

“That’s one of the reasons I love gynecologic oncology. I have the opportunity to know my patients through all the stages they experience as part of their cancer. I’d like to think that allows me a better opportunity to get to know them and help them recognize the value of palliative care,” Dr. Mullins said.

Opioids remain a staple in pain management for cancer, but there is little guidance around how to treat patients who have a history of opioid misuse.

Recently, a group of palliative and addiction medicine specialists developed strategies to help frontline clinicians manage patients with advanced cancer-related pain and opioid use disorder.

“There is a tendency to ignore treatment of opioid use disorder in advanced cancer patients because people think: ‘Oh, this person has bigger fish to fry,’ but that’s not a very patient-centric way of looking at things,” senior author Jessica Merlin, MD, PhD, with the University of Pittsburgh, said in a news release.

“We know that opioid use disorder is a really important factor in quality of life, so addressing opioid addiction and prescription opioid misuse in people with advanced cancer is really critical,” Dr. Merlin added.

The study was published online in JAMA Oncology.

To improve care for people with advanced cancer and cancer-related pain, the researchers first assessed how clinicians currently treat patients with opioid complexity.

Using an online Delphi platform, the team invited 120 clinicians with expertise in palliative care, pain management, and addiction medicine to weigh in on three common clinical scenarios – a patient with a recent history of untreated opioid use disorder, a patient taking more opioids than prescribed, and a patient using nonprescribed benzodiazepines.

For a patient with cancer and a recent history of untreated opioid use disorder, regardless of prognosis, the panel deemed it appropriate to begin treatment with buprenorphine/naloxone for pain but inappropriate to refer the patient to a methadone clinic. The panel felt that going to a methadone clinic would be too burdensome for a patient with advanced cancer and not possible for those with limited prognoses.

“This underscores the importance of access to [opioid use disorder] treatment in cancer treatment settings, including non–addiction specialists waivered to prescribe buprenorphine/naloxone and addiction specialists for more complex cases,” the authors wrote.

For a patient with untreated opioid use disorder, the panel deemed split-dose methadone (two to three times daily) appropriate in those with limited prognosis of weeks to months but was uncertain about the suitability of this approach for patients with longer prognoses of a year or longer.

The appropriateness of initiating treatment with a full-agonist opioid was considered uncertain for a patient with limited prognosis and inappropriate for a patient with longer prognosis.

For a patient with cancer pain and no medical history of opioid use disorder but taking more opioids than prescribed, regardless of prognosis, the panel felt it was appropriate to increase monitoring and inappropriate to taper opioids. The panel was not certain about whether to increase opioids based on the patient’s account of what they need or transition to buprenorphine/naloxone.

For a patient with no history of opioid use disorder who was prescribed traditional opioids for pain and had a positive urine drug test for nonprescribed benzodiazepines, regardless of prognosis, the panel felt it was appropriate to continue opioids with close monitoring and inappropriate to taper opioids or transition to buprenorphine/naloxone.

The researchers said that improving education around buprenorphine and cancer pain management in the context of opioid use disorder or misuse is needed.

In a related editorial, two experts noted that the patients considered in this “important article” require considerable time and expertise from an interdisciplinary team.

“It is important that cancer centers establish and fund such teams mainly as a safety measure for these patients and also as a major contribution to the care of all patients with cancer,” wrote Joseph Arthur, MD, and Eduardo Bruera, MD, with the University of Texas MD Anderson Cancer Center, Houston.

In the wider context, Dr. Arthur and Dr. Bruera highlighted how treatments for patients with advanced cancer have evolved over the past 3 decades, yet patients have continued to be given opioids to address cancer-related pain. Developing more sophisticated drugs that relieve pain without significant side effects or addictive properties is imperative.

Dr. Arthur and Dr. Bruera said the study authors “appropriately emphasize the value of delivering compassionate and expert care for these particularly complex cases and the importance of conducting research on the best ways to alleviate the suffering in this rapidly growing patient population.”

This research was supported by Cambia Health Foundation and the National Institute of Nursing Research. Dr. Merlin, Dr. Arthur, and Dr. Bruera reported no relevant disclosures.

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

Opioids remain a staple in pain management for cancer, but there is little guidance around how to treat patients who have a history of opioid misuse.

Recently, a group of palliative and addiction medicine specialists developed strategies to help frontline clinicians manage patients with advanced cancer-related pain and opioid use disorder.

“There is a tendency to ignore treatment of opioid use disorder in advanced cancer patients because people think: ‘Oh, this person has bigger fish to fry,’ but that’s not a very patient-centric way of looking at things,” senior author Jessica Merlin, MD, PhD, with the University of Pittsburgh, said in a news release.

“We know that opioid use disorder is a really important factor in quality of life, so addressing opioid addiction and prescription opioid misuse in people with advanced cancer is really critical,” Dr. Merlin added.

The study was published online in JAMA Oncology.

To improve care for people with advanced cancer and cancer-related pain, the researchers first assessed how clinicians currently treat patients with opioid complexity.

Using an online Delphi platform, the team invited 120 clinicians with expertise in palliative care, pain management, and addiction medicine to weigh in on three common clinical scenarios – a patient with a recent history of untreated opioid use disorder, a patient taking more opioids than prescribed, and a patient using nonprescribed benzodiazepines.

For a patient with cancer and a recent history of untreated opioid use disorder, regardless of prognosis, the panel deemed it appropriate to begin treatment with buprenorphine/naloxone for pain but inappropriate to refer the patient to a methadone clinic. The panel felt that going to a methadone clinic would be too burdensome for a patient with advanced cancer and not possible for those with limited prognoses.

“This underscores the importance of access to [opioid use disorder] treatment in cancer treatment settings, including non–addiction specialists waivered to prescribe buprenorphine/naloxone and addiction specialists for more complex cases,” the authors wrote.

For a patient with untreated opioid use disorder, the panel deemed split-dose methadone (two to three times daily) appropriate in those with limited prognosis of weeks to months but was uncertain about the suitability of this approach for patients with longer prognoses of a year or longer.

The appropriateness of initiating treatment with a full-agonist opioid was considered uncertain for a patient with limited prognosis and inappropriate for a patient with longer prognosis.

For a patient with cancer pain and no medical history of opioid use disorder but taking more opioids than prescribed, regardless of prognosis, the panel felt it was appropriate to increase monitoring and inappropriate to taper opioids. The panel was not certain about whether to increase opioids based on the patient’s account of what they need or transition to buprenorphine/naloxone.

For a patient with no history of opioid use disorder who was prescribed traditional opioids for pain and had a positive urine drug test for nonprescribed benzodiazepines, regardless of prognosis, the panel felt it was appropriate to continue opioids with close monitoring and inappropriate to taper opioids or transition to buprenorphine/naloxone.

The researchers said that improving education around buprenorphine and cancer pain management in the context of opioid use disorder or misuse is needed.

In a related editorial, two experts noted that the patients considered in this “important article” require considerable time and expertise from an interdisciplinary team.

“It is important that cancer centers establish and fund such teams mainly as a safety measure for these patients and also as a major contribution to the care of all patients with cancer,” wrote Joseph Arthur, MD, and Eduardo Bruera, MD, with the University of Texas MD Anderson Cancer Center, Houston.

In the wider context, Dr. Arthur and Dr. Bruera highlighted how treatments for patients with advanced cancer have evolved over the past 3 decades, yet patients have continued to be given opioids to address cancer-related pain. Developing more sophisticated drugs that relieve pain without significant side effects or addictive properties is imperative.

Dr. Arthur and Dr. Bruera said the study authors “appropriately emphasize the value of delivering compassionate and expert care for these particularly complex cases and the importance of conducting research on the best ways to alleviate the suffering in this rapidly growing patient population.”

This research was supported by Cambia Health Foundation and the National Institute of Nursing Research. Dr. Merlin, Dr. Arthur, and Dr. Bruera reported no relevant disclosures.

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

Opioids remain a staple in pain management for cancer, but there is little guidance around how to treat patients who have a history of opioid misuse.

Recently, a group of palliative and addiction medicine specialists developed strategies to help frontline clinicians manage patients with advanced cancer-related pain and opioid use disorder.

“There is a tendency to ignore treatment of opioid use disorder in advanced cancer patients because people think: ‘Oh, this person has bigger fish to fry,’ but that’s not a very patient-centric way of looking at things,” senior author Jessica Merlin, MD, PhD, with the University of Pittsburgh, said in a news release.

“We know that opioid use disorder is a really important factor in quality of life, so addressing opioid addiction and prescription opioid misuse in people with advanced cancer is really critical,” Dr. Merlin added.

The study was published online in JAMA Oncology.

To improve care for people with advanced cancer and cancer-related pain, the researchers first assessed how clinicians currently treat patients with opioid complexity.

Using an online Delphi platform, the team invited 120 clinicians with expertise in palliative care, pain management, and addiction medicine to weigh in on three common clinical scenarios – a patient with a recent history of untreated opioid use disorder, a patient taking more opioids than prescribed, and a patient using nonprescribed benzodiazepines.

For a patient with cancer and a recent history of untreated opioid use disorder, regardless of prognosis, the panel deemed it appropriate to begin treatment with buprenorphine/naloxone for pain but inappropriate to refer the patient to a methadone clinic. The panel felt that going to a methadone clinic would be too burdensome for a patient with advanced cancer and not possible for those with limited prognoses.

“This underscores the importance of access to [opioid use disorder] treatment in cancer treatment settings, including non–addiction specialists waivered to prescribe buprenorphine/naloxone and addiction specialists for more complex cases,” the authors wrote.

For a patient with untreated opioid use disorder, the panel deemed split-dose methadone (two to three times daily) appropriate in those with limited prognosis of weeks to months but was uncertain about the suitability of this approach for patients with longer prognoses of a year or longer.

The appropriateness of initiating treatment with a full-agonist opioid was considered uncertain for a patient with limited prognosis and inappropriate for a patient with longer prognosis.

For a patient with cancer pain and no medical history of opioid use disorder but taking more opioids than prescribed, regardless of prognosis, the panel felt it was appropriate to increase monitoring and inappropriate to taper opioids. The panel was not certain about whether to increase opioids based on the patient’s account of what they need or transition to buprenorphine/naloxone.

For a patient with no history of opioid use disorder who was prescribed traditional opioids for pain and had a positive urine drug test for nonprescribed benzodiazepines, regardless of prognosis, the panel felt it was appropriate to continue opioids with close monitoring and inappropriate to taper opioids or transition to buprenorphine/naloxone.

The researchers said that improving education around buprenorphine and cancer pain management in the context of opioid use disorder or misuse is needed.

In a related editorial, two experts noted that the patients considered in this “important article” require considerable time and expertise from an interdisciplinary team.

“It is important that cancer centers establish and fund such teams mainly as a safety measure for these patients and also as a major contribution to the care of all patients with cancer,” wrote Joseph Arthur, MD, and Eduardo Bruera, MD, with the University of Texas MD Anderson Cancer Center, Houston.

In the wider context, Dr. Arthur and Dr. Bruera highlighted how treatments for patients with advanced cancer have evolved over the past 3 decades, yet patients have continued to be given opioids to address cancer-related pain. Developing more sophisticated drugs that relieve pain without significant side effects or addictive properties is imperative.

Dr. Arthur and Dr. Bruera said the study authors “appropriately emphasize the value of delivering compassionate and expert care for these particularly complex cases and the importance of conducting research on the best ways to alleviate the suffering in this rapidly growing patient population.”

This research was supported by Cambia Health Foundation and the National Institute of Nursing Research. Dr. Merlin, Dr. Arthur, and Dr. Bruera reported no relevant disclosures.

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

Findings from a cohort study highlight a potential role of tumor grade for predicting mucosal head and neck squamous cell carcinoma response to immunotherapy, researchers report in JAMA Otolaryngology–Head & Neck Surgery.

The analysis, which was among patients with either high-grade or low-grade recurrent or metastatic mucosal head and neck squamous cell carcinoma (HNSCC) tumors, revealed that tumor grade was independently associated with immunotherapy response.

“Generally, one would expect high-grade tumors to do worse because they are more aggressive,” said Rajarsi Mandal, MD, the study’s lead author. “But it’s thought that high-grade tumors have higher degrees of chromosomal instability with a lot more mutations generated throughout the genome of these tumors ... and we know that higher mutation rates correlate with higher responses to immunotherapy.”

Researchers found that the proportion of patients having a beneficial response to immunotherapy was larger for patients with high grade tumors (12 of 35; 34.3%) than those with low grade tumors (2 of 25, 8.0%) (difference, 26.3%; 95% confidence interval, 7.3%-45.3%). The odds of having a clinically beneficial response to immunotherapy was increased 5.35-fold (95% CI, 1.04-27.37) in patients with high-grade tumors. Among four patients with low-grade tumors and eight patients with high-grade tumors with available tumor mutational burden data, the mean tumor mutational burden was greater for patients with high-grade tumors (mean [standard deviation], 8.6 [5.4] mut/Mb; n = 8) than for patients with low grade tumors (mean [SD], 3.6 [1.1] mut/Mb; n = 4) (difference, 5.0 mut/Mb; 95% CI, −1.4 to 11.4 mut/Mb; Cohen d, 1.2).

“High tumor grade is not a guarantee but it possibly provides an easy biomarker and a good rationale to say that there’s a better chance the patient will respond to immune checkpoint inhibition,” said Dr. Mandal who is a head and neck cancer surgeon with the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore.

Previous studies of HNSCC tumors that are refractory to traditional therapies, including surgery, chemotherapy, and radiation therapy, have demonstrated a clinically beneficial response to immune checkpoint inhibitors (ICIs). An association between increased tumor mutational burden and beneficial response to ICIs has been shown in other cancers.

Researchers hypothesized that tumor histological grade may be associated with responses to immune checkpoint blockade, and designed their study to examine the association between tumor grade and immunotherapy response in patients treated with ICIs for recurrent or metastatic mucosal HNSCC.

In a single-center retrospective cohort study, investigators reviewed the medical records of 60 adult patients (mean age, 64.6 years; 85% male) with a primary mucosal HNSCC tumor treated with an immune checkpoint inhibitor (pembrolizumab, nivolumab, ipilimumab, or durvalumab) treated between July 1, 2015, and Jan. 22, 2020. They stratified them into those with low grade tumors (well differentiated and moderately differentiated) and those with high grade tumors (poorly differentiated). A clinically beneficial immunotherapy response, defined as complete response or partial response was the primary outcome.

Thirty-eight patients in the study cohort were current or former smokers. The most common primary tumor sight was at the oropharynx. Outcomes among those with high-grade tumors were improved, compared with those with low-grade tumors, for median progression-free survival (5.9 months vs. 3.3 months), median overall survival (16.6 months vs. 15.0 months, and risk of death (hazard ratio, 0.94).

The study’s main limitation was its small sample size and small number of patients who had a clinically beneficial immunotherapy response.

Dr. Mandal had no conflicts of interest to disclose.

Findings from a cohort study highlight a potential role of tumor grade for predicting mucosal head and neck squamous cell carcinoma response to immunotherapy, researchers report in JAMA Otolaryngology–Head & Neck Surgery.

The analysis, which was among patients with either high-grade or low-grade recurrent or metastatic mucosal head and neck squamous cell carcinoma (HNSCC) tumors, revealed that tumor grade was independently associated with immunotherapy response.

“Generally, one would expect high-grade tumors to do worse because they are more aggressive,” said Rajarsi Mandal, MD, the study’s lead author. “But it’s thought that high-grade tumors have higher degrees of chromosomal instability with a lot more mutations generated throughout the genome of these tumors ... and we know that higher mutation rates correlate with higher responses to immunotherapy.”

Researchers found that the proportion of patients having a beneficial response to immunotherapy was larger for patients with high grade tumors (12 of 35; 34.3%) than those with low grade tumors (2 of 25, 8.0%) (difference, 26.3%; 95% confidence interval, 7.3%-45.3%). The odds of having a clinically beneficial response to immunotherapy was increased 5.35-fold (95% CI, 1.04-27.37) in patients with high-grade tumors. Among four patients with low-grade tumors and eight patients with high-grade tumors with available tumor mutational burden data, the mean tumor mutational burden was greater for patients with high-grade tumors (mean [standard deviation], 8.6 [5.4] mut/Mb; n = 8) than for patients with low grade tumors (mean [SD], 3.6 [1.1] mut/Mb; n = 4) (difference, 5.0 mut/Mb; 95% CI, −1.4 to 11.4 mut/Mb; Cohen d, 1.2).

“High tumor grade is not a guarantee but it possibly provides an easy biomarker and a good rationale to say that there’s a better chance the patient will respond to immune checkpoint inhibition,” said Dr. Mandal who is a head and neck cancer surgeon with the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore.

Previous studies of HNSCC tumors that are refractory to traditional therapies, including surgery, chemotherapy, and radiation therapy, have demonstrated a clinically beneficial response to immune checkpoint inhibitors (ICIs). An association between increased tumor mutational burden and beneficial response to ICIs has been shown in other cancers.

Researchers hypothesized that tumor histological grade may be associated with responses to immune checkpoint blockade, and designed their study to examine the association between tumor grade and immunotherapy response in patients treated with ICIs for recurrent or metastatic mucosal HNSCC.

In a single-center retrospective cohort study, investigators reviewed the medical records of 60 adult patients (mean age, 64.6 years; 85% male) with a primary mucosal HNSCC tumor treated with an immune checkpoint inhibitor (pembrolizumab, nivolumab, ipilimumab, or durvalumab) treated between July 1, 2015, and Jan. 22, 2020. They stratified them into those with low grade tumors (well differentiated and moderately differentiated) and those with high grade tumors (poorly differentiated). A clinically beneficial immunotherapy response, defined as complete response or partial response was the primary outcome.

Thirty-eight patients in the study cohort were current or former smokers. The most common primary tumor sight was at the oropharynx. Outcomes among those with high-grade tumors were improved, compared with those with low-grade tumors, for median progression-free survival (5.9 months vs. 3.3 months), median overall survival (16.6 months vs. 15.0 months, and risk of death (hazard ratio, 0.94).

The study’s main limitation was its small sample size and small number of patients who had a clinically beneficial immunotherapy response.

Dr. Mandal had no conflicts of interest to disclose.

Findings from a cohort study highlight a potential role of tumor grade for predicting mucosal head and neck squamous cell carcinoma response to immunotherapy, researchers report in JAMA Otolaryngology–Head & Neck Surgery.

The analysis, which was among patients with either high-grade or low-grade recurrent or metastatic mucosal head and neck squamous cell carcinoma (HNSCC) tumors, revealed that tumor grade was independently associated with immunotherapy response.

“Generally, one would expect high-grade tumors to do worse because they are more aggressive,” said Rajarsi Mandal, MD, the study’s lead author. “But it’s thought that high-grade tumors have higher degrees of chromosomal instability with a lot more mutations generated throughout the genome of these tumors ... and we know that higher mutation rates correlate with higher responses to immunotherapy.”

Researchers found that the proportion of patients having a beneficial response to immunotherapy was larger for patients with high grade tumors (12 of 35; 34.3%) than those with low grade tumors (2 of 25, 8.0%) (difference, 26.3%; 95% confidence interval, 7.3%-45.3%). The odds of having a clinically beneficial response to immunotherapy was increased 5.35-fold (95% CI, 1.04-27.37) in patients with high-grade tumors. Among four patients with low-grade tumors and eight patients with high-grade tumors with available tumor mutational burden data, the mean tumor mutational burden was greater for patients with high-grade tumors (mean [standard deviation], 8.6 [5.4] mut/Mb; n = 8) than for patients with low grade tumors (mean [SD], 3.6 [1.1] mut/Mb; n = 4) (difference, 5.0 mut/Mb; 95% CI, −1.4 to 11.4 mut/Mb; Cohen d, 1.2).

“High tumor grade is not a guarantee but it possibly provides an easy biomarker and a good rationale to say that there’s a better chance the patient will respond to immune checkpoint inhibition,” said Dr. Mandal who is a head and neck cancer surgeon with the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore.

Previous studies of HNSCC tumors that are refractory to traditional therapies, including surgery, chemotherapy, and radiation therapy, have demonstrated a clinically beneficial response to immune checkpoint inhibitors (ICIs). An association between increased tumor mutational burden and beneficial response to ICIs has been shown in other cancers.

Researchers hypothesized that tumor histological grade may be associated with responses to immune checkpoint blockade, and designed their study to examine the association between tumor grade and immunotherapy response in patients treated with ICIs for recurrent or metastatic mucosal HNSCC.

In a single-center retrospective cohort study, investigators reviewed the medical records of 60 adult patients (mean age, 64.6 years; 85% male) with a primary mucosal HNSCC tumor treated with an immune checkpoint inhibitor (pembrolizumab, nivolumab, ipilimumab, or durvalumab) treated between July 1, 2015, and Jan. 22, 2020. They stratified them into those with low grade tumors (well differentiated and moderately differentiated) and those with high grade tumors (poorly differentiated). A clinically beneficial immunotherapy response, defined as complete response or partial response was the primary outcome.

Thirty-eight patients in the study cohort were current or former smokers. The most common primary tumor sight was at the oropharynx. Outcomes among those with high-grade tumors were improved, compared with those with low-grade tumors, for median progression-free survival (5.9 months vs. 3.3 months), median overall survival (16.6 months vs. 15.0 months, and risk of death (hazard ratio, 0.94).

The study’s main limitation was its small sample size and small number of patients who had a clinically beneficial immunotherapy response.

Dr. Mandal had no conflicts of interest to disclose.

An experimental cancer drug could be promising for some people hospitalized with COVID-19, a new study shows.

The medication, called sabizabulin and given as a pill, reduced by half the risk of death among participants. It could be more effective than other drugs for those severely sick with COVID-19, The New York Times reports.

The manufacturer, Veru, is seeking emergency use authorization from the Food and Drug Administration. Hospitalized COVID-19 patients currently have only a few pharmaceutical options.

Sabizabulin blocks cells from building molecular cables that carry material from one part of a cell to another. It was created to fight cancer, because tumor cells need those cables (called microtubules) to grow quickly.

Researchers tried it against COVID-19 2 years ago, because viral replication also requires microtubules to bring pieces of new viruses together.

To participate in the small trial, patients had to be receiving oxygen or on a ventilator and at a high risk of dying from COVID-19, “with risk factors such as hypertension, advanced age or obesity,” the Times reported.

A total of 134 patients received the medicine; 70 got a placebo. Among those receiving sabizabulin, 20.2% died within 2 months; 45.1% of those who took the placebo died.

One infectious disease expert told the Times that the high mortality rate of those on the placebo could mean the study was too small to offer conclusive results.

“The 45% mortality rate in the control group jumps out at me as rather high,” said David Boulware, MD, of the University of Minnesota.

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

An experimental cancer drug could be promising for some people hospitalized with COVID-19, a new study shows.

The medication, called sabizabulin and given as a pill, reduced by half the risk of death among participants. It could be more effective than other drugs for those severely sick with COVID-19, The New York Times reports.

The manufacturer, Veru, is seeking emergency use authorization from the Food and Drug Administration. Hospitalized COVID-19 patients currently have only a few pharmaceutical options.

Sabizabulin blocks cells from building molecular cables that carry material from one part of a cell to another. It was created to fight cancer, because tumor cells need those cables (called microtubules) to grow quickly.

Researchers tried it against COVID-19 2 years ago, because viral replication also requires microtubules to bring pieces of new viruses together.

To participate in the small trial, patients had to be receiving oxygen or on a ventilator and at a high risk of dying from COVID-19, “with risk factors such as hypertension, advanced age or obesity,” the Times reported.

A total of 134 patients received the medicine; 70 got a placebo. Among those receiving sabizabulin, 20.2% died within 2 months; 45.1% of those who took the placebo died.

One infectious disease expert told the Times that the high mortality rate of those on the placebo could mean the study was too small to offer conclusive results.

“The 45% mortality rate in the control group jumps out at me as rather high,” said David Boulware, MD, of the University of Minnesota.

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

An experimental cancer drug could be promising for some people hospitalized with COVID-19, a new study shows.

The medication, called sabizabulin and given as a pill, reduced by half the risk of death among participants. It could be more effective than other drugs for those severely sick with COVID-19, The New York Times reports.

The manufacturer, Veru, is seeking emergency use authorization from the Food and Drug Administration. Hospitalized COVID-19 patients currently have only a few pharmaceutical options.

Sabizabulin blocks cells from building molecular cables that carry material from one part of a cell to another. It was created to fight cancer, because tumor cells need those cables (called microtubules) to grow quickly.

Researchers tried it against COVID-19 2 years ago, because viral replication also requires microtubules to bring pieces of new viruses together.

To participate in the small trial, patients had to be receiving oxygen or on a ventilator and at a high risk of dying from COVID-19, “with risk factors such as hypertension, advanced age or obesity,” the Times reported.

A total of 134 patients received the medicine; 70 got a placebo. Among those receiving sabizabulin, 20.2% died within 2 months; 45.1% of those who took the placebo died.

One infectious disease expert told the Times that the high mortality rate of those on the placebo could mean the study was too small to offer conclusive results.

“The 45% mortality rate in the control group jumps out at me as rather high,” said David Boulware, MD, of the University of Minnesota.

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

Almost half of adult patients with eosinophilic esophagitis (EoE) reported poor adherence to long-term medical and dietary therapy, with age younger than 40 years and low necessity beliefs being the strongest predictors, a new study finds.

Clinicians need to spend more time discussing the need for EoE therapy with their patients, especially if they are younger, according to lead author Maria L. Haasnoot, MD, of Amsterdam University Medical Center (UMC), the Netherlands, and colleagues.

“Chronic treatment is necessary to maintain suppression of the inflammation and prevent negative outcomes in the long-term,” they write.

Until the recent approval of dupilumab (Dupixent) by the U.S. Food and Drug Administration, patients with EoE relied upon off-label options, including proton pump inhibitors and swallowed topical steroids, as well as dietary interventions for ongoing suppression of inflammation. But only about 1 in 6 patients achieve complete remission at 5 years, according to Dr. Haasnoot and colleagues.

“It is uncertain to what degree limited adherence to treatment [plays] a role in the limited long-term effects of treatment,” they write.

The findings were published online in American Journal of Gastroenterology.
 

Addressing a knowledge gap

The cross-sectional study involved 177 adult patients with EoE treated at Amsterdam UMC, who were prescribed dietary or medical maintenance therapy. Of note, some patients were treated with budesonide, which is approved for EoE in Europe but not in the United States.

Median participant age was 43 years, with a male-skewed distribution (71% men). Patients had been on EoE treatment for 2-6 years. Most (76%) were on medical treatments. Nearly half were on diets that avoided one to five food groups, with some on both medical treatments and elimination diets.

Using a link sent by mail, participants completed the online Medication Adherence Rating Scale, along with several other questionnaires, such as the Beliefs about Medicine Questionnaire, to measure secondary outcomes, including a patient’s view of how necessary or disruptive maintenance therapy is in their life.

The overall prevalence of poor adherence to therapy was high (41.8%), including a nonsignificant difference in adherence between medical and dietary therapies.

“It might come as a surprise that dietary-treated patients are certainly not less adherent to treatment than medically treated patients,” the authors write, noting that the opposite is usually true.

Multivariate logistic regression showed that patients younger than 40 years were more than twice as likely to be poorly adherent (odds ratio, 2.571; 95% confidence interval, 1.195-5.532). Those with low necessity beliefs were more than four times as likely to be poorly adherent (OR, 4.423; 95% CI, 2.169-9.016). Other factors linked to poor adherence were patients with longer disease duration and more severe symptoms.

“Clinicians should pay more attention to treatment adherence, particularly in younger patients,” the authors conclude. “The necessity of treatment should be actively discussed, and efforts should be done to take doubts away, as this may improve treatment adherence and subsequently may improve treatment effects and long-term outcomes.”
 

More patient education needed

According to Jennifer L. Horsley-Silva, MD, of Mayo Clinic, Scottsdale, Ariz., “This study is important, as it is one of the first studies to investigate the rate of treatment adherence in EoE patients and attempts to identify factors associated with adherence both in medically and dietary treated patients.”

Dr. Horsley-Silva commented that the findings align with recent research she and her colleagues conducted at the Mayo Clinic, where few patients successfully completed a six-food elimination diet, even when paired with a dietitian. As with the present study, success trended lower among younger adults. “These findings highlight the need for physicians treating EoE to motivate all patients, but especially younger patients, by discussing disease pathophysiology and explaining the reason for maintenance treatment early on,” Dr. Horsley-Silva said.

Conversations should also address the discordance between symptoms and histologic disease, patient doubts and concerns, and other barriers to adherence, she noted.

“Shared decisionmaking is of utmost importance when deciding upon a maintenance treatment strategy and should be readdressed continually,” she added.

Gary W. Falk, MD, of Penn Medicine, Philadelphia, said that patients with EoE may be poorly adherent because therapies tend to be complicated and people often forget to take their medications, especially when their symptoms improve, even though this is a poor indicator of underlying disease. The discordance between symptoms and histology is “not commonly appreciated by the EoE GI community,” he noted.

Patients may benefit from knowing that untreated or undertreated EoE increases the risk for strictures and stenoses, need for dilation, and frequency of food bolus impactions, Dr. Falk said.

“The other thing we know is that once someone is induced into remission, and they stay on therapy ... long-term remission can be maintained,” he added.
 

The impact of Dupilumab

John Leung, MD, of Boston Food Allergy Center, also cited the complexities of EoE therapies as reason for poor adherence, though he believes this paradigm will shift now that dupilumab has been approved. Dupilumab injections are “just once a week, so it’s much easier in terms of frequency,” Dr. Leung said. “I would expect that the compliance [for dupilumab] will be better” than for older therapies.

Dr. Leung, who helped conduct the dupilumab clinical trials contributing to its approval for EoE and receives speaking honoraria from manufacturer Regeneron/Sanofi, said that dupilumab also overcomes the challenges with elimination diets while offering relief for concomitant conditions, such as “asthma, eczema, food allergies, and seasonal allergies.”

But Dr. Falk, who also worked on the dupilumab clinical trials, said the situation is “not straightforward,” even with FDA approval.

“There are going to be significant costs with [prescribing dupilumab], because it’s a biologic,” Dr. Falk said.

Dr. Falk also pointed out that prior authorization will be required, and until more studies can be conducted, the true impact of once-weekly dosing versus daily dosing remains unknown.

“I would say [dupilumab] has the potential to improve adherence, but we need to see if that’s going to be the case or not,” Dr. Falk said.

The authors disclosed relationships with Dr. Falk Pharma, AstraZeneca, and Sanofi/Regeneron (the manufacturers of Dupixent [dupilumab]), among others. Dr. Horsley-Silva, Dr. Falk, and Dr. Leung conducted clinical trials for dupilumab on behalf of Sanofi/Regeneron, with Dr. Leung also disclosing speaking honoraria from Sanofi/Regeneron. Dr. Horsley-Silva has acted as a clinical trial site principal investigator for Allakos and Celgene/Bristol-Myers Squibb.

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

Almost half of adult patients with eosinophilic esophagitis (EoE) reported poor adherence to long-term medical and dietary therapy, with age younger than 40 years and low necessity beliefs being the strongest predictors, a new study finds.

Clinicians need to spend more time discussing the need for EoE therapy with their patients, especially if they are younger, according to lead author Maria L. Haasnoot, MD, of Amsterdam University Medical Center (UMC), the Netherlands, and colleagues.

“Chronic treatment is necessary to maintain suppression of the inflammation and prevent negative outcomes in the long-term,” they write.

Until the recent approval of dupilumab (Dupixent) by the U.S. Food and Drug Administration, patients with EoE relied upon off-label options, including proton pump inhibitors and swallowed topical steroids, as well as dietary interventions for ongoing suppression of inflammation. But only about 1 in 6 patients achieve complete remission at 5 years, according to Dr. Haasnoot and colleagues.

“It is uncertain to what degree limited adherence to treatment [plays] a role in the limited long-term effects of treatment,” they write.

The findings were published online in American Journal of Gastroenterology.
 

Addressing a knowledge gap

The cross-sectional study involved 177 adult patients with EoE treated at Amsterdam UMC, who were prescribed dietary or medical maintenance therapy. Of note, some patients were treated with budesonide, which is approved for EoE in Europe but not in the United States.

Median participant age was 43 years, with a male-skewed distribution (71% men). Patients had been on EoE treatment for 2-6 years. Most (76%) were on medical treatments. Nearly half were on diets that avoided one to five food groups, with some on both medical treatments and elimination diets.

Using a link sent by mail, participants completed the online Medication Adherence Rating Scale, along with several other questionnaires, such as the Beliefs about Medicine Questionnaire, to measure secondary outcomes, including a patient’s view of how necessary or disruptive maintenance therapy is in their life.

The overall prevalence of poor adherence to therapy was high (41.8%), including a nonsignificant difference in adherence between medical and dietary therapies.

“It might come as a surprise that dietary-treated patients are certainly not less adherent to treatment than medically treated patients,” the authors write, noting that the opposite is usually true.

Multivariate logistic regression showed that patients younger than 40 years were more than twice as likely to be poorly adherent (odds ratio, 2.571; 95% confidence interval, 1.195-5.532). Those with low necessity beliefs were more than four times as likely to be poorly adherent (OR, 4.423; 95% CI, 2.169-9.016). Other factors linked to poor adherence were patients with longer disease duration and more severe symptoms.

“Clinicians should pay more attention to treatment adherence, particularly in younger patients,” the authors conclude. “The necessity of treatment should be actively discussed, and efforts should be done to take doubts away, as this may improve treatment adherence and subsequently may improve treatment effects and long-term outcomes.”
 

More patient education needed

According to Jennifer L. Horsley-Silva, MD, of Mayo Clinic, Scottsdale, Ariz., “This study is important, as it is one of the first studies to investigate the rate of treatment adherence in EoE patients and attempts to identify factors associated with adherence both in medically and dietary treated patients.”

Dr. Horsley-Silva commented that the findings align with recent research she and her colleagues conducted at the Mayo Clinic, where few patients successfully completed a six-food elimination diet, even when paired with a dietitian. As with the present study, success trended lower among younger adults. “These findings highlight the need for physicians treating EoE to motivate all patients, but especially younger patients, by discussing disease pathophysiology and explaining the reason for maintenance treatment early on,” Dr. Horsley-Silva said.

Conversations should also address the discordance between symptoms and histologic disease, patient doubts and concerns, and other barriers to adherence, she noted.

“Shared decisionmaking is of utmost importance when deciding upon a maintenance treatment strategy and should be readdressed continually,” she added.

Gary W. Falk, MD, of Penn Medicine, Philadelphia, said that patients with EoE may be poorly adherent because therapies tend to be complicated and people often forget to take their medications, especially when their symptoms improve, even though this is a poor indicator of underlying disease. The discordance between symptoms and histology is “not commonly appreciated by the EoE GI community,” he noted.

Patients may benefit from knowing that untreated or undertreated EoE increases the risk for strictures and stenoses, need for dilation, and frequency of food bolus impactions, Dr. Falk said.

“The other thing we know is that once someone is induced into remission, and they stay on therapy ... long-term remission can be maintained,” he added.
 

The impact of Dupilumab

John Leung, MD, of Boston Food Allergy Center, also cited the complexities of EoE therapies as reason for poor adherence, though he believes this paradigm will shift now that dupilumab has been approved. Dupilumab injections are “just once a week, so it’s much easier in terms of frequency,” Dr. Leung said. “I would expect that the compliance [for dupilumab] will be better” than for older therapies.

Dr. Leung, who helped conduct the dupilumab clinical trials contributing to its approval for EoE and receives speaking honoraria from manufacturer Regeneron/Sanofi, said that dupilumab also overcomes the challenges with elimination diets while offering relief for concomitant conditions, such as “asthma, eczema, food allergies, and seasonal allergies.”

But Dr. Falk, who also worked on the dupilumab clinical trials, said the situation is “not straightforward,” even with FDA approval.

“There are going to be significant costs with [prescribing dupilumab], because it’s a biologic,” Dr. Falk said.

Dr. Falk also pointed out that prior authorization will be required, and until more studies can be conducted, the true impact of once-weekly dosing versus daily dosing remains unknown.

“I would say [dupilumab] has the potential to improve adherence, but we need to see if that’s going to be the case or not,” Dr. Falk said.

The authors disclosed relationships with Dr. Falk Pharma, AstraZeneca, and Sanofi/Regeneron (the manufacturers of Dupixent [dupilumab]), among others. Dr. Horsley-Silva, Dr. Falk, and Dr. Leung conducted clinical trials for dupilumab on behalf of Sanofi/Regeneron, with Dr. Leung also disclosing speaking honoraria from Sanofi/Regeneron. Dr. Horsley-Silva has acted as a clinical trial site principal investigator for Allakos and Celgene/Bristol-Myers Squibb.

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

Almost half of adult patients with eosinophilic esophagitis (EoE) reported poor adherence to long-term medical and dietary therapy, with age younger than 40 years and low necessity beliefs being the strongest predictors, a new study finds.

Clinicians need to spend more time discussing the need for EoE therapy with their patients, especially if they are younger, according to lead author Maria L. Haasnoot, MD, of Amsterdam University Medical Center (UMC), the Netherlands, and colleagues.

“Chronic treatment is necessary to maintain suppression of the inflammation and prevent negative outcomes in the long-term,” they write.

Until the recent approval of dupilumab (Dupixent) by the U.S. Food and Drug Administration, patients with EoE relied upon off-label options, including proton pump inhibitors and swallowed topical steroids, as well as dietary interventions for ongoing suppression of inflammation. But only about 1 in 6 patients achieve complete remission at 5 years, according to Dr. Haasnoot and colleagues.

“It is uncertain to what degree limited adherence to treatment [plays] a role in the limited long-term effects of treatment,” they write.

The findings were published online in American Journal of Gastroenterology.
 

Addressing a knowledge gap

The cross-sectional study involved 177 adult patients with EoE treated at Amsterdam UMC, who were prescribed dietary or medical maintenance therapy. Of note, some patients were treated with budesonide, which is approved for EoE in Europe but not in the United States.

Median participant age was 43 years, with a male-skewed distribution (71% men). Patients had been on EoE treatment for 2-6 years. Most (76%) were on medical treatments. Nearly half were on diets that avoided one to five food groups, with some on both medical treatments and elimination diets.

Using a link sent by mail, participants completed the online Medication Adherence Rating Scale, along with several other questionnaires, such as the Beliefs about Medicine Questionnaire, to measure secondary outcomes, including a patient’s view of how necessary or disruptive maintenance therapy is in their life.

The overall prevalence of poor adherence to therapy was high (41.8%), including a nonsignificant difference in adherence between medical and dietary therapies.

“It might come as a surprise that dietary-treated patients are certainly not less adherent to treatment than medically treated patients,” the authors write, noting that the opposite is usually true.

Multivariate logistic regression showed that patients younger than 40 years were more than twice as likely to be poorly adherent (odds ratio, 2.571; 95% confidence interval, 1.195-5.532). Those with low necessity beliefs were more than four times as likely to be poorly adherent (OR, 4.423; 95% CI, 2.169-9.016). Other factors linked to poor adherence were patients with longer disease duration and more severe symptoms.

“Clinicians should pay more attention to treatment adherence, particularly in younger patients,” the authors conclude. “The necessity of treatment should be actively discussed, and efforts should be done to take doubts away, as this may improve treatment adherence and subsequently may improve treatment effects and long-term outcomes.”
 

More patient education needed

According to Jennifer L. Horsley-Silva, MD, of Mayo Clinic, Scottsdale, Ariz., “This study is important, as it is one of the first studies to investigate the rate of treatment adherence in EoE patients and attempts to identify factors associated with adherence both in medically and dietary treated patients.”

Dr. Horsley-Silva commented that the findings align with recent research she and her colleagues conducted at the Mayo Clinic, where few patients successfully completed a six-food elimination diet, even when paired with a dietitian. As with the present study, success trended lower among younger adults. “These findings highlight the need for physicians treating EoE to motivate all patients, but especially younger patients, by discussing disease pathophysiology and explaining the reason for maintenance treatment early on,” Dr. Horsley-Silva said.

Conversations should also address the discordance between symptoms and histologic disease, patient doubts and concerns, and other barriers to adherence, she noted.

“Shared decisionmaking is of utmost importance when deciding upon a maintenance treatment strategy and should be readdressed continually,” she added.

Gary W. Falk, MD, of Penn Medicine, Philadelphia, said that patients with EoE may be poorly adherent because therapies tend to be complicated and people often forget to take their medications, especially when their symptoms improve, even though this is a poor indicator of underlying disease. The discordance between symptoms and histology is “not commonly appreciated by the EoE GI community,” he noted.

Patients may benefit from knowing that untreated or undertreated EoE increases the risk for strictures and stenoses, need for dilation, and frequency of food bolus impactions, Dr. Falk said.

“The other thing we know is that once someone is induced into remission, and they stay on therapy ... long-term remission can be maintained,” he added.
 

The impact of Dupilumab

John Leung, MD, of Boston Food Allergy Center, also cited the complexities of EoE therapies as reason for poor adherence, though he believes this paradigm will shift now that dupilumab has been approved. Dupilumab injections are “just once a week, so it’s much easier in terms of frequency,” Dr. Leung said. “I would expect that the compliance [for dupilumab] will be better” than for older therapies.

Dr. Leung, who helped conduct the dupilumab clinical trials contributing to its approval for EoE and receives speaking honoraria from manufacturer Regeneron/Sanofi, said that dupilumab also overcomes the challenges with elimination diets while offering relief for concomitant conditions, such as “asthma, eczema, food allergies, and seasonal allergies.”

But Dr. Falk, who also worked on the dupilumab clinical trials, said the situation is “not straightforward,” even with FDA approval.

“There are going to be significant costs with [prescribing dupilumab], because it’s a biologic,” Dr. Falk said.

Dr. Falk also pointed out that prior authorization will be required, and until more studies can be conducted, the true impact of once-weekly dosing versus daily dosing remains unknown.

“I would say [dupilumab] has the potential to improve adherence, but we need to see if that’s going to be the case or not,” Dr. Falk said.

The authors disclosed relationships with Dr. Falk Pharma, AstraZeneca, and Sanofi/Regeneron (the manufacturers of Dupixent [dupilumab]), among others. Dr. Horsley-Silva, Dr. Falk, and Dr. Leung conducted clinical trials for dupilumab on behalf of Sanofi/Regeneron, with Dr. Leung also disclosing speaking honoraria from Sanofi/Regeneron. Dr. Horsley-Silva has acted as a clinical trial site principal investigator for Allakos and Celgene/Bristol-Myers Squibb.

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

When Amy Moser had a simple urinary tract infection in her late 20s, her doctor prescribed Cipro, a powerful antibiotic used to treat anthrax and some of the most fearsome bacterial infections.

Nearly 2 weeks after she finished her treatment, her left kneecap dislocated while she was trying on a swimsuit at a retail store. Shortly afterward, she had painful ligament ruptures in her wrists, then her shoulder dislocated, followed by three Achilles tendon tears.

“That’s when I fell apart,” says Ms. Moser, a Phoenix health blogger and book author. “From that moment on, for almost the next 2.5 years consistently, I had new tendon tears every few weeks.”

Ms. Moser’s doctors had no answer for what was causing her injuries, all of which required surgical fixes. A married mother of three, she was otherwise healthy and fit. So, after her third Achilles tear, she turned to the FDA’s website for answers. There, she found many warnings about side effects of Cipro, Levaquin, and other so-called fluoroquinolones, including risks for tendon and ligament injuries.

“When all the ruptures started to happen, my doctor kept asking me if I’d ever taken Levaquin, and every time I was like, ‘No.’ So I did what all doctors don’t want you to do: I Googled ‘Levaquin,’ ” she recalls.

Her search led to FDA warnings and articles about the possibility of tendon and ligament ruptures with fluroquinolones.

“That was the first time I’d ever even heard that word ‘fluroquinolones,’ and I found Cipro on that list ... and I realized that I’d just been prescribed that before everything started,” she says.

That was 12 years ago. Since then, the FDA has issued more warnings about fluoroquinolone risks. In that time, Ms. Moser, now 40, has had more than 30 surgeries to correct tendon ruptures and injuries, including a double-knee replacement this year.

“I am in chronic pain all the time,” she says. “I am chronically injured. I have a lot of tears that I’ve not fixed because they’re very complicated, and I don’t know if the rest of my body can handle the strain of recovering from those surgeries.”

Ms. Moser’s is hardly an isolated case. Since the 1980s, more than 60,000 patients have reported hundreds of thousands of serious events linked to fluoroquinolones to the FDA, including 6,575 reports of deaths.

The most common side effects were tendon rupture, as well as neurological and psychiatric symptoms. But experts estimate only 1%-10% of such events are reported to the FDA. That suggests that fluoroquinolones might have harmed hundreds of thousands of people in the United States alone, says Charles Bennett, MD, a hematologist at the University of South Carolina’s College of Pharmacy, Columbia.

Yet despite the many patient reports and FDA warnings on dangerous side effects, many doctors continue to wrongly prescribe fluoroquinolones for simple urinary tract infections, sinus infections, and respiratory issues better treated with less risky antibiotics.

“There probably is overprescription by primary care doctors for urinary tract infections and respiratory infections, when there could be alternatives that are safer to use,” says Amesh Adalja, MD, an infectious disease specialist and senior scholar with the Johns Hopkins Center for Health Security.

“I would say that’s probably the case in the outpatient setting, not necessarily in the hospital setting or among infectious disease doctors ... but I think it’s important to say there are still some judicious uses of fluoroquinolones,” he says. “However, there probably is a lot of injudicious use of fluoroquinolones along with many other antibiotics in the primary care setting.”
 

FDA warnings on fluoroquinolones

Fluoroquinolones are a class of broad-spectrum antibiotics used for decades to treat certain bacterial infections.

FDA-approved fluoroquinolones include ciprofloxacin (Cipro), ciprofloxacin extended-release tablets, delafloxacin (Baxdela), gemifloxacin (Factive) levofloxacin (Levaquin), moxifloxacin (Avelox), and ofloxacin (Floxin). More than 60 generic versions of these brand-name medicines are also on the market, making them among the most prescribed antibiotics in the U.S.

Over the past 2 decades, a wide range of physical and mental health side effects have been tied to fluoroquinolones. As a result of these “adverse event reports” and research published in medical literature, the FDA has required an escalating series of warnings and safety labeling changes for doctors who prescribe these drugs.

• In 2008, the FDA first added a “black box” warning to fluoroquinolones, citing an increased risk of tendinitis and tendon rupture in patients prescribed these meds.
• In 2011, the agency required the warning label to include risks of worsening symptoms for those with myasthenia gravis, a chronic autoimmune disease that causes muscle weakness, vision problems, and speech problems.
• In 2013, regulators required updated labels noting the potential for irreversible peripheral neuropathy (serious nerve damage).
• In 2016, the FDA issued its strongest warning against the use of such antibiotics for simple bacterial infections – such as uncomplicated urinary tract infections (UTIs), acute sinusitis, and acute bronchitis – saying the “association of fluoroquinolones with disabling and potentially permanent side effects involving tendons, muscles, joints, nerves and the central nervous system ... outweighs the benefits for patients.”
• And in 2018, regulators required safety labeling changes to include warnings about the risks of aortic aneurysm – a life-threatening enlargement of the main vessel that delivers blood to the body – as well as mental health side effects and serious blood sugar disturbances.

But FDA regulators have stopped short of barring fluoroquinolone use in the treatment of bacterial infections, citing the benefits for certain conditions.

“For some patients, the benefits of fluoroquinolones may continue to outweigh the risks for treatment of serious bacterial infections, such as pneumonia or intra-abdominal infections,” said former FDA Commissioner Scott Gottlieb, MD, “but there are other serious, known risks associated with these strong antibiotics that must be carefully weighed when considering their use.”

In December 2021, a study published in the journal JAMA Network Open found the FDA’s warnings may have helped lower prescribing of the drugs in Medicare patients. But not all doctors have been responsive to those warnings, researchers found.

“An overall decline in change over time and an immediate change in fluoroquinolone prescribing was observed after the 2016 FDA warning,” the authors concluded. “Certain physicians, such as primary care physicians, were more responsive to FDA warnings than others. ... Findings of this study suggest that identifying the association of physician and organizational characteristics with fluoroquinolone prescribing practices could help in developing mechanisms for improving de-adoption.”

Some critics say the FDA should do more to spotlight the dangers of fluoroquinolones and require doctors and patients to sign checklist consent forms to show they are aware of the potential side effects of these drugs.

Rachel Brummert, a patient advocate who sits on an FDA consumer advisory board, believes the FDA needs to improve its communication to doctors on fluoroquinolone risks and get tougher with those who continue to inappropriately prescribe the drugs.

“I think there needs to be a system in place, where if something comes down from the FDA about a drug, the physician has to sign off on it, the patient has to sign off on it and mark that they understand that there are these ‘black box’ warnings,” says Ms. Brummert, 52, a representative on the FDA’s Medical Devices Advisory Committee.

As an example, she points to Australia’s medical laws requiring doctors and patients to sign a checklist before any fluoroquinolone prescription is approved.

“When a physician prescribes a fluoroquinolone antibiotic, there’s a checklist – does the patient have an infection, is it a simple infection, do they have allergies?” she notes. “And you can’t even get the prescription out – it won’t even print out, it won’t go into the system – unless you check all of the boxes. But we don’t do that here. We don’t have that type of system right now.”

Ms. Brummert says such a system might have prevented the harm from taking Levaquin her doctor prescribed for a suspected sinus infection in 2006.

Soon after she began taking the antibiotic, she ruptured her Achilles tendon, requiring surgery. By 2009, she’d had three ruptures, each needing surgical fixes. To date, she’s had more than 30 surgeries to correct tendon ruptures. She’s also had seizures, blood pressure issues, depression, chronic pain, and memory problems she attributes to taking Levaquin.

As it turns out, her doctor misdiagnosed her condition – a misstep that would have been averted with a system like Australia’s, which requires doctors to verify the presence of a bacterial infection through a simple test before prescribing a fluoroquinolone.

“When I got the Levaquin, it was for a suspected sinus infection that it turned out I didn’t even have in the first place,” she notes. “So, I took the Levaquin basically for nothing. But what I would have asked my doctor had I known is: ‘Why should I take something so strong for so simple an infection?’

“It seems common sense to me now that you don’t prescribe something that can kill anthrax for a simple sinus infection. It’s like an atom bomb killing a mosquito. I agree that there are uses for these drugs, but they are being overprescribed. And so, here I am 16 years later – I’m still rupturing, I’m still having surgery, and I’m still in pain – all for something I didn’t even need medicine for in the first place.”
 

Should guidelines be stronger?

So, why are so many doctors continuing to prescribe fluoroquinolones for simple infections? Dr. Adalja and other experts say several things are at work.

For one thing, Dr. Adalja notes, fluoroquinolones are broad-spectrum antibiotics that are effective against dangerous germs, including “gram-negative” bacterial infections, and are “100% bioavailable.” That means they are as effective when given in pill form as they are if put directly into a vein. So they can be used in an outpatient setting or to allow a patient to be discharged from a hospital sooner because they don’t need an IV to receive treatment.

“There are still some uses for these drugs because they are so bioavailable, and I think that drives some of the use, and those are legitimate uses, knowing that there are risks when you do it,” he says. “But no drug is without risks, and you have to weigh risks and benefits – that’s what medicine is about: deciding what the best drug is for a patient.”

But Dr. Adalja says the overprescription of fluoroquinolones is part of the larger trend of antibiotic overuse. That is driving up antibiotic resistance, which in turn is another thing leading doctors to turn to Cipro and other fluoroquinolones after other drugs have proven ineffective.

“You can’t separate this from the fact that 80% of antibiotic prescriptions in the outpatient setting are probably illegitimate or not warranted,” he notes. “And because fluoroquinolones are highly effective drugs against certain pathogens, they are the go-to [drug] for many people who are prescribing antibiotics.”

That’s why patients should be wary whenever a doctor prescribes a fluoroquinolone, or any drug to treat a suspected infection, he says.

“Any time a patient is getting prescribed an antibiotic by a physician, they should ask: ‘Do I really need this antibiotic?’ That should be the first question they ask,” he advises. “And if they’re getting a fluoroquinolone, they may want to ask: ‘Is this the best antibiotic for me?’ ”
 

What you can do

Ms. Brummert and Ms. Moser say they are sharing their stories to raise awareness of the dangers of fluoroquinolones.

Ms. Moser has published a book on her experiences, “The Magnificent Story of a Lame Author,” and provides a wealth of consumer resources on her blog: Mountains and Mustard Seeds.

“As much as I hate what has happened to me, it has put me in a place where I am glad that I can inform other patients,” she says.

Ms. Brummert supplements her advocacy work as an FDA adviser with useful materials she provides on her website: Drugwatch.com.

“Pain into purpose – that’s what I call it,” she says. “I can’t change what happened to me, but I can warn others.”

The upshot for patients?

• the FDA’s Drug Safety Communication on Fluoroquinolones online to learn more about the risks and benefits of these powerful antibiotics.
• If you believe you’ve been harmed by fluoroquinolones, MedWatch website to report your experiences.

Ms. Brummert also advises patients to ask 12 critical questions of any doctor who wants to prescribe a fluoroquinolone, including the following listed on her website:

• For what condition is this medication prescribed, and is there another drug specific to my condition?
• What are the risks associated with this medication, and do the benefits outweigh them?
• Will this medication interact with my other drugs and/or other health conditions?
• What are the “boxed” warnings for this medication, and where can I report adverse events?

“I would also do my own research,” she says. “I wouldn’t just take a prescription from a physician and just say, ‘OK, doctor knows best.’ ”

Ms. Moser agrees that you have to be your own patient advocate and not simply take a doctor’s advice on any medical issue without having a deeper conversation.

“I’ve had arguments with doctors who legitimately did not believe me when I told them what happened to me,” she says. “And I actually told them, ‘Go get your Physicians’ Desk Reference [for prescription drugs]’ and they opened the book in front of me and read the warnings. Obviously, they had not been keeping up with the added warnings. So, I do think that doctors do need to be better informed.”

“So, yes, it’s the FDA’s responsibility, but it is also the doctors’ responsibility to make sure that they’re watching out for the side effects and they’re reporting them when their patients come up with them and making those connections.”

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

When Amy Moser had a simple urinary tract infection in her late 20s, her doctor prescribed Cipro, a powerful antibiotic used to treat anthrax and some of the most fearsome bacterial infections.

Nearly 2 weeks after she finished her treatment, her left kneecap dislocated while she was trying on a swimsuit at a retail store. Shortly afterward, she had painful ligament ruptures in her wrists, then her shoulder dislocated, followed by three Achilles tendon tears.

“That’s when I fell apart,” says Ms. Moser, a Phoenix health blogger and book author. “From that moment on, for almost the next 2.5 years consistently, I had new tendon tears every few weeks.”

Ms. Moser’s doctors had no answer for what was causing her injuries, all of which required surgical fixes. A married mother of three, she was otherwise healthy and fit. So, after her third Achilles tear, she turned to the FDA’s website for answers. There, she found many warnings about side effects of Cipro, Levaquin, and other so-called fluoroquinolones, including risks for tendon and ligament injuries.

“When all the ruptures started to happen, my doctor kept asking me if I’d ever taken Levaquin, and every time I was like, ‘No.’ So I did what all doctors don’t want you to do: I Googled ‘Levaquin,’ ” she recalls.

Her search led to FDA warnings and articles about the possibility of tendon and ligament ruptures with fluroquinolones.

“That was the first time I’d ever even heard that word ‘fluroquinolones,’ and I found Cipro on that list ... and I realized that I’d just been prescribed that before everything started,” she says.

That was 12 years ago. Since then, the FDA has issued more warnings about fluoroquinolone risks. In that time, Ms. Moser, now 40, has had more than 30 surgeries to correct tendon ruptures and injuries, including a double-knee replacement this year.

“I am in chronic pain all the time,” she says. “I am chronically injured. I have a lot of tears that I’ve not fixed because they’re very complicated, and I don’t know if the rest of my body can handle the strain of recovering from those surgeries.”

Ms. Moser’s is hardly an isolated case. Since the 1980s, more than 60,000 patients have reported hundreds of thousands of serious events linked to fluoroquinolones to the FDA, including 6,575 reports of deaths.

The most common side effects were tendon rupture, as well as neurological and psychiatric symptoms. But experts estimate only 1%-10% of such events are reported to the FDA. That suggests that fluoroquinolones might have harmed hundreds of thousands of people in the United States alone, says Charles Bennett, MD, a hematologist at the University of South Carolina’s College of Pharmacy, Columbia.

Yet despite the many patient reports and FDA warnings on dangerous side effects, many doctors continue to wrongly prescribe fluoroquinolones for simple urinary tract infections, sinus infections, and respiratory issues better treated with less risky antibiotics.

“There probably is overprescription by primary care doctors for urinary tract infections and respiratory infections, when there could be alternatives that are safer to use,” says Amesh Adalja, MD, an infectious disease specialist and senior scholar with the Johns Hopkins Center for Health Security.

“I would say that’s probably the case in the outpatient setting, not necessarily in the hospital setting or among infectious disease doctors ... but I think it’s important to say there are still some judicious uses of fluoroquinolones,” he says. “However, there probably is a lot of injudicious use of fluoroquinolones along with many other antibiotics in the primary care setting.”
 

FDA warnings on fluoroquinolones

Fluoroquinolones are a class of broad-spectrum antibiotics used for decades to treat certain bacterial infections.

FDA-approved fluoroquinolones include ciprofloxacin (Cipro), ciprofloxacin extended-release tablets, delafloxacin (Baxdela), gemifloxacin (Factive) levofloxacin (Levaquin), moxifloxacin (Avelox), and ofloxacin (Floxin). More than 60 generic versions of these brand-name medicines are also on the market, making them among the most prescribed antibiotics in the U.S.

Over the past 2 decades, a wide range of physical and mental health side effects have been tied to fluoroquinolones. As a result of these “adverse event reports” and research published in medical literature, the FDA has required an escalating series of warnings and safety labeling changes for doctors who prescribe these drugs.

• In 2008, the FDA first added a “black box” warning to fluoroquinolones, citing an increased risk of tendinitis and tendon rupture in patients prescribed these meds.
• In 2011, the agency required the warning label to include risks of worsening symptoms for those with myasthenia gravis, a chronic autoimmune disease that causes muscle weakness, vision problems, and speech problems.
• In 2013, regulators required updated labels noting the potential for irreversible peripheral neuropathy (serious nerve damage).
• In 2016, the FDA issued its strongest warning against the use of such antibiotics for simple bacterial infections – such as uncomplicated urinary tract infections (UTIs), acute sinusitis, and acute bronchitis – saying the “association of fluoroquinolones with disabling and potentially permanent side effects involving tendons, muscles, joints, nerves and the central nervous system ... outweighs the benefits for patients.”
• And in 2018, regulators required safety labeling changes to include warnings about the risks of aortic aneurysm – a life-threatening enlargement of the main vessel that delivers blood to the body – as well as mental health side effects and serious blood sugar disturbances.

But FDA regulators have stopped short of barring fluoroquinolone use in the treatment of bacterial infections, citing the benefits for certain conditions.

“For some patients, the benefits of fluoroquinolones may continue to outweigh the risks for treatment of serious bacterial infections, such as pneumonia or intra-abdominal infections,” said former FDA Commissioner Scott Gottlieb, MD, “but there are other serious, known risks associated with these strong antibiotics that must be carefully weighed when considering their use.”

In December 2021, a study published in the journal JAMA Network Open found the FDA’s warnings may have helped lower prescribing of the drugs in Medicare patients. But not all doctors have been responsive to those warnings, researchers found.

“An overall decline in change over time and an immediate change in fluoroquinolone prescribing was observed after the 2016 FDA warning,” the authors concluded. “Certain physicians, such as primary care physicians, were more responsive to FDA warnings than others. ... Findings of this study suggest that identifying the association of physician and organizational characteristics with fluoroquinolone prescribing practices could help in developing mechanisms for improving de-adoption.”

Some critics say the FDA should do more to spotlight the dangers of fluoroquinolones and require doctors and patients to sign checklist consent forms to show they are aware of the potential side effects of these drugs.

Rachel Brummert, a patient advocate who sits on an FDA consumer advisory board, believes the FDA needs to improve its communication to doctors on fluoroquinolone risks and get tougher with those who continue to inappropriately prescribe the drugs.

“I think there needs to be a system in place, where if something comes down from the FDA about a drug, the physician has to sign off on it, the patient has to sign off on it and mark that they understand that there are these ‘black box’ warnings,” says Ms. Brummert, 52, a representative on the FDA’s Medical Devices Advisory Committee.

As an example, she points to Australia’s medical laws requiring doctors and patients to sign a checklist before any fluoroquinolone prescription is approved.

“When a physician prescribes a fluoroquinolone antibiotic, there’s a checklist – does the patient have an infection, is it a simple infection, do they have allergies?” she notes. “And you can’t even get the prescription out – it won’t even print out, it won’t go into the system – unless you check all of the boxes. But we don’t do that here. We don’t have that type of system right now.”

Ms. Brummert says such a system might have prevented the harm from taking Levaquin her doctor prescribed for a suspected sinus infection in 2006.

Soon after she began taking the antibiotic, she ruptured her Achilles tendon, requiring surgery. By 2009, she’d had three ruptures, each needing surgical fixes. To date, she’s had more than 30 surgeries to correct tendon ruptures. She’s also had seizures, blood pressure issues, depression, chronic pain, and memory problems she attributes to taking Levaquin.

As it turns out, her doctor misdiagnosed her condition – a misstep that would have been averted with a system like Australia’s, which requires doctors to verify the presence of a bacterial infection through a simple test before prescribing a fluoroquinolone.

“When I got the Levaquin, it was for a suspected sinus infection that it turned out I didn’t even have in the first place,” she notes. “So, I took the Levaquin basically for nothing. But what I would have asked my doctor had I known is: ‘Why should I take something so strong for so simple an infection?’

“It seems common sense to me now that you don’t prescribe something that can kill anthrax for a simple sinus infection. It’s like an atom bomb killing a mosquito. I agree that there are uses for these drugs, but they are being overprescribed. And so, here I am 16 years later – I’m still rupturing, I’m still having surgery, and I’m still in pain – all for something I didn’t even need medicine for in the first place.”
 

Should guidelines be stronger?

So, why are so many doctors continuing to prescribe fluoroquinolones for simple infections? Dr. Adalja and other experts say several things are at work.

For one thing, Dr. Adalja notes, fluoroquinolones are broad-spectrum antibiotics that are effective against dangerous germs, including “gram-negative” bacterial infections, and are “100% bioavailable.” That means they are as effective when given in pill form as they are if put directly into a vein. So they can be used in an outpatient setting or to allow a patient to be discharged from a hospital sooner because they don’t need an IV to receive treatment.

“There are still some uses for these drugs because they are so bioavailable, and I think that drives some of the use, and those are legitimate uses, knowing that there are risks when you do it,” he says. “But no drug is without risks, and you have to weigh risks and benefits – that’s what medicine is about: deciding what the best drug is for a patient.”

But Dr. Adalja says the overprescription of fluoroquinolones is part of the larger trend of antibiotic overuse. That is driving up antibiotic resistance, which in turn is another thing leading doctors to turn to Cipro and other fluoroquinolones after other drugs have proven ineffective.

“You can’t separate this from the fact that 80% of antibiotic prescriptions in the outpatient setting are probably illegitimate or not warranted,” he notes. “And because fluoroquinolones are highly effective drugs against certain pathogens, they are the go-to [drug] for many people who are prescribing antibiotics.”

That’s why patients should be wary whenever a doctor prescribes a fluoroquinolone, or any drug to treat a suspected infection, he says.

“Any time a patient is getting prescribed an antibiotic by a physician, they should ask: ‘Do I really need this antibiotic?’ That should be the first question they ask,” he advises. “And if they’re getting a fluoroquinolone, they may want to ask: ‘Is this the best antibiotic for me?’ ”
 

What you can do

Ms. Brummert and Ms. Moser say they are sharing their stories to raise awareness of the dangers of fluoroquinolones.

Ms. Moser has published a book on her experiences, “The Magnificent Story of a Lame Author,” and provides a wealth of consumer resources on her blog: Mountains and Mustard Seeds.

“As much as I hate what has happened to me, it has put me in a place where I am glad that I can inform other patients,” she says.

Ms. Brummert supplements her advocacy work as an FDA adviser with useful materials she provides on her website: Drugwatch.com.

“Pain into purpose – that’s what I call it,” she says. “I can’t change what happened to me, but I can warn others.”

The upshot for patients?

• the FDA’s Drug Safety Communication on Fluoroquinolones online to learn more about the risks and benefits of these powerful antibiotics.
• If you believe you’ve been harmed by fluoroquinolones, MedWatch website to report your experiences.

Ms. Brummert also advises patients to ask 12 critical questions of any doctor who wants to prescribe a fluoroquinolone, including the following listed on her website:

• For what condition is this medication prescribed, and is there another drug specific to my condition?
• What are the risks associated with this medication, and do the benefits outweigh them?
• Will this medication interact with my other drugs and/or other health conditions?
• What are the “boxed” warnings for this medication, and where can I report adverse events?

“I would also do my own research,” she says. “I wouldn’t just take a prescription from a physician and just say, ‘OK, doctor knows best.’ ”

Ms. Moser agrees that you have to be your own patient advocate and not simply take a doctor’s advice on any medical issue without having a deeper conversation.

“I’ve had arguments with doctors who legitimately did not believe me when I told them what happened to me,” she says. “And I actually told them, ‘Go get your Physicians’ Desk Reference [for prescription drugs]’ and they opened the book in front of me and read the warnings. Obviously, they had not been keeping up with the added warnings. So, I do think that doctors do need to be better informed.”

“So, yes, it’s the FDA’s responsibility, but it is also the doctors’ responsibility to make sure that they’re watching out for the side effects and they’re reporting them when their patients come up with them and making those connections.”

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

When Amy Moser had a simple urinary tract infection in her late 20s, her doctor prescribed Cipro, a powerful antibiotic used to treat anthrax and some of the most fearsome bacterial infections.

Nearly 2 weeks after she finished her treatment, her left kneecap dislocated while she was trying on a swimsuit at a retail store. Shortly afterward, she had painful ligament ruptures in her wrists, then her shoulder dislocated, followed by three Achilles tendon tears.

“That’s when I fell apart,” says Ms. Moser, a Phoenix health blogger and book author. “From that moment on, for almost the next 2.5 years consistently, I had new tendon tears every few weeks.”

Ms. Moser’s doctors had no answer for what was causing her injuries, all of which required surgical fixes. A married mother of three, she was otherwise healthy and fit. So, after her third Achilles tear, she turned to the FDA’s website for answers. There, she found many warnings about side effects of Cipro, Levaquin, and other so-called fluoroquinolones, including risks for tendon and ligament injuries.

“When all the ruptures started to happen, my doctor kept asking me if I’d ever taken Levaquin, and every time I was like, ‘No.’ So I did what all doctors don’t want you to do: I Googled ‘Levaquin,’ ” she recalls.

Her search led to FDA warnings and articles about the possibility of tendon and ligament ruptures with fluroquinolones.

“That was the first time I’d ever even heard that word ‘fluroquinolones,’ and I found Cipro on that list ... and I realized that I’d just been prescribed that before everything started,” she says.

That was 12 years ago. Since then, the FDA has issued more warnings about fluoroquinolone risks. In that time, Ms. Moser, now 40, has had more than 30 surgeries to correct tendon ruptures and injuries, including a double-knee replacement this year.

“I am in chronic pain all the time,” she says. “I am chronically injured. I have a lot of tears that I’ve not fixed because they’re very complicated, and I don’t know if the rest of my body can handle the strain of recovering from those surgeries.”

Ms. Moser’s is hardly an isolated case. Since the 1980s, more than 60,000 patients have reported hundreds of thousands of serious events linked to fluoroquinolones to the FDA, including 6,575 reports of deaths.

The most common side effects were tendon rupture, as well as neurological and psychiatric symptoms. But experts estimate only 1%-10% of such events are reported to the FDA. That suggests that fluoroquinolones might have harmed hundreds of thousands of people in the United States alone, says Charles Bennett, MD, a hematologist at the University of South Carolina’s College of Pharmacy, Columbia.

Yet despite the many patient reports and FDA warnings on dangerous side effects, many doctors continue to wrongly prescribe fluoroquinolones for simple urinary tract infections, sinus infections, and respiratory issues better treated with less risky antibiotics.

“There probably is overprescription by primary care doctors for urinary tract infections and respiratory infections, when there could be alternatives that are safer to use,” says Amesh Adalja, MD, an infectious disease specialist and senior scholar with the Johns Hopkins Center for Health Security.

“I would say that’s probably the case in the outpatient setting, not necessarily in the hospital setting or among infectious disease doctors ... but I think it’s important to say there are still some judicious uses of fluoroquinolones,” he says. “However, there probably is a lot of injudicious use of fluoroquinolones along with many other antibiotics in the primary care setting.”
 

FDA warnings on fluoroquinolones

Fluoroquinolones are a class of broad-spectrum antibiotics used for decades to treat certain bacterial infections.

FDA-approved fluoroquinolones include ciprofloxacin (Cipro), ciprofloxacin extended-release tablets, delafloxacin (Baxdela), gemifloxacin (Factive) levofloxacin (Levaquin), moxifloxacin (Avelox), and ofloxacin (Floxin). More than 60 generic versions of these brand-name medicines are also on the market, making them among the most prescribed antibiotics in the U.S.

Over the past 2 decades, a wide range of physical and mental health side effects have been tied to fluoroquinolones. As a result of these “adverse event reports” and research published in medical literature, the FDA has required an escalating series of warnings and safety labeling changes for doctors who prescribe these drugs.

• In 2008, the FDA first added a “black box” warning to fluoroquinolones, citing an increased risk of tendinitis and tendon rupture in patients prescribed these meds.
• In 2011, the agency required the warning label to include risks of worsening symptoms for those with myasthenia gravis, a chronic autoimmune disease that causes muscle weakness, vision problems, and speech problems.
• In 2013, regulators required updated labels noting the potential for irreversible peripheral neuropathy (serious nerve damage).
• In 2016, the FDA issued its strongest warning against the use of such antibiotics for simple bacterial infections – such as uncomplicated urinary tract infections (UTIs), acute sinusitis, and acute bronchitis – saying the “association of fluoroquinolones with disabling and potentially permanent side effects involving tendons, muscles, joints, nerves and the central nervous system ... outweighs the benefits for patients.”
• And in 2018, regulators required safety labeling changes to include warnings about the risks of aortic aneurysm – a life-threatening enlargement of the main vessel that delivers blood to the body – as well as mental health side effects and serious blood sugar disturbances.

But FDA regulators have stopped short of barring fluoroquinolone use in the treatment of bacterial infections, citing the benefits for certain conditions.

“For some patients, the benefits of fluoroquinolones may continue to outweigh the risks for treatment of serious bacterial infections, such as pneumonia or intra-abdominal infections,” said former FDA Commissioner Scott Gottlieb, MD, “but there are other serious, known risks associated with these strong antibiotics that must be carefully weighed when considering their use.”

In December 2021, a study published in the journal JAMA Network Open found the FDA’s warnings may have helped lower prescribing of the drugs in Medicare patients. But not all doctors have been responsive to those warnings, researchers found.

“An overall decline in change over time and an immediate change in fluoroquinolone prescribing was observed after the 2016 FDA warning,” the authors concluded. “Certain physicians, such as primary care physicians, were more responsive to FDA warnings than others. ... Findings of this study suggest that identifying the association of physician and organizational characteristics with fluoroquinolone prescribing practices could help in developing mechanisms for improving de-adoption.”

Some critics say the FDA should do more to spotlight the dangers of fluoroquinolones and require doctors and patients to sign checklist consent forms to show they are aware of the potential side effects of these drugs.

Rachel Brummert, a patient advocate who sits on an FDA consumer advisory board, believes the FDA needs to improve its communication to doctors on fluoroquinolone risks and get tougher with those who continue to inappropriately prescribe the drugs.

“I think there needs to be a system in place, where if something comes down from the FDA about a drug, the physician has to sign off on it, the patient has to sign off on it and mark that they understand that there are these ‘black box’ warnings,” says Ms. Brummert, 52, a representative on the FDA’s Medical Devices Advisory Committee.

As an example, she points to Australia’s medical laws requiring doctors and patients to sign a checklist before any fluoroquinolone prescription is approved.

“When a physician prescribes a fluoroquinolone antibiotic, there’s a checklist – does the patient have an infection, is it a simple infection, do they have allergies?” she notes. “And you can’t even get the prescription out – it won’t even print out, it won’t go into the system – unless you check all of the boxes. But we don’t do that here. We don’t have that type of system right now.”

Ms. Brummert says such a system might have prevented the harm from taking Levaquin her doctor prescribed for a suspected sinus infection in 2006.

Soon after she began taking the antibiotic, she ruptured her Achilles tendon, requiring surgery. By 2009, she’d had three ruptures, each needing surgical fixes. To date, she’s had more than 30 surgeries to correct tendon ruptures. She’s also had seizures, blood pressure issues, depression, chronic pain, and memory problems she attributes to taking Levaquin.

As it turns out, her doctor misdiagnosed her condition – a misstep that would have been averted with a system like Australia’s, which requires doctors to verify the presence of a bacterial infection through a simple test before prescribing a fluoroquinolone.

“When I got the Levaquin, it was for a suspected sinus infection that it turned out I didn’t even have in the first place,” she notes. “So, I took the Levaquin basically for nothing. But what I would have asked my doctor had I known is: ‘Why should I take something so strong for so simple an infection?’

“It seems common sense to me now that you don’t prescribe something that can kill anthrax for a simple sinus infection. It’s like an atom bomb killing a mosquito. I agree that there are uses for these drugs, but they are being overprescribed. And so, here I am 16 years later – I’m still rupturing, I’m still having surgery, and I’m still in pain – all for something I didn’t even need medicine for in the first place.”
 

Should guidelines be stronger?

So, why are so many doctors continuing to prescribe fluoroquinolones for simple infections? Dr. Adalja and other experts say several things are at work.

For one thing, Dr. Adalja notes, fluoroquinolones are broad-spectrum antibiotics that are effective against dangerous germs, including “gram-negative” bacterial infections, and are “100% bioavailable.” That means they are as effective when given in pill form as they are if put directly into a vein. So they can be used in an outpatient setting or to allow a patient to be discharged from a hospital sooner because they don’t need an IV to receive treatment.

“There are still some uses for these drugs because they are so bioavailable, and I think that drives some of the use, and those are legitimate uses, knowing that there are risks when you do it,” he says. “But no drug is without risks, and you have to weigh risks and benefits – that’s what medicine is about: deciding what the best drug is for a patient.”

But Dr. Adalja says the overprescription of fluoroquinolones is part of the larger trend of antibiotic overuse. That is driving up antibiotic resistance, which in turn is another thing leading doctors to turn to Cipro and other fluoroquinolones after other drugs have proven ineffective.

“You can’t separate this from the fact that 80% of antibiotic prescriptions in the outpatient setting are probably illegitimate or not warranted,” he notes. “And because fluoroquinolones are highly effective drugs against certain pathogens, they are the go-to [drug] for many people who are prescribing antibiotics.”

That’s why patients should be wary whenever a doctor prescribes a fluoroquinolone, or any drug to treat a suspected infection, he says.

“Any time a patient is getting prescribed an antibiotic by a physician, they should ask: ‘Do I really need this antibiotic?’ That should be the first question they ask,” he advises. “And if they’re getting a fluoroquinolone, they may want to ask: ‘Is this the best antibiotic for me?’ ”
 

What you can do

Ms. Brummert and Ms. Moser say they are sharing their stories to raise awareness of the dangers of fluoroquinolones.

Ms. Moser has published a book on her experiences, “The Magnificent Story of a Lame Author,” and provides a wealth of consumer resources on her blog: Mountains and Mustard Seeds.

“As much as I hate what has happened to me, it has put me in a place where I am glad that I can inform other patients,” she says.

Ms. Brummert supplements her advocacy work as an FDA adviser with useful materials she provides on her website: Drugwatch.com.

“Pain into purpose – that’s what I call it,” she says. “I can’t change what happened to me, but I can warn others.”

The upshot for patients?

• the FDA’s Drug Safety Communication on Fluoroquinolones online to learn more about the risks and benefits of these powerful antibiotics.
• If you believe you’ve been harmed by fluoroquinolones, MedWatch website to report your experiences.

Ms. Brummert also advises patients to ask 12 critical questions of any doctor who wants to prescribe a fluoroquinolone, including the following listed on her website:

• For what condition is this medication prescribed, and is there another drug specific to my condition?
• What are the risks associated with this medication, and do the benefits outweigh them?
• Will this medication interact with my other drugs and/or other health conditions?
• What are the “boxed” warnings for this medication, and where can I report adverse events?

“I would also do my own research,” she says. “I wouldn’t just take a prescription from a physician and just say, ‘OK, doctor knows best.’ ”

Ms. Moser agrees that you have to be your own patient advocate and not simply take a doctor’s advice on any medical issue without having a deeper conversation.

“I’ve had arguments with doctors who legitimately did not believe me when I told them what happened to me,” she says. “And I actually told them, ‘Go get your Physicians’ Desk Reference [for prescription drugs]’ and they opened the book in front of me and read the warnings. Obviously, they had not been keeping up with the added warnings. So, I do think that doctors do need to be better informed.”

“So, yes, it’s the FDA’s responsibility, but it is also the doctors’ responsibility to make sure that they’re watching out for the side effects and they’re reporting them when their patients come up with them and making those connections.”

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