Clinical Edge Journal Scan

Mahalingam et al in the Journal of Maternal-Fetal & Neonatal Medicine reported the risk of preterm birth among women with uterine fibroids who underwent myomectomy versus those who did not prior to pregnancy. In this retrospective cohort study, the team evaluated 290 women with a viable intrauterine pregnancy and history of uterine fibroids and compared two groups: 70 with history of a prior myomectomy and 220 who did not undergo myomectomy and had at least 1 fibroid of size 5 cm or more detected at less than 21 weeks’ gestation. The team found that women who underwent prior myomectomy versus those who did not were more likely to deliver preterm < 37 weeks gestation (35% vs 21%; P = .02) and deliver a mean 1.4 weeks earlier (36.3±3.6 vs 37.7±3.7 weeks gestation; P = .02). Patients with history of myomectomy had a higher C-section rate (88% vs 53%, P < 0.001). However, when the authors controlled for late preterm pre-labor C-sections recommended by physicians in the myomectomy cohort (n=5), the difference in preterm birth was not significant between the groups.

Lee et al reported that MRI can potentially predict the benefit of GnRH-agonist treatment prior to for large fibroids. In this retrospective analysis published in Acta Radiologica, 30 patients with large uterine fibroids received GnRH agonist prior to uterine artery embolization (UAE) with MRI evaluation before and after treatment. Indications for GnRH-agonist treatment (monthly 3.75 mg leuprolide acetate injections) included intramural or subserosal fibroids > 10 cm in diameter or pedunculated submucosal fibroids > 8 cm, as well as contrast enhancement observed on T1-weighted (T1W) images. Mean maximum fibroid diameter was 11.1 + 1.9 cm and mean number of GnRH-agonist injections received was 2.8. Signal intensity (SI) of the predominant fibroid on T2-weighted (T2W) images was referenced to the SI of the rectus abdominus muscle (F/R). For predicting a volume reduction rate of the large fibroid of >50%, the optimal cut-off value of F/R was 2.58 (sensitivity 80%, specificity 80%). Likewise, large fibroids with a volume rate reduction of <30% had an optimal cut-off volume of 1.69 (sensitivity 100%, specificity 70%). From a clinical perspective, both surgeons and radiologists could use SI of the predominant fibroid on T2W to predict response to GnRH agonist pretreatment.

Mahalingam et al in the Journal of Maternal-Fetal & Neonatal Medicine reported the risk of preterm birth among women with uterine fibroids who underwent myomectomy versus those who did not prior to pregnancy. In this retrospective cohort study, the team evaluated 290 women with a viable intrauterine pregnancy and history of uterine fibroids and compared two groups: 70 with history of a prior myomectomy and 220 who did not undergo myomectomy and had at least 1 fibroid of size 5 cm or more detected at less than 21 weeks’ gestation. The team found that women who underwent prior myomectomy versus those who did not were more likely to deliver preterm < 37 weeks gestation (35% vs 21%; P = .02) and deliver a mean 1.4 weeks earlier (36.3±3.6 vs 37.7±3.7 weeks gestation; P = .02). Patients with history of myomectomy had a higher C-section rate (88% vs 53%, P < 0.001). However, when the authors controlled for late preterm pre-labor C-sections recommended by physicians in the myomectomy cohort (n=5), the difference in preterm birth was not significant between the groups.

Lee et al reported that MRI can potentially predict the benefit of GnRH-agonist treatment prior to for large fibroids. In this retrospective analysis published in Acta Radiologica, 30 patients with large uterine fibroids received GnRH agonist prior to uterine artery embolization (UAE) with MRI evaluation before and after treatment. Indications for GnRH-agonist treatment (monthly 3.75 mg leuprolide acetate injections) included intramural or subserosal fibroids > 10 cm in diameter or pedunculated submucosal fibroids > 8 cm, as well as contrast enhancement observed on T1-weighted (T1W) images. Mean maximum fibroid diameter was 11.1 + 1.9 cm and mean number of GnRH-agonist injections received was 2.8. Signal intensity (SI) of the predominant fibroid on T2-weighted (T2W) images was referenced to the SI of the rectus abdominus muscle (F/R). For predicting a volume reduction rate of the large fibroid of >50%, the optimal cut-off value of F/R was 2.58 (sensitivity 80%, specificity 80%). Likewise, large fibroids with a volume rate reduction of <30% had an optimal cut-off volume of 1.69 (sensitivity 100%, specificity 70%). From a clinical perspective, both surgeons and radiologists could use SI of the predominant fibroid on T2W to predict response to GnRH agonist pretreatment.

Mahalingam et al in the Journal of Maternal-Fetal & Neonatal Medicine reported the risk of preterm birth among women with uterine fibroids who underwent myomectomy versus those who did not prior to pregnancy. In this retrospective cohort study, the team evaluated 290 women with a viable intrauterine pregnancy and history of uterine fibroids and compared two groups: 70 with history of a prior myomectomy and 220 who did not undergo myomectomy and had at least 1 fibroid of size 5 cm or more detected at less than 21 weeks’ gestation. The team found that women who underwent prior myomectomy versus those who did not were more likely to deliver preterm < 37 weeks gestation (35% vs 21%; P = .02) and deliver a mean 1.4 weeks earlier (36.3±3.6 vs 37.7±3.7 weeks gestation; P = .02). Patients with history of myomectomy had a higher C-section rate (88% vs 53%, P < 0.001). However, when the authors controlled for late preterm pre-labor C-sections recommended by physicians in the myomectomy cohort (n=5), the difference in preterm birth was not significant between the groups.

Lee et al reported that MRI can potentially predict the benefit of GnRH-agonist treatment prior to for large fibroids. In this retrospective analysis published in Acta Radiologica, 30 patients with large uterine fibroids received GnRH agonist prior to uterine artery embolization (UAE) with MRI evaluation before and after treatment. Indications for GnRH-agonist treatment (monthly 3.75 mg leuprolide acetate injections) included intramural or subserosal fibroids > 10 cm in diameter or pedunculated submucosal fibroids > 8 cm, as well as contrast enhancement observed on T1-weighted (T1W) images. Mean maximum fibroid diameter was 11.1 + 1.9 cm and mean number of GnRH-agonist injections received was 2.8. Signal intensity (SI) of the predominant fibroid on T2-weighted (T2W) images was referenced to the SI of the rectus abdominus muscle (F/R). For predicting a volume reduction rate of the large fibroid of >50%, the optimal cut-off value of F/R was 2.58 (sensitivity 80%, specificity 80%). Likewise, large fibroids with a volume rate reduction of <30% had an optimal cut-off volume of 1.69 (sensitivity 100%, specificity 70%). From a clinical perspective, both surgeons and radiologists could use SI of the predominant fibroid on T2W to predict response to GnRH agonist pretreatment.

Biologic therapy is generally reserved for patients with more moderate-to-severe psoriasis, often defined as BSA ≥10% or PASI of ≥10. Notably, these criteria are all clinician-performed. The Dermatology Life Quality Index (DLQI) measures the impact of the disease on the patient with a score of 0-5, 6-10, and 11-30 indicating mild, moderate, and severe disease, respectively. In a cross-sectional, observational study, 72.4% of psoriasis patients who qualified for systemic therapy initiation based on PASI and/or BSA had a DLQI of less than 10. Conversely, 10.4% of patients with a DLQI score higher than 10 did not qualify for systemic therapy based on PASI and/or BSA. This study highlights the complementary value of considering both clinician and patient determinants of disease severity when choosing a psoriasis therapy (Barbieri JS et al.)

With so many therapeutic options, it is increasingly common for patients to switch from one biologic to another. Many factors that go into the decision to switch therapies. A retrospective study of 115 adult patients with psoriasis found that the primary factor driving switching was lack of sufficient efficacy in treating skin disease. Having concomitant psoriatic arthritis increased the likelihood of switching by 2.69-fold (Akdogan N et al.). These findings suggest that shared decision making with dermatology, rheumatology, and the patient may help in choosing a treatment plan that best addresses both skin and joints.

One consideration when counseling patients about their likelihood of response to a second or third biologic is that in several clinical trials, biologic-naïve patients tend to have higher PASI responses to biologics than do heavier and biologic-experienced patients. A recent retrospective study found that receiving one or more biologic receiving was associated with a lower likelihood of achieving a PASI75 response to guselkumab (Hung YT et al.). However, in a real-life multicenter study including 57 adult patients with moderate-to-severe psoriasis receiving risankizumab, more biologic-experienced patients reached PASI 100 at weeks 36 and 52 (71.8% and 69.2%, respectively) compared with biologic-naïve patients (50.0% and 37.5%, respectively) (Gerdes S et al.). While both studies were small and no firm conclusions or comparisons can be drawn, real-world data from large multicenter studies that evaluate multiple therapies may guide us in choosing the best therapy for challenging patients who are often underrepresented in clinical trials. Understanding how switching within vs. between classes (TNF, IL-17, and IL-23 inhibitors) impacts efficacy will also help in making choices about biologic switches.

Biologic therapy is generally reserved for patients with more moderate-to-severe psoriasis, often defined as BSA ≥10% or PASI of ≥10. Notably, these criteria are all clinician-performed. The Dermatology Life Quality Index (DLQI) measures the impact of the disease on the patient with a score of 0-5, 6-10, and 11-30 indicating mild, moderate, and severe disease, respectively. In a cross-sectional, observational study, 72.4% of psoriasis patients who qualified for systemic therapy initiation based on PASI and/or BSA had a DLQI of less than 10. Conversely, 10.4% of patients with a DLQI score higher than 10 did not qualify for systemic therapy based on PASI and/or BSA. This study highlights the complementary value of considering both clinician and patient determinants of disease severity when choosing a psoriasis therapy (Barbieri JS et al.)

With so many therapeutic options, it is increasingly common for patients to switch from one biologic to another. Many factors that go into the decision to switch therapies. A retrospective study of 115 adult patients with psoriasis found that the primary factor driving switching was lack of sufficient efficacy in treating skin disease. Having concomitant psoriatic arthritis increased the likelihood of switching by 2.69-fold (Akdogan N et al.). These findings suggest that shared decision making with dermatology, rheumatology, and the patient may help in choosing a treatment plan that best addresses both skin and joints.

One consideration when counseling patients about their likelihood of response to a second or third biologic is that in several clinical trials, biologic-naïve patients tend to have higher PASI responses to biologics than do heavier and biologic-experienced patients. A recent retrospective study found that receiving one or more biologic receiving was associated with a lower likelihood of achieving a PASI75 response to guselkumab (Hung YT et al.). However, in a real-life multicenter study including 57 adult patients with moderate-to-severe psoriasis receiving risankizumab, more biologic-experienced patients reached PASI 100 at weeks 36 and 52 (71.8% and 69.2%, respectively) compared with biologic-naïve patients (50.0% and 37.5%, respectively) (Gerdes S et al.). While both studies were small and no firm conclusions or comparisons can be drawn, real-world data from large multicenter studies that evaluate multiple therapies may guide us in choosing the best therapy for challenging patients who are often underrepresented in clinical trials. Understanding how switching within vs. between classes (TNF, IL-17, and IL-23 inhibitors) impacts efficacy will also help in making choices about biologic switches.

Biologic therapy is generally reserved for patients with more moderate-to-severe psoriasis, often defined as BSA ≥10% or PASI of ≥10. Notably, these criteria are all clinician-performed. The Dermatology Life Quality Index (DLQI) measures the impact of the disease on the patient with a score of 0-5, 6-10, and 11-30 indicating mild, moderate, and severe disease, respectively. In a cross-sectional, observational study, 72.4% of psoriasis patients who qualified for systemic therapy initiation based on PASI and/or BSA had a DLQI of less than 10. Conversely, 10.4% of patients with a DLQI score higher than 10 did not qualify for systemic therapy based on PASI and/or BSA. This study highlights the complementary value of considering both clinician and patient determinants of disease severity when choosing a psoriasis therapy (Barbieri JS et al.)

With so many therapeutic options, it is increasingly common for patients to switch from one biologic to another. Many factors that go into the decision to switch therapies. A retrospective study of 115 adult patients with psoriasis found that the primary factor driving switching was lack of sufficient efficacy in treating skin disease. Having concomitant psoriatic arthritis increased the likelihood of switching by 2.69-fold (Akdogan N et al.). These findings suggest that shared decision making with dermatology, rheumatology, and the patient may help in choosing a treatment plan that best addresses both skin and joints.

One consideration when counseling patients about their likelihood of response to a second or third biologic is that in several clinical trials, biologic-naïve patients tend to have higher PASI responses to biologics than do heavier and biologic-experienced patients. A recent retrospective study found that receiving one or more biologic receiving was associated with a lower likelihood of achieving a PASI75 response to guselkumab (Hung YT et al.). However, in a real-life multicenter study including 57 adult patients with moderate-to-severe psoriasis receiving risankizumab, more biologic-experienced patients reached PASI 100 at weeks 36 and 52 (71.8% and 69.2%, respectively) compared with biologic-naïve patients (50.0% and 37.5%, respectively) (Gerdes S et al.). While both studies were small and no firm conclusions or comparisons can be drawn, real-world data from large multicenter studies that evaluate multiple therapies may guide us in choosing the best therapy for challenging patients who are often underrepresented in clinical trials. Understanding how switching within vs. between classes (TNF, IL-17, and IL-23 inhibitors) impacts efficacy will also help in making choices about biologic switches.

Similarly, Lin et al report the results of an international study of adults from 99 countries, which utilized longitudinal mobile based surveys to examine risk factors associated with SARS-CoV-2 infection. The mobile surveys captured baseline characteristics and behaviors of participants, and data was reported out for the study period of March to October 2020 (before vaccines were available). Adjusting for demographics, education level, a proxy for occupational risk, as well as medical comorbidities, authors found that greater number of non-household contacts, attending events with 10 or more individuals and restaurant visits predicted higher risk of SARS-CoV-2. Alternatively, older age was associated with lower risk, likely because of the protective behaviors undertaken by many in the older age group.

Lastly, the RECoVERED Study (Wynberg, at al), based in Netherlands, followed recently diagnosed laboratory confirmed SARS-CoV-2 patients for a year, initially with three in person visits (where disease severity was determined based on vital signs and level of care needed) within the first month of illness and then monthly online surveys. Authors utilized a survey examining severity of 18 symptoms based on the World Health Organization Case Report Form. Authors found 86.7% of those with initial severe disease [95% confidence interval {CI} = 76.5–92.7%]), 63.8%  of those moderate disease 63.8% [95% CI = 54.8–71.5%], and 30.7% of those with mild disease [95% CI = 21.1–40.9%] had at least one persistent symptom at 12 weeks.  Fatigue was the most common symptom reported at 12 weeks overall, but among those with moderate and severe disease, dyspnea and myalgia also persisted frequently. After one years of follow up, about one-fifth still had one persistent symptom. Over half of those with initial severe disease reported symptom persistence (52.5% [95% CI = 38.0–65.1%]). In a multivariable Cox proportional hazard model, female sex and higher BMI were associated with slower recovery. One limitation of the study was that was no control group recruited.

Similarly, Lin et al report the results of an international study of adults from 99 countries, which utilized longitudinal mobile based surveys to examine risk factors associated with SARS-CoV-2 infection. The mobile surveys captured baseline characteristics and behaviors of participants, and data was reported out for the study period of March to October 2020 (before vaccines were available). Adjusting for demographics, education level, a proxy for occupational risk, as well as medical comorbidities, authors found that greater number of non-household contacts, attending events with 10 or more individuals and restaurant visits predicted higher risk of SARS-CoV-2. Alternatively, older age was associated with lower risk, likely because of the protective behaviors undertaken by many in the older age group.

Lastly, the RECoVERED Study (Wynberg, at al), based in Netherlands, followed recently diagnosed laboratory confirmed SARS-CoV-2 patients for a year, initially with three in person visits (where disease severity was determined based on vital signs and level of care needed) within the first month of illness and then monthly online surveys. Authors utilized a survey examining severity of 18 symptoms based on the World Health Organization Case Report Form. Authors found 86.7% of those with initial severe disease [95% confidence interval {CI} = 76.5–92.7%]), 63.8%  of those moderate disease 63.8% [95% CI = 54.8–71.5%], and 30.7% of those with mild disease [95% CI = 21.1–40.9%] had at least one persistent symptom at 12 weeks.  Fatigue was the most common symptom reported at 12 weeks overall, but among those with moderate and severe disease, dyspnea and myalgia also persisted frequently. After one years of follow up, about one-fifth still had one persistent symptom. Over half of those with initial severe disease reported symptom persistence (52.5% [95% CI = 38.0–65.1%]). In a multivariable Cox proportional hazard model, female sex and higher BMI were associated with slower recovery. One limitation of the study was that was no control group recruited.

Similarly, Lin et al report the results of an international study of adults from 99 countries, which utilized longitudinal mobile based surveys to examine risk factors associated with SARS-CoV-2 infection. The mobile surveys captured baseline characteristics and behaviors of participants, and data was reported out for the study period of March to October 2020 (before vaccines were available). Adjusting for demographics, education level, a proxy for occupational risk, as well as medical comorbidities, authors found that greater number of non-household contacts, attending events with 10 or more individuals and restaurant visits predicted higher risk of SARS-CoV-2. Alternatively, older age was associated with lower risk, likely because of the protective behaviors undertaken by many in the older age group.

Lastly, the RECoVERED Study (Wynberg, at al), based in Netherlands, followed recently diagnosed laboratory confirmed SARS-CoV-2 patients for a year, initially with three in person visits (where disease severity was determined based on vital signs and level of care needed) within the first month of illness and then monthly online surveys. Authors utilized a survey examining severity of 18 symptoms based on the World Health Organization Case Report Form. Authors found 86.7% of those with initial severe disease [95% confidence interval {CI} = 76.5–92.7%]), 63.8%  of those moderate disease 63.8% [95% CI = 54.8–71.5%], and 30.7% of those with mild disease [95% CI = 21.1–40.9%] had at least one persistent symptom at 12 weeks.  Fatigue was the most common symptom reported at 12 weeks overall, but among those with moderate and severe disease, dyspnea and myalgia also persisted frequently. After one years of follow up, about one-fifth still had one persistent symptom. Over half of those with initial severe disease reported symptom persistence (52.5% [95% CI = 38.0–65.1%]). In a multivariable Cox proportional hazard model, female sex and higher BMI were associated with slower recovery. One limitation of the study was that was no control group recruited.

Biosimilar medications have received significant attention recently in the treatment of rheumatoid arthritis (RA), though the effects of switching from the reference drug to a biosimilar is not known. The study by Fleischmann et al¹ looks at the safety and efficacy, as well as immunogenicity, of biosimilar adalimumab (ADL-PF) compared to the reference ADL-EU (European Union sourced adalimumab) in a randomized double-blind study. Patients were randomized to start and continue ADL-PF or start ADL-EU and switch to ADL-PF at week 26 or 52. Immunogenicity was measured using anti-drug antibodies (ADA). American College of Rheumatology (ACR20) response rates were similar among all groups, while ACR50 and ACR70 response rates were numerically lower in the week 52 switch group. ADA development was comparable between groups. Data were analyzed using descriptive statistics, but overall, safety, efficacy, and immunogenicity were similar between patients maintained on ADL-PF and those switched from ADL-EU at week 26 or 52.

Statins have long been associated with musculoskeletal symptoms in patients, but have also been postulated to have anti-inflammatory and immunomodulatory effects. Complicating the relationship is the knowledge that inflammation increases cardiovascular risk in RA patients. In a case-control study, Peterson et al² used an administrative database to examine the influence of statin use on development of RA. Cases were identified based on ICD-9 coding as well as a prescription for methotrexate after diagnosis. They were matched 1:1 with controls based on demographics and year of diagnosis. Statin use was evaluated. Statin use was associated with a small increase in risk of RA, which was diminished after adjusting for hyperlipidemia; a trend towards increase in risk with higher dose and duration of statin use was not statistically significant. Beyond this, the reduced risk after adjustment for hyperlipidemia is hard to interpret as an explanation of cause or effect of autoimmunity, and, given the small magnitude of increases and decreases in risk, may not be clinically meaningful.

In addition to patients with RA having a higher burden of cardiovascular disease necessitating use of statins, they also have a high risk of progressive secondary osteoarthritis requiring joint replacement surgery. Chang et al³ used a national claims-based dataset from China to examine risk of total knee or hip replacement (TKR and THR, respectively) in patients with RA. From 2000-2013 (ie, the onset of the biologic era), TKR and THR rates were examined in a cohort of biologic disease-modifying antirheumatic drug (bDMARD) users compared to conventional synthetic DMARD (csDMARD) users. Adjusted hazard ratios (HR) were lower for both TKD and THR in bDMARD users. Though RA activity was not examined, combined with the knowledge of the association of disease severity with bDMARD use, this study lends evidence to the benefits of more aggressive treatment.

Finally, much is made of the link between bDMARD and targeted synthetic DMARD use and malignancy due to reduced immunosurveillance, but concrete evidence is conflicting. Wetzman et al⁴ performed a systematic review of studies of patients with inflammatory arthritis (RA, psoriatic arthritis, and Ankylosing spondylitis) looking at cancer relapse or occurrence of new cancer. An increase in skin cancers (HR 1.32) was noted, but reassuringly no other increase in risk of recurrent or new cancer was seen.

References

1. Fleischmann R et al. Long-term efficacy, safety, and immunogenicity of the adalimumab biosimilar, PF-06410293, in patients with rheumatoid arthritis after switching from reference adalimumab (Humira®) or continuing biosimilar therapy: week 52–92 data from a randomized, double-blind, phase 3 trialArthritis Res Ther. 2021(Sep 25);23:248.
2. Peterson MN et al. Risk of rheumatoid arthritis diagnosis in statin users in a large nationwide US study. Arthritis Res Ther. 2021(Sep 18):23:244.
3. Chang YS et al. Effects of biologics on reducing the risks of total knee replacement and total hip replacement in rheumatoid arthritis. Rheumatology (Oxford). 2021(Sep 17):keab671.
4. Wetzman A et al. Risk of cancer after initiation of targeted therapies in patients with rheumatoid arthritis and a prior cancer: systematic review with meta-analysis. Arthritis Care Res (Hoboken). 2021(Sep 21): acr.24784.

Biosimilar medications have received significant attention recently in the treatment of rheumatoid arthritis (RA), though the effects of switching from the reference drug to a biosimilar is not known. The study by Fleischmann et al¹ looks at the safety and efficacy, as well as immunogenicity, of biosimilar adalimumab (ADL-PF) compared to the reference ADL-EU (European Union sourced adalimumab) in a randomized double-blind study. Patients were randomized to start and continue ADL-PF or start ADL-EU and switch to ADL-PF at week 26 or 52. Immunogenicity was measured using anti-drug antibodies (ADA). American College of Rheumatology (ACR20) response rates were similar among all groups, while ACR50 and ACR70 response rates were numerically lower in the week 52 switch group. ADA development was comparable between groups. Data were analyzed using descriptive statistics, but overall, safety, efficacy, and immunogenicity were similar between patients maintained on ADL-PF and those switched from ADL-EU at week 26 or 52.

Statins have long been associated with musculoskeletal symptoms in patients, but have also been postulated to have anti-inflammatory and immunomodulatory effects. Complicating the relationship is the knowledge that inflammation increases cardiovascular risk in RA patients. In a case-control study, Peterson et al² used an administrative database to examine the influence of statin use on development of RA. Cases were identified based on ICD-9 coding as well as a prescription for methotrexate after diagnosis. They were matched 1:1 with controls based on demographics and year of diagnosis. Statin use was evaluated. Statin use was associated with a small increase in risk of RA, which was diminished after adjusting for hyperlipidemia; a trend towards increase in risk with higher dose and duration of statin use was not statistically significant. Beyond this, the reduced risk after adjustment for hyperlipidemia is hard to interpret as an explanation of cause or effect of autoimmunity, and, given the small magnitude of increases and decreases in risk, may not be clinically meaningful.

In addition to patients with RA having a higher burden of cardiovascular disease necessitating use of statins, they also have a high risk of progressive secondary osteoarthritis requiring joint replacement surgery. Chang et al³ used a national claims-based dataset from China to examine risk of total knee or hip replacement (TKR and THR, respectively) in patients with RA. From 2000-2013 (ie, the onset of the biologic era), TKR and THR rates were examined in a cohort of biologic disease-modifying antirheumatic drug (bDMARD) users compared to conventional synthetic DMARD (csDMARD) users. Adjusted hazard ratios (HR) were lower for both TKD and THR in bDMARD users. Though RA activity was not examined, combined with the knowledge of the association of disease severity with bDMARD use, this study lends evidence to the benefits of more aggressive treatment.

Finally, much is made of the link between bDMARD and targeted synthetic DMARD use and malignancy due to reduced immunosurveillance, but concrete evidence is conflicting. Wetzman et al⁴ performed a systematic review of studies of patients with inflammatory arthritis (RA, psoriatic arthritis, and Ankylosing spondylitis) looking at cancer relapse or occurrence of new cancer. An increase in skin cancers (HR 1.32) was noted, but reassuringly no other increase in risk of recurrent or new cancer was seen.

References

1. Fleischmann R et al. Long-term efficacy, safety, and immunogenicity of the adalimumab biosimilar, PF-06410293, in patients with rheumatoid arthritis after switching from reference adalimumab (Humira®) or continuing biosimilar therapy: week 52–92 data from a randomized, double-blind, phase 3 trialArthritis Res Ther. 2021(Sep 25);23:248.
2. Peterson MN et al. Risk of rheumatoid arthritis diagnosis in statin users in a large nationwide US study. Arthritis Res Ther. 2021(Sep 18):23:244.
3. Chang YS et al. Effects of biologics on reducing the risks of total knee replacement and total hip replacement in rheumatoid arthritis. Rheumatology (Oxford). 2021(Sep 17):keab671.
4. Wetzman A et al. Risk of cancer after initiation of targeted therapies in patients with rheumatoid arthritis and a prior cancer: systematic review with meta-analysis. Arthritis Care Res (Hoboken). 2021(Sep 21): acr.24784.

Biosimilar medications have received significant attention recently in the treatment of rheumatoid arthritis (RA), though the effects of switching from the reference drug to a biosimilar is not known. The study by Fleischmann et al¹ looks at the safety and efficacy, as well as immunogenicity, of biosimilar adalimumab (ADL-PF) compared to the reference ADL-EU (European Union sourced adalimumab) in a randomized double-blind study. Patients were randomized to start and continue ADL-PF or start ADL-EU and switch to ADL-PF at week 26 or 52. Immunogenicity was measured using anti-drug antibodies (ADA). American College of Rheumatology (ACR20) response rates were similar among all groups, while ACR50 and ACR70 response rates were numerically lower in the week 52 switch group. ADA development was comparable between groups. Data were analyzed using descriptive statistics, but overall, safety, efficacy, and immunogenicity were similar between patients maintained on ADL-PF and those switched from ADL-EU at week 26 or 52.

Statins have long been associated with musculoskeletal symptoms in patients, but have also been postulated to have anti-inflammatory and immunomodulatory effects. Complicating the relationship is the knowledge that inflammation increases cardiovascular risk in RA patients. In a case-control study, Peterson et al² used an administrative database to examine the influence of statin use on development of RA. Cases were identified based on ICD-9 coding as well as a prescription for methotrexate after diagnosis. They were matched 1:1 with controls based on demographics and year of diagnosis. Statin use was evaluated. Statin use was associated with a small increase in risk of RA, which was diminished after adjusting for hyperlipidemia; a trend towards increase in risk with higher dose and duration of statin use was not statistically significant. Beyond this, the reduced risk after adjustment for hyperlipidemia is hard to interpret as an explanation of cause or effect of autoimmunity, and, given the small magnitude of increases and decreases in risk, may not be clinically meaningful.

In addition to patients with RA having a higher burden of cardiovascular disease necessitating use of statins, they also have a high risk of progressive secondary osteoarthritis requiring joint replacement surgery. Chang et al³ used a national claims-based dataset from China to examine risk of total knee or hip replacement (TKR and THR, respectively) in patients with RA. From 2000-2013 (ie, the onset of the biologic era), TKR and THR rates were examined in a cohort of biologic disease-modifying antirheumatic drug (bDMARD) users compared to conventional synthetic DMARD (csDMARD) users. Adjusted hazard ratios (HR) were lower for both TKD and THR in bDMARD users. Though RA activity was not examined, combined with the knowledge of the association of disease severity with bDMARD use, this study lends evidence to the benefits of more aggressive treatment.

Finally, much is made of the link between bDMARD and targeted synthetic DMARD use and malignancy due to reduced immunosurveillance, but concrete evidence is conflicting. Wetzman et al⁴ performed a systematic review of studies of patients with inflammatory arthritis (RA, psoriatic arthritis, and Ankylosing spondylitis) looking at cancer relapse or occurrence of new cancer. An increase in skin cancers (HR 1.32) was noted, but reassuringly no other increase in risk of recurrent or new cancer was seen.

References

1. Fleischmann R et al. Long-term efficacy, safety, and immunogenicity of the adalimumab biosimilar, PF-06410293, in patients with rheumatoid arthritis after switching from reference adalimumab (Humira®) or continuing biosimilar therapy: week 52–92 data from a randomized, double-blind, phase 3 trialArthritis Res Ther. 2021(Sep 25);23:248.
2. Peterson MN et al. Risk of rheumatoid arthritis diagnosis in statin users in a large nationwide US study. Arthritis Res Ther. 2021(Sep 18):23:244.
3. Chang YS et al. Effects of biologics on reducing the risks of total knee replacement and total hip replacement in rheumatoid arthritis. Rheumatology (Oxford). 2021(Sep 17):keab671.
4. Wetzman A et al. Risk of cancer after initiation of targeted therapies in patients with rheumatoid arthritis and a prior cancer: systematic review with meta-analysis. Arthritis Care Res (Hoboken). 2021(Sep 21): acr.24784.

There have been quite a few papers published in October that have provided further insights into psoriatic arthritis (PsA). Understanding risk factors for developing PsA in patients with psoriasis is of ongoing interest, but there is limited data on the relationship between the severity of psoriasis and the risk of developing PsA especially in the USA population. Using the Optum electronic health records (EHR) database, Merola et al¹ assessed the incidence, prevalence, and predictors of PsA among 114,868 patients with psoriasis between January 1, 2009, and March 31, 2019. The severity of psoriasis was determined by treatment received during the 1 year after psoriasis diagnosis as follows: mild (89.3%) topicals and phototherapy only; moderate (5.5%) nonbiologic systemic therapies (acitretin, apremilast, cyclosporine, methotrexate), and severe (5.2%) biologic therapies (adalimumab, certolizumab pegol, etanercept, golimumab, guselkumab, infliximab, ixekizumab, secukinumab, ustekinumab). They found that the overall incidence of PsA was 2.9 (95% CI 2.9-3.0) events per 100 patient-years of follow up (PY). The incidence (100 PY, 95% CI) by severity was lowest (2.1 [95% CI 2.1-2.1]) in the mild, higher in the moderate (9.9 [95% CI 9.5-10.4]), and highest (17.6 [95% CI 16.9-18.3]) in the severe psoriasis category. The study thus confirms that patients with more severe psoriasis have higher risk of developing PsA.

The effect of treatment of psoriasis on the development of PsA is also have great interest. Recent studies² have indicated that biologic treatment of psoriasis may reduce the incidence of PsA. However, Meer et al³ in a retrospective cohort study using of 1,93,709 patients with psoriasis without PsA in the Optum Insights EHR database report that biologic use was associated with the development of PsA among patients with psoriasis. After propensity score matching, the hazard ratio was 2.14 (95% CI 2.00-2.28) for patients on biologics compared to those on oral therapy or phototherapy. Such studies are influenced by confounding factors ,by indication, and protopathic bias and hence prospective studies are warranted.

Better treatment outcomes are likely if patient priorities are taken into account when choosing a therapy. However, there are few studies addressing this issue. Sumpton et al⁴ conducted a discrete choice experiment in patients with PsA in Sydney, Australia, to assess preferences for different attributes of biologics. They identified the following attributes in order of preference: oral route (compared to subcutaneous and intravenous routes), avoiding severe side effects, increasing ability to attend to normal activities, avoiding infections, improvement in enthesitis pain, improvement in psoriasis, increasing chance of remission and improvement in joint pain. Thus, patients valued ease of administration, avoiding side effects, and physical function more when choosing a therapy. With increased availability of treatment choices, developing decision support systems that facilitate shared decision making between patients and clinicians is required to improve care of PsA patients.

Ultrasound is increasingly being used at the point of care in rheumatology, but until now ultrasound was not used as a primary outcome in a clinical trial. In the first randomized, placebo-controlled, phase III study using power Doppler ultrasound (PDUS) D’Agostino et al⁵ demonstrated that treatment with secukinumab (dosed according to psoriasis severity) led to statistically significant improvement in synovitis measured using the Global European League Against Rheumatism and Outcome Measures in Rheumatoid Arthritis Clinical Trials Synovitis Score (GLOESS) compared to placebo. Thus, secukinumab, an IL-17A inhibitor, reduces synovitis as detected by ultrasound as well as symptoms and clinical signs of PsA.

References

1. Merola JF et al. Incidence and Prevalence of Psoriatic Arthritis in Patients With Psoriasis Stratified by Psoriasis Disease Severity: Retrospective Analysis of a US Electronic Health Records Database. J Am Acad Dermatol. 2021(Sep 18):S0190-9622(21)02494-4.
2. Acosta Felquer ML et al. Treating the skin with biologics in patients with psoriasis decreases the incidence of psoriatic arthritis. Ann Rheum Dis. 2021 (Jul 19):annrheumdis-2021-220865.
3. Meer E et al. Does biologic therapy impact the development of PsA among patients with psoriasis? Ann Rheum Dis. 2021(Oct 6):annrheumdis-2021-220761.
4. Sumpton D et al. Preferences for biologic treatment in patients with psoriatic arthritis: a discrete choice experiment. Arthritis Care Res (Hoboken). 2021(Sep 13):acr.24782
5. D'Agostino MA et al. Response to secukinumab on synovitis using power Doppler ultrasound in psoriatic arthritis: 12-week results from a phase III study, ULTIMATE. Rheumatology (Oxford). 2021(Sep 16):keab628.

There have been quite a few papers published in October that have provided further insights into psoriatic arthritis (PsA). Understanding risk factors for developing PsA in patients with psoriasis is of ongoing interest, but there is limited data on the relationship between the severity of psoriasis and the risk of developing PsA especially in the USA population. Using the Optum electronic health records (EHR) database, Merola et al¹ assessed the incidence, prevalence, and predictors of PsA among 114,868 patients with psoriasis between January 1, 2009, and March 31, 2019. The severity of psoriasis was determined by treatment received during the 1 year after psoriasis diagnosis as follows: mild (89.3%) topicals and phototherapy only; moderate (5.5%) nonbiologic systemic therapies (acitretin, apremilast, cyclosporine, methotrexate), and severe (5.2%) biologic therapies (adalimumab, certolizumab pegol, etanercept, golimumab, guselkumab, infliximab, ixekizumab, secukinumab, ustekinumab). They found that the overall incidence of PsA was 2.9 (95% CI 2.9-3.0) events per 100 patient-years of follow up (PY). The incidence (100 PY, 95% CI) by severity was lowest (2.1 [95% CI 2.1-2.1]) in the mild, higher in the moderate (9.9 [95% CI 9.5-10.4]), and highest (17.6 [95% CI 16.9-18.3]) in the severe psoriasis category. The study thus confirms that patients with more severe psoriasis have higher risk of developing PsA.

The effect of treatment of psoriasis on the development of PsA is also have great interest. Recent studies² have indicated that biologic treatment of psoriasis may reduce the incidence of PsA. However, Meer et al³ in a retrospective cohort study using of 1,93,709 patients with psoriasis without PsA in the Optum Insights EHR database report that biologic use was associated with the development of PsA among patients with psoriasis. After propensity score matching, the hazard ratio was 2.14 (95% CI 2.00-2.28) for patients on biologics compared to those on oral therapy or phototherapy. Such studies are influenced by confounding factors ,by indication, and protopathic bias and hence prospective studies are warranted.

Better treatment outcomes are likely if patient priorities are taken into account when choosing a therapy. However, there are few studies addressing this issue. Sumpton et al⁴ conducted a discrete choice experiment in patients with PsA in Sydney, Australia, to assess preferences for different attributes of biologics. They identified the following attributes in order of preference: oral route (compared to subcutaneous and intravenous routes), avoiding severe side effects, increasing ability to attend to normal activities, avoiding infections, improvement in enthesitis pain, improvement in psoriasis, increasing chance of remission and improvement in joint pain. Thus, patients valued ease of administration, avoiding side effects, and physical function more when choosing a therapy. With increased availability of treatment choices, developing decision support systems that facilitate shared decision making between patients and clinicians is required to improve care of PsA patients.

Ultrasound is increasingly being used at the point of care in rheumatology, but until now ultrasound was not used as a primary outcome in a clinical trial. In the first randomized, placebo-controlled, phase III study using power Doppler ultrasound (PDUS) D’Agostino et al⁵ demonstrated that treatment with secukinumab (dosed according to psoriasis severity) led to statistically significant improvement in synovitis measured using the Global European League Against Rheumatism and Outcome Measures in Rheumatoid Arthritis Clinical Trials Synovitis Score (GLOESS) compared to placebo. Thus, secukinumab, an IL-17A inhibitor, reduces synovitis as detected by ultrasound as well as symptoms and clinical signs of PsA.

References

1. Merola JF et al. Incidence and Prevalence of Psoriatic Arthritis in Patients With Psoriasis Stratified by Psoriasis Disease Severity: Retrospective Analysis of a US Electronic Health Records Database. J Am Acad Dermatol. 2021(Sep 18):S0190-9622(21)02494-4.
2. Acosta Felquer ML et al. Treating the skin with biologics in patients with psoriasis decreases the incidence of psoriatic arthritis. Ann Rheum Dis. 2021 (Jul 19):annrheumdis-2021-220865.
3. Meer E et al. Does biologic therapy impact the development of PsA among patients with psoriasis? Ann Rheum Dis. 2021(Oct 6):annrheumdis-2021-220761.
4. Sumpton D et al. Preferences for biologic treatment in patients with psoriatic arthritis: a discrete choice experiment. Arthritis Care Res (Hoboken). 2021(Sep 13):acr.24782
5. D'Agostino MA et al. Response to secukinumab on synovitis using power Doppler ultrasound in psoriatic arthritis: 12-week results from a phase III study, ULTIMATE. Rheumatology (Oxford). 2021(Sep 16):keab628.

There have been quite a few papers published in October that have provided further insights into psoriatic arthritis (PsA). Understanding risk factors for developing PsA in patients with psoriasis is of ongoing interest, but there is limited data on the relationship between the severity of psoriasis and the risk of developing PsA especially in the USA population. Using the Optum electronic health records (EHR) database, Merola et al¹ assessed the incidence, prevalence, and predictors of PsA among 114,868 patients with psoriasis between January 1, 2009, and March 31, 2019. The severity of psoriasis was determined by treatment received during the 1 year after psoriasis diagnosis as follows: mild (89.3%) topicals and phototherapy only; moderate (5.5%) nonbiologic systemic therapies (acitretin, apremilast, cyclosporine, methotrexate), and severe (5.2%) biologic therapies (adalimumab, certolizumab pegol, etanercept, golimumab, guselkumab, infliximab, ixekizumab, secukinumab, ustekinumab). They found that the overall incidence of PsA was 2.9 (95% CI 2.9-3.0) events per 100 patient-years of follow up (PY). The incidence (100 PY, 95% CI) by severity was lowest (2.1 [95% CI 2.1-2.1]) in the mild, higher in the moderate (9.9 [95% CI 9.5-10.4]), and highest (17.6 [95% CI 16.9-18.3]) in the severe psoriasis category. The study thus confirms that patients with more severe psoriasis have higher risk of developing PsA.

The effect of treatment of psoriasis on the development of PsA is also have great interest. Recent studies² have indicated that biologic treatment of psoriasis may reduce the incidence of PsA. However, Meer et al³ in a retrospective cohort study using of 1,93,709 patients with psoriasis without PsA in the Optum Insights EHR database report that biologic use was associated with the development of PsA among patients with psoriasis. After propensity score matching, the hazard ratio was 2.14 (95% CI 2.00-2.28) for patients on biologics compared to those on oral therapy or phototherapy. Such studies are influenced by confounding factors ,by indication, and protopathic bias and hence prospective studies are warranted.

Better treatment outcomes are likely if patient priorities are taken into account when choosing a therapy. However, there are few studies addressing this issue. Sumpton et al⁴ conducted a discrete choice experiment in patients with PsA in Sydney, Australia, to assess preferences for different attributes of biologics. They identified the following attributes in order of preference: oral route (compared to subcutaneous and intravenous routes), avoiding severe side effects, increasing ability to attend to normal activities, avoiding infections, improvement in enthesitis pain, improvement in psoriasis, increasing chance of remission and improvement in joint pain. Thus, patients valued ease of administration, avoiding side effects, and physical function more when choosing a therapy. With increased availability of treatment choices, developing decision support systems that facilitate shared decision making between patients and clinicians is required to improve care of PsA patients.

Ultrasound is increasingly being used at the point of care in rheumatology, but until now ultrasound was not used as a primary outcome in a clinical trial. In the first randomized, placebo-controlled, phase III study using power Doppler ultrasound (PDUS) D’Agostino et al⁵ demonstrated that treatment with secukinumab (dosed according to psoriasis severity) led to statistically significant improvement in synovitis measured using the Global European League Against Rheumatism and Outcome Measures in Rheumatoid Arthritis Clinical Trials Synovitis Score (GLOESS) compared to placebo. Thus, secukinumab, an IL-17A inhibitor, reduces synovitis as detected by ultrasound as well as symptoms and clinical signs of PsA.

References

1. Merola JF et al. Incidence and Prevalence of Psoriatic Arthritis in Patients With Psoriasis Stratified by Psoriasis Disease Severity: Retrospective Analysis of a US Electronic Health Records Database. J Am Acad Dermatol. 2021(Sep 18):S0190-9622(21)02494-4.
2. Acosta Felquer ML et al. Treating the skin with biologics in patients with psoriasis decreases the incidence of psoriatic arthritis. Ann Rheum Dis. 2021 (Jul 19):annrheumdis-2021-220865.
3. Meer E et al. Does biologic therapy impact the development of PsA among patients with psoriasis? Ann Rheum Dis. 2021(Oct 6):annrheumdis-2021-220761.
4. Sumpton D et al. Preferences for biologic treatment in patients with psoriatic arthritis: a discrete choice experiment. Arthritis Care Res (Hoboken). 2021(Sep 13):acr.24782
5. D'Agostino MA et al. Response to secukinumab on synovitis using power Doppler ultrasound in psoriatic arthritis: 12-week results from a phase III study, ULTIMATE. Rheumatology (Oxford). 2021(Sep 16):keab628.

While this month’s journal scan for clinical research reviews in exocrine pancreatic insufficiency (EPI) may not reveal a landmark paper, there certainly are novel findings worthy of note.  In particular researchers Halabitska and Babinets¹ from Ternopil National Medical University in Ukraine¹ looked at the impact of NSAID use on fecal elastase and nutritional parameters in patients with baseline EPI.

The researchers’ primary aim is based on the idea that osteoarthritis (OA) accounts for a significant global disease burden, particularly in advanced age with other concomitant comorbidities, yet most attention is paid to the study of peptic ulcer disease (PUD) and nonsteroidal anti-inflammatory drug (NSAID)-related enteropathies of the gastrointestinal tract after NSAID use. Researchers state, “however, no studies have been found to study the effect of NSAIDs on the progression of EPI and the development of trophological disorders, especially under conditions of primary OA comorbidity with diseases accompanied by EPI.”

This study included 87 adult patients with primary OA along with EPI and 30 healthy controls. The patients in the interventional group received a 14-day course of NSAIDs which are officially recommended for the treatment of pain in primary OA (15 mg/day meloxicam, 200 mg/day nimesulide, 150 mg/day diclofenac sodium).  Fecal α-elastase levels were analyzed before and after NSAID treatment in patients with primary OA and concomitant EPI. After NSAID treatment, there was a statistically significant decrease in EPI levels, which was most pronounced in the subgroup of patients with EPI from chronic pancreatitis. Further, the levels of trophologic parameters (magnesium, calcium, iron, zinc, selenium, albumin, and vitamins A, E, and K) decreased significantly after NSAID treatment (all P < .05).

The authors concluded that NSAID use likely worsens EPI and nutritional parameters in patients with primary osteoarthritis with concomitant EPI at baseline. This is potentially practice changing, which might suggest that a closer monitoring of EPI parameters during a course of NSAID treatment is needed. Patients with EPI are of course already at risk of fat soluble vitamin deficiencies, and it may provide only more reason to check and replenish micronutrients and vitamin levels after a course of NSAID therapy. 

References

1. Halabitska IM et al. Different consequences of the treatment of osteoarthritis in gastrointestinal comorbidity with exocrine pancreatic insufficiency. Fam Med Prim Care Rev. 2021 (Oct 5);23(4):10.5114/fmpcr.2021.108207.

While this month’s journal scan for clinical research reviews in exocrine pancreatic insufficiency (EPI) may not reveal a landmark paper, there certainly are novel findings worthy of note.  In particular researchers Halabitska and Babinets¹ from Ternopil National Medical University in Ukraine¹ looked at the impact of NSAID use on fecal elastase and nutritional parameters in patients with baseline EPI.

The researchers’ primary aim is based on the idea that osteoarthritis (OA) accounts for a significant global disease burden, particularly in advanced age with other concomitant comorbidities, yet most attention is paid to the study of peptic ulcer disease (PUD) and nonsteroidal anti-inflammatory drug (NSAID)-related enteropathies of the gastrointestinal tract after NSAID use. Researchers state, “however, no studies have been found to study the effect of NSAIDs on the progression of EPI and the development of trophological disorders, especially under conditions of primary OA comorbidity with diseases accompanied by EPI.”

This study included 87 adult patients with primary OA along with EPI and 30 healthy controls. The patients in the interventional group received a 14-day course of NSAIDs which are officially recommended for the treatment of pain in primary OA (15 mg/day meloxicam, 200 mg/day nimesulide, 150 mg/day diclofenac sodium).  Fecal α-elastase levels were analyzed before and after NSAID treatment in patients with primary OA and concomitant EPI. After NSAID treatment, there was a statistically significant decrease in EPI levels, which was most pronounced in the subgroup of patients with EPI from chronic pancreatitis. Further, the levels of trophologic parameters (magnesium, calcium, iron, zinc, selenium, albumin, and vitamins A, E, and K) decreased significantly after NSAID treatment (all P < .05).

The authors concluded that NSAID use likely worsens EPI and nutritional parameters in patients with primary osteoarthritis with concomitant EPI at baseline. This is potentially practice changing, which might suggest that a closer monitoring of EPI parameters during a course of NSAID treatment is needed. Patients with EPI are of course already at risk of fat soluble vitamin deficiencies, and it may provide only more reason to check and replenish micronutrients and vitamin levels after a course of NSAID therapy. 

References

1. Halabitska IM et al. Different consequences of the treatment of osteoarthritis in gastrointestinal comorbidity with exocrine pancreatic insufficiency. Fam Med Prim Care Rev. 2021 (Oct 5);23(4):10.5114/fmpcr.2021.108207.

While this month’s journal scan for clinical research reviews in exocrine pancreatic insufficiency (EPI) may not reveal a landmark paper, there certainly are novel findings worthy of note.  In particular researchers Halabitska and Babinets¹ from Ternopil National Medical University in Ukraine¹ looked at the impact of NSAID use on fecal elastase and nutritional parameters in patients with baseline EPI.

The researchers’ primary aim is based on the idea that osteoarthritis (OA) accounts for a significant global disease burden, particularly in advanced age with other concomitant comorbidities, yet most attention is paid to the study of peptic ulcer disease (PUD) and nonsteroidal anti-inflammatory drug (NSAID)-related enteropathies of the gastrointestinal tract after NSAID use. Researchers state, “however, no studies have been found to study the effect of NSAIDs on the progression of EPI and the development of trophological disorders, especially under conditions of primary OA comorbidity with diseases accompanied by EPI.”

This study included 87 adult patients with primary OA along with EPI and 30 healthy controls. The patients in the interventional group received a 14-day course of NSAIDs which are officially recommended for the treatment of pain in primary OA (15 mg/day meloxicam, 200 mg/day nimesulide, 150 mg/day diclofenac sodium).  Fecal α-elastase levels were analyzed before and after NSAID treatment in patients with primary OA and concomitant EPI. After NSAID treatment, there was a statistically significant decrease in EPI levels, which was most pronounced in the subgroup of patients with EPI from chronic pancreatitis. Further, the levels of trophologic parameters (magnesium, calcium, iron, zinc, selenium, albumin, and vitamins A, E, and K) decreased significantly after NSAID treatment (all P < .05).

The authors concluded that NSAID use likely worsens EPI and nutritional parameters in patients with primary osteoarthritis with concomitant EPI at baseline. This is potentially practice changing, which might suggest that a closer monitoring of EPI parameters during a course of NSAID treatment is needed. Patients with EPI are of course already at risk of fat soluble vitamin deficiencies, and it may provide only more reason to check and replenish micronutrients and vitamin levels after a course of NSAID therapy. 

References

1. Halabitska IM et al. Different consequences of the treatment of osteoarthritis in gastrointestinal comorbidity with exocrine pancreatic insufficiency. Fam Med Prim Care Rev. 2021 (Oct 5);23(4):10.5114/fmpcr.2021.108207.

In the study by Aggarwal et al., the investigators evaluated whether molecular subtypes as identified from biopsies of metastatic tumors in patients with metastatic castrate resistant prostate cancer (mCRPC) could result in improved prediction of response to therapies. In this retrospective study of 4 distinct cohorts, 45% of tumors were classified as luminal and 55% were classified as basal. Luminal tumors exhibited increased expression of androgen receptor pathway genes, and patients with luminal tumors had better survival after treatment with ASI compared with those with basal tumors. Genomic analyses of mCRPC metastases are challenging due to processing issues that can arise if bone decalcification needs to be done; therefore, this study provides an important next step to aid in the design appropriate clinical trials to investigate whether such genomic subtyping results in improved patient outcomes.

            In the study by Saad et al, the investigators evaluated whether the addition of the androgen receptor inhibitor apalutamide added to abiraterone would result in a higher radiographic progression free survival (rPFS) compared with abiraterone alone in patients with mCRPC. The combination resulted in an improvement in rPFS (24 versus 16.6 months); however, there was no improvement in overall survival. These results are similar to the Alliance A0321201 study, where enzalutamide was added to abiraterone, and no overall survival was observed. Further study is needed to determine if this combination strategy can work.

            Supportive care aside from ASIs or chemotherapy directed against prostate cancer is also of critical importance to patients with metastatic prostate cancer. Previous studies have demonstrated that BMAs, such as denosumab or zoledronic acid, result in the prevention of skeletal-related events (SREs) in patients with mCRPC. However, this same benefit has not been demonstrated in metastatic castrate sensitive prostate cancer (mCSPC); therefore, BMAs are not recommended in this population unless they are at high risk for osteoporotic fracture. Mitchell et al. evaluated a retrospective cohort identified from Surveillance, Epidemiology, and End Results (SEER)-Medicare data to determine the number of patients with likely mCSPC treated with a BMA (defined as prescribed a BMA within 180 or 90 days after initial diagnosis of metastatic disease). A significant number of patients with likely mCSPC were prescribed BMAs within 180 days of diagnosis (23.6% of the cohort) and within 90 days (18.4% of the cohort). It is likely that most of these patients inappropriately received BMAs and were potentially subject to unnecessary costs and toxicity. Further study of strategies to reduce inappropriate BMA use could lead to less toxicity and lower costs.

In the study by Aggarwal et al., the investigators evaluated whether molecular subtypes as identified from biopsies of metastatic tumors in patients with metastatic castrate resistant prostate cancer (mCRPC) could result in improved prediction of response to therapies. In this retrospective study of 4 distinct cohorts, 45% of tumors were classified as luminal and 55% were classified as basal. Luminal tumors exhibited increased expression of androgen receptor pathway genes, and patients with luminal tumors had better survival after treatment with ASI compared with those with basal tumors. Genomic analyses of mCRPC metastases are challenging due to processing issues that can arise if bone decalcification needs to be done; therefore, this study provides an important next step to aid in the design appropriate clinical trials to investigate whether such genomic subtyping results in improved patient outcomes.

            In the study by Saad et al, the investigators evaluated whether the addition of the androgen receptor inhibitor apalutamide added to abiraterone would result in a higher radiographic progression free survival (rPFS) compared with abiraterone alone in patients with mCRPC. The combination resulted in an improvement in rPFS (24 versus 16.6 months); however, there was no improvement in overall survival. These results are similar to the Alliance A0321201 study, where enzalutamide was added to abiraterone, and no overall survival was observed. Further study is needed to determine if this combination strategy can work.

            Supportive care aside from ASIs or chemotherapy directed against prostate cancer is also of critical importance to patients with metastatic prostate cancer. Previous studies have demonstrated that BMAs, such as denosumab or zoledronic acid, result in the prevention of skeletal-related events (SREs) in patients with mCRPC. However, this same benefit has not been demonstrated in metastatic castrate sensitive prostate cancer (mCSPC); therefore, BMAs are not recommended in this population unless they are at high risk for osteoporotic fracture. Mitchell et al. evaluated a retrospective cohort identified from Surveillance, Epidemiology, and End Results (SEER)-Medicare data to determine the number of patients with likely mCSPC treated with a BMA (defined as prescribed a BMA within 180 or 90 days after initial diagnosis of metastatic disease). A significant number of patients with likely mCSPC were prescribed BMAs within 180 days of diagnosis (23.6% of the cohort) and within 90 days (18.4% of the cohort). It is likely that most of these patients inappropriately received BMAs and were potentially subject to unnecessary costs and toxicity. Further study of strategies to reduce inappropriate BMA use could lead to less toxicity and lower costs.

In the study by Aggarwal et al., the investigators evaluated whether molecular subtypes as identified from biopsies of metastatic tumors in patients with metastatic castrate resistant prostate cancer (mCRPC) could result in improved prediction of response to therapies. In this retrospective study of 4 distinct cohorts, 45% of tumors were classified as luminal and 55% were classified as basal. Luminal tumors exhibited increased expression of androgen receptor pathway genes, and patients with luminal tumors had better survival after treatment with ASI compared with those with basal tumors. Genomic analyses of mCRPC metastases are challenging due to processing issues that can arise if bone decalcification needs to be done; therefore, this study provides an important next step to aid in the design appropriate clinical trials to investigate whether such genomic subtyping results in improved patient outcomes.

            In the study by Saad et al, the investigators evaluated whether the addition of the androgen receptor inhibitor apalutamide added to abiraterone would result in a higher radiographic progression free survival (rPFS) compared with abiraterone alone in patients with mCRPC. The combination resulted in an improvement in rPFS (24 versus 16.6 months); however, there was no improvement in overall survival. These results are similar to the Alliance A0321201 study, where enzalutamide was added to abiraterone, and no overall survival was observed. Further study is needed to determine if this combination strategy can work.

            Supportive care aside from ASIs or chemotherapy directed against prostate cancer is also of critical importance to patients with metastatic prostate cancer. Previous studies have demonstrated that BMAs, such as denosumab or zoledronic acid, result in the prevention of skeletal-related events (SREs) in patients with mCRPC. However, this same benefit has not been demonstrated in metastatic castrate sensitive prostate cancer (mCSPC); therefore, BMAs are not recommended in this population unless they are at high risk for osteoporotic fracture. Mitchell et al. evaluated a retrospective cohort identified from Surveillance, Epidemiology, and End Results (SEER)-Medicare data to determine the number of patients with likely mCSPC treated with a BMA (defined as prescribed a BMA within 180 or 90 days after initial diagnosis of metastatic disease). A significant number of patients with likely mCSPC were prescribed BMAs within 180 days of diagnosis (23.6% of the cohort) and within 90 days (18.4% of the cohort). It is likely that most of these patients inappropriately received BMAs and were potentially subject to unnecessary costs and toxicity. Further study of strategies to reduce inappropriate BMA use could lead to less toxicity and lower costs.

This month, two studies reported on the addition of novel therapies to the backbone of low dose cytarabine. The first study, evaluated the role of adding quizartinib to low-dose cytarabine (LDAC) in older patients with acute myeloid leukemia (AML) not suitable for intensive chemotherapy. The addition of quizartinib to LDAC vs. LDAC alone improved survival and response in older patients with AML with an FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation who were unfit for intensive chemotherapy (IC). Among patients with FLT3-ITD mutation, LDAC+quizartinib improved response in 38% of patients vs. 0% of patients receiving LDAC alone (P = .02). The 2-year overall survival also improved significantly in patients receiving LDAC+quizartinib (hazard ratio [HR] 0.36; P = .024). The study included 202 older patients with AML (de novo AML 63%; secondary AML 25%; high-risk myelodysplastic syndrome 11%) unsuitable for IC with (n = 27) or without FLT3-ITD mutation randomly assigned to receive LDAC+quizartinib or LDAC alone.¹

The second study evaluated the combination of LDAC with venetoclax vs. placebo in treatment-naive patients with AML ineligible for IC. LDAC+venetoclax vs. LDAC+placebo improved median overall survival (HR 0.70; P = .04), along with higher rates of complete response (CR) or CR with incomplete hematologic recovery (CRi) (48.3% vs. 13.2%; P < .001) and postbaseline red blood cell and platelet transfusion independence (39.2% vs. 17.6%; P = .002). This was a post hoc analysis performed after an additional 6 months of follow-up of the phase 3 VIALE-C trial, including 211 adult patients with AML who were treatment-naive and unsuitable for IC. Patients were randomly assigned to receive LDAC with venetoclax (n = 143) or placebo (n = 68).² This study was previously reported with a shorter follow up and ddi not demonstrate a survival difference for LDAC+venetoclax vs. LDAC alone. It is very reassuring to see these results with longer follow-up with an improvement of the median overall survival from 4.1 months with LDAC alone to 8.4 months with LDAC+venetoclax. In addition, responses were seen in patients who had prior hypomethylating agents. The CR, CR/CRi and CR/CR with partial hematologic recovery (CRh) rates were 7%, 29%, and 21% respectively.

Finally in a study by Roboz et al. patients who received oral azacytidine as maintenance had no worsening of fatigue or health-related quality of life. Maintenance therapy with oral azacitidine (oral-AZA) did not negatively affect fatigue and health-related quality of life (HrQoL) in patients with acute myeloid leukemia (AML) in complete remission (CR) or CR with incomplete hematologic recovery (CRi) after intensive chemotherapy (IC). Effects of oral-AZA on fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue: difference in overall least square mean change [D] −0.89; 95% CI −2.37- 0.59) and HrQoL (EQ-5D-3L health utility index: D −0.01; 95% CI, −0.03-0.01; EQ-5D visual analog: D −0.95; 95% CI, −4.38-2.47) were comparable to placebo. Findings are from the QUAZAR AML-001 trial, including 444 patients with AML with intermediate- or poor-risk cytogenetics at diagnosis and unsuitable for transplantation. The patients were randomly assigned to receive either oral-AZA (n = 225) or placebo (n = 219) in first CR/CRi after IC. One caveat is that the assessments were performed on Day 1 of each 28 day cycle, which may have allowed for the recovery from side effects of oral azacytidine.³

References

1. Dennis M et al. Randomised evaluation of quizartinib and low-dose ara-C vs low-dose ara-C in older acute myeloid leukemia patients. Blood Adv. 2021 Oct 1.
2. Wei AH et al. 6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy. Blood Cancer J. 2021;11:163.
3. Roboz GJ et al. Oral azacitidine preserves favorable level of fatigue and health-related quality of life for patients with acute myeloid leukemia in remission: results from the phase 3, placebo-controlled QUAZAR AML-001 trial. Haematologica. 2021 Sep 23.

This month, two studies reported on the addition of novel therapies to the backbone of low dose cytarabine. The first study, evaluated the role of adding quizartinib to low-dose cytarabine (LDAC) in older patients with acute myeloid leukemia (AML) not suitable for intensive chemotherapy. The addition of quizartinib to LDAC vs. LDAC alone improved survival and response in older patients with AML with an FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation who were unfit for intensive chemotherapy (IC). Among patients with FLT3-ITD mutation, LDAC+quizartinib improved response in 38% of patients vs. 0% of patients receiving LDAC alone (P = .02). The 2-year overall survival also improved significantly in patients receiving LDAC+quizartinib (hazard ratio [HR] 0.36; P = .024). The study included 202 older patients with AML (de novo AML 63%; secondary AML 25%; high-risk myelodysplastic syndrome 11%) unsuitable for IC with (n = 27) or without FLT3-ITD mutation randomly assigned to receive LDAC+quizartinib or LDAC alone.¹

The second study evaluated the combination of LDAC with venetoclax vs. placebo in treatment-naive patients with AML ineligible for IC. LDAC+venetoclax vs. LDAC+placebo improved median overall survival (HR 0.70; P = .04), along with higher rates of complete response (CR) or CR with incomplete hematologic recovery (CRi) (48.3% vs. 13.2%; P < .001) and postbaseline red blood cell and platelet transfusion independence (39.2% vs. 17.6%; P = .002). This was a post hoc analysis performed after an additional 6 months of follow-up of the phase 3 VIALE-C trial, including 211 adult patients with AML who were treatment-naive and unsuitable for IC. Patients were randomly assigned to receive LDAC with venetoclax (n = 143) or placebo (n = 68).² This study was previously reported with a shorter follow up and ddi not demonstrate a survival difference for LDAC+venetoclax vs. LDAC alone. It is very reassuring to see these results with longer follow-up with an improvement of the median overall survival from 4.1 months with LDAC alone to 8.4 months with LDAC+venetoclax. In addition, responses were seen in patients who had prior hypomethylating agents. The CR, CR/CRi and CR/CR with partial hematologic recovery (CRh) rates were 7%, 29%, and 21% respectively.

Finally in a study by Roboz et al. patients who received oral azacytidine as maintenance had no worsening of fatigue or health-related quality of life. Maintenance therapy with oral azacitidine (oral-AZA) did not negatively affect fatigue and health-related quality of life (HrQoL) in patients with acute myeloid leukemia (AML) in complete remission (CR) or CR with incomplete hematologic recovery (CRi) after intensive chemotherapy (IC). Effects of oral-AZA on fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue: difference in overall least square mean change [D] −0.89; 95% CI −2.37- 0.59) and HrQoL (EQ-5D-3L health utility index: D −0.01; 95% CI, −0.03-0.01; EQ-5D visual analog: D −0.95; 95% CI, −4.38-2.47) were comparable to placebo. Findings are from the QUAZAR AML-001 trial, including 444 patients with AML with intermediate- or poor-risk cytogenetics at diagnosis and unsuitable for transplantation. The patients were randomly assigned to receive either oral-AZA (n = 225) or placebo (n = 219) in first CR/CRi after IC. One caveat is that the assessments were performed on Day 1 of each 28 day cycle, which may have allowed for the recovery from side effects of oral azacytidine.³

References

1. Dennis M et al. Randomised evaluation of quizartinib and low-dose ara-C vs low-dose ara-C in older acute myeloid leukemia patients. Blood Adv. 2021 Oct 1.
2. Wei AH et al. 6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy. Blood Cancer J. 2021;11:163.
3. Roboz GJ et al. Oral azacitidine preserves favorable level of fatigue and health-related quality of life for patients with acute myeloid leukemia in remission: results from the phase 3, placebo-controlled QUAZAR AML-001 trial. Haematologica. 2021 Sep 23.

This month, two studies reported on the addition of novel therapies to the backbone of low dose cytarabine. The first study, evaluated the role of adding quizartinib to low-dose cytarabine (LDAC) in older patients with acute myeloid leukemia (AML) not suitable for intensive chemotherapy. The addition of quizartinib to LDAC vs. LDAC alone improved survival and response in older patients with AML with an FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation who were unfit for intensive chemotherapy (IC). Among patients with FLT3-ITD mutation, LDAC+quizartinib improved response in 38% of patients vs. 0% of patients receiving LDAC alone (P = .02). The 2-year overall survival also improved significantly in patients receiving LDAC+quizartinib (hazard ratio [HR] 0.36; P = .024). The study included 202 older patients with AML (de novo AML 63%; secondary AML 25%; high-risk myelodysplastic syndrome 11%) unsuitable for IC with (n = 27) or without FLT3-ITD mutation randomly assigned to receive LDAC+quizartinib or LDAC alone.¹

The second study evaluated the combination of LDAC with venetoclax vs. placebo in treatment-naive patients with AML ineligible for IC. LDAC+venetoclax vs. LDAC+placebo improved median overall survival (HR 0.70; P = .04), along with higher rates of complete response (CR) or CR with incomplete hematologic recovery (CRi) (48.3% vs. 13.2%; P < .001) and postbaseline red blood cell and platelet transfusion independence (39.2% vs. 17.6%; P = .002). This was a post hoc analysis performed after an additional 6 months of follow-up of the phase 3 VIALE-C trial, including 211 adult patients with AML who were treatment-naive and unsuitable for IC. Patients were randomly assigned to receive LDAC with venetoclax (n = 143) or placebo (n = 68).² This study was previously reported with a shorter follow up and ddi not demonstrate a survival difference for LDAC+venetoclax vs. LDAC alone. It is very reassuring to see these results with longer follow-up with an improvement of the median overall survival from 4.1 months with LDAC alone to 8.4 months with LDAC+venetoclax. In addition, responses were seen in patients who had prior hypomethylating agents. The CR, CR/CRi and CR/CR with partial hematologic recovery (CRh) rates were 7%, 29%, and 21% respectively.

Finally in a study by Roboz et al. patients who received oral azacytidine as maintenance had no worsening of fatigue or health-related quality of life. Maintenance therapy with oral azacitidine (oral-AZA) did not negatively affect fatigue and health-related quality of life (HrQoL) in patients with acute myeloid leukemia (AML) in complete remission (CR) or CR with incomplete hematologic recovery (CRi) after intensive chemotherapy (IC). Effects of oral-AZA on fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue: difference in overall least square mean change [D] −0.89; 95% CI −2.37- 0.59) and HrQoL (EQ-5D-3L health utility index: D −0.01; 95% CI, −0.03-0.01; EQ-5D visual analog: D −0.95; 95% CI, −4.38-2.47) were comparable to placebo. Findings are from the QUAZAR AML-001 trial, including 444 patients with AML with intermediate- or poor-risk cytogenetics at diagnosis and unsuitable for transplantation. The patients were randomly assigned to receive either oral-AZA (n = 225) or placebo (n = 219) in first CR/CRi after IC. One caveat is that the assessments were performed on Day 1 of each 28 day cycle, which may have allowed for the recovery from side effects of oral azacytidine.³

References

1. Dennis M et al. Randomised evaluation of quizartinib and low-dose ara-C vs low-dose ara-C in older acute myeloid leukemia patients. Blood Adv. 2021 Oct 1.
2. Wei AH et al. 6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy. Blood Cancer J. 2021;11:163.
3. Roboz GJ et al. Oral azacitidine preserves favorable level of fatigue and health-related quality of life for patients with acute myeloid leukemia in remission: results from the phase 3, placebo-controlled QUAZAR AML-001 trial. Haematologica. 2021 Sep 23.

Tyrosine kinase inhibitors are the mainstay of systemic HCC therapy, however treatment at FDA-approved doses frequently leads to unacceptable toxicities, leading to reductions in the prescribed dose. Tokunaga et al. investigated whether lenvatinib dose intensity affects outcomes of patients with unresectable HCC. This was a retrospective analysis of 100 patients who received lenvatinib in the first- or later-line settings. Fifty-one patients started lenvatinib at the standard dose and 49 patients at a reduced dose. Dose reduction was carried out in 29 patients during cycle 1, and 62 patients during all cycles, with the cumulative dose reduction rate in all cycles of 79.9%.  Upon analysis, the authors confirmed that tumor responses and stable disease on lenvatinib correlated favorably with overall survival (OS) and time to progression (TTP). In addition, they found that higher dose intensity correlated with a higher response rate, though most (56%) patients were unable to maintain the recommended dose intensity due to unacceptable adverse events. In the final analysis, dose modification was not negatively associated with OS, TTP, or disease control with lenvatinib. Therefore, it remains reasonable to adjust the dose of lenvatinib to minimize toxicity that would affect adversely patient quality of life. Disease control remains the best predictor of longer survival, though it does not seem that highest doses of lenvatinib are needed to achieve that benefit.

Cabozantinib is approved for previously treated patients with unresectable HCC based on the phase III CELESTIAL trial that enrolled patients with Child Pugh A liver disease who had received up to two previous systemic treatments, one of which was sorafenib. This study demonstrated a statistically significant improvement in overall- and disease-free survival. Kelley et al analyzed the outcomes based on the albumin-bilirubin (ALBI) grade, an objective measure of liver function, of patients in the CELESTIAL trial. ALBI scores were retrospectively calculated based on baseline serum albumin and total bilirubin. The median OS was 17.5 months in the cabozantinib arm versus 11.4 months in the placebo arm for the ALBI grade 1 subgroup, and 8.0 months in the cabozantinib arm versus 6.4 months in the placebo arm for the ALBI grade 2 subgroup. The authors concluded that cabozantinib benefits patients with unresectable HCC irrespective of their ALBI grade, though liver dysfunction remains a poor prognostic indicator in patients with HCC.

Finally, Liu et al analyzed 27 patients with HCC (8 with extrahepatic spread) who received a combination of chemotherapy via hepatic artery infusion, anti-PD-1 immunotherapy, and tyrosine kinase inhibitor. Combination chemotherapy and immunotherapy resulted in a median progression-free survival of 10.6 months with a median 12.9 months’ follow up; the objective response rate was 63.0% and the disease control rate was 92.6%. The authors concluded that this combination of therapies was effective and well-tolerated, with a confirmatory phase 3 study planned.

Tyrosine kinase inhibitors are the mainstay of systemic HCC therapy, however treatment at FDA-approved doses frequently leads to unacceptable toxicities, leading to reductions in the prescribed dose. Tokunaga et al. investigated whether lenvatinib dose intensity affects outcomes of patients with unresectable HCC. This was a retrospective analysis of 100 patients who received lenvatinib in the first- or later-line settings. Fifty-one patients started lenvatinib at the standard dose and 49 patients at a reduced dose. Dose reduction was carried out in 29 patients during cycle 1, and 62 patients during all cycles, with the cumulative dose reduction rate in all cycles of 79.9%.  Upon analysis, the authors confirmed that tumor responses and stable disease on lenvatinib correlated favorably with overall survival (OS) and time to progression (TTP). In addition, they found that higher dose intensity correlated with a higher response rate, though most (56%) patients were unable to maintain the recommended dose intensity due to unacceptable adverse events. In the final analysis, dose modification was not negatively associated with OS, TTP, or disease control with lenvatinib. Therefore, it remains reasonable to adjust the dose of lenvatinib to minimize toxicity that would affect adversely patient quality of life. Disease control remains the best predictor of longer survival, though it does not seem that highest doses of lenvatinib are needed to achieve that benefit.

Cabozantinib is approved for previously treated patients with unresectable HCC based on the phase III CELESTIAL trial that enrolled patients with Child Pugh A liver disease who had received up to two previous systemic treatments, one of which was sorafenib. This study demonstrated a statistically significant improvement in overall- and disease-free survival. Kelley et al analyzed the outcomes based on the albumin-bilirubin (ALBI) grade, an objective measure of liver function, of patients in the CELESTIAL trial. ALBI scores were retrospectively calculated based on baseline serum albumin and total bilirubin. The median OS was 17.5 months in the cabozantinib arm versus 11.4 months in the placebo arm for the ALBI grade 1 subgroup, and 8.0 months in the cabozantinib arm versus 6.4 months in the placebo arm for the ALBI grade 2 subgroup. The authors concluded that cabozantinib benefits patients with unresectable HCC irrespective of their ALBI grade, though liver dysfunction remains a poor prognostic indicator in patients with HCC.

Finally, Liu et al analyzed 27 patients with HCC (8 with extrahepatic spread) who received a combination of chemotherapy via hepatic artery infusion, anti-PD-1 immunotherapy, and tyrosine kinase inhibitor. Combination chemotherapy and immunotherapy resulted in a median progression-free survival of 10.6 months with a median 12.9 months’ follow up; the objective response rate was 63.0% and the disease control rate was 92.6%. The authors concluded that this combination of therapies was effective and well-tolerated, with a confirmatory phase 3 study planned.

Tyrosine kinase inhibitors are the mainstay of systemic HCC therapy, however treatment at FDA-approved doses frequently leads to unacceptable toxicities, leading to reductions in the prescribed dose. Tokunaga et al. investigated whether lenvatinib dose intensity affects outcomes of patients with unresectable HCC. This was a retrospective analysis of 100 patients who received lenvatinib in the first- or later-line settings. Fifty-one patients started lenvatinib at the standard dose and 49 patients at a reduced dose. Dose reduction was carried out in 29 patients during cycle 1, and 62 patients during all cycles, with the cumulative dose reduction rate in all cycles of 79.9%.  Upon analysis, the authors confirmed that tumor responses and stable disease on lenvatinib correlated favorably with overall survival (OS) and time to progression (TTP). In addition, they found that higher dose intensity correlated with a higher response rate, though most (56%) patients were unable to maintain the recommended dose intensity due to unacceptable adverse events. In the final analysis, dose modification was not negatively associated with OS, TTP, or disease control with lenvatinib. Therefore, it remains reasonable to adjust the dose of lenvatinib to minimize toxicity that would affect adversely patient quality of life. Disease control remains the best predictor of longer survival, though it does not seem that highest doses of lenvatinib are needed to achieve that benefit.

Cabozantinib is approved for previously treated patients with unresectable HCC based on the phase III CELESTIAL trial that enrolled patients with Child Pugh A liver disease who had received up to two previous systemic treatments, one of which was sorafenib. This study demonstrated a statistically significant improvement in overall- and disease-free survival. Kelley et al analyzed the outcomes based on the albumin-bilirubin (ALBI) grade, an objective measure of liver function, of patients in the CELESTIAL trial. ALBI scores were retrospectively calculated based on baseline serum albumin and total bilirubin. The median OS was 17.5 months in the cabozantinib arm versus 11.4 months in the placebo arm for the ALBI grade 1 subgroup, and 8.0 months in the cabozantinib arm versus 6.4 months in the placebo arm for the ALBI grade 2 subgroup. The authors concluded that cabozantinib benefits patients with unresectable HCC irrespective of their ALBI grade, though liver dysfunction remains a poor prognostic indicator in patients with HCC.

Finally, Liu et al analyzed 27 patients with HCC (8 with extrahepatic spread) who received a combination of chemotherapy via hepatic artery infusion, anti-PD-1 immunotherapy, and tyrosine kinase inhibitor. Combination chemotherapy and immunotherapy resulted in a median progression-free survival of 10.6 months with a median 12.9 months’ follow up; the objective response rate was 63.0% and the disease control rate was 92.6%. The authors concluded that this combination of therapies was effective and well-tolerated, with a confirmatory phase 3 study planned.

The tide may finally be shifting as drugs targeting specific KRAS mutations have made their way into the clinic, and there is particular excitement around the oral WEE1 inhibitor, adavosertib (AZD1775). WEE1 is a cell cycle regulatory protein and WEE1 inhibition may have increased activity in tumors with DNA repair deficiency. In a phase 2 maintenance study, Seligmann and colleagues randomized 69 patients with RAS- and TP53-mutated mCRC with stable disease or better after 16 weeks of induction chemotherapy 2:1 to receive adavosertib vs active monitoring. Median progression-free survival (mPFS) was significant improved with adavosertib (3.61 vs 1.68 months), and patients with left-sided primary tumors appears to derive more benefit. While this finding needs to be further explored in larger clinical trials, it is exciting that there may finally be a new treatment option for patients with this specific molecular subtype of mCRC.

Another maintenance mCRC trial of interest is the PANAMA trial, a phase 2 study in which 248 patients with RAS wild-type mCRC were randomized 1:1 to 5-fluorouracil/leucovorin with or without panitumumab, an anti-epidermal growth factor receptor antibody, following induction chemotherapy with 6 cycles FOLFOX/panitumumab. Modest and co-workers report that mPFS was significantly improved with continuing panitumumab in the maintenance setting (8.8 vs. 5.7 months), and there was a trend towards an overall survival benefit as well. This study further supports continuing anti-EGFR therapy with maintenance chemotherapy for patients with RAS wild-type mCRC.

Finally, in stage III CRC, there is a big movement towards using circulating tumor DNA (ctDNA) as a method to monitor disease recurrence by detecting minimal residual disease based on tumor DNA being shed into the bloodstream. Henriksen et al. evaluated 168 patients with stage III CRC who underwent surgical resection and plasma ctDNA testing using 16 patient-specific DNA variants (tumor tissue-informed testing). The rates of recurrence were much higher in patients with detectable ctDNA post-operatively and/or after the completion of adjuvant chemotherapy, whereas those patients with persistently undetectable ctDNA did not recur. ctDNA is a powerful new technology that we are still learning how to best harness in the clinic, and this study demonstrates its prognostic value and potential ability to detect recurrence prior to standard imaging surveillance. Moreover, the rate of ctDNA rise was also prognostic of survival. ctDNA testing is likely to become standard of care in the management of stage II/III colorectal cancer in the very near future, and we hope that eventually it may be able to predict who needs to receive adjuvant chemotherapy and who does not.

The tide may finally be shifting as drugs targeting specific KRAS mutations have made their way into the clinic, and there is particular excitement around the oral WEE1 inhibitor, adavosertib (AZD1775). WEE1 is a cell cycle regulatory protein and WEE1 inhibition may have increased activity in tumors with DNA repair deficiency. In a phase 2 maintenance study, Seligmann and colleagues randomized 69 patients with RAS- and TP53-mutated mCRC with stable disease or better after 16 weeks of induction chemotherapy 2:1 to receive adavosertib vs active monitoring. Median progression-free survival (mPFS) was significant improved with adavosertib (3.61 vs 1.68 months), and patients with left-sided primary tumors appears to derive more benefit. While this finding needs to be further explored in larger clinical trials, it is exciting that there may finally be a new treatment option for patients with this specific molecular subtype of mCRC.

Another maintenance mCRC trial of interest is the PANAMA trial, a phase 2 study in which 248 patients with RAS wild-type mCRC were randomized 1:1 to 5-fluorouracil/leucovorin with or without panitumumab, an anti-epidermal growth factor receptor antibody, following induction chemotherapy with 6 cycles FOLFOX/panitumumab. Modest and co-workers report that mPFS was significantly improved with continuing panitumumab in the maintenance setting (8.8 vs. 5.7 months), and there was a trend towards an overall survival benefit as well. This study further supports continuing anti-EGFR therapy with maintenance chemotherapy for patients with RAS wild-type mCRC.

Finally, in stage III CRC, there is a big movement towards using circulating tumor DNA (ctDNA) as a method to monitor disease recurrence by detecting minimal residual disease based on tumor DNA being shed into the bloodstream. Henriksen et al. evaluated 168 patients with stage III CRC who underwent surgical resection and plasma ctDNA testing using 16 patient-specific DNA variants (tumor tissue-informed testing). The rates of recurrence were much higher in patients with detectable ctDNA post-operatively and/or after the completion of adjuvant chemotherapy, whereas those patients with persistently undetectable ctDNA did not recur. ctDNA is a powerful new technology that we are still learning how to best harness in the clinic, and this study demonstrates its prognostic value and potential ability to detect recurrence prior to standard imaging surveillance. Moreover, the rate of ctDNA rise was also prognostic of survival. ctDNA testing is likely to become standard of care in the management of stage II/III colorectal cancer in the very near future, and we hope that eventually it may be able to predict who needs to receive adjuvant chemotherapy and who does not.

The tide may finally be shifting as drugs targeting specific KRAS mutations have made their way into the clinic, and there is particular excitement around the oral WEE1 inhibitor, adavosertib (AZD1775). WEE1 is a cell cycle regulatory protein and WEE1 inhibition may have increased activity in tumors with DNA repair deficiency. In a phase 2 maintenance study, Seligmann and colleagues randomized 69 patients with RAS- and TP53-mutated mCRC with stable disease or better after 16 weeks of induction chemotherapy 2:1 to receive adavosertib vs active monitoring. Median progression-free survival (mPFS) was significant improved with adavosertib (3.61 vs 1.68 months), and patients with left-sided primary tumors appears to derive more benefit. While this finding needs to be further explored in larger clinical trials, it is exciting that there may finally be a new treatment option for patients with this specific molecular subtype of mCRC.

Another maintenance mCRC trial of interest is the PANAMA trial, a phase 2 study in which 248 patients with RAS wild-type mCRC were randomized 1:1 to 5-fluorouracil/leucovorin with or without panitumumab, an anti-epidermal growth factor receptor antibody, following induction chemotherapy with 6 cycles FOLFOX/panitumumab. Modest and co-workers report that mPFS was significantly improved with continuing panitumumab in the maintenance setting (8.8 vs. 5.7 months), and there was a trend towards an overall survival benefit as well. This study further supports continuing anti-EGFR therapy with maintenance chemotherapy for patients with RAS wild-type mCRC.

Finally, in stage III CRC, there is a big movement towards using circulating tumor DNA (ctDNA) as a method to monitor disease recurrence by detecting minimal residual disease based on tumor DNA being shed into the bloodstream. Henriksen et al. evaluated 168 patients with stage III CRC who underwent surgical resection and plasma ctDNA testing using 16 patient-specific DNA variants (tumor tissue-informed testing). The rates of recurrence were much higher in patients with detectable ctDNA post-operatively and/or after the completion of adjuvant chemotherapy, whereas those patients with persistently undetectable ctDNA did not recur. ctDNA is a powerful new technology that we are still learning how to best harness in the clinic, and this study demonstrates its prognostic value and potential ability to detect recurrence prior to standard imaging surveillance. Moreover, the rate of ctDNA rise was also prognostic of survival. ctDNA testing is likely to become standard of care in the management of stage II/III colorectal cancer in the very near future, and we hope that eventually it may be able to predict who needs to receive adjuvant chemotherapy and who does not.