Clinical Edge Journal Scan

Key clinical point: Alcohol intake slightly reduced the likelihood of migraine attacks 48 hours after consumption in an English-speaking cohort of patients with episodic migraine who identified themselves as mostly low-dose alcohol consumers.

Major finding: The probability of migraine attack 48 hours after consuming alcohol was 25% lower than that after no alcohol consumption (adjusted odds ratio 0.75; 95% CI 0.68-0.82); however, alcohol consumption had no significant effect on migraine probability 24 hours after consumption.

Study details: This observational prospective cohort study included 487 patients with episodic migraine who reported 5913 migraine attacks and were alcohol consumers.

Disclosures: The study was partially funded by Curelator, Inc. M Vives-Mestres and A Casanova declared receiving consulting fees and holding stock options in Curelator, Inc. N Rosen reported ties with a headache society, journals, and various other sources.

Source: Vives-Mestres M et al. Alcohol as a trigger of migraine attacks in people with migraine. Results from a large prospective cohort study in English-speaking countries. Headache. 2022;62:1329-1338. (Nov 27). Doi: 10.1111/head.14428

Key clinical point: Alcohol intake slightly reduced the likelihood of migraine attacks 48 hours after consumption in an English-speaking cohort of patients with episodic migraine who identified themselves as mostly low-dose alcohol consumers.

Major finding: The probability of migraine attack 48 hours after consuming alcohol was 25% lower than that after no alcohol consumption (adjusted odds ratio 0.75; 95% CI 0.68-0.82); however, alcohol consumption had no significant effect on migraine probability 24 hours after consumption.

Study details: This observational prospective cohort study included 487 patients with episodic migraine who reported 5913 migraine attacks and were alcohol consumers.

Disclosures: The study was partially funded by Curelator, Inc. M Vives-Mestres and A Casanova declared receiving consulting fees and holding stock options in Curelator, Inc. N Rosen reported ties with a headache society, journals, and various other sources.

Source: Vives-Mestres M et al. Alcohol as a trigger of migraine attacks in people with migraine. Results from a large prospective cohort study in English-speaking countries. Headache. 2022;62:1329-1338. (Nov 27). Doi: 10.1111/head.14428

Key clinical point: Alcohol intake slightly reduced the likelihood of migraine attacks 48 hours after consumption in an English-speaking cohort of patients with episodic migraine who identified themselves as mostly low-dose alcohol consumers.

Major finding: The probability of migraine attack 48 hours after consuming alcohol was 25% lower than that after no alcohol consumption (adjusted odds ratio 0.75; 95% CI 0.68-0.82); however, alcohol consumption had no significant effect on migraine probability 24 hours after consumption.

Study details: This observational prospective cohort study included 487 patients with episodic migraine who reported 5913 migraine attacks and were alcohol consumers.

Disclosures: The study was partially funded by Curelator, Inc. M Vives-Mestres and A Casanova declared receiving consulting fees and holding stock options in Curelator, Inc. N Rosen reported ties with a headache society, journals, and various other sources.

Source: Vives-Mestres M et al. Alcohol as a trigger of migraine attacks in people with migraine. Results from a large prospective cohort study in English-speaking countries. Headache. 2022;62:1329-1338. (Nov 27). Doi: 10.1111/head.14428

Key clinical point: Once-daily atogepant at doses of 30 and 60 mg significantly improved the performance of social, work-related, and daily activities compared with placebo in patients with episodic migraine.

Major finding: At week 12, atogepant (30 and 60 mg) vs placebo significantly improved Migraine-Specific Quality of Life Questionnaire version 2.1 Role Function-Restrictive (least-squares mean difference [LSMD] 10.08 and 10.8, respectively; both P < .0001). Atogepant at doses of 30 and 60 mg significantly improved monthly Activity Impairment in Migraine-Diary Performance of Daily Activities (P = .0003 and P < .0001, respectively) and Physical Impairment (P = .001 and P < .0001, respectively) scores across the 12-week treatment.

Study details: Findings are from the phase 3, ADVANCE trial including 873 patients with episodic migraine who were randomly assigned to receive once-daily atogepant (10, 30, or 60 mg) or placebo.

Disclosures: This study was sponsored by AbbVie/Allergan. Four authors declared being current or former employees of or holding stocks in AbbVie. The lead author and several other authors reported ties with various sources, including AbbVie.

Source: Lipton RB et al. Effect of atogepant for preventive migraine treatment on patient-reported outcomes in the randomized, double-blind, phase 3 ADVANCE trial. Neurology. 2022 (Nov 17). Doi: 10.1212/WNL.0000000000201568

Key clinical point: Once-daily atogepant at doses of 30 and 60 mg significantly improved the performance of social, work-related, and daily activities compared with placebo in patients with episodic migraine.

Major finding: At week 12, atogepant (30 and 60 mg) vs placebo significantly improved Migraine-Specific Quality of Life Questionnaire version 2.1 Role Function-Restrictive (least-squares mean difference [LSMD] 10.08 and 10.8, respectively; both P < .0001). Atogepant at doses of 30 and 60 mg significantly improved monthly Activity Impairment in Migraine-Diary Performance of Daily Activities (P = .0003 and P < .0001, respectively) and Physical Impairment (P = .001 and P < .0001, respectively) scores across the 12-week treatment.

Study details: Findings are from the phase 3, ADVANCE trial including 873 patients with episodic migraine who were randomly assigned to receive once-daily atogepant (10, 30, or 60 mg) or placebo.

Disclosures: This study was sponsored by AbbVie/Allergan. Four authors declared being current or former employees of or holding stocks in AbbVie. The lead author and several other authors reported ties with various sources, including AbbVie.

Source: Lipton RB et al. Effect of atogepant for preventive migraine treatment on patient-reported outcomes in the randomized, double-blind, phase 3 ADVANCE trial. Neurology. 2022 (Nov 17). Doi: 10.1212/WNL.0000000000201568

Key clinical point: Once-daily atogepant at doses of 30 and 60 mg significantly improved the performance of social, work-related, and daily activities compared with placebo in patients with episodic migraine.

Major finding: At week 12, atogepant (30 and 60 mg) vs placebo significantly improved Migraine-Specific Quality of Life Questionnaire version 2.1 Role Function-Restrictive (least-squares mean difference [LSMD] 10.08 and 10.8, respectively; both P < .0001). Atogepant at doses of 30 and 60 mg significantly improved monthly Activity Impairment in Migraine-Diary Performance of Daily Activities (P = .0003 and P < .0001, respectively) and Physical Impairment (P = .001 and P < .0001, respectively) scores across the 12-week treatment.

Study details: Findings are from the phase 3, ADVANCE trial including 873 patients with episodic migraine who were randomly assigned to receive once-daily atogepant (10, 30, or 60 mg) or placebo.

Disclosures: This study was sponsored by AbbVie/Allergan. Four authors declared being current or former employees of or holding stocks in AbbVie. The lead author and several other authors reported ties with various sources, including AbbVie.

Source: Lipton RB et al. Effect of atogepant for preventive migraine treatment on patient-reported outcomes in the randomized, double-blind, phase 3 ADVANCE trial. Neurology. 2022 (Nov 17). Doi: 10.1212/WNL.0000000000201568

We are in the golden age of atopic dermatitis (AD) drug development. We are fortunate to have numerous topicals, oral systemics, and biologics recently approved or in late-stage clinical development. Yet, we are still lacking effective strategies for primary prevention of incident AD and secondary prevention of AD exacerbations.

Kottner and colleagues published the results from the ADAPI study of 150 infants who were at an enhanced risk for AD. The children were randomly assigned to receive either a skincare regimen that was standardized or unstandardized skincare preferred by parents. They found that in the first year of life, the overall cumulative incidence rate of AD was similar between standardized skincare and skincare preferred by parents (P = .999).

Bradshaw and colleagues also published results from the BEEP study (a 5-year prospective study) of 1394 infants who were at high risk for AD. The children were randomly assigned to receive either emollient for the first year plus standard skincare or standard skincare alone. They found a similar proportion of children were clinically diagnosed with AD between 12 and 60 months in the emollient plus skincare group vs skincare alone group (31% vs 28%; adjusted relative risk 1.10; 95% CI 0.93-1.30). Unfortunately, the results from both studies are consistent with earlier results from BEEP, as well as other studies, and did not show that early application of emollients successfully prevent AD.

The use of applying emollients for primary prevention is unclear. However, proactive application of topical corticosteroids (TCS) and other topical nonsteroidal agents is well accepted in AD treatment guidelines for secondary prevention of AD exacerbations.¹  Although, a recent study from Kamiya and colleagues suggested that proactive application of topical corticosteroids may not work as well as we think. They conducted an open-label, active-controlled, parallel-group study of 49 pediatric patients with moderate to severe AD who achieved remission with potent TCS. The children were then randomly assigned to receive proactive therapy with or discontinuation of TCS. The authors found no significant decrease in relapse rates with proactive vs no proactive treatment groups (8.33% vs 20.0%; P = .0859). I don't think these results will change our guidelines. But I do think these results raise important questions about the myriad aspects of proactive therapy that require appropriate counseling, including frequency of application per week (1-3 times), choice of therapies (corticosteroid or nonsteroidal agent), additional emollient use, bathing practice, etc. I personally would strongly recommend use of proactive therapy in clinical practice, but these results highlight that it is not a magic bullet for all patients either.

Additional Reference

1. Boguniewicz M, Fonacier L, Guttman-Yassky E, et al. Atopic dermatitis yardstick: practical recommendations for an evolving therapeutic landscape. Ann Allergy Asthma Immunol. 2018;120:10-22.e2. Doi: 10.1016/j.anai.2017.10.039

We are in the golden age of atopic dermatitis (AD) drug development. We are fortunate to have numerous topicals, oral systemics, and biologics recently approved or in late-stage clinical development. Yet, we are still lacking effective strategies for primary prevention of incident AD and secondary prevention of AD exacerbations.

Kottner and colleagues published the results from the ADAPI study of 150 infants who were at an enhanced risk for AD. The children were randomly assigned to receive either a skincare regimen that was standardized or unstandardized skincare preferred by parents. They found that in the first year of life, the overall cumulative incidence rate of AD was similar between standardized skincare and skincare preferred by parents (P = .999).

Bradshaw and colleagues also published results from the BEEP study (a 5-year prospective study) of 1394 infants who were at high risk for AD. The children were randomly assigned to receive either emollient for the first year plus standard skincare or standard skincare alone. They found a similar proportion of children were clinically diagnosed with AD between 12 and 60 months in the emollient plus skincare group vs skincare alone group (31% vs 28%; adjusted relative risk 1.10; 95% CI 0.93-1.30). Unfortunately, the results from both studies are consistent with earlier results from BEEP, as well as other studies, and did not show that early application of emollients successfully prevent AD.

The use of applying emollients for primary prevention is unclear. However, proactive application of topical corticosteroids (TCS) and other topical nonsteroidal agents is well accepted in AD treatment guidelines for secondary prevention of AD exacerbations.¹  Although, a recent study from Kamiya and colleagues suggested that proactive application of topical corticosteroids may not work as well as we think. They conducted an open-label, active-controlled, parallel-group study of 49 pediatric patients with moderate to severe AD who achieved remission with potent TCS. The children were then randomly assigned to receive proactive therapy with or discontinuation of TCS. The authors found no significant decrease in relapse rates with proactive vs no proactive treatment groups (8.33% vs 20.0%; P = .0859). I don't think these results will change our guidelines. But I do think these results raise important questions about the myriad aspects of proactive therapy that require appropriate counseling, including frequency of application per week (1-3 times), choice of therapies (corticosteroid or nonsteroidal agent), additional emollient use, bathing practice, etc. I personally would strongly recommend use of proactive therapy in clinical practice, but these results highlight that it is not a magic bullet for all patients either.

Additional Reference

1. Boguniewicz M, Fonacier L, Guttman-Yassky E, et al. Atopic dermatitis yardstick: practical recommendations for an evolving therapeutic landscape. Ann Allergy Asthma Immunol. 2018;120:10-22.e2. Doi: 10.1016/j.anai.2017.10.039

We are in the golden age of atopic dermatitis (AD) drug development. We are fortunate to have numerous topicals, oral systemics, and biologics recently approved or in late-stage clinical development. Yet, we are still lacking effective strategies for primary prevention of incident AD and secondary prevention of AD exacerbations.

Kottner and colleagues published the results from the ADAPI study of 150 infants who were at an enhanced risk for AD. The children were randomly assigned to receive either a skincare regimen that was standardized or unstandardized skincare preferred by parents. They found that in the first year of life, the overall cumulative incidence rate of AD was similar between standardized skincare and skincare preferred by parents (P = .999).

Bradshaw and colleagues also published results from the BEEP study (a 5-year prospective study) of 1394 infants who were at high risk for AD. The children were randomly assigned to receive either emollient for the first year plus standard skincare or standard skincare alone. They found a similar proportion of children were clinically diagnosed with AD between 12 and 60 months in the emollient plus skincare group vs skincare alone group (31% vs 28%; adjusted relative risk 1.10; 95% CI 0.93-1.30). Unfortunately, the results from both studies are consistent with earlier results from BEEP, as well as other studies, and did not show that early application of emollients successfully prevent AD.

The use of applying emollients for primary prevention is unclear. However, proactive application of topical corticosteroids (TCS) and other topical nonsteroidal agents is well accepted in AD treatment guidelines for secondary prevention of AD exacerbations.¹  Although, a recent study from Kamiya and colleagues suggested that proactive application of topical corticosteroids may not work as well as we think. They conducted an open-label, active-controlled, parallel-group study of 49 pediatric patients with moderate to severe AD who achieved remission with potent TCS. The children were then randomly assigned to receive proactive therapy with or discontinuation of TCS. The authors found no significant decrease in relapse rates with proactive vs no proactive treatment groups (8.33% vs 20.0%; P = .0859). I don't think these results will change our guidelines. But I do think these results raise important questions about the myriad aspects of proactive therapy that require appropriate counseling, including frequency of application per week (1-3 times), choice of therapies (corticosteroid or nonsteroidal agent), additional emollient use, bathing practice, etc. I personally would strongly recommend use of proactive therapy in clinical practice, but these results highlight that it is not a magic bullet for all patients either.

Additional Reference

1. Boguniewicz M, Fonacier L, Guttman-Yassky E, et al. Atopic dermatitis yardstick: practical recommendations for an evolving therapeutic landscape. Ann Allergy Asthma Immunol. 2018;120:10-22.e2. Doi: 10.1016/j.anai.2017.10.039

This month, we will take a look at three new studies investigating risk factors and treatments for headache in children.

Stress has long been noted to be one of the most consistent triggers for migraine attacks. Much has been written and studied regarding the effect of migraine on mood in adults; however, few studies have done the same in the pediatric and adolescent population. Childhood trauma has been associated with the development of chronic migraine as an adult, and behavioral treatments, such as cognitive-behavioral therapy and biofeedback, are considered as effective or more effective for migraine prevention in children compared with preventive medications. Falla and colleagues have quantified the risk for anxiety and depression in children and adolescents with migraine.

The "internalization of symptoms" is defined by the authors as an individual's tendency to react to stress with physical symptoms, including anxiety and depression. These are thought to be elevated in children and adolescents with many effects, including migraine. However, no correlation has yet been shown. Beyond the internalization of symptoms, specific psychiatric diagnoses may also be more prominent in this population.

This study was a meta-analysis of data pooled from studies that assessed migraine-related symptoms as they relate to disorders on the spectrum of anxiety, depression, and trauma-related disorders. Any studies with participants older than 18 years were excluded from this analysis. A total of 80 studies were included. Anxiety symptoms were seen to be significantly higher in children and adolescents with migraine compared to controls and the odds of having an anxiety disorder were higher among those with migraine compared with controls. Depressive symptoms were also significantly higher; however, this effect size was much smaller. The incidence of migraine was not different than that of other headache disorders.

Many patients describe stress as a trigger for migraine and other headache attacks. Mood disorders and childhood trauma are associated with the development of chronic migraine as an adult. This study reveals a two-way connection between mood disorders and headache diagnoses in children. Screening for the underlying symptoms of depression and anxiety should be done when evaluating children and adolescents for headache disorders, and there should be a focus on the treatment of these conditions in addition to treating the headache symptoms.

There are, unfortunately, very few acute pediatric migraine trials. Only a handful of medications have actually been investigated for the treatment of migraine in children younger than 12 years, and only one migraine-specific medication, rizatriptan, is approved in the United States for pediatric use. Because of this, many argue that children and adolescents with migraines end up overusing over-the-counter medication options, increasing the risk for medication overuse headache. In addition, many patients need nonoral acute migraine treatments due to nausea and vomiting or rapid onset migraine attacks.

Yonker and colleagues conducted a phase 3, randomized, double-blind, multicenter trial that only enrolled patients aged 6-11 years, all of whom had a diagnosis of episodic migraine (< 15 days of migraine per month). Children that weighed < 50 kg were given a randomly assigned lower dose of 1 mg or 2.5 mg zolmitriptan nasal spray, and those who weighed > 50 kg were randomly assigned to either 2.5 mg or 5 mg, which is the standard adult dose.

The primary outcome was a standard 2-hour pain freedom level; secondary outcomes included the proportion of improvement at 0.5, 1, and 24 hours post-dose, as well as sustained headache response for the following 2-24 hours and time to rescue medication use. Although 300 patients were enrolled and taken through the run-in process, 114 were discontinued either due to placebo response or because they had no treated migraine during the run-in phase. The mean age was 9.2 years and half of the patients were girls (of note, this is considered an appropriate proportion for pediatric migraine).

The primary endpoint of 2-hour pain freedom was not met; however, more patients in the high-dose treatment group were pain-free after 2 hours than in the placebo group. Several secondary endpoints did achieve statistical significance, including pain-free status at 1 hour post-dose, as well as headache response at 0.5, 1, and 2 hours — all of which were lower in the high-dose treatment group. The lower-dose treatment group was statistically similar to placebo for all the timepoints noted above. Treatment-related adverse events were rare in all groups.

This study did not meet its primary efficacy endpoint. However, it does show safety and effectiveness, enough at least to broaden the use of zolmitriptan for pediatric migraine. Many more effective medications for migraine treatment in adults should follow the lead of this group to find better and more specific treatments for children with migraine.

As we noted above, childhood trauma is associated with the development of chronic migraine in adulthood. Prior studies have defined childhood trauma as physical or emotional abuse primarily, and the correlation between childhood illnesses and headache disorder has not previously been determined. Davidsson and colleagues published a study in the Journal of Cancer Epidemiology that reviewed nationwide database registers longitudinally to better understand this potential risk factor.

The Danish Cancer Register was reviewed for the purpose of identifying anyone in the general Danish population who developed a diagnosis of cancer before age 20 years. The individual identification numbers in that register were linked to data in other nationwide registers for the purpose of determining whether those individuals initiated migraine-specific medications or were admitted for an inpatient hospitalization for migraine. Study participants were also grouped based on cancer type, specifically hematologic cancers involving chemotherapy and central nervous system-directed therapies, brain tumors needing intracranial surgery or radiation to the brain, blastomas or other solid tumors outside of the central nervous system, sarcomas treated with an alkylating chemotherapy, and all other carcinomas.

Among all individuals diagnosed with a childhood cancer, there was a significant increase in overall risk for the need to initiate antimigraine medication. Of interest, this was higher in those diagnosed in their teenage years. Migraine hospitalization was also noted to be higher in nearly all strata, with the exception of those diagnosed with cancer prior to the age of 5 years. The highest risk was also noted in individuals with hematologic cancers, blastomas, and brain tumors as opposed to those with sarcomas and other carcinomas. The highest cumulative risk for migraine remains in those who were diagnosed with cancer between ages 15 and 19 years.

This month, we will take a look at three new studies investigating risk factors and treatments for headache in children.

Stress has long been noted to be one of the most consistent triggers for migraine attacks. Much has been written and studied regarding the effect of migraine on mood in adults; however, few studies have done the same in the pediatric and adolescent population. Childhood trauma has been associated with the development of chronic migraine as an adult, and behavioral treatments, such as cognitive-behavioral therapy and biofeedback, are considered as effective or more effective for migraine prevention in children compared with preventive medications. Falla and colleagues have quantified the risk for anxiety and depression in children and adolescents with migraine.

The "internalization of symptoms" is defined by the authors as an individual's tendency to react to stress with physical symptoms, including anxiety and depression. These are thought to be elevated in children and adolescents with many effects, including migraine. However, no correlation has yet been shown. Beyond the internalization of symptoms, specific psychiatric diagnoses may also be more prominent in this population.

This study was a meta-analysis of data pooled from studies that assessed migraine-related symptoms as they relate to disorders on the spectrum of anxiety, depression, and trauma-related disorders. Any studies with participants older than 18 years were excluded from this analysis. A total of 80 studies were included. Anxiety symptoms were seen to be significantly higher in children and adolescents with migraine compared to controls and the odds of having an anxiety disorder were higher among those with migraine compared with controls. Depressive symptoms were also significantly higher; however, this effect size was much smaller. The incidence of migraine was not different than that of other headache disorders.

Many patients describe stress as a trigger for migraine and other headache attacks. Mood disorders and childhood trauma are associated with the development of chronic migraine as an adult. This study reveals a two-way connection between mood disorders and headache diagnoses in children. Screening for the underlying symptoms of depression and anxiety should be done when evaluating children and adolescents for headache disorders, and there should be a focus on the treatment of these conditions in addition to treating the headache symptoms.

There are, unfortunately, very few acute pediatric migraine trials. Only a handful of medications have actually been investigated for the treatment of migraine in children younger than 12 years, and only one migraine-specific medication, rizatriptan, is approved in the United States for pediatric use. Because of this, many argue that children and adolescents with migraines end up overusing over-the-counter medication options, increasing the risk for medication overuse headache. In addition, many patients need nonoral acute migraine treatments due to nausea and vomiting or rapid onset migraine attacks.

Yonker and colleagues conducted a phase 3, randomized, double-blind, multicenter trial that only enrolled patients aged 6-11 years, all of whom had a diagnosis of episodic migraine (< 15 days of migraine per month). Children that weighed < 50 kg were given a randomly assigned lower dose of 1 mg or 2.5 mg zolmitriptan nasal spray, and those who weighed > 50 kg were randomly assigned to either 2.5 mg or 5 mg, which is the standard adult dose.

The primary outcome was a standard 2-hour pain freedom level; secondary outcomes included the proportion of improvement at 0.5, 1, and 24 hours post-dose, as well as sustained headache response for the following 2-24 hours and time to rescue medication use. Although 300 patients were enrolled and taken through the run-in process, 114 were discontinued either due to placebo response or because they had no treated migraine during the run-in phase. The mean age was 9.2 years and half of the patients were girls (of note, this is considered an appropriate proportion for pediatric migraine).

The primary endpoint of 2-hour pain freedom was not met; however, more patients in the high-dose treatment group were pain-free after 2 hours than in the placebo group. Several secondary endpoints did achieve statistical significance, including pain-free status at 1 hour post-dose, as well as headache response at 0.5, 1, and 2 hours — all of which were lower in the high-dose treatment group. The lower-dose treatment group was statistically similar to placebo for all the timepoints noted above. Treatment-related adverse events were rare in all groups.

This study did not meet its primary efficacy endpoint. However, it does show safety and effectiveness, enough at least to broaden the use of zolmitriptan for pediatric migraine. Many more effective medications for migraine treatment in adults should follow the lead of this group to find better and more specific treatments for children with migraine.

As we noted above, childhood trauma is associated with the development of chronic migraine in adulthood. Prior studies have defined childhood trauma as physical or emotional abuse primarily, and the correlation between childhood illnesses and headache disorder has not previously been determined. Davidsson and colleagues published a study in the Journal of Cancer Epidemiology that reviewed nationwide database registers longitudinally to better understand this potential risk factor.

The Danish Cancer Register was reviewed for the purpose of identifying anyone in the general Danish population who developed a diagnosis of cancer before age 20 years. The individual identification numbers in that register were linked to data in other nationwide registers for the purpose of determining whether those individuals initiated migraine-specific medications or were admitted for an inpatient hospitalization for migraine. Study participants were also grouped based on cancer type, specifically hematologic cancers involving chemotherapy and central nervous system-directed therapies, brain tumors needing intracranial surgery or radiation to the brain, blastomas or other solid tumors outside of the central nervous system, sarcomas treated with an alkylating chemotherapy, and all other carcinomas.

Among all individuals diagnosed with a childhood cancer, there was a significant increase in overall risk for the need to initiate antimigraine medication. Of interest, this was higher in those diagnosed in their teenage years. Migraine hospitalization was also noted to be higher in nearly all strata, with the exception of those diagnosed with cancer prior to the age of 5 years. The highest risk was also noted in individuals with hematologic cancers, blastomas, and brain tumors as opposed to those with sarcomas and other carcinomas. The highest cumulative risk for migraine remains in those who were diagnosed with cancer between ages 15 and 19 years.

This month, we will take a look at three new studies investigating risk factors and treatments for headache in children.

Stress has long been noted to be one of the most consistent triggers for migraine attacks. Much has been written and studied regarding the effect of migraine on mood in adults; however, few studies have done the same in the pediatric and adolescent population. Childhood trauma has been associated with the development of chronic migraine as an adult, and behavioral treatments, such as cognitive-behavioral therapy and biofeedback, are considered as effective or more effective for migraine prevention in children compared with preventive medications. Falla and colleagues have quantified the risk for anxiety and depression in children and adolescents with migraine.

The "internalization of symptoms" is defined by the authors as an individual's tendency to react to stress with physical symptoms, including anxiety and depression. These are thought to be elevated in children and adolescents with many effects, including migraine. However, no correlation has yet been shown. Beyond the internalization of symptoms, specific psychiatric diagnoses may also be more prominent in this population.

This study was a meta-analysis of data pooled from studies that assessed migraine-related symptoms as they relate to disorders on the spectrum of anxiety, depression, and trauma-related disorders. Any studies with participants older than 18 years were excluded from this analysis. A total of 80 studies were included. Anxiety symptoms were seen to be significantly higher in children and adolescents with migraine compared to controls and the odds of having an anxiety disorder were higher among those with migraine compared with controls. Depressive symptoms were also significantly higher; however, this effect size was much smaller. The incidence of migraine was not different than that of other headache disorders.

Many patients describe stress as a trigger for migraine and other headache attacks. Mood disorders and childhood trauma are associated with the development of chronic migraine as an adult. This study reveals a two-way connection between mood disorders and headache diagnoses in children. Screening for the underlying symptoms of depression and anxiety should be done when evaluating children and adolescents for headache disorders, and there should be a focus on the treatment of these conditions in addition to treating the headache symptoms.

There are, unfortunately, very few acute pediatric migraine trials. Only a handful of medications have actually been investigated for the treatment of migraine in children younger than 12 years, and only one migraine-specific medication, rizatriptan, is approved in the United States for pediatric use. Because of this, many argue that children and adolescents with migraines end up overusing over-the-counter medication options, increasing the risk for medication overuse headache. In addition, many patients need nonoral acute migraine treatments due to nausea and vomiting or rapid onset migraine attacks.

Yonker and colleagues conducted a phase 3, randomized, double-blind, multicenter trial that only enrolled patients aged 6-11 years, all of whom had a diagnosis of episodic migraine (< 15 days of migraine per month). Children that weighed < 50 kg were given a randomly assigned lower dose of 1 mg or 2.5 mg zolmitriptan nasal spray, and those who weighed > 50 kg were randomly assigned to either 2.5 mg or 5 mg, which is the standard adult dose.

The primary outcome was a standard 2-hour pain freedom level; secondary outcomes included the proportion of improvement at 0.5, 1, and 24 hours post-dose, as well as sustained headache response for the following 2-24 hours and time to rescue medication use. Although 300 patients were enrolled and taken through the run-in process, 114 were discontinued either due to placebo response or because they had no treated migraine during the run-in phase. The mean age was 9.2 years and half of the patients were girls (of note, this is considered an appropriate proportion for pediatric migraine).

The primary endpoint of 2-hour pain freedom was not met; however, more patients in the high-dose treatment group were pain-free after 2 hours than in the placebo group. Several secondary endpoints did achieve statistical significance, including pain-free status at 1 hour post-dose, as well as headache response at 0.5, 1, and 2 hours — all of which were lower in the high-dose treatment group. The lower-dose treatment group was statistically similar to placebo for all the timepoints noted above. Treatment-related adverse events were rare in all groups.

This study did not meet its primary efficacy endpoint. However, it does show safety and effectiveness, enough at least to broaden the use of zolmitriptan for pediatric migraine. Many more effective medications for migraine treatment in adults should follow the lead of this group to find better and more specific treatments for children with migraine.

As we noted above, childhood trauma is associated with the development of chronic migraine in adulthood. Prior studies have defined childhood trauma as physical or emotional abuse primarily, and the correlation between childhood illnesses and headache disorder has not previously been determined. Davidsson and colleagues published a study in the Journal of Cancer Epidemiology that reviewed nationwide database registers longitudinally to better understand this potential risk factor.

The Danish Cancer Register was reviewed for the purpose of identifying anyone in the general Danish population who developed a diagnosis of cancer before age 20 years. The individual identification numbers in that register were linked to data in other nationwide registers for the purpose of determining whether those individuals initiated migraine-specific medications or were admitted for an inpatient hospitalization for migraine. Study participants were also grouped based on cancer type, specifically hematologic cancers involving chemotherapy and central nervous system-directed therapies, brain tumors needing intracranial surgery or radiation to the brain, blastomas or other solid tumors outside of the central nervous system, sarcomas treated with an alkylating chemotherapy, and all other carcinomas.

Among all individuals diagnosed with a childhood cancer, there was a significant increase in overall risk for the need to initiate antimigraine medication. Of interest, this was higher in those diagnosed in their teenage years. Migraine hospitalization was also noted to be higher in nearly all strata, with the exception of those diagnosed with cancer prior to the age of 5 years. The highest risk was also noted in individuals with hematologic cancers, blastomas, and brain tumors as opposed to those with sarcomas and other carcinomas. The highest cumulative risk for migraine remains in those who were diagnosed with cancer between ages 15 and 19 years.

Several studies have addressed the efficacy of COVID vaccines in patients with autoimmune and rheumatic diseases owing to the concern for possible reduced vaccine immunogenicity in patients who are immunocompromised or taking immunosuppressive medications. With the availability of additional booster doses for the COVID vaccines, the effect of immunosuppressive medications on the humoral response to mRNA vaccines has been of increased interest in terms of counseling patients on how to manage their medications and vaccine timing. Prior studies have suggested that holding methotrexate after COVID vaccine administration improves antibody response to the COVID vaccine. Stahl and colleagues performed a retrospective study to look at vaccine response to a third (booster) dose in patients with rheumatoid arthritis (RA) over 65 years of age (vs those under 65 years of age) and found that patients over 65 receiving methotrexate had lower levels of neutralizing antibodies than did those receiving other treatments for RA, whereas no differences were seen with different treatments among patients under 65. Although COVID vaccine guidance continues to evolve, this finding raises the possibility of a need to tailor guidance in older patients with RA. However, the finding is far from conclusive given the small number of patients in the study.

In addition to COVID vaccine efficacy, the possibility of vaccine-related adverse effects has been a topic of concern in the rheumatology community, especially regarding the potential for a flare of autoimmune diseases. Anxiety regarding adverse effects may also exacerbate COVID vaccine hesitancy among some people. Naveen and colleagues performed an online international cross-sectional survey study regarding rheumatic diseases and 7-day adverse events. Over 9000 people completed the survey, about half of whom had autoimmune diseases (including nonrheumatic autoimmune diseases). Roughly three quarters of patients with RA reported adverse effects, with differences seen in frequencies of events between the different vaccine manufacturers. However, the majority of these adverse effects were minor (such as fatigue, headache, and body ache), without substantial differences between those with inactive and those with active RA.

The treat-to-target strategy is well-accepted in treatment of RA and pursuit of improved long-term disease outcomes. Hartman and colleagues evaluated the effect of using a treat-to-target strategy starting with the combination therapy with RA-light (COBRA-light) protocol (with initial methotrexate and tapering prednisolone) in early RA. Patients who were deemed at high risk for worsening RA (n = 150) received COBRA-light, whereas those in the low-risk category (n = 40) received methotrexate monotherapy. At 13 weeks, nonresponders were randomized to intensification or continuation of their regimens, with a primary endpoint of European Alliance of Associations for Rheumatology (EULAR) response and secondary endpoint of Disease Activity Score (DAS44). After 13 weeks, 73% of patients in the high-risk category achieved the targets of EULAR good response and DAS44 < 1.6, whereas after 26 weeks, 80% of patients who received intensified therapy and 44% of those who continued their regimens reached the target, though these numbers were small. Overall, the strategy appears to be successful in treatment of early RA in patients at high risk for disease progression, but it does lead to increased use of higher chronic glucocorticoid doses. In addition, the small numbers of patients in the low-risk category, as well as their less aggressive treatment, does not allow for a nuanced analysis of the best initial treatment in this group of patients.

Finally, a cohort study by Takanashi and colleagues evaluated the rates of seropositivity for rheumatoid factor (RF) and anti–cyclic citrullinated peptide (anti-CCP) in patients diagnosed with RA and its association with demographic categories. Seropositivity was associated with smoking and family history of RA, as expected. Among the 1685 patients, 83% of whom were women, older age at RA diagnosis was associated with seronegativity for RF and CCP in women but not in men. The decline in seropositivity with age among women cannot be further evaluated with the limited information in this small study and may have to do with other factors, including erosive or inflammatory osteoarthritis.

Several studies have addressed the efficacy of COVID vaccines in patients with autoimmune and rheumatic diseases owing to the concern for possible reduced vaccine immunogenicity in patients who are immunocompromised or taking immunosuppressive medications. With the availability of additional booster doses for the COVID vaccines, the effect of immunosuppressive medications on the humoral response to mRNA vaccines has been of increased interest in terms of counseling patients on how to manage their medications and vaccine timing. Prior studies have suggested that holding methotrexate after COVID vaccine administration improves antibody response to the COVID vaccine. Stahl and colleagues performed a retrospective study to look at vaccine response to a third (booster) dose in patients with rheumatoid arthritis (RA) over 65 years of age (vs those under 65 years of age) and found that patients over 65 receiving methotrexate had lower levels of neutralizing antibodies than did those receiving other treatments for RA, whereas no differences were seen with different treatments among patients under 65. Although COVID vaccine guidance continues to evolve, this finding raises the possibility of a need to tailor guidance in older patients with RA. However, the finding is far from conclusive given the small number of patients in the study.

In addition to COVID vaccine efficacy, the possibility of vaccine-related adverse effects has been a topic of concern in the rheumatology community, especially regarding the potential for a flare of autoimmune diseases. Anxiety regarding adverse effects may also exacerbate COVID vaccine hesitancy among some people. Naveen and colleagues performed an online international cross-sectional survey study regarding rheumatic diseases and 7-day adverse events. Over 9000 people completed the survey, about half of whom had autoimmune diseases (including nonrheumatic autoimmune diseases). Roughly three quarters of patients with RA reported adverse effects, with differences seen in frequencies of events between the different vaccine manufacturers. However, the majority of these adverse effects were minor (such as fatigue, headache, and body ache), without substantial differences between those with inactive and those with active RA.

The treat-to-target strategy is well-accepted in treatment of RA and pursuit of improved long-term disease outcomes. Hartman and colleagues evaluated the effect of using a treat-to-target strategy starting with the combination therapy with RA-light (COBRA-light) protocol (with initial methotrexate and tapering prednisolone) in early RA. Patients who were deemed at high risk for worsening RA (n = 150) received COBRA-light, whereas those in the low-risk category (n = 40) received methotrexate monotherapy. At 13 weeks, nonresponders were randomized to intensification or continuation of their regimens, with a primary endpoint of European Alliance of Associations for Rheumatology (EULAR) response and secondary endpoint of Disease Activity Score (DAS44). After 13 weeks, 73% of patients in the high-risk category achieved the targets of EULAR good response and DAS44 < 1.6, whereas after 26 weeks, 80% of patients who received intensified therapy and 44% of those who continued their regimens reached the target, though these numbers were small. Overall, the strategy appears to be successful in treatment of early RA in patients at high risk for disease progression, but it does lead to increased use of higher chronic glucocorticoid doses. In addition, the small numbers of patients in the low-risk category, as well as their less aggressive treatment, does not allow for a nuanced analysis of the best initial treatment in this group of patients.

Finally, a cohort study by Takanashi and colleagues evaluated the rates of seropositivity for rheumatoid factor (RF) and anti–cyclic citrullinated peptide (anti-CCP) in patients diagnosed with RA and its association with demographic categories. Seropositivity was associated with smoking and family history of RA, as expected. Among the 1685 patients, 83% of whom were women, older age at RA diagnosis was associated with seronegativity for RF and CCP in women but not in men. The decline in seropositivity with age among women cannot be further evaluated with the limited information in this small study and may have to do with other factors, including erosive or inflammatory osteoarthritis.

Several studies have addressed the efficacy of COVID vaccines in patients with autoimmune and rheumatic diseases owing to the concern for possible reduced vaccine immunogenicity in patients who are immunocompromised or taking immunosuppressive medications. With the availability of additional booster doses for the COVID vaccines, the effect of immunosuppressive medications on the humoral response to mRNA vaccines has been of increased interest in terms of counseling patients on how to manage their medications and vaccine timing. Prior studies have suggested that holding methotrexate after COVID vaccine administration improves antibody response to the COVID vaccine. Stahl and colleagues performed a retrospective study to look at vaccine response to a third (booster) dose in patients with rheumatoid arthritis (RA) over 65 years of age (vs those under 65 years of age) and found that patients over 65 receiving methotrexate had lower levels of neutralizing antibodies than did those receiving other treatments for RA, whereas no differences were seen with different treatments among patients under 65. Although COVID vaccine guidance continues to evolve, this finding raises the possibility of a need to tailor guidance in older patients with RA. However, the finding is far from conclusive given the small number of patients in the study.

In addition to COVID vaccine efficacy, the possibility of vaccine-related adverse effects has been a topic of concern in the rheumatology community, especially regarding the potential for a flare of autoimmune diseases. Anxiety regarding adverse effects may also exacerbate COVID vaccine hesitancy among some people. Naveen and colleagues performed an online international cross-sectional survey study regarding rheumatic diseases and 7-day adverse events. Over 9000 people completed the survey, about half of whom had autoimmune diseases (including nonrheumatic autoimmune diseases). Roughly three quarters of patients with RA reported adverse effects, with differences seen in frequencies of events between the different vaccine manufacturers. However, the majority of these adverse effects were minor (such as fatigue, headache, and body ache), without substantial differences between those with inactive and those with active RA.

The treat-to-target strategy is well-accepted in treatment of RA and pursuit of improved long-term disease outcomes. Hartman and colleagues evaluated the effect of using a treat-to-target strategy starting with the combination therapy with RA-light (COBRA-light) protocol (with initial methotrexate and tapering prednisolone) in early RA. Patients who were deemed at high risk for worsening RA (n = 150) received COBRA-light, whereas those in the low-risk category (n = 40) received methotrexate monotherapy. At 13 weeks, nonresponders were randomized to intensification or continuation of their regimens, with a primary endpoint of European Alliance of Associations for Rheumatology (EULAR) response and secondary endpoint of Disease Activity Score (DAS44). After 13 weeks, 73% of patients in the high-risk category achieved the targets of EULAR good response and DAS44 < 1.6, whereas after 26 weeks, 80% of patients who received intensified therapy and 44% of those who continued their regimens reached the target, though these numbers were small. Overall, the strategy appears to be successful in treatment of early RA in patients at high risk for disease progression, but it does lead to increased use of higher chronic glucocorticoid doses. In addition, the small numbers of patients in the low-risk category, as well as their less aggressive treatment, does not allow for a nuanced analysis of the best initial treatment in this group of patients.

Finally, a cohort study by Takanashi and colleagues evaluated the rates of seropositivity for rheumatoid factor (RF) and anti–cyclic citrullinated peptide (anti-CCP) in patients diagnosed with RA and its association with demographic categories. Seropositivity was associated with smoking and family history of RA, as expected. Among the 1685 patients, 83% of whom were women, older age at RA diagnosis was associated with seronegativity for RF and CCP in women but not in men. The decline in seropositivity with age among women cannot be further evaluated with the limited information in this small study and may have to do with other factors, including erosive or inflammatory osteoarthritis.

A study by Hofheinz and colleagues evaluated whether targeting the human epidermal growth factor receptor 2 (HER2) pathway can improve outcomes in early-stage esophagogastric adenocarcinoma (EGA).¹ About 15%-20% of EGA overexpress HER2. In the metastatic setting, anti-HER2 therapies have an established role. Trastuzumab in combination with chemotherapy has been part of standard treatment for these tumors for over a decade and now immunotherapy, based on the ongoing KEYNOTE-811 study, has been proven effective as well.^2,3 However, prior attempts to effectively target HER2 in the early stage have not been successful.⁴

A phase 2 trial conducted by the AIO EGA Study Group evaluated the addition of trastuzumab and pertuzumab to FLOT (fluorouracil, leucovorin, oxaliplatin, docetaxel) chemotherapy in resectable HER2-positive EGA. The trial closed early, before planned full accrual, when the results of the JACOB trial, which evaluated the addition of pertuzumab in the metastatic setting, came out as negative.⁵ However, the results are still worth discussing here. A total of 81 patients were enrolled in this study (40 in the experimental arm and 41 in the chemotherapy-only control arm). Pathologic complete response was significantly improved with the addition of anti-HER2 therapy (35% vs 12%; P = .02). The rates of R0 resection and surgical complications were similar. Median disease-free survival was not reached in the experimental arm (26 months in the control arm). This study suggests that evaluation of anti-HER2 agents in combination with chemotherapy is warranted. Given the promising results of the KEYNOTE-811 study, future studies should consider incorporative immunotherapy as well.

The Neo-PLANET phase 2 study by Tang and colleagues evaluated the addition of camrelizumab (anti-PD1 antibody) to concurrent chemoradiation in the treatment of advanced EGA.⁶ The 36 patients enrolled in this study received induction chemotherapy with capecitabine and oxaliplatin followed by chemoradiation with the same chemotherapy backbone. Camrelizumab was added from the time of all chemotherapy initiation. The pathologic complete response observed (33.3%) compared favorably to historical references. No new safety signals were identified. Current standards for resectable EGA include adjuvant nivolumab in patients who have residual disease at the time of resection post chemoradiation. This study demonstrated that the addition of immunotherapy earlier in the treatment course is safe and possibly efficacious. The prospective randomized phase 2/3 ECOG-ACRIN 2174 study will evaluate the addition of nivolumab to chemoradiation, as well as the addition of ipilimumab to nivolumab in the adjuvant setting, and will answer the question regarding the benefits of immunotherapy used earlier in the course of disease in a prospective randomized manner (NCT03604991).

The study by de Jongh and colleagues evaluated the pattern of lymph node metastasis after neoadjuvant chemotherapy with relation to the location of the primary gastric tumor. Tumors from 212 patients who were previously enrolled in the Dutch LOGICA trial comparing laparoscopy vs open D2 gastrectomy were included in this analysis. Although the primary tumor location (proximal vs distal) was associated with a higher frequency of metastasis to certain lymph node groups, this relationship was not exclusive. As such, the extent of lymphadenectomy should not depend on the primary location of the tumor and is not affected by neoadjuvant chemotherapy.

Additional References

1. Hofheinz R-D, Merx K, Haag GM, et al. FLOT versus FLOT/trastuzumab/pertuzumab perioperative therapy of human epidermal growth factor receptor 2–positive resectable esophagogastric adenocarcinoma: A randomized phase II trial of the AIO EGA Study Group. J Clin Oncol. 2022;40:3750-3761. Doi: 10.1200/JCO.22.00380

2. Janjigian YY, Kawazoe A, Yañez P, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021;600:727-730. Doi: 10.1038/s41586-021-04161-3

3. Bang Y-J, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687-697. Doi: 10.1016/S0140-6736(10)61121-X

4. Safran HP, Winter K, Hilson D, et al. Trastuzumab with trimodality treatment for oesophageal adenocarcinoma with HER2 overexpression (NRG Oncology/RTOG 1010): A multicentre, randomised, phase 3 trial. Lancet Oncol. 2022;23:259-269. Doi: 10.1016/S1470-2045(21)00718-X

5. Tabernero J, Hoff PM, Shen L, et al. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): Final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2018:19:1372-1384. Doi: 10.1016/S1470-2045(18)30481-9

6. Tang Z, Wang Y, Liu D, et al. The Neo-PLANET phase II trial of neoadjuvant camrelizumab plus concurrent chemoradiotherapy in locally advanced adenocarcinoma of stomach or gastroesophageal junction. Nat Commun 2022;13:6807. Doi: 10.1038/s41467-022-34403-5

A study by Hofheinz and colleagues evaluated whether targeting the human epidermal growth factor receptor 2 (HER2) pathway can improve outcomes in early-stage esophagogastric adenocarcinoma (EGA).¹ About 15%-20% of EGA overexpress HER2. In the metastatic setting, anti-HER2 therapies have an established role. Trastuzumab in combination with chemotherapy has been part of standard treatment for these tumors for over a decade and now immunotherapy, based on the ongoing KEYNOTE-811 study, has been proven effective as well.^2,3 However, prior attempts to effectively target HER2 in the early stage have not been successful.⁴

A phase 2 trial conducted by the AIO EGA Study Group evaluated the addition of trastuzumab and pertuzumab to FLOT (fluorouracil, leucovorin, oxaliplatin, docetaxel) chemotherapy in resectable HER2-positive EGA. The trial closed early, before planned full accrual, when the results of the JACOB trial, which evaluated the addition of pertuzumab in the metastatic setting, came out as negative.⁵ However, the results are still worth discussing here. A total of 81 patients were enrolled in this study (40 in the experimental arm and 41 in the chemotherapy-only control arm). Pathologic complete response was significantly improved with the addition of anti-HER2 therapy (35% vs 12%; P = .02). The rates of R0 resection and surgical complications were similar. Median disease-free survival was not reached in the experimental arm (26 months in the control arm). This study suggests that evaluation of anti-HER2 agents in combination with chemotherapy is warranted. Given the promising results of the KEYNOTE-811 study, future studies should consider incorporative immunotherapy as well.

The Neo-PLANET phase 2 study by Tang and colleagues evaluated the addition of camrelizumab (anti-PD1 antibody) to concurrent chemoradiation in the treatment of advanced EGA.⁶ The 36 patients enrolled in this study received induction chemotherapy with capecitabine and oxaliplatin followed by chemoradiation with the same chemotherapy backbone. Camrelizumab was added from the time of all chemotherapy initiation. The pathologic complete response observed (33.3%) compared favorably to historical references. No new safety signals were identified. Current standards for resectable EGA include adjuvant nivolumab in patients who have residual disease at the time of resection post chemoradiation. This study demonstrated that the addition of immunotherapy earlier in the treatment course is safe and possibly efficacious. The prospective randomized phase 2/3 ECOG-ACRIN 2174 study will evaluate the addition of nivolumab to chemoradiation, as well as the addition of ipilimumab to nivolumab in the adjuvant setting, and will answer the question regarding the benefits of immunotherapy used earlier in the course of disease in a prospective randomized manner (NCT03604991).

The study by de Jongh and colleagues evaluated the pattern of lymph node metastasis after neoadjuvant chemotherapy with relation to the location of the primary gastric tumor. Tumors from 212 patients who were previously enrolled in the Dutch LOGICA trial comparing laparoscopy vs open D2 gastrectomy were included in this analysis. Although the primary tumor location (proximal vs distal) was associated with a higher frequency of metastasis to certain lymph node groups, this relationship was not exclusive. As such, the extent of lymphadenectomy should not depend on the primary location of the tumor and is not affected by neoadjuvant chemotherapy.

Additional References

1. Hofheinz R-D, Merx K, Haag GM, et al. FLOT versus FLOT/trastuzumab/pertuzumab perioperative therapy of human epidermal growth factor receptor 2–positive resectable esophagogastric adenocarcinoma: A randomized phase II trial of the AIO EGA Study Group. J Clin Oncol. 2022;40:3750-3761. Doi: 10.1200/JCO.22.00380

2. Janjigian YY, Kawazoe A, Yañez P, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021;600:727-730. Doi: 10.1038/s41586-021-04161-3

3. Bang Y-J, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687-697. Doi: 10.1016/S0140-6736(10)61121-X

4. Safran HP, Winter K, Hilson D, et al. Trastuzumab with trimodality treatment for oesophageal adenocarcinoma with HER2 overexpression (NRG Oncology/RTOG 1010): A multicentre, randomised, phase 3 trial. Lancet Oncol. 2022;23:259-269. Doi: 10.1016/S1470-2045(21)00718-X

5. Tabernero J, Hoff PM, Shen L, et al. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): Final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2018:19:1372-1384. Doi: 10.1016/S1470-2045(18)30481-9

6. Tang Z, Wang Y, Liu D, et al. The Neo-PLANET phase II trial of neoadjuvant camrelizumab plus concurrent chemoradiotherapy in locally advanced adenocarcinoma of stomach or gastroesophageal junction. Nat Commun 2022;13:6807. Doi: 10.1038/s41467-022-34403-5

A study by Hofheinz and colleagues evaluated whether targeting the human epidermal growth factor receptor 2 (HER2) pathway can improve outcomes in early-stage esophagogastric adenocarcinoma (EGA).¹ About 15%-20% of EGA overexpress HER2. In the metastatic setting, anti-HER2 therapies have an established role. Trastuzumab in combination with chemotherapy has been part of standard treatment for these tumors for over a decade and now immunotherapy, based on the ongoing KEYNOTE-811 study, has been proven effective as well.^2,3 However, prior attempts to effectively target HER2 in the early stage have not been successful.⁴

A phase 2 trial conducted by the AIO EGA Study Group evaluated the addition of trastuzumab and pertuzumab to FLOT (fluorouracil, leucovorin, oxaliplatin, docetaxel) chemotherapy in resectable HER2-positive EGA. The trial closed early, before planned full accrual, when the results of the JACOB trial, which evaluated the addition of pertuzumab in the metastatic setting, came out as negative.⁵ However, the results are still worth discussing here. A total of 81 patients were enrolled in this study (40 in the experimental arm and 41 in the chemotherapy-only control arm). Pathologic complete response was significantly improved with the addition of anti-HER2 therapy (35% vs 12%; P = .02). The rates of R0 resection and surgical complications were similar. Median disease-free survival was not reached in the experimental arm (26 months in the control arm). This study suggests that evaluation of anti-HER2 agents in combination with chemotherapy is warranted. Given the promising results of the KEYNOTE-811 study, future studies should consider incorporative immunotherapy as well.

The Neo-PLANET phase 2 study by Tang and colleagues evaluated the addition of camrelizumab (anti-PD1 antibody) to concurrent chemoradiation in the treatment of advanced EGA.⁶ The 36 patients enrolled in this study received induction chemotherapy with capecitabine and oxaliplatin followed by chemoradiation with the same chemotherapy backbone. Camrelizumab was added from the time of all chemotherapy initiation. The pathologic complete response observed (33.3%) compared favorably to historical references. No new safety signals were identified. Current standards for resectable EGA include adjuvant nivolumab in patients who have residual disease at the time of resection post chemoradiation. This study demonstrated that the addition of immunotherapy earlier in the treatment course is safe and possibly efficacious. The prospective randomized phase 2/3 ECOG-ACRIN 2174 study will evaluate the addition of nivolumab to chemoradiation, as well as the addition of ipilimumab to nivolumab in the adjuvant setting, and will answer the question regarding the benefits of immunotherapy used earlier in the course of disease in a prospective randomized manner (NCT03604991).

The study by de Jongh and colleagues evaluated the pattern of lymph node metastasis after neoadjuvant chemotherapy with relation to the location of the primary gastric tumor. Tumors from 212 patients who were previously enrolled in the Dutch LOGICA trial comparing laparoscopy vs open D2 gastrectomy were included in this analysis. Although the primary tumor location (proximal vs distal) was associated with a higher frequency of metastasis to certain lymph node groups, this relationship was not exclusive. As such, the extent of lymphadenectomy should not depend on the primary location of the tumor and is not affected by neoadjuvant chemotherapy.

Additional References

1. Hofheinz R-D, Merx K, Haag GM, et al. FLOT versus FLOT/trastuzumab/pertuzumab perioperative therapy of human epidermal growth factor receptor 2–positive resectable esophagogastric adenocarcinoma: A randomized phase II trial of the AIO EGA Study Group. J Clin Oncol. 2022;40:3750-3761. Doi: 10.1200/JCO.22.00380

2. Janjigian YY, Kawazoe A, Yañez P, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021;600:727-730. Doi: 10.1038/s41586-021-04161-3

3. Bang Y-J, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687-697. Doi: 10.1016/S0140-6736(10)61121-X

4. Safran HP, Winter K, Hilson D, et al. Trastuzumab with trimodality treatment for oesophageal adenocarcinoma with HER2 overexpression (NRG Oncology/RTOG 1010): A multicentre, randomised, phase 3 trial. Lancet Oncol. 2022;23:259-269. Doi: 10.1016/S1470-2045(21)00718-X

5. Tabernero J, Hoff PM, Shen L, et al. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): Final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2018:19:1372-1384. Doi: 10.1016/S1470-2045(18)30481-9

6. Tang Z, Wang Y, Liu D, et al. The Neo-PLANET phase II trial of neoadjuvant camrelizumab plus concurrent chemoradiotherapy in locally advanced adenocarcinoma of stomach or gastroesophageal junction. Nat Commun 2022;13:6807. Doi: 10.1038/s41467-022-34403-5

Research published during the past month focused mostly on sex differences, biomarkers, and treatment. Sex differences in psoriatic arthritis (PsA) are a significant focus of current research. One major question is how clinical features differ between men and women. Furer and colleagues investigated differences in musculoskeletal ultrasonographic features between men and women with PsA. In a prospective study including 70 men and 88 women, they demonstrated that although the total synovitis and tenosynovitis scores were similar between the two sexes, compared with women, men had higher total ultrasound and gray scale enthesitis scores (both P = .01) and sonographic active inflammatory score (P = .005). Given the uncertainty associated with the clinical diagnosis of enthesitis, this study emphasizes the importance of careful ultrasonographic evaluation when evaluating enthesitis patients, especially women.

It is important to investigate pregnancy outcomes in women with inflammatory arthritis, including PsA, to appropriately counsel and manage patients in the reproductive-age group. Preeclampsia is an important pregnancy outcome that is less well studied in PsA. Secher and colleagues analyzed data from registries in Sweden and Denmark that included singleton pregnant women with rheumatoid arthritis (n = 1739), axial spondyloarthritis (n = 819), and PsA (n = 489) who were matched with 17,390, 8190, and 4890 control pregnant women, respectively. They found that compared with the control women, the risk for preeclampsia was much higher in women with PsA (adjusted odds ratio [aOR; adjusted for country, maternal age, parity, year of delivery, body mass index (BMI), smoking, and education] 1.85; 95% CI 1.10-3.12), with the risk being primarily driven by the receipt of monotherapy for PsA before pregnancy (aOR 2.72; 95% CI 1.44-5.13), probably reflecting the presence of more severe disease. Women with PsA who tend to have higher BMI and active disease need to be counseled about the risk for preeclampsia and be carefully monitored.

The Disease Activity index for PsA (DAPSA) is a validated instrument used in clinical practice to assess PsA disease activity. One drawback of this instrument is that it requires testing for C-reactive protein (CRP), the results of which may not be available immediately, making it difficult to use DAPSA for implementing treating-to-target strategies during a clinic visit. To alleviate this issue, a quick quantitative CRP (qCRP) assay was developed. In a multicenter, cross-sectional study including 104 patients with PsA and available CRP values (measured by routine laboratory and qCRP assays), Proft and colleagues demonstrated that 98.1% of patients were similarly categorized into disease activity groups (remission and low, moderate, and high disease activity) using DAPSA based on qCRP (Q-DAPSA) and DAPSA. The agreement between the two instruments was excellent (weighted Cohen kappa 0.980; 95% CI 0.952-1.000). Thus, the Q-DAPSA may be used in place of DAPSA when evaluating PsA disease activity.

Regarding treatment, in an exploratory analysis of SELECT-PsA 1, McInnes and colleagues demonstrated that, at week 104, a similar proportion of patients receiving 15/30 mg upadacitinib vs adalimumab achieved ≥ 20% improvement in the American College of Rheumatology (ACR20) criteria (69.0%/69.5% vs 63.4%), whereas significantly more patients receiving 30 mg upadacitinib vs adalimumab achieved minimal disease activity (45.9% vs 37.8%; P < .05). The safety profiles of upadacitinib and adalimumab were comparable. Moreover, analyses of 52-week outcome data from the ongoing phase 3 KEEPsAKE 1 study of risankizumab (IL-23 inhibitor) by Kristensen and colleagues showed that among patients who received risankizumab continuously, the ACR20 response increased from 57.3% at week 24 to 70.0% at week 52. No new safety signals were identified. Thus, upadacitinib and risankizumab are newer, safe, and effective disease-modifying antirheumatic drugs for PsA.

Research published during the past month focused mostly on sex differences, biomarkers, and treatment. Sex differences in psoriatic arthritis (PsA) are a significant focus of current research. One major question is how clinical features differ between men and women. Furer and colleagues investigated differences in musculoskeletal ultrasonographic features between men and women with PsA. In a prospective study including 70 men and 88 women, they demonstrated that although the total synovitis and tenosynovitis scores were similar between the two sexes, compared with women, men had higher total ultrasound and gray scale enthesitis scores (both P = .01) and sonographic active inflammatory score (P = .005). Given the uncertainty associated with the clinical diagnosis of enthesitis, this study emphasizes the importance of careful ultrasonographic evaluation when evaluating enthesitis patients, especially women.

It is important to investigate pregnancy outcomes in women with inflammatory arthritis, including PsA, to appropriately counsel and manage patients in the reproductive-age group. Preeclampsia is an important pregnancy outcome that is less well studied in PsA. Secher and colleagues analyzed data from registries in Sweden and Denmark that included singleton pregnant women with rheumatoid arthritis (n = 1739), axial spondyloarthritis (n = 819), and PsA (n = 489) who were matched with 17,390, 8190, and 4890 control pregnant women, respectively. They found that compared with the control women, the risk for preeclampsia was much higher in women with PsA (adjusted odds ratio [aOR; adjusted for country, maternal age, parity, year of delivery, body mass index (BMI), smoking, and education] 1.85; 95% CI 1.10-3.12), with the risk being primarily driven by the receipt of monotherapy for PsA before pregnancy (aOR 2.72; 95% CI 1.44-5.13), probably reflecting the presence of more severe disease. Women with PsA who tend to have higher BMI and active disease need to be counseled about the risk for preeclampsia and be carefully monitored.

The Disease Activity index for PsA (DAPSA) is a validated instrument used in clinical practice to assess PsA disease activity. One drawback of this instrument is that it requires testing for C-reactive protein (CRP), the results of which may not be available immediately, making it difficult to use DAPSA for implementing treating-to-target strategies during a clinic visit. To alleviate this issue, a quick quantitative CRP (qCRP) assay was developed. In a multicenter, cross-sectional study including 104 patients with PsA and available CRP values (measured by routine laboratory and qCRP assays), Proft and colleagues demonstrated that 98.1% of patients were similarly categorized into disease activity groups (remission and low, moderate, and high disease activity) using DAPSA based on qCRP (Q-DAPSA) and DAPSA. The agreement between the two instruments was excellent (weighted Cohen kappa 0.980; 95% CI 0.952-1.000). Thus, the Q-DAPSA may be used in place of DAPSA when evaluating PsA disease activity.

Regarding treatment, in an exploratory analysis of SELECT-PsA 1, McInnes and colleagues demonstrated that, at week 104, a similar proportion of patients receiving 15/30 mg upadacitinib vs adalimumab achieved ≥ 20% improvement in the American College of Rheumatology (ACR20) criteria (69.0%/69.5% vs 63.4%), whereas significantly more patients receiving 30 mg upadacitinib vs adalimumab achieved minimal disease activity (45.9% vs 37.8%; P < .05). The safety profiles of upadacitinib and adalimumab were comparable. Moreover, analyses of 52-week outcome data from the ongoing phase 3 KEEPsAKE 1 study of risankizumab (IL-23 inhibitor) by Kristensen and colleagues showed that among patients who received risankizumab continuously, the ACR20 response increased from 57.3% at week 24 to 70.0% at week 52. No new safety signals were identified. Thus, upadacitinib and risankizumab are newer, safe, and effective disease-modifying antirheumatic drugs for PsA.

Research published during the past month focused mostly on sex differences, biomarkers, and treatment. Sex differences in psoriatic arthritis (PsA) are a significant focus of current research. One major question is how clinical features differ between men and women. Furer and colleagues investigated differences in musculoskeletal ultrasonographic features between men and women with PsA. In a prospective study including 70 men and 88 women, they demonstrated that although the total synovitis and tenosynovitis scores were similar between the two sexes, compared with women, men had higher total ultrasound and gray scale enthesitis scores (both P = .01) and sonographic active inflammatory score (P = .005). Given the uncertainty associated with the clinical diagnosis of enthesitis, this study emphasizes the importance of careful ultrasonographic evaluation when evaluating enthesitis patients, especially women.

It is important to investigate pregnancy outcomes in women with inflammatory arthritis, including PsA, to appropriately counsel and manage patients in the reproductive-age group. Preeclampsia is an important pregnancy outcome that is less well studied in PsA. Secher and colleagues analyzed data from registries in Sweden and Denmark that included singleton pregnant women with rheumatoid arthritis (n = 1739), axial spondyloarthritis (n = 819), and PsA (n = 489) who were matched with 17,390, 8190, and 4890 control pregnant women, respectively. They found that compared with the control women, the risk for preeclampsia was much higher in women with PsA (adjusted odds ratio [aOR; adjusted for country, maternal age, parity, year of delivery, body mass index (BMI), smoking, and education] 1.85; 95% CI 1.10-3.12), with the risk being primarily driven by the receipt of monotherapy for PsA before pregnancy (aOR 2.72; 95% CI 1.44-5.13), probably reflecting the presence of more severe disease. Women with PsA who tend to have higher BMI and active disease need to be counseled about the risk for preeclampsia and be carefully monitored.

The Disease Activity index for PsA (DAPSA) is a validated instrument used in clinical practice to assess PsA disease activity. One drawback of this instrument is that it requires testing for C-reactive protein (CRP), the results of which may not be available immediately, making it difficult to use DAPSA for implementing treating-to-target strategies during a clinic visit. To alleviate this issue, a quick quantitative CRP (qCRP) assay was developed. In a multicenter, cross-sectional study including 104 patients with PsA and available CRP values (measured by routine laboratory and qCRP assays), Proft and colleagues demonstrated that 98.1% of patients were similarly categorized into disease activity groups (remission and low, moderate, and high disease activity) using DAPSA based on qCRP (Q-DAPSA) and DAPSA. The agreement between the two instruments was excellent (weighted Cohen kappa 0.980; 95% CI 0.952-1.000). Thus, the Q-DAPSA may be used in place of DAPSA when evaluating PsA disease activity.

Regarding treatment, in an exploratory analysis of SELECT-PsA 1, McInnes and colleagues demonstrated that, at week 104, a similar proportion of patients receiving 15/30 mg upadacitinib vs adalimumab achieved ≥ 20% improvement in the American College of Rheumatology (ACR20) criteria (69.0%/69.5% vs 63.4%), whereas significantly more patients receiving 30 mg upadacitinib vs adalimumab achieved minimal disease activity (45.9% vs 37.8%; P < .05). The safety profiles of upadacitinib and adalimumab were comparable. Moreover, analyses of 52-week outcome data from the ongoing phase 3 KEEPsAKE 1 study of risankizumab (IL-23 inhibitor) by Kristensen and colleagues showed that among patients who received risankizumab continuously, the ACR20 response increased from 57.3% at week 24 to 70.0% at week 52. No new safety signals were identified. Thus, upadacitinib and risankizumab are newer, safe, and effective disease-modifying antirheumatic drugs for PsA.

Hatanaka and colleagues investigated whether the etiology of the underlying liver disease affected the efficacy of atezolizumab and bevacizumab (A/B). They reported the results of a retrospective cohort study of 323 patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C hepatocellular carcinoma and Child-Pugh class A cirrhosis who started A/B between September 2020 and December 2021. Patients with viral infection were defined as those who were either serum anti–hepatitis C antibody (anti-HCV Ab)- or hepatitis B surface antigen (HBs-Ag)-positive, while patients with nonviral infection was defined as those who were both serum anti-HCV Ab- and HBs-Ag-negative. After propensity matching, no significant difference in response rate ([RR] 20.6% vs 24.6% in viral and nonviral patients), disease control rate (68.3% vs 69.0%), progression-free survival ([PFS] 7.0 months vs 6.2 months), or 12-month overall survival ([OS] 65.5% vs 71.7%) was seen. The authors concluded that the underlying etiology of liver disease in patients with HCC does not affect the response to treatment with A/B.

Scheiner and colleagues evaluated the efficacy of immunotherapy in patients with HCC who had already received immune checkpoint inhibitors (ICI) in a previous line of therapy. The authors reported the results of an international, retrospective multicenter study of 58 patients with HCC who received at least two lines of ICI-based therapies. The first ICI was discontinued due to disease progression in 90%. Nonetheless, the RR to the second ICI was 26% (compared with 22% for the first ICI), with a time-to-progression (TTP) of 5.4 months (95% CI, 3.0-7.7) for the first ICI and 5.2 months (95% CI, 3.3-7.0) for the second ICI. Grade 3/4 treatment-related adverse events were observed in 16% and 17% of patients with the first and second ICI, respectively. Therefore, the authors believe that ICI rechallenge is safe and results in a treatment benefit for a similar proportion of HCC patients, as is seen with the first ICI treatment. They suggest that ICI-based regimens should be studied in prospective trials of patients who progressed on first-line immunotherapy.

Finally, Kim and colleagues reported outcomes of patients who developed anti-drug antibodies (ADA) against atezolizumab while on A/B. In this prospective cohort study, 174 patients with advanced HCC who were treated with first-line A/B were tested for serum ADA levels prior to treatment and at 3 weeks (cycle 2 day 1 [C2D1]). Clinically, patients with progressive disease exhibited higher ADA levels (median 65.2 [0-520.4] ng/mL) at C2D1 than responders (0-117.5 ng/mL). Patients with high ADA levels at C2D1 had a reduced response rate (29%-34% vs 7-11%) and worse PFS and OS. The investigators found that very high ADA levels (≥ 1000 ng/mL) at 3 weeks were consistently associated with poor clinical outcomes due to reduced systemic exposure to atezolizumab and impaired proliferation and activation of peripheral CD8-positive T cells. They suggested future validation and standardization of ADA assays to optimize treatment with atezolizumab in patients with uHCC.

Hatanaka and colleagues investigated whether the etiology of the underlying liver disease affected the efficacy of atezolizumab and bevacizumab (A/B). They reported the results of a retrospective cohort study of 323 patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C hepatocellular carcinoma and Child-Pugh class A cirrhosis who started A/B between September 2020 and December 2021. Patients with viral infection were defined as those who were either serum anti–hepatitis C antibody (anti-HCV Ab)- or hepatitis B surface antigen (HBs-Ag)-positive, while patients with nonviral infection was defined as those who were both serum anti-HCV Ab- and HBs-Ag-negative. After propensity matching, no significant difference in response rate ([RR] 20.6% vs 24.6% in viral and nonviral patients), disease control rate (68.3% vs 69.0%), progression-free survival ([PFS] 7.0 months vs 6.2 months), or 12-month overall survival ([OS] 65.5% vs 71.7%) was seen. The authors concluded that the underlying etiology of liver disease in patients with HCC does not affect the response to treatment with A/B.

Scheiner and colleagues evaluated the efficacy of immunotherapy in patients with HCC who had already received immune checkpoint inhibitors (ICI) in a previous line of therapy. The authors reported the results of an international, retrospective multicenter study of 58 patients with HCC who received at least two lines of ICI-based therapies. The first ICI was discontinued due to disease progression in 90%. Nonetheless, the RR to the second ICI was 26% (compared with 22% for the first ICI), with a time-to-progression (TTP) of 5.4 months (95% CI, 3.0-7.7) for the first ICI and 5.2 months (95% CI, 3.3-7.0) for the second ICI. Grade 3/4 treatment-related adverse events were observed in 16% and 17% of patients with the first and second ICI, respectively. Therefore, the authors believe that ICI rechallenge is safe and results in a treatment benefit for a similar proportion of HCC patients, as is seen with the first ICI treatment. They suggest that ICI-based regimens should be studied in prospective trials of patients who progressed on first-line immunotherapy.

Finally, Kim and colleagues reported outcomes of patients who developed anti-drug antibodies (ADA) against atezolizumab while on A/B. In this prospective cohort study, 174 patients with advanced HCC who were treated with first-line A/B were tested for serum ADA levels prior to treatment and at 3 weeks (cycle 2 day 1 [C2D1]). Clinically, patients with progressive disease exhibited higher ADA levels (median 65.2 [0-520.4] ng/mL) at C2D1 than responders (0-117.5 ng/mL). Patients with high ADA levels at C2D1 had a reduced response rate (29%-34% vs 7-11%) and worse PFS and OS. The investigators found that very high ADA levels (≥ 1000 ng/mL) at 3 weeks were consistently associated with poor clinical outcomes due to reduced systemic exposure to atezolizumab and impaired proliferation and activation of peripheral CD8-positive T cells. They suggested future validation and standardization of ADA assays to optimize treatment with atezolizumab in patients with uHCC.

Hatanaka and colleagues investigated whether the etiology of the underlying liver disease affected the efficacy of atezolizumab and bevacizumab (A/B). They reported the results of a retrospective cohort study of 323 patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C hepatocellular carcinoma and Child-Pugh class A cirrhosis who started A/B between September 2020 and December 2021. Patients with viral infection were defined as those who were either serum anti–hepatitis C antibody (anti-HCV Ab)- or hepatitis B surface antigen (HBs-Ag)-positive, while patients with nonviral infection was defined as those who were both serum anti-HCV Ab- and HBs-Ag-negative. After propensity matching, no significant difference in response rate ([RR] 20.6% vs 24.6% in viral and nonviral patients), disease control rate (68.3% vs 69.0%), progression-free survival ([PFS] 7.0 months vs 6.2 months), or 12-month overall survival ([OS] 65.5% vs 71.7%) was seen. The authors concluded that the underlying etiology of liver disease in patients with HCC does not affect the response to treatment with A/B.

Scheiner and colleagues evaluated the efficacy of immunotherapy in patients with HCC who had already received immune checkpoint inhibitors (ICI) in a previous line of therapy. The authors reported the results of an international, retrospective multicenter study of 58 patients with HCC who received at least two lines of ICI-based therapies. The first ICI was discontinued due to disease progression in 90%. Nonetheless, the RR to the second ICI was 26% (compared with 22% for the first ICI), with a time-to-progression (TTP) of 5.4 months (95% CI, 3.0-7.7) for the first ICI and 5.2 months (95% CI, 3.3-7.0) for the second ICI. Grade 3/4 treatment-related adverse events were observed in 16% and 17% of patients with the first and second ICI, respectively. Therefore, the authors believe that ICI rechallenge is safe and results in a treatment benefit for a similar proportion of HCC patients, as is seen with the first ICI treatment. They suggest that ICI-based regimens should be studied in prospective trials of patients who progressed on first-line immunotherapy.

Finally, Kim and colleagues reported outcomes of patients who developed anti-drug antibodies (ADA) against atezolizumab while on A/B. In this prospective cohort study, 174 patients with advanced HCC who were treated with first-line A/B were tested for serum ADA levels prior to treatment and at 3 weeks (cycle 2 day 1 [C2D1]). Clinically, patients with progressive disease exhibited higher ADA levels (median 65.2 [0-520.4] ng/mL) at C2D1 than responders (0-117.5 ng/mL). Patients with high ADA levels at C2D1 had a reduced response rate (29%-34% vs 7-11%) and worse PFS and OS. The investigators found that very high ADA levels (≥ 1000 ng/mL) at 3 weeks were consistently associated with poor clinical outcomes due to reduced systemic exposure to atezolizumab and impaired proliferation and activation of peripheral CD8-positive T cells. They suggested future validation and standardization of ADA assays to optimize treatment with atezolizumab in patients with uHCC.

Hatanaka and colleagues investigated whether the etiology of the underlying liver disease affected the efficacy of atezolizumab and bevacizumab (A/B). They reported the results of a retrospective cohort study of 323 patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C hepatocellular carcinoma and Child-Pugh class A cirrhosis who started A/B between September 2020 and December 2021. Patients with viral infection were defined as those who were either serum anti–hepatitis C antibody (anti-HCV Ab)- or hepatitis B surface antigen (HBs-Ag)-positive, while patients with nonviral infection was defined as those who were both serum anti-HCV Ab- and HBs-Ag-negative. After propensity matching, no significant difference in response rate ([RR] 20.6% vs 24.6% in viral and nonviral patients), disease control rate (68.3% vs 69.0%), progression-free survival ([PFS] 7.0 months vs 6.2 months), or 12-month overall survival ([OS] 65.5% vs 71.7%) was seen. The authors concluded that the underlying etiology of liver disease in patients with HCC does not affect the response to treatment with A/B.

Scheiner and colleagues evaluated the efficacy of immunotherapy in patients with HCC who had already received immune checkpoint inhibitors (ICI) in a previous line of therapy. The authors reported the results of an international, retrospective multicenter study of 58 patients with HCC who received at least two lines of ICI-based therapies. The first ICI was discontinued due to disease progression in 90%. Nonetheless, the RR to the second ICI was 26% (compared with 22% for the first ICI), with a time-to-progression (TTP) of 5.4 months (95% CI, 3.0-7.7) for the first ICI and 5.2 months (95% CI, 3.3-7.0) for the second ICI. Grade 3/4 treatment-related adverse events were observed in 16% and 17% of patients with the first and second ICI, respectively. Therefore, the authors believe that ICI rechallenge is safe and results in a treatment benefit for a similar proportion of HCC patients, as is seen with the first ICI treatment. They suggest that ICI-based regimens should be studied in prospective trials of patients who progressed on first-line immunotherapy.

Finally, Kim and colleagues reported outcomes of patients who developed anti-drug antibodies (ADA) against atezolizumab while on A/B. In this prospective cohort study, 174 patients with advanced HCC who were treated with first-line A/B were tested for serum ADA levels prior to treatment and at 3 weeks (cycle 2 day 1 [C2D1]). Clinically, patients with progressive disease exhibited higher ADA levels (median 65.2 [0-520.4] ng/mL) at C2D1 than responders (0-117.5 ng/mL). Patients with high ADA levels at C2D1 had a reduced response rate (29%-34% vs 7-11%) and worse PFS and OS. The investigators found that very high ADA levels (≥ 1000 ng/mL) at 3 weeks were consistently associated with poor clinical outcomes due to reduced systemic exposure to atezolizumab and impaired proliferation and activation of peripheral CD8-positive T cells. They suggested future validation and standardization of ADA assays to optimize treatment with atezolizumab in patients with uHCC.

Hatanaka and colleagues investigated whether the etiology of the underlying liver disease affected the efficacy of atezolizumab and bevacizumab (A/B). They reported the results of a retrospective cohort study of 323 patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C hepatocellular carcinoma and Child-Pugh class A cirrhosis who started A/B between September 2020 and December 2021. Patients with viral infection were defined as those who were either serum anti–hepatitis C antibody (anti-HCV Ab)- or hepatitis B surface antigen (HBs-Ag)-positive, while patients with nonviral infection was defined as those who were both serum anti-HCV Ab- and HBs-Ag-negative. After propensity matching, no significant difference in response rate ([RR] 20.6% vs 24.6% in viral and nonviral patients), disease control rate (68.3% vs 69.0%), progression-free survival ([PFS] 7.0 months vs 6.2 months), or 12-month overall survival ([OS] 65.5% vs 71.7%) was seen. The authors concluded that the underlying etiology of liver disease in patients with HCC does not affect the response to treatment with A/B.

Scheiner and colleagues evaluated the efficacy of immunotherapy in patients with HCC who had already received immune checkpoint inhibitors (ICI) in a previous line of therapy. The authors reported the results of an international, retrospective multicenter study of 58 patients with HCC who received at least two lines of ICI-based therapies. The first ICI was discontinued due to disease progression in 90%. Nonetheless, the RR to the second ICI was 26% (compared with 22% for the first ICI), with a time-to-progression (TTP) of 5.4 months (95% CI, 3.0-7.7) for the first ICI and 5.2 months (95% CI, 3.3-7.0) for the second ICI. Grade 3/4 treatment-related adverse events were observed in 16% and 17% of patients with the first and second ICI, respectively. Therefore, the authors believe that ICI rechallenge is safe and results in a treatment benefit for a similar proportion of HCC patients, as is seen with the first ICI treatment. They suggest that ICI-based regimens should be studied in prospective trials of patients who progressed on first-line immunotherapy.

Finally, Kim and colleagues reported outcomes of patients who developed anti-drug antibodies (ADA) against atezolizumab while on A/B. In this prospective cohort study, 174 patients with advanced HCC who were treated with first-line A/B were tested for serum ADA levels prior to treatment and at 3 weeks (cycle 2 day 1 [C2D1]). Clinically, patients with progressive disease exhibited higher ADA levels (median 65.2 [0-520.4] ng/mL) at C2D1 than responders (0-117.5 ng/mL). Patients with high ADA levels at C2D1 had a reduced response rate (29%-34% vs 7-11%) and worse PFS and OS. The investigators found that very high ADA levels (≥ 1000 ng/mL) at 3 weeks were consistently associated with poor clinical outcomes due to reduced systemic exposure to atezolizumab and impaired proliferation and activation of peripheral CD8-positive T cells. They suggested future validation and standardization of ADA assays to optimize treatment with atezolizumab in patients with uHCC.

Hatanaka and colleagues investigated whether the etiology of the underlying liver disease affected the efficacy of atezolizumab and bevacizumab (A/B). They reported the results of a retrospective cohort study of 323 patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C hepatocellular carcinoma and Child-Pugh class A cirrhosis who started A/B between September 2020 and December 2021. Patients with viral infection were defined as those who were either serum anti–hepatitis C antibody (anti-HCV Ab)- or hepatitis B surface antigen (HBs-Ag)-positive, while patients with nonviral infection was defined as those who were both serum anti-HCV Ab- and HBs-Ag-negative. After propensity matching, no significant difference in response rate ([RR] 20.6% vs 24.6% in viral and nonviral patients), disease control rate (68.3% vs 69.0%), progression-free survival ([PFS] 7.0 months vs 6.2 months), or 12-month overall survival ([OS] 65.5% vs 71.7%) was seen. The authors concluded that the underlying etiology of liver disease in patients with HCC does not affect the response to treatment with A/B.

Scheiner and colleagues evaluated the efficacy of immunotherapy in patients with HCC who had already received immune checkpoint inhibitors (ICI) in a previous line of therapy. The authors reported the results of an international, retrospective multicenter study of 58 patients with HCC who received at least two lines of ICI-based therapies. The first ICI was discontinued due to disease progression in 90%. Nonetheless, the RR to the second ICI was 26% (compared with 22% for the first ICI), with a time-to-progression (TTP) of 5.4 months (95% CI, 3.0-7.7) for the first ICI and 5.2 months (95% CI, 3.3-7.0) for the second ICI. Grade 3/4 treatment-related adverse events were observed in 16% and 17% of patients with the first and second ICI, respectively. Therefore, the authors believe that ICI rechallenge is safe and results in a treatment benefit for a similar proportion of HCC patients, as is seen with the first ICI treatment. They suggest that ICI-based regimens should be studied in prospective trials of patients who progressed on first-line immunotherapy.

Finally, Kim and colleagues reported outcomes of patients who developed anti-drug antibodies (ADA) against atezolizumab while on A/B. In this prospective cohort study, 174 patients with advanced HCC who were treated with first-line A/B were tested for serum ADA levels prior to treatment and at 3 weeks (cycle 2 day 1 [C2D1]). Clinically, patients with progressive disease exhibited higher ADA levels (median 65.2 [0-520.4] ng/mL) at C2D1 than responders (0-117.5 ng/mL). Patients with high ADA levels at C2D1 had a reduced response rate (29%-34% vs 7-11%) and worse PFS and OS. The investigators found that very high ADA levels (≥ 1000 ng/mL) at 3 weeks were consistently associated with poor clinical outcomes due to reduced systemic exposure to atezolizumab and impaired proliferation and activation of peripheral CD8-positive T cells. They suggested future validation and standardization of ADA assays to optimize treatment with atezolizumab in patients with uHCC.

Taxanes are an integral component of various treatment regimens for all stages of breast cancer. As survival outcomes have improved, it has become increasingly important to focus on the long-term quality-of-life impact of treatment. Neurotoxicity is a well-recognized potential side effect of taxane chemotherapy. In a prospective cohort study including 1234 patients diagnosed with breast cancer and receiving taxanes, the risk for patient-reported chemotherapy-induced peripheral neuropathy (CIPN) were lower in the paclitaxel (HR 0.59; P = .008) and docetaxel (HR 0.65; P = .02) groups vs the nab-paclitaxel group. There was less sensory discomfort reported with paclitaxel (HR 0.44; P < .001) and docetaxel (HR 0.52; P < .001) vs nab-paclitaxel; however, reported motor and autonomic symptoms were not significantly lower than in the nab-paclitaxel group (Mo et al). An area of research interest is the identification of biomarkers that may predict a higher likelihood of CIPN development, to aid in early detection and intervention.³

Management strategies for breast cancer diagnosed in older women should take into consideration age and competing medical comorbidities, and hormone receptor–positive histology is the most common subtype in this population. Some older women may be too frail or unfit for surgery, and furthermore, some may prefer to avoid surgery, even if it is considered a safe approach. A retrospective study including 91 older (≥ 70 years) patients with estrogen receptor–positive (ER+) breast cancer who underwent definitive endocrine therapy demonstrated a twofold higher mortality risk than the risk of needing invasive local treatment (surgery or radiation). The 5-year cumulative risks of undergoing invasive local treatment and having uncontrolled disease were 28% and 16%, respectively, whereas the 5-year cumulative overall survival was 42% (Gooijer et al). Although the majority of older women with ER+ early breast cancer will obtain a survival benefit with surgery plus endocrine therapy compared with primary endocrine therapy, there is a selected group with limited life expectancy owing to age, functional status, or medical comorbidities for whom it is appropriate to offer primary endocrine therapy, because breast cancer–specific survival may not be negatively affected.⁴

Additional References

1. Schmid P, Cortes J, Dent R, et al; for the KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567. Doi: 10.1056/NEJMoa2112651
2. Harbeck N, Rastogi P, Martin M, et al; on behalf of the monarchE Committee Members. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32:1571-1581. Doi: 10.1016/j.annonc.2021.09.015
3. Rodwin RL, Siddiq NZ, Ehrlich BE, Lustberg MB. Biomarkers of chemotherapy-induced peripheral neuropathy: current status and future directions. Front Pain Res (Lausanne). 2022;3:864910. Doi: 10.3389/fpain.2022.864910
4. Wyld L, Reed MW, Morgan J, et al. Bridging the age gap in breast cancer. Impacts of omission of breast cancer surgery in older women with oestrogen receptor positive early breast cancer. A risk stratified analysis of survival outcomes and quality of life. Eur J Cancer. 2021;142:48-62. Doi: 10.1016/j.ejca.2020.10.015

Taxanes are an integral component of various treatment regimens for all stages of breast cancer. As survival outcomes have improved, it has become increasingly important to focus on the long-term quality-of-life impact of treatment. Neurotoxicity is a well-recognized potential side effect of taxane chemotherapy. In a prospective cohort study including 1234 patients diagnosed with breast cancer and receiving taxanes, the risk for patient-reported chemotherapy-induced peripheral neuropathy (CIPN) were lower in the paclitaxel (HR 0.59; P = .008) and docetaxel (HR 0.65; P = .02) groups vs the nab-paclitaxel group. There was less sensory discomfort reported with paclitaxel (HR 0.44; P < .001) and docetaxel (HR 0.52; P < .001) vs nab-paclitaxel; however, reported motor and autonomic symptoms were not significantly lower than in the nab-paclitaxel group (Mo et al). An area of research interest is the identification of biomarkers that may predict a higher likelihood of CIPN development, to aid in early detection and intervention.³

Management strategies for breast cancer diagnosed in older women should take into consideration age and competing medical comorbidities, and hormone receptor–positive histology is the most common subtype in this population. Some older women may be too frail or unfit for surgery, and furthermore, some may prefer to avoid surgery, even if it is considered a safe approach. A retrospective study including 91 older (≥ 70 years) patients with estrogen receptor–positive (ER+) breast cancer who underwent definitive endocrine therapy demonstrated a twofold higher mortality risk than the risk of needing invasive local treatment (surgery or radiation). The 5-year cumulative risks of undergoing invasive local treatment and having uncontrolled disease were 28% and 16%, respectively, whereas the 5-year cumulative overall survival was 42% (Gooijer et al). Although the majority of older women with ER+ early breast cancer will obtain a survival benefit with surgery plus endocrine therapy compared with primary endocrine therapy, there is a selected group with limited life expectancy owing to age, functional status, or medical comorbidities for whom it is appropriate to offer primary endocrine therapy, because breast cancer–specific survival may not be negatively affected.⁴

Additional References

1. Schmid P, Cortes J, Dent R, et al; for the KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567. Doi: 10.1056/NEJMoa2112651
2. Harbeck N, Rastogi P, Martin M, et al; on behalf of the monarchE Committee Members. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32:1571-1581. Doi: 10.1016/j.annonc.2021.09.015
3. Rodwin RL, Siddiq NZ, Ehrlich BE, Lustberg MB. Biomarkers of chemotherapy-induced peripheral neuropathy: current status and future directions. Front Pain Res (Lausanne). 2022;3:864910. Doi: 10.3389/fpain.2022.864910
4. Wyld L, Reed MW, Morgan J, et al. Bridging the age gap in breast cancer. Impacts of omission of breast cancer surgery in older women with oestrogen receptor positive early breast cancer. A risk stratified analysis of survival outcomes and quality of life. Eur J Cancer. 2021;142:48-62. Doi: 10.1016/j.ejca.2020.10.015

Taxanes are an integral component of various treatment regimens for all stages of breast cancer. As survival outcomes have improved, it has become increasingly important to focus on the long-term quality-of-life impact of treatment. Neurotoxicity is a well-recognized potential side effect of taxane chemotherapy. In a prospective cohort study including 1234 patients diagnosed with breast cancer and receiving taxanes, the risk for patient-reported chemotherapy-induced peripheral neuropathy (CIPN) were lower in the paclitaxel (HR 0.59; P = .008) and docetaxel (HR 0.65; P = .02) groups vs the nab-paclitaxel group. There was less sensory discomfort reported with paclitaxel (HR 0.44; P < .001) and docetaxel (HR 0.52; P < .001) vs nab-paclitaxel; however, reported motor and autonomic symptoms were not significantly lower than in the nab-paclitaxel group (Mo et al). An area of research interest is the identification of biomarkers that may predict a higher likelihood of CIPN development, to aid in early detection and intervention.³

Management strategies for breast cancer diagnosed in older women should take into consideration age and competing medical comorbidities, and hormone receptor–positive histology is the most common subtype in this population. Some older women may be too frail or unfit for surgery, and furthermore, some may prefer to avoid surgery, even if it is considered a safe approach. A retrospective study including 91 older (≥ 70 years) patients with estrogen receptor–positive (ER+) breast cancer who underwent definitive endocrine therapy demonstrated a twofold higher mortality risk than the risk of needing invasive local treatment (surgery or radiation). The 5-year cumulative risks of undergoing invasive local treatment and having uncontrolled disease were 28% and 16%, respectively, whereas the 5-year cumulative overall survival was 42% (Gooijer et al). Although the majority of older women with ER+ early breast cancer will obtain a survival benefit with surgery plus endocrine therapy compared with primary endocrine therapy, there is a selected group with limited life expectancy owing to age, functional status, or medical comorbidities for whom it is appropriate to offer primary endocrine therapy, because breast cancer–specific survival may not be negatively affected.⁴

Additional References

1. Schmid P, Cortes J, Dent R, et al; for the KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567. Doi: 10.1056/NEJMoa2112651
2. Harbeck N, Rastogi P, Martin M, et al; on behalf of the monarchE Committee Members. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32:1571-1581. Doi: 10.1016/j.annonc.2021.09.015
3. Rodwin RL, Siddiq NZ, Ehrlich BE, Lustberg MB. Biomarkers of chemotherapy-induced peripheral neuropathy: current status and future directions. Front Pain Res (Lausanne). 2022;3:864910. Doi: 10.3389/fpain.2022.864910
4. Wyld L, Reed MW, Morgan J, et al. Bridging the age gap in breast cancer. Impacts of omission of breast cancer surgery in older women with oestrogen receptor positive early breast cancer. A risk stratified analysis of survival outcomes and quality of life. Eur J Cancer. 2021;142:48-62. Doi: 10.1016/j.ejca.2020.10.015