Study Overview

Objective. To determine whether a non–tumor necrosis factor (TNF)-targeted drug is more effective than a second anti-TNF drug in rheumatoid arthritis (RA) patients who have had an inadequate response to a first anti-TNF drug.

Design. 52-week pragmatic, multicenter, open-label, parallel-group, randomized clinical trial (the “Rotation or Change” trial).

Setting and participants. 300 patients who were at least 18 years old were recruited from December 2009 to August 2012 from 47 French clinical centers. These patients had to have a diagnosis of RA according to the 1987 American College of Rheumatology criteria, presence of erosions, a DAS28-ESR (a measure of disease burden using patient global health, tender and swollen joint counts, and the erythrocyte sedimentation rate) of 3.2 or more, and insufficient response to an anti-TNF according to the physician (based on 1 or more of: persistent tender and swollen joints, persistent disease activity according to patient global assessment, elevated levels of acute-phase reactants, and dependence on analgesics, nonsteroidal anti-inflammatory drugs, or corticosteroids). In addition, patients had to have a stable dose of oral corticosteroids of 15 mg/d or less of equivalent prednisone within 4 weeks before enrollment, a stable dose of synthetic disease-modifying antirheumatic drugs (DMARDs) within 4 weeks of enrollment, and informed written consent. Exclusion criteria included cessation of the first anti-TNF agent due only to an adverse event, previous treatment with 2 or more anti-TNF agents, previous treatment with abatacept, rituximab, or tocilizumab, a contraindication to all anti-TNF agents and other biologics such as an infection or cancer, pregnancy and breastfeeding.

Intervention. Patients were randomly assigned in equal proportions to receive either a non-TNF biologic (abatacept, rituximab, or tocilizumab) or a second anti-TNF agent (adalimumab, certolizumab, etanercept, infliximab, or golimumab); the choice of agent after randomization was decided by the physician. The starting dose and frequency of treatment was predetermined. Golimumab was not available for use at the time of this study. The choice of future dosing and frequency of the treatment was left up to the treating physician in both groups. The assigned drug treatments continued for 12 months but were allowed to be discontinued for adverse events, patient choice, or inefficacy. Treatment and dose adjustments for oral corticosteroids and glucocorticoid intra-articular injections were allowed for both treatment groups.

Main outcome measures. The primary outcome was the proportion of patients at week 24 with a good or moderate European League Against Rheumatism (EULAR) response. A good EULAR response is defined as a decrease in DAS28-ESR of more than 1.2 points leading to a score of 3.2 or lower while a moderate EULAR response is defined as a decrease of more than 0.6 and resulting in a score of 5.1 points or lower. Secondary end points were EULAR response at weeks 12 and 52, DAS28-ESR at weeks 12, 24, and 52, low disease activity (DAS28-ESR < 3.2) and remission (DAS28-ESR < 2.6) at weeks 12, 24, and 52, mean oral corticosteroid use at weeks 24 and 52, therapeutic maintenance (defined as the proportion of patients who did not discontinue the assigned biologic treatment) at weeks 24 and 52, and health assessment questionnaire (HAQ) score (range, 0–3 with 0 representing the best and 3 the worst outcomes) at weeks 12, 24, and 52. Safety including serious adverse events as well as serious infections was also evaluated throughout the study.

Main results. 300 patients were randomized. The 2 groups were not different with regard to demographic and disease characteristics. In the non-TNF group of 150 patients, 33 of 146 patients (23%) received abatacept, 41 (28%) rituximab, and 70 (48%) tocilizumab; 2 patients (1%) did not receive the intervention as planned, 1 patient received adalimumab and 1 patient received no treatment. For the anti-TNF group, 57 of 146 patients (39%) received adalimumab, 23 (16%) certolizumab, 53 (36%) etanercept, and 8 (5%) infliximab. Five patients (3%) did not receive the intervention assigned as 2 patients received rituximab, 1 patient received tocilizumab, and 2 patients received no treatment. About two-thirds of patients in each group received concomitant methotrexate and about half in each group received oral corticosteroids.

With regard to the primary outcome, at week 24 101 of 146 patients (69%) in the non-TNF group and 76 (52%) in the second anti-TNF group achieved a good or moderate EULAR response, with 39% with a good response and 30% with a moderate response in the non-TNF group and 21% with a good response and 31% with a moderate response in the second anti-TNF group (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.27 to 3.37; P = 0.004, with imputation of missing data; absolute difference, 17.2%; 95% CI, 6.2% to 28.2%). The DAS28-ESR was lower in the non-TNF group (mean difference adjusted for baseline differences, −0.43; 95% CI, −0.72 to −0.14; P = 0.004). More patients in the non-TNF group vs the second anti-TNF group showed low disease activity at week 24 (45% vs 28%; OR, 2.09; 95% CI, 1.27 to 3.43; P = 0.004) and at week 52 (41% vs 23%; OR, 2.26; 95% CI, 1.33 to 3.86; P = 0.003).

The mean DAS28-ESR change from baseline was greater for patients in the non-TNF group than for patients in the second anti-TNF group with a 24-week mean difference of −0.43 (95% CI,−0.72 to −0.14; P = 0.004) and 52-week mean difference of −0.38 (95% CI, −0.69 to −0.08; P = 0.01).

The proportion of EULAR good and moderate responders at week 24 did not significantly differ with abatacept, rituximab, and tocilizumab treatment. The therapeutic maintenance rate, defined as the proportion of patients who continued the biologic treatment, was found to be significantly higher at weeks 24 and 52 in the non-TNF group than in the second anti-TNF group. The mean change from baseline to weeks 24 and 52 in the level of prednisone doses was not significantly different between patients between treatment groups.

With respect to safety, 16 patients (11%) in the non-TNF group experienced 18 serious adverse events and 8 patients (5%) in the second anti-TNF group experienced 13 events (P = 0.10) with 7 patients (5%) in each group developing serious infections.

Conclusion. In patients with RA previously treated with an anti-TNF drug with an inadequate response, the use of a non-TNF biologic agent was found to be more effective in achieving a good or moderate disease activity response at 24 weeks compared with a second anti-TNF medication.

Commentary

In patients with RA who have shown an inadequate response to methotrexate, TNF-α inhibitors have been shown to improve quality of life. However, it has been shown that almost one-third of patients have an insufficient and inadequate response to anti-TNF agents and continue to have persistent disease activity [1–3].Alternative treatments are therefore needed, but there is currently little guidance available for choosing the next treatment.

There are 3 placebo-controlled trials that have shown that switching to a non–TNF-targeted therapy may be appropriate [4–6]. The most commonly used non-TNF agents are abatacept, rituximab, and tocilizumab. However, there is evidence that switching to another anti-TNF agent after failure of a first can also be a good choice, as the molecular structure of TNF-inhibitors and their affinity for membrane and TNF-α vary. There were 2 randomized placebo-controlled trials that reported that approximately half of patients with RA with insufficient response to a TNF-α inhibitor responded to a second anti-TNF drug [7,8].

Although there have been observational studies addressing this question, this is the first randomized controlled trial to evaluate the efficacy of a non-TNF-targeted biologic compared to a second anti-TNF drug to treat RA in patients with an insufficient response to a first anti-TNF drug. Data showed that at week 24, 69% in the non-TNF group and 52% in the anti-TNF group achieved a good or moderate EULAR response. The non-TNF treatment was also associated with a better EULAR response than a second anti-TNF drug at weeks 12 and 52. The DAS28-ESR and the number of patients achieving low disease activity status were found to be greater at months 6 and 12 in the non-TNF group than in the second anti-TNF group. One strength of the study is its pragmatic design—the study evaluated the  effectiveness of interventions under real-life, routine practice conditions where physicians often choose one drug over another for reasons based on the habits or characteristics of the patient. The comparison of strategies and not individual drugs more appropriately addresses the questions that physicians face in daily practice. However, there were some limitations including the lack of blinding by participants, the exclusion of some biologic agents such as golimunab, the lack of assessment of individual drug efficacy, and the fact that approximately 40% of patients in each group did not have concomitant treatment with methotrexate, an agent known to improve the efficacy of most biologic agents.

Applications for Clinical Practice

This is the first randomized controlled trial to evaluate the efficacy of a non-TNF-targeted biologic vs. a second anti-TNF in patients with RA who have an insufficient response to a first anti-TNF drug. Further studies addressing the limitations identified in this study are needed before physicians can employ these findings in clinical practice.

—Anita Laloo, MD

Study Overview

Objective. To determine whether a non–tumor necrosis factor (TNF)-targeted drug is more effective than a second anti-TNF drug in rheumatoid arthritis (RA) patients who have had an inadequate response to a first anti-TNF drug.

Design. 52-week pragmatic, multicenter, open-label, parallel-group, randomized clinical trial (the “Rotation or Change” trial).

Setting and participants. 300 patients who were at least 18 years old were recruited from December 2009 to August 2012 from 47 French clinical centers. These patients had to have a diagnosis of RA according to the 1987 American College of Rheumatology criteria, presence of erosions, a DAS28-ESR (a measure of disease burden using patient global health, tender and swollen joint counts, and the erythrocyte sedimentation rate) of 3.2 or more, and insufficient response to an anti-TNF according to the physician (based on 1 or more of: persistent tender and swollen joints, persistent disease activity according to patient global assessment, elevated levels of acute-phase reactants, and dependence on analgesics, nonsteroidal anti-inflammatory drugs, or corticosteroids). In addition, patients had to have a stable dose of oral corticosteroids of 15 mg/d or less of equivalent prednisone within 4 weeks before enrollment, a stable dose of synthetic disease-modifying antirheumatic drugs (DMARDs) within 4 weeks of enrollment, and informed written consent. Exclusion criteria included cessation of the first anti-TNF agent due only to an adverse event, previous treatment with 2 or more anti-TNF agents, previous treatment with abatacept, rituximab, or tocilizumab, a contraindication to all anti-TNF agents and other biologics such as an infection or cancer, pregnancy and breastfeeding.

Intervention. Patients were randomly assigned in equal proportions to receive either a non-TNF biologic (abatacept, rituximab, or tocilizumab) or a second anti-TNF agent (adalimumab, certolizumab, etanercept, infliximab, or golimumab); the choice of agent after randomization was decided by the physician. The starting dose and frequency of treatment was predetermined. Golimumab was not available for use at the time of this study. The choice of future dosing and frequency of the treatment was left up to the treating physician in both groups. The assigned drug treatments continued for 12 months but were allowed to be discontinued for adverse events, patient choice, or inefficacy. Treatment and dose adjustments for oral corticosteroids and glucocorticoid intra-articular injections were allowed for both treatment groups.

Main outcome measures. The primary outcome was the proportion of patients at week 24 with a good or moderate European League Against Rheumatism (EULAR) response. A good EULAR response is defined as a decrease in DAS28-ESR of more than 1.2 points leading to a score of 3.2 or lower while a moderate EULAR response is defined as a decrease of more than 0.6 and resulting in a score of 5.1 points or lower. Secondary end points were EULAR response at weeks 12 and 52, DAS28-ESR at weeks 12, 24, and 52, low disease activity (DAS28-ESR < 3.2) and remission (DAS28-ESR < 2.6) at weeks 12, 24, and 52, mean oral corticosteroid use at weeks 24 and 52, therapeutic maintenance (defined as the proportion of patients who did not discontinue the assigned biologic treatment) at weeks 24 and 52, and health assessment questionnaire (HAQ) score (range, 0–3 with 0 representing the best and 3 the worst outcomes) at weeks 12, 24, and 52. Safety including serious adverse events as well as serious infections was also evaluated throughout the study.

Main results. 300 patients were randomized. The 2 groups were not different with regard to demographic and disease characteristics. In the non-TNF group of 150 patients, 33 of 146 patients (23%) received abatacept, 41 (28%) rituximab, and 70 (48%) tocilizumab; 2 patients (1%) did not receive the intervention as planned, 1 patient received adalimumab and 1 patient received no treatment. For the anti-TNF group, 57 of 146 patients (39%) received adalimumab, 23 (16%) certolizumab, 53 (36%) etanercept, and 8 (5%) infliximab. Five patients (3%) did not receive the intervention assigned as 2 patients received rituximab, 1 patient received tocilizumab, and 2 patients received no treatment. About two-thirds of patients in each group received concomitant methotrexate and about half in each group received oral corticosteroids.

With regard to the primary outcome, at week 24 101 of 146 patients (69%) in the non-TNF group and 76 (52%) in the second anti-TNF group achieved a good or moderate EULAR response, with 39% with a good response and 30% with a moderate response in the non-TNF group and 21% with a good response and 31% with a moderate response in the second anti-TNF group (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.27 to 3.37; P = 0.004, with imputation of missing data; absolute difference, 17.2%; 95% CI, 6.2% to 28.2%). The DAS28-ESR was lower in the non-TNF group (mean difference adjusted for baseline differences, −0.43; 95% CI, −0.72 to −0.14; P = 0.004). More patients in the non-TNF group vs the second anti-TNF group showed low disease activity at week 24 (45% vs 28%; OR, 2.09; 95% CI, 1.27 to 3.43; P = 0.004) and at week 52 (41% vs 23%; OR, 2.26; 95% CI, 1.33 to 3.86; P = 0.003).

The mean DAS28-ESR change from baseline was greater for patients in the non-TNF group than for patients in the second anti-TNF group with a 24-week mean difference of −0.43 (95% CI,−0.72 to −0.14; P = 0.004) and 52-week mean difference of −0.38 (95% CI, −0.69 to −0.08; P = 0.01).

The proportion of EULAR good and moderate responders at week 24 did not significantly differ with abatacept, rituximab, and tocilizumab treatment. The therapeutic maintenance rate, defined as the proportion of patients who continued the biologic treatment, was found to be significantly higher at weeks 24 and 52 in the non-TNF group than in the second anti-TNF group. The mean change from baseline to weeks 24 and 52 in the level of prednisone doses was not significantly different between patients between treatment groups.

With respect to safety, 16 patients (11%) in the non-TNF group experienced 18 serious adverse events and 8 patients (5%) in the second anti-TNF group experienced 13 events (P = 0.10) with 7 patients (5%) in each group developing serious infections.

Conclusion. In patients with RA previously treated with an anti-TNF drug with an inadequate response, the use of a non-TNF biologic agent was found to be more effective in achieving a good or moderate disease activity response at 24 weeks compared with a second anti-TNF medication.

Commentary

In patients with RA who have shown an inadequate response to methotrexate, TNF-α inhibitors have been shown to improve quality of life. However, it has been shown that almost one-third of patients have an insufficient and inadequate response to anti-TNF agents and continue to have persistent disease activity [1–3].Alternative treatments are therefore needed, but there is currently little guidance available for choosing the next treatment.

There are 3 placebo-controlled trials that have shown that switching to a non–TNF-targeted therapy may be appropriate [4–6]. The most commonly used non-TNF agents are abatacept, rituximab, and tocilizumab. However, there is evidence that switching to another anti-TNF agent after failure of a first can also be a good choice, as the molecular structure of TNF-inhibitors and their affinity for membrane and TNF-α vary. There were 2 randomized placebo-controlled trials that reported that approximately half of patients with RA with insufficient response to a TNF-α inhibitor responded to a second anti-TNF drug [7,8].

Although there have been observational studies addressing this question, this is the first randomized controlled trial to evaluate the efficacy of a non-TNF-targeted biologic compared to a second anti-TNF drug to treat RA in patients with an insufficient response to a first anti-TNF drug. Data showed that at week 24, 69% in the non-TNF group and 52% in the anti-TNF group achieved a good or moderate EULAR response. The non-TNF treatment was also associated with a better EULAR response than a second anti-TNF drug at weeks 12 and 52. The DAS28-ESR and the number of patients achieving low disease activity status were found to be greater at months 6 and 12 in the non-TNF group than in the second anti-TNF group. One strength of the study is its pragmatic design—the study evaluated the  effectiveness of interventions under real-life, routine practice conditions where physicians often choose one drug over another for reasons based on the habits or characteristics of the patient. The comparison of strategies and not individual drugs more appropriately addresses the questions that physicians face in daily practice. However, there were some limitations including the lack of blinding by participants, the exclusion of some biologic agents such as golimunab, the lack of assessment of individual drug efficacy, and the fact that approximately 40% of patients in each group did not have concomitant treatment with methotrexate, an agent known to improve the efficacy of most biologic agents.

Applications for Clinical Practice

This is the first randomized controlled trial to evaluate the efficacy of a non-TNF-targeted biologic vs. a second anti-TNF in patients with RA who have an insufficient response to a first anti-TNF drug. Further studies addressing the limitations identified in this study are needed before physicians can employ these findings in clinical practice.

—Anita Laloo, MD

Study Overview

Objective. To determine whether a non–tumor necrosis factor (TNF)-targeted drug is more effective than a second anti-TNF drug in rheumatoid arthritis (RA) patients who have had an inadequate response to a first anti-TNF drug.

Design. 52-week pragmatic, multicenter, open-label, parallel-group, randomized clinical trial (the “Rotation or Change” trial).

Setting and participants. 300 patients who were at least 18 years old were recruited from December 2009 to August 2012 from 47 French clinical centers. These patients had to have a diagnosis of RA according to the 1987 American College of Rheumatology criteria, presence of erosions, a DAS28-ESR (a measure of disease burden using patient global health, tender and swollen joint counts, and the erythrocyte sedimentation rate) of 3.2 or more, and insufficient response to an anti-TNF according to the physician (based on 1 or more of: persistent tender and swollen joints, persistent disease activity according to patient global assessment, elevated levels of acute-phase reactants, and dependence on analgesics, nonsteroidal anti-inflammatory drugs, or corticosteroids). In addition, patients had to have a stable dose of oral corticosteroids of 15 mg/d or less of equivalent prednisone within 4 weeks before enrollment, a stable dose of synthetic disease-modifying antirheumatic drugs (DMARDs) within 4 weeks of enrollment, and informed written consent. Exclusion criteria included cessation of the first anti-TNF agent due only to an adverse event, previous treatment with 2 or more anti-TNF agents, previous treatment with abatacept, rituximab, or tocilizumab, a contraindication to all anti-TNF agents and other biologics such as an infection or cancer, pregnancy and breastfeeding.

Intervention. Patients were randomly assigned in equal proportions to receive either a non-TNF biologic (abatacept, rituximab, or tocilizumab) or a second anti-TNF agent (adalimumab, certolizumab, etanercept, infliximab, or golimumab); the choice of agent after randomization was decided by the physician. The starting dose and frequency of treatment was predetermined. Golimumab was not available for use at the time of this study. The choice of future dosing and frequency of the treatment was left up to the treating physician in both groups. The assigned drug treatments continued for 12 months but were allowed to be discontinued for adverse events, patient choice, or inefficacy. Treatment and dose adjustments for oral corticosteroids and glucocorticoid intra-articular injections were allowed for both treatment groups.

Main outcome measures. The primary outcome was the proportion of patients at week 24 with a good or moderate European League Against Rheumatism (EULAR) response. A good EULAR response is defined as a decrease in DAS28-ESR of more than 1.2 points leading to a score of 3.2 or lower while a moderate EULAR response is defined as a decrease of more than 0.6 and resulting in a score of 5.1 points or lower. Secondary end points were EULAR response at weeks 12 and 52, DAS28-ESR at weeks 12, 24, and 52, low disease activity (DAS28-ESR < 3.2) and remission (DAS28-ESR < 2.6) at weeks 12, 24, and 52, mean oral corticosteroid use at weeks 24 and 52, therapeutic maintenance (defined as the proportion of patients who did not discontinue the assigned biologic treatment) at weeks 24 and 52, and health assessment questionnaire (HAQ) score (range, 0–3 with 0 representing the best and 3 the worst outcomes) at weeks 12, 24, and 52. Safety including serious adverse events as well as serious infections was also evaluated throughout the study.

Main results. 300 patients were randomized. The 2 groups were not different with regard to demographic and disease characteristics. In the non-TNF group of 150 patients, 33 of 146 patients (23%) received abatacept, 41 (28%) rituximab, and 70 (48%) tocilizumab; 2 patients (1%) did not receive the intervention as planned, 1 patient received adalimumab and 1 patient received no treatment. For the anti-TNF group, 57 of 146 patients (39%) received adalimumab, 23 (16%) certolizumab, 53 (36%) etanercept, and 8 (5%) infliximab. Five patients (3%) did not receive the intervention assigned as 2 patients received rituximab, 1 patient received tocilizumab, and 2 patients received no treatment. About two-thirds of patients in each group received concomitant methotrexate and about half in each group received oral corticosteroids.

With regard to the primary outcome, at week 24 101 of 146 patients (69%) in the non-TNF group and 76 (52%) in the second anti-TNF group achieved a good or moderate EULAR response, with 39% with a good response and 30% with a moderate response in the non-TNF group and 21% with a good response and 31% with a moderate response in the second anti-TNF group (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.27 to 3.37; P = 0.004, with imputation of missing data; absolute difference, 17.2%; 95% CI, 6.2% to 28.2%). The DAS28-ESR was lower in the non-TNF group (mean difference adjusted for baseline differences, −0.43; 95% CI, −0.72 to −0.14; P = 0.004). More patients in the non-TNF group vs the second anti-TNF group showed low disease activity at week 24 (45% vs 28%; OR, 2.09; 95% CI, 1.27 to 3.43; P = 0.004) and at week 52 (41% vs 23%; OR, 2.26; 95% CI, 1.33 to 3.86; P = 0.003).

The mean DAS28-ESR change from baseline was greater for patients in the non-TNF group than for patients in the second anti-TNF group with a 24-week mean difference of −0.43 (95% CI,−0.72 to −0.14; P = 0.004) and 52-week mean difference of −0.38 (95% CI, −0.69 to −0.08; P = 0.01).

The proportion of EULAR good and moderate responders at week 24 did not significantly differ with abatacept, rituximab, and tocilizumab treatment. The therapeutic maintenance rate, defined as the proportion of patients who continued the biologic treatment, was found to be significantly higher at weeks 24 and 52 in the non-TNF group than in the second anti-TNF group. The mean change from baseline to weeks 24 and 52 in the level of prednisone doses was not significantly different between patients between treatment groups.

With respect to safety, 16 patients (11%) in the non-TNF group experienced 18 serious adverse events and 8 patients (5%) in the second anti-TNF group experienced 13 events (P = 0.10) with 7 patients (5%) in each group developing serious infections.

Conclusion. In patients with RA previously treated with an anti-TNF drug with an inadequate response, the use of a non-TNF biologic agent was found to be more effective in achieving a good or moderate disease activity response at 24 weeks compared with a second anti-TNF medication.

Commentary

In patients with RA who have shown an inadequate response to methotrexate, TNF-α inhibitors have been shown to improve quality of life. However, it has been shown that almost one-third of patients have an insufficient and inadequate response to anti-TNF agents and continue to have persistent disease activity [1–3].Alternative treatments are therefore needed, but there is currently little guidance available for choosing the next treatment.

There are 3 placebo-controlled trials that have shown that switching to a non–TNF-targeted therapy may be appropriate [4–6]. The most commonly used non-TNF agents are abatacept, rituximab, and tocilizumab. However, there is evidence that switching to another anti-TNF agent after failure of a first can also be a good choice, as the molecular structure of TNF-inhibitors and their affinity for membrane and TNF-α vary. There were 2 randomized placebo-controlled trials that reported that approximately half of patients with RA with insufficient response to a TNF-α inhibitor responded to a second anti-TNF drug [7,8].

Although there have been observational studies addressing this question, this is the first randomized controlled trial to evaluate the efficacy of a non-TNF-targeted biologic compared to a second anti-TNF drug to treat RA in patients with an insufficient response to a first anti-TNF drug. Data showed that at week 24, 69% in the non-TNF group and 52% in the anti-TNF group achieved a good or moderate EULAR response. The non-TNF treatment was also associated with a better EULAR response than a second anti-TNF drug at weeks 12 and 52. The DAS28-ESR and the number of patients achieving low disease activity status were found to be greater at months 6 and 12 in the non-TNF group than in the second anti-TNF group. One strength of the study is its pragmatic design—the study evaluated the  effectiveness of interventions under real-life, routine practice conditions where physicians often choose one drug over another for reasons based on the habits or characteristics of the patient. The comparison of strategies and not individual drugs more appropriately addresses the questions that physicians face in daily practice. However, there were some limitations including the lack of blinding by participants, the exclusion of some biologic agents such as golimunab, the lack of assessment of individual drug efficacy, and the fact that approximately 40% of patients in each group did not have concomitant treatment with methotrexate, an agent known to improve the efficacy of most biologic agents.

Applications for Clinical Practice

This is the first randomized controlled trial to evaluate the efficacy of a non-TNF-targeted biologic vs. a second anti-TNF in patients with RA who have an insufficient response to a first anti-TNF drug. Further studies addressing the limitations identified in this study are needed before physicians can employ these findings in clinical practice.

—Anita Laloo, MD

SAN DIEGO – Tyrosine kinase inhibitors have dramatically improved survival for patients with chronic myeloid leukemia, but for some patients with solid stable remissions, halving the TKI dose or even stopping therapy altogether, at least temporarily, appears to be safe and to offer both health and financial benefits,

In the British Destiny [De-escalation and Stopping Treatment of Imatinib, Nilotinib, or Sprycel (dasatinib)], there were 12 molecular relapses occurring between the second and twelfth month of dose reduction among 174 patients with either an MR3 or MR4 molecular response, and all patients had restoration of molecular remissions after resumption of full dose TKIs.

Coinvestigator Mhairi Copland, MD, PhD, of the University of Glasgow, Scotland, discussed in a video interview the potential clinical benefits of lower-dose therapy in patients in stable CML remissions, and notes that de-escalation strategy is associated with a nearly 50% saving in costs compared with full-dose TKI therapy.

SAN DIEGO – Tyrosine kinase inhibitors have dramatically improved survival for patients with chronic myeloid leukemia, but for some patients with solid stable remissions, halving the TKI dose or even stopping therapy altogether, at least temporarily, appears to be safe and to offer both health and financial benefits,

In the British Destiny [De-escalation and Stopping Treatment of Imatinib, Nilotinib, or Sprycel (dasatinib)], there were 12 molecular relapses occurring between the second and twelfth month of dose reduction among 174 patients with either an MR3 or MR4 molecular response, and all patients had restoration of molecular remissions after resumption of full dose TKIs.

Coinvestigator Mhairi Copland, MD, PhD, of the University of Glasgow, Scotland, discussed in a video interview the potential clinical benefits of lower-dose therapy in patients in stable CML remissions, and notes that de-escalation strategy is associated with a nearly 50% saving in costs compared with full-dose TKI therapy.

SAN DIEGO – Tyrosine kinase inhibitors have dramatically improved survival for patients with chronic myeloid leukemia, but for some patients with solid stable remissions, halving the TKI dose or even stopping therapy altogether, at least temporarily, appears to be safe and to offer both health and financial benefits,

In the British Destiny [De-escalation and Stopping Treatment of Imatinib, Nilotinib, or Sprycel (dasatinib)], there were 12 molecular relapses occurring between the second and twelfth month of dose reduction among 174 patients with either an MR3 or MR4 molecular response, and all patients had restoration of molecular remissions after resumption of full dose TKIs.

Coinvestigator Mhairi Copland, MD, PhD, of the University of Glasgow, Scotland, discussed in a video interview the potential clinical benefits of lower-dose therapy in patients in stable CML remissions, and notes that de-escalation strategy is associated with a nearly 50% saving in costs compared with full-dose TKI therapy.

SAN DIEGO – Venetoclax has shown preliminary good results as an investigational monotherapy in patients with relapsed/refractory multiple myeloma, based on phase I data reported at the annual meeting of the American Society of Hematology.

Shaji Kumar, MD, of the Mayo Clinic, Rochester, Minn., reported that venetoclax monotherapy had anti-myeloma activity in a dose-finding study among patients treated with a median of five previous therapies. As would be expected, the best responses to the small-molecule BCL-2 inhibitor were seen primarily in patients with t(11;14) chromosomal aberrations and high BCL-2, low BCL-XL and low MCL-1 expression levels.

In a video interview, Dr. Kumar discussed the results of this early-stage research as well as ongoing studies that are beginning to examine venetoclax in combination regimens for multiple myeloma.

mdales@frontlinemedcom.com
On Twitter @maryjodales

SAN DIEGO – Venetoclax has shown preliminary good results as an investigational monotherapy in patients with relapsed/refractory multiple myeloma, based on phase I data reported at the annual meeting of the American Society of Hematology.

Shaji Kumar, MD, of the Mayo Clinic, Rochester, Minn., reported that venetoclax monotherapy had anti-myeloma activity in a dose-finding study among patients treated with a median of five previous therapies. As would be expected, the best responses to the small-molecule BCL-2 inhibitor were seen primarily in patients with t(11;14) chromosomal aberrations and high BCL-2, low BCL-XL and low MCL-1 expression levels.

In a video interview, Dr. Kumar discussed the results of this early-stage research as well as ongoing studies that are beginning to examine venetoclax in combination regimens for multiple myeloma.

mdales@frontlinemedcom.com
On Twitter @maryjodales

SAN DIEGO – Venetoclax has shown preliminary good results as an investigational monotherapy in patients with relapsed/refractory multiple myeloma, based on phase I data reported at the annual meeting of the American Society of Hematology.

Shaji Kumar, MD, of the Mayo Clinic, Rochester, Minn., reported that venetoclax monotherapy had anti-myeloma activity in a dose-finding study among patients treated with a median of five previous therapies. As would be expected, the best responses to the small-molecule BCL-2 inhibitor were seen primarily in patients with t(11;14) chromosomal aberrations and high BCL-2, low BCL-XL and low MCL-1 expression levels.

In a video interview, Dr. Kumar discussed the results of this early-stage research as well as ongoing studies that are beginning to examine venetoclax in combination regimens for multiple myeloma.

mdales@frontlinemedcom.com
On Twitter @maryjodales

VIENNA – Many lung cancer patients would like to work with their physicians to reach a shared decision about their care, but often feel inadequately informed to comfortably participate in the decision process.

Patient decision aids offer a way to address this knowledge and participation gap, Laurie E. Gaspar, MD, said in a video interview at the World Conference on Lung Cancer, sponsored by the International Association for the Study of Lung Cancer.

Mitchel L. Zoler/Frontline Medical News

mzoler@frontlinemedcom.com
On Twitter @mitchelzoler

VIENNA – Many lung cancer patients would like to work with their physicians to reach a shared decision about their care, but often feel inadequately informed to comfortably participate in the decision process.

Patient decision aids offer a way to address this knowledge and participation gap, Laurie E. Gaspar, MD, said in a video interview at the World Conference on Lung Cancer, sponsored by the International Association for the Study of Lung Cancer.

Mitchel L. Zoler/Frontline Medical News

mzoler@frontlinemedcom.com
On Twitter @mitchelzoler

VIENNA – Many lung cancer patients would like to work with their physicians to reach a shared decision about their care, but often feel inadequately informed to comfortably participate in the decision process.

Patient decision aids offer a way to address this knowledge and participation gap, Laurie E. Gaspar, MD, said in a video interview at the World Conference on Lung Cancer, sponsored by the International Association for the Study of Lung Cancer.

Mitchel L. Zoler/Frontline Medical News

mzoler@frontlinemedcom.com
On Twitter @mitchelzoler

Study Overview

Objective. To evaluate the efficacy and safety of the CDK4/6 inhibitor ribociclib in combination with letrozole as initial therapy in patients with hormone-receptor (HR)–positive, human epidermal growth factor receptor 2 (HER-2)–negative advanced breast cancer.

Design. Pre-planned interim analysis of a randomized, double-blind, phase 3 clinical trial.

Setting and participants. This study enrolled patients in 29 countries at 223 centers. A total of 668 postmenopausal women underwent randomization, with 334 assigned to receive ribociclib plus letrozole and 334 assigned to receive placebo plus letrozole. All women had HR-positive, HER-2 negative recurrent or metastatic breast cancer and had not received prior systemic therapy. Enrolled patients had either measurable disease on imaging or at least 1 lytic bone lesion. All patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were excluded if they had received prior therapy with a CDK4/6 inhibitor, previous systemic chemotherapy or endocrine therapy. If a patient received an aromatase inhibitor for neoadjuvant or adjuvant therapy, the disease-free interval needed to be more than 12 months to be included in the study. Patients with inflammatory breast cancer or central nervous system involvement were also excluded. Normal cardiac function (normal QT interval) was required for enrollment. The randomization was stratified by presence of liver or lung metastases.

Intervention. The patients were randomized to oral ribociclib 600 mg per day 3 weeks on, 1 week off in a 28-day treatment cycle plus letrozole 2.5 mg daily or placebo plus letrozole. The dosing of ribociclib was based on a prior phase 1 study [1]. Treatment was continued until disease progression, unacceptable toxicity, discontinuation, or death. Dose reductions of ribociclib were allowed; however, dose reductions of letrozole were not permitted. Crossover between treatment arms was not allowed. Patients were assessed with computed tomo-graphy at the time of randomization, every 8 weeks for the first 18 months and every 12 weeks there-after. Patients were monitored for hematological toxicity each cycle. Electrocardiographic assessment was done at screening, on day 15 of cycle 1 and on day 1 of all subsequent cycles to monitor for QT prolongation.

Main outcome measures. The primary outcome was progression-free survival. The secondary outcomes were overall survival, overall response rate (complete or partial response), clinical benefit rate, and safety. Clinical benefit rate was defined as overall response plus stable disease lasting 24 weeks or more. A prespecified interim analysis was planned after disease progression or death was reported in 211 of 302 patients (70%).

Results. The baseline characteristics were balanced between the 2 groups. Visceral disease was present in 58.8% and bone-only disease in 22% of the patients. The median duration of therapy exposure was 13 months in the ribociclib group and 12.4 months in the placebo group. The median duration of follow-up was 15.3 months. After 18 months, progression-free survival was 63% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib/letrozole group versus 42.2% (95% CI, 34.8 to 49.5) in the placebo group (P < 0.001). The median progression-free survival was not met in the combination group (95% CI, 19.3 to not reached) versus 14.7 months (95% CI, 13.0 to 16.5) in the placebo group. The improved progression-free survival was seen across all subgroups. The overall response rate was higher in the combination arm (52.7% vs. 37.1%) as was the clinical benefit rate (80.1% vs. 71.8%). Serious adverse events occurred in 21.3% of patients in the ribociclib group and 11.8% in the placebo group. Serious adverse events were attributed to the study drug in 7.5% of the ribociclib group and 1.5% of the placebo group. The most common adverse events were myelosuppression, nausea, fatigue and diarrhea. Grade 3 and 4 neutropenia was noted in 59.3% in the ribociclib group versus < 1% in the placebo arm. The discontinuation rate due to adverse events in the ribociclib and placebo groups was 7.5% versus 2.1%, respectively. The most common reason for discontinuation was disease progression in 26% in the ribociclib group and 43.7% in the placebo group. Three deaths occurred in the ribociclib group and one in the placebo group. Interruptions in ribociclib occurred in 76.9% of patients. Dose reductions occurred in 53.9% of patients in the ribociclib group versus 7% in the placebo group. The most common reason a dose reduction occurred was neutropenia.

Conclusion. First-line treatment with ribociclib plus letrozole in postmenopausal women with HR-positive, HER-2 negative advanced breast cancer was associated with significantly longer progression-free survival compared with letrozole plus placebo. The improved progression-free survival was seen across all subgroups.

Commentary

Nearly 80% of all breast cancers express hormone receptor positivity. Hormonal therapy has been an important component of treatment for women with hormone-positive breast cancer in both the local and metastatic setting. Many tumors will eventually develop resistance to such therapy with the median progression-free survival with first-line endocrine therapy alone being around 9 months [2]. Cyclin dependent kinases 4 and 6 (CDK4/6) play an important role in estrogen-receptor signaling and cell cycle progression. CDK 4/6 mediates progression through the cell cycle from G1 to S phase via phosphorylation and inactivation of the retinoblastoma tumor suppressor protein [3]. Overexpression of CDK 4/6 in hormone receptor positive breast cancer is thought to play an important role in the development of endocrine therapy resistance [4].

The previously published PALOMA-2 trial, which compared treatment with the CDK 4/6 inhibitor palbociclib plus letrozole with letrozole alone, reported a significant improvement in progression-free survival with the addition of palbociclib (24.8 months vs. 14.5 months) in the front-line setting for women with advanced, hormone-positive breast cancer [5]. The improved progression-free survival with palbociclib was seen across all subgroups with a favorable toxicity profile. The current study represents the second randomized trial to show that the addition of CDK4/6 inhibitor to endocrine-based therapy significantly improves progression-free survival. This benefit was also seen across all patient subgroups including those with liver and lung metastases. In addition, the combination of ribociclib and letrozole also show significantly higher rates of overall response compared with placebo. In general, the addition of ribociclib to letrozole was well tolerated with a very low rate (7.5%) of discontinuation of therapy. Although neutropenia was a frequent complication in the ribociclib group febrile neutropenia occurred in only 1.5% of patients.

The incorporation of CDK4/6 inhibitors to endocrine-based therapy in the front-line setting has proven effective with an impressive early separation of the progression-free survival curves. Both the PALOMA-2 trial and the current MONALEESA-2 trial have shown similar results with approximately 40% improvement in progression-free survival. Whether the results seen in these trials will translate into an improvement in overall survival is yet to be determined. The results of these 2 trial suggest that CDK4/6 inhibitors have activity in both patients who have not received previous treatment with endocrine therapy and in those who received adjuvant endocrine therapy with late (> 12 months) relapse. Further determination of the subset of women who would benefit from the addition of CDK4/6 inhibitors remains an important clinical question. There are currently no clinical biomarkers that can be used to predict whether a patient would benefit from the addition of these medications.

Applications for Clinical Practice

The results of the current trial represent an exciting step forward in the treatment of advanced breast cancer. Palbociclib in combination with endocrine therapy is currently incorporated into clinical practice. The cost of these agents remains a concern; however, most insurance policies will cover them. Clinical trials are ongoing in the neoadjuvant and adjuvant setting for early breast cancer.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy and safety of the CDK4/6 inhibitor ribociclib in combination with letrozole as initial therapy in patients with hormone-receptor (HR)–positive, human epidermal growth factor receptor 2 (HER-2)–negative advanced breast cancer.

Design. Pre-planned interim analysis of a randomized, double-blind, phase 3 clinical trial.

Setting and participants. This study enrolled patients in 29 countries at 223 centers. A total of 668 postmenopausal women underwent randomization, with 334 assigned to receive ribociclib plus letrozole and 334 assigned to receive placebo plus letrozole. All women had HR-positive, HER-2 negative recurrent or metastatic breast cancer and had not received prior systemic therapy. Enrolled patients had either measurable disease on imaging or at least 1 lytic bone lesion. All patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were excluded if they had received prior therapy with a CDK4/6 inhibitor, previous systemic chemotherapy or endocrine therapy. If a patient received an aromatase inhibitor for neoadjuvant or adjuvant therapy, the disease-free interval needed to be more than 12 months to be included in the study. Patients with inflammatory breast cancer or central nervous system involvement were also excluded. Normal cardiac function (normal QT interval) was required for enrollment. The randomization was stratified by presence of liver or lung metastases.

Intervention. The patients were randomized to oral ribociclib 600 mg per day 3 weeks on, 1 week off in a 28-day treatment cycle plus letrozole 2.5 mg daily or placebo plus letrozole. The dosing of ribociclib was based on a prior phase 1 study [1]. Treatment was continued until disease progression, unacceptable toxicity, discontinuation, or death. Dose reductions of ribociclib were allowed; however, dose reductions of letrozole were not permitted. Crossover between treatment arms was not allowed. Patients were assessed with computed tomo-graphy at the time of randomization, every 8 weeks for the first 18 months and every 12 weeks there-after. Patients were monitored for hematological toxicity each cycle. Electrocardiographic assessment was done at screening, on day 15 of cycle 1 and on day 1 of all subsequent cycles to monitor for QT prolongation.

Main outcome measures. The primary outcome was progression-free survival. The secondary outcomes were overall survival, overall response rate (complete or partial response), clinical benefit rate, and safety. Clinical benefit rate was defined as overall response plus stable disease lasting 24 weeks or more. A prespecified interim analysis was planned after disease progression or death was reported in 211 of 302 patients (70%).

Results. The baseline characteristics were balanced between the 2 groups. Visceral disease was present in 58.8% and bone-only disease in 22% of the patients. The median duration of therapy exposure was 13 months in the ribociclib group and 12.4 months in the placebo group. The median duration of follow-up was 15.3 months. After 18 months, progression-free survival was 63% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib/letrozole group versus 42.2% (95% CI, 34.8 to 49.5) in the placebo group (P < 0.001). The median progression-free survival was not met in the combination group (95% CI, 19.3 to not reached) versus 14.7 months (95% CI, 13.0 to 16.5) in the placebo group. The improved progression-free survival was seen across all subgroups. The overall response rate was higher in the combination arm (52.7% vs. 37.1%) as was the clinical benefit rate (80.1% vs. 71.8%). Serious adverse events occurred in 21.3% of patients in the ribociclib group and 11.8% in the placebo group. Serious adverse events were attributed to the study drug in 7.5% of the ribociclib group and 1.5% of the placebo group. The most common adverse events were myelosuppression, nausea, fatigue and diarrhea. Grade 3 and 4 neutropenia was noted in 59.3% in the ribociclib group versus < 1% in the placebo arm. The discontinuation rate due to adverse events in the ribociclib and placebo groups was 7.5% versus 2.1%, respectively. The most common reason for discontinuation was disease progression in 26% in the ribociclib group and 43.7% in the placebo group. Three deaths occurred in the ribociclib group and one in the placebo group. Interruptions in ribociclib occurred in 76.9% of patients. Dose reductions occurred in 53.9% of patients in the ribociclib group versus 7% in the placebo group. The most common reason a dose reduction occurred was neutropenia.

Conclusion. First-line treatment with ribociclib plus letrozole in postmenopausal women with HR-positive, HER-2 negative advanced breast cancer was associated with significantly longer progression-free survival compared with letrozole plus placebo. The improved progression-free survival was seen across all subgroups.

Commentary

Nearly 80% of all breast cancers express hormone receptor positivity. Hormonal therapy has been an important component of treatment for women with hormone-positive breast cancer in both the local and metastatic setting. Many tumors will eventually develop resistance to such therapy with the median progression-free survival with first-line endocrine therapy alone being around 9 months [2]. Cyclin dependent kinases 4 and 6 (CDK4/6) play an important role in estrogen-receptor signaling and cell cycle progression. CDK 4/6 mediates progression through the cell cycle from G1 to S phase via phosphorylation and inactivation of the retinoblastoma tumor suppressor protein [3]. Overexpression of CDK 4/6 in hormone receptor positive breast cancer is thought to play an important role in the development of endocrine therapy resistance [4].

The previously published PALOMA-2 trial, which compared treatment with the CDK 4/6 inhibitor palbociclib plus letrozole with letrozole alone, reported a significant improvement in progression-free survival with the addition of palbociclib (24.8 months vs. 14.5 months) in the front-line setting for women with advanced, hormone-positive breast cancer [5]. The improved progression-free survival with palbociclib was seen across all subgroups with a favorable toxicity profile. The current study represents the second randomized trial to show that the addition of CDK4/6 inhibitor to endocrine-based therapy significantly improves progression-free survival. This benefit was also seen across all patient subgroups including those with liver and lung metastases. In addition, the combination of ribociclib and letrozole also show significantly higher rates of overall response compared with placebo. In general, the addition of ribociclib to letrozole was well tolerated with a very low rate (7.5%) of discontinuation of therapy. Although neutropenia was a frequent complication in the ribociclib group febrile neutropenia occurred in only 1.5% of patients.

The incorporation of CDK4/6 inhibitors to endocrine-based therapy in the front-line setting has proven effective with an impressive early separation of the progression-free survival curves. Both the PALOMA-2 trial and the current MONALEESA-2 trial have shown similar results with approximately 40% improvement in progression-free survival. Whether the results seen in these trials will translate into an improvement in overall survival is yet to be determined. The results of these 2 trial suggest that CDK4/6 inhibitors have activity in both patients who have not received previous treatment with endocrine therapy and in those who received adjuvant endocrine therapy with late (> 12 months) relapse. Further determination of the subset of women who would benefit from the addition of CDK4/6 inhibitors remains an important clinical question. There are currently no clinical biomarkers that can be used to predict whether a patient would benefit from the addition of these medications.

Applications for Clinical Practice

The results of the current trial represent an exciting step forward in the treatment of advanced breast cancer. Palbociclib in combination with endocrine therapy is currently incorporated into clinical practice. The cost of these agents remains a concern; however, most insurance policies will cover them. Clinical trials are ongoing in the neoadjuvant and adjuvant setting for early breast cancer.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy and safety of the CDK4/6 inhibitor ribociclib in combination with letrozole as initial therapy in patients with hormone-receptor (HR)–positive, human epidermal growth factor receptor 2 (HER-2)–negative advanced breast cancer.

Design. Pre-planned interim analysis of a randomized, double-blind, phase 3 clinical trial.

Setting and participants. This study enrolled patients in 29 countries at 223 centers. A total of 668 postmenopausal women underwent randomization, with 334 assigned to receive ribociclib plus letrozole and 334 assigned to receive placebo plus letrozole. All women had HR-positive, HER-2 negative recurrent or metastatic breast cancer and had not received prior systemic therapy. Enrolled patients had either measurable disease on imaging or at least 1 lytic bone lesion. All patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were excluded if they had received prior therapy with a CDK4/6 inhibitor, previous systemic chemotherapy or endocrine therapy. If a patient received an aromatase inhibitor for neoadjuvant or adjuvant therapy, the disease-free interval needed to be more than 12 months to be included in the study. Patients with inflammatory breast cancer or central nervous system involvement were also excluded. Normal cardiac function (normal QT interval) was required for enrollment. The randomization was stratified by presence of liver or lung metastases.

Intervention. The patients were randomized to oral ribociclib 600 mg per day 3 weeks on, 1 week off in a 28-day treatment cycle plus letrozole 2.5 mg daily or placebo plus letrozole. The dosing of ribociclib was based on a prior phase 1 study [1]. Treatment was continued until disease progression, unacceptable toxicity, discontinuation, or death. Dose reductions of ribociclib were allowed; however, dose reductions of letrozole were not permitted. Crossover between treatment arms was not allowed. Patients were assessed with computed tomo-graphy at the time of randomization, every 8 weeks for the first 18 months and every 12 weeks there-after. Patients were monitored for hematological toxicity each cycle. Electrocardiographic assessment was done at screening, on day 15 of cycle 1 and on day 1 of all subsequent cycles to monitor for QT prolongation.

Main outcome measures. The primary outcome was progression-free survival. The secondary outcomes were overall survival, overall response rate (complete or partial response), clinical benefit rate, and safety. Clinical benefit rate was defined as overall response plus stable disease lasting 24 weeks or more. A prespecified interim analysis was planned after disease progression or death was reported in 211 of 302 patients (70%).

Results. The baseline characteristics were balanced between the 2 groups. Visceral disease was present in 58.8% and bone-only disease in 22% of the patients. The median duration of therapy exposure was 13 months in the ribociclib group and 12.4 months in the placebo group. The median duration of follow-up was 15.3 months. After 18 months, progression-free survival was 63% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib/letrozole group versus 42.2% (95% CI, 34.8 to 49.5) in the placebo group (P < 0.001). The median progression-free survival was not met in the combination group (95% CI, 19.3 to not reached) versus 14.7 months (95% CI, 13.0 to 16.5) in the placebo group. The improved progression-free survival was seen across all subgroups. The overall response rate was higher in the combination arm (52.7% vs. 37.1%) as was the clinical benefit rate (80.1% vs. 71.8%). Serious adverse events occurred in 21.3% of patients in the ribociclib group and 11.8% in the placebo group. Serious adverse events were attributed to the study drug in 7.5% of the ribociclib group and 1.5% of the placebo group. The most common adverse events were myelosuppression, nausea, fatigue and diarrhea. Grade 3 and 4 neutropenia was noted in 59.3% in the ribociclib group versus < 1% in the placebo arm. The discontinuation rate due to adverse events in the ribociclib and placebo groups was 7.5% versus 2.1%, respectively. The most common reason for discontinuation was disease progression in 26% in the ribociclib group and 43.7% in the placebo group. Three deaths occurred in the ribociclib group and one in the placebo group. Interruptions in ribociclib occurred in 76.9% of patients. Dose reductions occurred in 53.9% of patients in the ribociclib group versus 7% in the placebo group. The most common reason a dose reduction occurred was neutropenia.

Conclusion. First-line treatment with ribociclib plus letrozole in postmenopausal women with HR-positive, HER-2 negative advanced breast cancer was associated with significantly longer progression-free survival compared with letrozole plus placebo. The improved progression-free survival was seen across all subgroups.

Commentary

Nearly 80% of all breast cancers express hormone receptor positivity. Hormonal therapy has been an important component of treatment for women with hormone-positive breast cancer in both the local and metastatic setting. Many tumors will eventually develop resistance to such therapy with the median progression-free survival with first-line endocrine therapy alone being around 9 months [2]. Cyclin dependent kinases 4 and 6 (CDK4/6) play an important role in estrogen-receptor signaling and cell cycle progression. CDK 4/6 mediates progression through the cell cycle from G1 to S phase via phosphorylation and inactivation of the retinoblastoma tumor suppressor protein [3]. Overexpression of CDK 4/6 in hormone receptor positive breast cancer is thought to play an important role in the development of endocrine therapy resistance [4].

The previously published PALOMA-2 trial, which compared treatment with the CDK 4/6 inhibitor palbociclib plus letrozole with letrozole alone, reported a significant improvement in progression-free survival with the addition of palbociclib (24.8 months vs. 14.5 months) in the front-line setting for women with advanced, hormone-positive breast cancer [5]. The improved progression-free survival with palbociclib was seen across all subgroups with a favorable toxicity profile. The current study represents the second randomized trial to show that the addition of CDK4/6 inhibitor to endocrine-based therapy significantly improves progression-free survival. This benefit was also seen across all patient subgroups including those with liver and lung metastases. In addition, the combination of ribociclib and letrozole also show significantly higher rates of overall response compared with placebo. In general, the addition of ribociclib to letrozole was well tolerated with a very low rate (7.5%) of discontinuation of therapy. Although neutropenia was a frequent complication in the ribociclib group febrile neutropenia occurred in only 1.5% of patients.

The incorporation of CDK4/6 inhibitors to endocrine-based therapy in the front-line setting has proven effective with an impressive early separation of the progression-free survival curves. Both the PALOMA-2 trial and the current MONALEESA-2 trial have shown similar results with approximately 40% improvement in progression-free survival. Whether the results seen in these trials will translate into an improvement in overall survival is yet to be determined. The results of these 2 trial suggest that CDK4/6 inhibitors have activity in both patients who have not received previous treatment with endocrine therapy and in those who received adjuvant endocrine therapy with late (> 12 months) relapse. Further determination of the subset of women who would benefit from the addition of CDK4/6 inhibitors remains an important clinical question. There are currently no clinical biomarkers that can be used to predict whether a patient would benefit from the addition of these medications.

Applications for Clinical Practice

The results of the current trial represent an exciting step forward in the treatment of advanced breast cancer. Palbociclib in combination with endocrine therapy is currently incorporated into clinical practice. The cost of these agents remains a concern; however, most insurance policies will cover them. Clinical trials are ongoing in the neoadjuvant and adjuvant setting for early breast cancer.

—Daniel Isaac, DO, MS

SAN DIEGO – Call it “7+3+1”: an experimental induction regimen combining standard chemotherapy with an antibody drug conjugate induced rapid and deep remissions in a majority of patients with newly diagnosed acute myeloid leukemia in a small study.

Among 42 evaluable patients with previously untreated AML, the combination of cytarabine and an anthracycline (7+3, also known as 3+7), and the investigational antibody drug conjugate vadastuximab talirine was associated with a 60% complete remission (CR) rate, and 17% complete remission with incomplete recovery of platelets (CRi), reported Harry P. Erba, MD, PhD, of the University of Alabama at Birmingham, who discussed the findings in a video interview.

Rapid complete remissions

In the phase Ib trial reported at ASH 2016 by Dr. Erba, adults aged 18-65 years with untreated primary or secondary AML (except acute promyelocytic leukemia) were enrolled.

The patients received 33A in combination with 7+3 induction therapy (cytarabine 100 mg/m² and daunorubicin 60 mg/m²) on days 1 and 4 of a 28-day treatment cycle. Patients were assessed for response on days 1 and 28 according to International Working Group Criteria.

Second induction regimens and postremission therapies were permitted at the investigators discretion, and did not include 33A.

The median patient age was 45.5 years. The patients had generally good performance status (Eastern Cooperative Oncology Group 0 or 1). In all, 17% of patients had secondary AML. In all, 12% had favorable cytogenetic risk disease, 50% had intermediate risk, and 36% had adverse risk. Ten percent of patients had NPM1 mutated disease, and 14% had FLT-3 mutations.

As noted, the composite CR/CRi rate was 76%, consisting of 60% CR and 17% CRI.

All five patients with favorable risk disease had a CR. The rate of CR/CRi was 86% among patients with intermediate-risk disease, and 60 for those with adverse-risk disease.

Of the 32 patients who achieved a CR or CRi, 94% did so after 1 cycle of therapy, and 25 were MRD negative, as evaluated by an independent laboratory using 10-color multi-parameter flow cytometry.

Treatment-related adverse hematologic events included febrile neutropenia (primarily grade 3) in 43% of patients, thrombocytopenia (mostly grade 4) in 38%, anemia (all grade 3) in 24%, and neutropenia (mostly grade 4) in 17%. Other treatment related events were similar to those seen with 7 + 3 alone, and included nausea, diarrhea, decreased appetite and fatigue, mostly grade 1 or 2. One patient had a grade 3 irreversible hepatic toxicity.

The death rate was 2%.

“What we felt we showed is that we were able to combine active doses of 33A with 7 + 3. The doses here were less than the doses used as a single agent, but all doses used in our phase 1b study, including lower doses that what we actually used here, showed complete remissions as a single agent.”

33A “added acceptable on-target myelosuppression. We saw platelet counts recovering to over 100,000, and neutrophils over 1,000 by about four-and-a-half to five weeks, which we felt was reasonable, and patients were able to go on to get post-remission therapy.

A randomized phase II trial comparing 33A and 7+3 to 7+3 alone is slated to launch in the first quarter of 2017.

Dr. Erba disclosed serving as a consultant to and receiving research funding from Seattle Genetics, which supported the study.

SAN DIEGO – Call it “7+3+1”: an experimental induction regimen combining standard chemotherapy with an antibody drug conjugate induced rapid and deep remissions in a majority of patients with newly diagnosed acute myeloid leukemia in a small study.

Among 42 evaluable patients with previously untreated AML, the combination of cytarabine and an anthracycline (7+3, also known as 3+7), and the investigational antibody drug conjugate vadastuximab talirine was associated with a 60% complete remission (CR) rate, and 17% complete remission with incomplete recovery of platelets (CRi), reported Harry P. Erba, MD, PhD, of the University of Alabama at Birmingham, who discussed the findings in a video interview.

Rapid complete remissions

In the phase Ib trial reported at ASH 2016 by Dr. Erba, adults aged 18-65 years with untreated primary or secondary AML (except acute promyelocytic leukemia) were enrolled.

The patients received 33A in combination with 7+3 induction therapy (cytarabine 100 mg/m² and daunorubicin 60 mg/m²) on days 1 and 4 of a 28-day treatment cycle. Patients were assessed for response on days 1 and 28 according to International Working Group Criteria.

Second induction regimens and postremission therapies were permitted at the investigators discretion, and did not include 33A.

The median patient age was 45.5 years. The patients had generally good performance status (Eastern Cooperative Oncology Group 0 or 1). In all, 17% of patients had secondary AML. In all, 12% had favorable cytogenetic risk disease, 50% had intermediate risk, and 36% had adverse risk. Ten percent of patients had NPM1 mutated disease, and 14% had FLT-3 mutations.

As noted, the composite CR/CRi rate was 76%, consisting of 60% CR and 17% CRI.

All five patients with favorable risk disease had a CR. The rate of CR/CRi was 86% among patients with intermediate-risk disease, and 60 for those with adverse-risk disease.

Of the 32 patients who achieved a CR or CRi, 94% did so after 1 cycle of therapy, and 25 were MRD negative, as evaluated by an independent laboratory using 10-color multi-parameter flow cytometry.

Treatment-related adverse hematologic events included febrile neutropenia (primarily grade 3) in 43% of patients, thrombocytopenia (mostly grade 4) in 38%, anemia (all grade 3) in 24%, and neutropenia (mostly grade 4) in 17%. Other treatment related events were similar to those seen with 7 + 3 alone, and included nausea, diarrhea, decreased appetite and fatigue, mostly grade 1 or 2. One patient had a grade 3 irreversible hepatic toxicity.

The death rate was 2%.

“What we felt we showed is that we were able to combine active doses of 33A with 7 + 3. The doses here were less than the doses used as a single agent, but all doses used in our phase 1b study, including lower doses that what we actually used here, showed complete remissions as a single agent.”

33A “added acceptable on-target myelosuppression. We saw platelet counts recovering to over 100,000, and neutrophils over 1,000 by about four-and-a-half to five weeks, which we felt was reasonable, and patients were able to go on to get post-remission therapy.

A randomized phase II trial comparing 33A and 7+3 to 7+3 alone is slated to launch in the first quarter of 2017.

Dr. Erba disclosed serving as a consultant to and receiving research funding from Seattle Genetics, which supported the study.

SAN DIEGO – Call it “7+3+1”: an experimental induction regimen combining standard chemotherapy with an antibody drug conjugate induced rapid and deep remissions in a majority of patients with newly diagnosed acute myeloid leukemia in a small study.

Among 42 evaluable patients with previously untreated AML, the combination of cytarabine and an anthracycline (7+3, also known as 3+7), and the investigational antibody drug conjugate vadastuximab talirine was associated with a 60% complete remission (CR) rate, and 17% complete remission with incomplete recovery of platelets (CRi), reported Harry P. Erba, MD, PhD, of the University of Alabama at Birmingham, who discussed the findings in a video interview.

Rapid complete remissions

In the phase Ib trial reported at ASH 2016 by Dr. Erba, adults aged 18-65 years with untreated primary or secondary AML (except acute promyelocytic leukemia) were enrolled.

The patients received 33A in combination with 7+3 induction therapy (cytarabine 100 mg/m² and daunorubicin 60 mg/m²) on days 1 and 4 of a 28-day treatment cycle. Patients were assessed for response on days 1 and 28 according to International Working Group Criteria.

Second induction regimens and postremission therapies were permitted at the investigators discretion, and did not include 33A.

The median patient age was 45.5 years. The patients had generally good performance status (Eastern Cooperative Oncology Group 0 or 1). In all, 17% of patients had secondary AML. In all, 12% had favorable cytogenetic risk disease, 50% had intermediate risk, and 36% had adverse risk. Ten percent of patients had NPM1 mutated disease, and 14% had FLT-3 mutations.

As noted, the composite CR/CRi rate was 76%, consisting of 60% CR and 17% CRI.

All five patients with favorable risk disease had a CR. The rate of CR/CRi was 86% among patients with intermediate-risk disease, and 60 for those with adverse-risk disease.

Of the 32 patients who achieved a CR or CRi, 94% did so after 1 cycle of therapy, and 25 were MRD negative, as evaluated by an independent laboratory using 10-color multi-parameter flow cytometry.

Treatment-related adverse hematologic events included febrile neutropenia (primarily grade 3) in 43% of patients, thrombocytopenia (mostly grade 4) in 38%, anemia (all grade 3) in 24%, and neutropenia (mostly grade 4) in 17%. Other treatment related events were similar to those seen with 7 + 3 alone, and included nausea, diarrhea, decreased appetite and fatigue, mostly grade 1 or 2. One patient had a grade 3 irreversible hepatic toxicity.

The death rate was 2%.

“What we felt we showed is that we were able to combine active doses of 33A with 7 + 3. The doses here were less than the doses used as a single agent, but all doses used in our phase 1b study, including lower doses that what we actually used here, showed complete remissions as a single agent.”

33A “added acceptable on-target myelosuppression. We saw platelet counts recovering to over 100,000, and neutrophils over 1,000 by about four-and-a-half to five weeks, which we felt was reasonable, and patients were able to go on to get post-remission therapy.

A randomized phase II trial comparing 33A and 7+3 to 7+3 alone is slated to launch in the first quarter of 2017.

Dr. Erba disclosed serving as a consultant to and receiving research funding from Seattle Genetics, which supported the study.

Study Overview

Objective. To evaluate whether higher BMI alone contributes to risk of cardiovascular disease (CVD) and death.

Study design. Cohort study of weight-discordant monozygotic twin pairs

Setting and participants. This study took place in Sweden, using a subset of data from the Swedish Twin Registry and the Screening Across Lifespan Twin (SALT) study, which aimed to screen Swedish twins born prior to 1958 for the development of “common complex diseases.” From a total of 44,820 individuals, the current study limited to a subset of 4046 monozygotic twin pairs where both twins had self-reported height and weight data, and where calculated body mass index (BMI) was discordant between the twins, defined as a difference > 0.01 kg/m². No other inclusion or exclusion criteria are mentioned. Data for the study were collected from several different sources, including telephone interviews (eg, height and weight, behaviors such as physical activity and smoking), national registries on health conditions (eg, myocardial infarction [MI], stroke, diabetes) or prescriptions (eg, diabetes medications), the national causes of death register, and a nationwide database containing socioeconomic variables (eg, income and education). The primary exposure of interest for this study was weight status, categorized as “leaner” or “heavier,” depending on the relative BMI of each twin in a given pair. “Leaner” twins were assumed to have lower adiposity than their “heavier” counterparts, and yet to have identical genetic makeup, thereby allowing the authors to eliminate the contribution of genetic confounding in evaluating the relationship between weight status and CVD risk. The classification system could mean that one person with a BMI of 26 kg/m² would be placed in the “leaner” category if their twin had a BMI of 28, while someone else in another twin pair but also with a BMI of 26 kg/m² might be classified in the “heavier” category if their twin had a BMI of 22. Twin pairs were followed for up to 15 years to assess for incident outcomes of interest, with baseline data collected between 1998 and 2002, and follow-up through 2013.

Main outcome measures. The primary outcome of interest was the occurrence of incident MI or death from any cause. As above, these outcomes were assessed using national disease and death registries spanning 1987-2013, and ICD-9 or -10 codes of interest. A secondary outcome of incident diabetes was also specified, presumably limited to development of type 2 diabetes mellitus, and identified using the same datasets, as well as the national prescription registry. Kaplan-Meier curves for incident MI and death were constructed comparing all “leaner” twins against all “heavier” twins, and Cox proportional hazards modeling was used to compare the hazard of the primary composite outcome between groups. Logistic regression was used to evaluate the odds of each outcome including diabetes incidence, and several models were built, ranging from an unadjusted model to one adjusting for a number of lifestyle factors (eg, smoking status, physical activity), baseline health conditions, and sociodemographic factors.

The authors separately examined risk of MI/death in the subgroup of twins where the “heavier” twin had a BMI ≤ 24.9 kg/m² at baseline (ie, despite being labeled “heavier” they still had a technically normal BMI), and examined the impact of weight trajectory prior to the defined baseline (eg, they were able to incorporate into models whether someone had been actively gaining or losing weight over time prior to the baseline exposure categorization). The authors also conducted several sensitivity analyses, including running models excluding twins with < 1 year of follow-up in an effort to insure that results of the main analysis were not biased due to differential loss to follow-up between exposure categories.

Results. Of the 4046 twin pairs in this study, 56% (2283 pairs) were female, and mean (SD) age at baseline was 57.6 (9.5) years. Race/ethnicity was not reported but presumably the vast majority, if not all, are non-Hispanic white, based on the country of origin. In comparing the group of “heavier” twins to “leaner” twins, several important baseline differences were found. By design, the “heavier” twins had significantly higher mean (SD) BMI at study baseline (25.9 [3.6] kg/m² vs. 23.9 [3.1] kg/m²) and reported greater increases in BMI over the 15–20 years preceding baseline (change since 1973 was +4.3 [2.9] BMI units for “heavier” twins, vs. +2.6 [2.6] for “leaner” twins). Smoking status differed significantly between groups, with 15% of “heavier” twins reporting they were current smokers versus ~21% of “leaner” twins. “Leaner” twins were also slightly more active than their “heavier” counterparts (50.4% reported getting “rather much or very much” exercise versus 46.5%). The groups were otherwise very similar with respect to marital status, educational level, income, and baseline diagnoses of MI, stroke, diabetes, cancer or alcohol abuse.

In fully adjusted models over a mean (SD) 12.4 (2.5)-year follow-up, “heavier” twins had a significantly lower odds of MI or death (combined) than “leaner” twins (odds ratio [OR] 0.75, 95% CI 0.63–0.91). Because the “heavier” vs. “leaner” dichotomy did not map to clinical definitions of overweight or obesity, the investigators also examined this primary outcome among subgroups with more clinical relevance. Being “heavier” actually had the greatest protective effect against MI/death (OR 0.61, 95% CI 0.46–0.80) among pairs where the so-called “heavier” twin had a normal BMI (< 25.0 kg/m²), and this subgroup appeared to be driving the overall finding of lower odds of MI/death in the “heavier” group as a whole. This pattern was underscored when examining the subgroup of twin pairs where the “heavier” twin had a BMI ≥ 30 kg/m² at baseline – in this group the protective effect of being “heavier” disappeared (OR 0.92, 95% CI 0.60 to 1.42). Besides not always reflecting clinically relevant weight categories, the “heavier” vs. “leaner” twin dichotomy could, in some cases, amount to a very small difference in BMI between twins (anything > 0.01 unit counted as discordant). As such, the investigators sought to examine whether their results held up when looking at pairs with a higher threshold for BMI discordance (1.0 to 7.0 units or more difference between twins), finding that risk of MI or death did not increase among the “heavier” group in these more widely split twin pairs, even when adjusting for smoking status and physical activity.

In contrast to the MI/mortality analyses, “heavier” twins did have significantly greater odds of developing diabetes during follow-up compared to their “leaner” counterparts (OR 1.94, 95% CI 1.51 to 2.48, adjusted for smoking and physical activity). Also unlike the MI/death analyses, this relationship of increased diabetes risk among “heavier” twins was enhanced by increasing BMI dissimilarity between twins, and among twins who had been gaining weight prior to baseline BMI measurement.

Sensitivity analyses excluding twins with less than 1 year of follow-up did not result in changes to the main findings—“heavier” twins still had similar odds of MI/death as “leaner” twins.

Conclusion. The authors conclude that among monozygotic twin pairs, where the possibility for genetic confounding has been eliminated, obesity is not causally associated with increased risk of MI or death, although the results do support an increased risk of developing incident diabetes among individuals with higher BMI.

Commentary

Obesity is a known risk factor for many chronic conditions, including diabetes, osteoarthritis, sleep apnea, and hypertension [1]. However, the relationship between obesity and cardiovascular outcomes, particularly coronary artery disease and death from heart disease, has been more controversial. Some epidemiologic studies have demonstrated reduced mortality risk among patients with obesity and heart failure, and even among those with established coronary artery disease—the so-called “obesity paradox” [2]. Others have observed that overweight older adults may have lower overall mortality compared to their normal weight counterparts [3]. On the other hand, it is known that obesity increases risk for diabetes, which is itself a clear and proven risk factor for CVD and death.

As the authors of the current study point out, genetic confounding may be a potential reason for the conflicting results produced in studies of the obesity–CVD risk relationship. In other words, patients who have genes that promote weight gain may also have genes that promote CVD, through pathways independent of excess adipose tissue, with these hidden pathways acting as confounders of the obesity–CVD relationship. By studying monozygotic twin pairs, who have identical genetic makeup but have developed differential weight status due to different environmental exposures, the investigators designed a study that would eliminate any genetic confounding and allow them to better isolate the relationship between higher BMI and CVD. This is an important topic area because, at a population level, we are faced with an immense number of adults who have obesity. Treatment of this condition is resource intense and it is critical that patients and health care systems understand the potential risk reduction that will be achieved with sustained weight loss.

The strengths of this study include the use of a very unique dataset with longitudinal measures on a large number of monozygotic twin pairs, and the authors’ ability to link this dataset with nationwide comprehensive datasets on health conditions, health care use (pharmacy), sociodemographics, and death. Sweden’s national registries are quite impressive and permit these types of studies in a way that would be very difficult to achieve in the United States, with its innumerable separate health care systems and few data sources that contain information on all citizens. Because of these multiple data sources, the authors were able to adjust for some important lifestyle factors that could easily confound the weight status-MI/death relationship, such as smoking and physical activity. Additionally, their models were able to factor in trajectory of weight on some individuals prior to baseline, rather than viewing baseline weight only as a “snapshot” which could risk missing an important trend of weight gain or loss over time, with important health implications.

There are several limitations of the study that are worth reviewing. First, and most importantly, as pointed out in a commentary associated with the article, the categorization of “leaner” and “heavier” can be somewhat misleading if the true question is whether or not excess adiposity is an independent driver of cardiovascular risk [4]. BMI, at the individual level, is not an ideal measure of adiposity and it does not speak to distribution of fat tissue, which is critically important in evaluating CVD risk [5]. For example, 2 siblings could have identical BMIs, but one might have significantly more lean mass in their legs and buttocks, and the other could have more central adipose tissue, translating to a much higher cardiovascular risk. Measures such as waist circumference are critical factors in addition to BMI to better understand an individual’s adipose tissue volume and distribution.

Although the authors did adjust for some self-reported behaviors that are important predictors of CVD (smoking, exercise), there is still potential for confounding due to unscreened or unreported exposures that differ systematically between “leaner” and “heavier” twins. Of note, smoking status—probably the single most important risk factor for CVD—was missing in 13% of the cohort, and no imputation techniques were used for missing data. Another limitation of this study is that its generalizability to more racial/ethnically diverse populations may be limited. Presumably, the patients in this study were non-Hispanic white Swedes, and whether or not these findings would be replicated in other groups, such as those of African or Asian ancestry, is not known.

Finally, the finding that “heavier” twins had greater odds of developing diabetes during follow-up is certainly consistent with existing literature. However, it is also known that diabetes is a strong risk factor for the development of CVD, including MI, and for death [6]. This raises the question of why the authors observed an increased diabetes risk yet no change in MI/death rates among heavier twins. Most likely the discrepancy is due to inadequate follow-up time of incident diabetes cases. Complications of diabetes can take a number of years to materialize, and, with an average of 12 years’ total follow-up in this study, there simply may not have been time to observe an increased risk of MI/death in heavier twins.

Applications for Clinical Practice

For patients interested in weight loss as a way of reducing CVD risk, this paper does not support the notion that lower body weight alone exerts direct influence on this endpoint. However, it reinforces the link between higher body weight and diabetes, which is a clear risk factor for CVD. Therefore, it still seems reasonable to advise patients who are at risk of diabetes that improving dietary quality, increasing cardiorespiratory fitness, and losing weight can reduce their long-term risk of CVD, even if indirectly so.

—Kristina Lewis, MD, MPH

Study Overview

Objective. To evaluate whether higher BMI alone contributes to risk of cardiovascular disease (CVD) and death.

Study design. Cohort study of weight-discordant monozygotic twin pairs

Setting and participants. This study took place in Sweden, using a subset of data from the Swedish Twin Registry and the Screening Across Lifespan Twin (SALT) study, which aimed to screen Swedish twins born prior to 1958 for the development of “common complex diseases.” From a total of 44,820 individuals, the current study limited to a subset of 4046 monozygotic twin pairs where both twins had self-reported height and weight data, and where calculated body mass index (BMI) was discordant between the twins, defined as a difference > 0.01 kg/m². No other inclusion or exclusion criteria are mentioned. Data for the study were collected from several different sources, including telephone interviews (eg, height and weight, behaviors such as physical activity and smoking), national registries on health conditions (eg, myocardial infarction [MI], stroke, diabetes) or prescriptions (eg, diabetes medications), the national causes of death register, and a nationwide database containing socioeconomic variables (eg, income and education). The primary exposure of interest for this study was weight status, categorized as “leaner” or “heavier,” depending on the relative BMI of each twin in a given pair. “Leaner” twins were assumed to have lower adiposity than their “heavier” counterparts, and yet to have identical genetic makeup, thereby allowing the authors to eliminate the contribution of genetic confounding in evaluating the relationship between weight status and CVD risk. The classification system could mean that one person with a BMI of 26 kg/m² would be placed in the “leaner” category if their twin had a BMI of 28, while someone else in another twin pair but also with a BMI of 26 kg/m² might be classified in the “heavier” category if their twin had a BMI of 22. Twin pairs were followed for up to 15 years to assess for incident outcomes of interest, with baseline data collected between 1998 and 2002, and follow-up through 2013.

Main outcome measures. The primary outcome of interest was the occurrence of incident MI or death from any cause. As above, these outcomes were assessed using national disease and death registries spanning 1987-2013, and ICD-9 or -10 codes of interest. A secondary outcome of incident diabetes was also specified, presumably limited to development of type 2 diabetes mellitus, and identified using the same datasets, as well as the national prescription registry. Kaplan-Meier curves for incident MI and death were constructed comparing all “leaner” twins against all “heavier” twins, and Cox proportional hazards modeling was used to compare the hazard of the primary composite outcome between groups. Logistic regression was used to evaluate the odds of each outcome including diabetes incidence, and several models were built, ranging from an unadjusted model to one adjusting for a number of lifestyle factors (eg, smoking status, physical activity), baseline health conditions, and sociodemographic factors.

The authors separately examined risk of MI/death in the subgroup of twins where the “heavier” twin had a BMI ≤ 24.9 kg/m² at baseline (ie, despite being labeled “heavier” they still had a technically normal BMI), and examined the impact of weight trajectory prior to the defined baseline (eg, they were able to incorporate into models whether someone had been actively gaining or losing weight over time prior to the baseline exposure categorization). The authors also conducted several sensitivity analyses, including running models excluding twins with < 1 year of follow-up in an effort to insure that results of the main analysis were not biased due to differential loss to follow-up between exposure categories.

Results. Of the 4046 twin pairs in this study, 56% (2283 pairs) were female, and mean (SD) age at baseline was 57.6 (9.5) years. Race/ethnicity was not reported but presumably the vast majority, if not all, are non-Hispanic white, based on the country of origin. In comparing the group of “heavier” twins to “leaner” twins, several important baseline differences were found. By design, the “heavier” twins had significantly higher mean (SD) BMI at study baseline (25.9 [3.6] kg/m² vs. 23.9 [3.1] kg/m²) and reported greater increases in BMI over the 15–20 years preceding baseline (change since 1973 was +4.3 [2.9] BMI units for “heavier” twins, vs. +2.6 [2.6] for “leaner” twins). Smoking status differed significantly between groups, with 15% of “heavier” twins reporting they were current smokers versus ~21% of “leaner” twins. “Leaner” twins were also slightly more active than their “heavier” counterparts (50.4% reported getting “rather much or very much” exercise versus 46.5%). The groups were otherwise very similar with respect to marital status, educational level, income, and baseline diagnoses of MI, stroke, diabetes, cancer or alcohol abuse.

In fully adjusted models over a mean (SD) 12.4 (2.5)-year follow-up, “heavier” twins had a significantly lower odds of MI or death (combined) than “leaner” twins (odds ratio [OR] 0.75, 95% CI 0.63–0.91). Because the “heavier” vs. “leaner” dichotomy did not map to clinical definitions of overweight or obesity, the investigators also examined this primary outcome among subgroups with more clinical relevance. Being “heavier” actually had the greatest protective effect against MI/death (OR 0.61, 95% CI 0.46–0.80) among pairs where the so-called “heavier” twin had a normal BMI (< 25.0 kg/m²), and this subgroup appeared to be driving the overall finding of lower odds of MI/death in the “heavier” group as a whole. This pattern was underscored when examining the subgroup of twin pairs where the “heavier” twin had a BMI ≥ 30 kg/m² at baseline – in this group the protective effect of being “heavier” disappeared (OR 0.92, 95% CI 0.60 to 1.42). Besides not always reflecting clinically relevant weight categories, the “heavier” vs. “leaner” twin dichotomy could, in some cases, amount to a very small difference in BMI between twins (anything > 0.01 unit counted as discordant). As such, the investigators sought to examine whether their results held up when looking at pairs with a higher threshold for BMI discordance (1.0 to 7.0 units or more difference between twins), finding that risk of MI or death did not increase among the “heavier” group in these more widely split twin pairs, even when adjusting for smoking status and physical activity.

In contrast to the MI/mortality analyses, “heavier” twins did have significantly greater odds of developing diabetes during follow-up compared to their “leaner” counterparts (OR 1.94, 95% CI 1.51 to 2.48, adjusted for smoking and physical activity). Also unlike the MI/death analyses, this relationship of increased diabetes risk among “heavier” twins was enhanced by increasing BMI dissimilarity between twins, and among twins who had been gaining weight prior to baseline BMI measurement.

Sensitivity analyses excluding twins with less than 1 year of follow-up did not result in changes to the main findings—“heavier” twins still had similar odds of MI/death as “leaner” twins.

Conclusion. The authors conclude that among monozygotic twin pairs, where the possibility for genetic confounding has been eliminated, obesity is not causally associated with increased risk of MI or death, although the results do support an increased risk of developing incident diabetes among individuals with higher BMI.

Commentary

Obesity is a known risk factor for many chronic conditions, including diabetes, osteoarthritis, sleep apnea, and hypertension [1]. However, the relationship between obesity and cardiovascular outcomes, particularly coronary artery disease and death from heart disease, has been more controversial. Some epidemiologic studies have demonstrated reduced mortality risk among patients with obesity and heart failure, and even among those with established coronary artery disease—the so-called “obesity paradox” [2]. Others have observed that overweight older adults may have lower overall mortality compared to their normal weight counterparts [3]. On the other hand, it is known that obesity increases risk for diabetes, which is itself a clear and proven risk factor for CVD and death.

As the authors of the current study point out, genetic confounding may be a potential reason for the conflicting results produced in studies of the obesity–CVD risk relationship. In other words, patients who have genes that promote weight gain may also have genes that promote CVD, through pathways independent of excess adipose tissue, with these hidden pathways acting as confounders of the obesity–CVD relationship. By studying monozygotic twin pairs, who have identical genetic makeup but have developed differential weight status due to different environmental exposures, the investigators designed a study that would eliminate any genetic confounding and allow them to better isolate the relationship between higher BMI and CVD. This is an important topic area because, at a population level, we are faced with an immense number of adults who have obesity. Treatment of this condition is resource intense and it is critical that patients and health care systems understand the potential risk reduction that will be achieved with sustained weight loss.

The strengths of this study include the use of a very unique dataset with longitudinal measures on a large number of monozygotic twin pairs, and the authors’ ability to link this dataset with nationwide comprehensive datasets on health conditions, health care use (pharmacy), sociodemographics, and death. Sweden’s national registries are quite impressive and permit these types of studies in a way that would be very difficult to achieve in the United States, with its innumerable separate health care systems and few data sources that contain information on all citizens. Because of these multiple data sources, the authors were able to adjust for some important lifestyle factors that could easily confound the weight status-MI/death relationship, such as smoking and physical activity. Additionally, their models were able to factor in trajectory of weight on some individuals prior to baseline, rather than viewing baseline weight only as a “snapshot” which could risk missing an important trend of weight gain or loss over time, with important health implications.

There are several limitations of the study that are worth reviewing. First, and most importantly, as pointed out in a commentary associated with the article, the categorization of “leaner” and “heavier” can be somewhat misleading if the true question is whether or not excess adiposity is an independent driver of cardiovascular risk [4]. BMI, at the individual level, is not an ideal measure of adiposity and it does not speak to distribution of fat tissue, which is critically important in evaluating CVD risk [5]. For example, 2 siblings could have identical BMIs, but one might have significantly more lean mass in their legs and buttocks, and the other could have more central adipose tissue, translating to a much higher cardiovascular risk. Measures such as waist circumference are critical factors in addition to BMI to better understand an individual’s adipose tissue volume and distribution.

Although the authors did adjust for some self-reported behaviors that are important predictors of CVD (smoking, exercise), there is still potential for confounding due to unscreened or unreported exposures that differ systematically between “leaner” and “heavier” twins. Of note, smoking status—probably the single most important risk factor for CVD—was missing in 13% of the cohort, and no imputation techniques were used for missing data. Another limitation of this study is that its generalizability to more racial/ethnically diverse populations may be limited. Presumably, the patients in this study were non-Hispanic white Swedes, and whether or not these findings would be replicated in other groups, such as those of African or Asian ancestry, is not known.

Finally, the finding that “heavier” twins had greater odds of developing diabetes during follow-up is certainly consistent with existing literature. However, it is also known that diabetes is a strong risk factor for the development of CVD, including MI, and for death [6]. This raises the question of why the authors observed an increased diabetes risk yet no change in MI/death rates among heavier twins. Most likely the discrepancy is due to inadequate follow-up time of incident diabetes cases. Complications of diabetes can take a number of years to materialize, and, with an average of 12 years’ total follow-up in this study, there simply may not have been time to observe an increased risk of MI/death in heavier twins.

Applications for Clinical Practice

For patients interested in weight loss as a way of reducing CVD risk, this paper does not support the notion that lower body weight alone exerts direct influence on this endpoint. However, it reinforces the link between higher body weight and diabetes, which is a clear risk factor for CVD. Therefore, it still seems reasonable to advise patients who are at risk of diabetes that improving dietary quality, increasing cardiorespiratory fitness, and losing weight can reduce their long-term risk of CVD, even if indirectly so.

—Kristina Lewis, MD, MPH

Study Overview

Objective. To evaluate whether higher BMI alone contributes to risk of cardiovascular disease (CVD) and death.

Study design. Cohort study of weight-discordant monozygotic twin pairs

Setting and participants. This study took place in Sweden, using a subset of data from the Swedish Twin Registry and the Screening Across Lifespan Twin (SALT) study, which aimed to screen Swedish twins born prior to 1958 for the development of “common complex diseases.” From a total of 44,820 individuals, the current study limited to a subset of 4046 monozygotic twin pairs where both twins had self-reported height and weight data, and where calculated body mass index (BMI) was discordant between the twins, defined as a difference > 0.01 kg/m². No other inclusion or exclusion criteria are mentioned. Data for the study were collected from several different sources, including telephone interviews (eg, height and weight, behaviors such as physical activity and smoking), national registries on health conditions (eg, myocardial infarction [MI], stroke, diabetes) or prescriptions (eg, diabetes medications), the national causes of death register, and a nationwide database containing socioeconomic variables (eg, income and education). The primary exposure of interest for this study was weight status, categorized as “leaner” or “heavier,” depending on the relative BMI of each twin in a given pair. “Leaner” twins were assumed to have lower adiposity than their “heavier” counterparts, and yet to have identical genetic makeup, thereby allowing the authors to eliminate the contribution of genetic confounding in evaluating the relationship between weight status and CVD risk. The classification system could mean that one person with a BMI of 26 kg/m² would be placed in the “leaner” category if their twin had a BMI of 28, while someone else in another twin pair but also with a BMI of 26 kg/m² might be classified in the “heavier” category if their twin had a BMI of 22. Twin pairs were followed for up to 15 years to assess for incident outcomes of interest, with baseline data collected between 1998 and 2002, and follow-up through 2013.

Main outcome measures. The primary outcome of interest was the occurrence of incident MI or death from any cause. As above, these outcomes were assessed using national disease and death registries spanning 1987-2013, and ICD-9 or -10 codes of interest. A secondary outcome of incident diabetes was also specified, presumably limited to development of type 2 diabetes mellitus, and identified using the same datasets, as well as the national prescription registry. Kaplan-Meier curves for incident MI and death were constructed comparing all “leaner” twins against all “heavier” twins, and Cox proportional hazards modeling was used to compare the hazard of the primary composite outcome between groups. Logistic regression was used to evaluate the odds of each outcome including diabetes incidence, and several models were built, ranging from an unadjusted model to one adjusting for a number of lifestyle factors (eg, smoking status, physical activity), baseline health conditions, and sociodemographic factors.

The authors separately examined risk of MI/death in the subgroup of twins where the “heavier” twin had a BMI ≤ 24.9 kg/m² at baseline (ie, despite being labeled “heavier” they still had a technically normal BMI), and examined the impact of weight trajectory prior to the defined baseline (eg, they were able to incorporate into models whether someone had been actively gaining or losing weight over time prior to the baseline exposure categorization). The authors also conducted several sensitivity analyses, including running models excluding twins with < 1 year of follow-up in an effort to insure that results of the main analysis were not biased due to differential loss to follow-up between exposure categories.

Results. Of the 4046 twin pairs in this study, 56% (2283 pairs) were female, and mean (SD) age at baseline was 57.6 (9.5) years. Race/ethnicity was not reported but presumably the vast majority, if not all, are non-Hispanic white, based on the country of origin. In comparing the group of “heavier” twins to “leaner” twins, several important baseline differences were found. By design, the “heavier” twins had significantly higher mean (SD) BMI at study baseline (25.9 [3.6] kg/m² vs. 23.9 [3.1] kg/m²) and reported greater increases in BMI over the 15–20 years preceding baseline (change since 1973 was +4.3 [2.9] BMI units for “heavier” twins, vs. +2.6 [2.6] for “leaner” twins). Smoking status differed significantly between groups, with 15% of “heavier” twins reporting they were current smokers versus ~21% of “leaner” twins. “Leaner” twins were also slightly more active than their “heavier” counterparts (50.4% reported getting “rather much or very much” exercise versus 46.5%). The groups were otherwise very similar with respect to marital status, educational level, income, and baseline diagnoses of MI, stroke, diabetes, cancer or alcohol abuse.

In fully adjusted models over a mean (SD) 12.4 (2.5)-year follow-up, “heavier” twins had a significantly lower odds of MI or death (combined) than “leaner” twins (odds ratio [OR] 0.75, 95% CI 0.63–0.91). Because the “heavier” vs. “leaner” dichotomy did not map to clinical definitions of overweight or obesity, the investigators also examined this primary outcome among subgroups with more clinical relevance. Being “heavier” actually had the greatest protective effect against MI/death (OR 0.61, 95% CI 0.46–0.80) among pairs where the so-called “heavier” twin had a normal BMI (< 25.0 kg/m²), and this subgroup appeared to be driving the overall finding of lower odds of MI/death in the “heavier” group as a whole. This pattern was underscored when examining the subgroup of twin pairs where the “heavier” twin had a BMI ≥ 30 kg/m² at baseline – in this group the protective effect of being “heavier” disappeared (OR 0.92, 95% CI 0.60 to 1.42). Besides not always reflecting clinically relevant weight categories, the “heavier” vs. “leaner” twin dichotomy could, in some cases, amount to a very small difference in BMI between twins (anything > 0.01 unit counted as discordant). As such, the investigators sought to examine whether their results held up when looking at pairs with a higher threshold for BMI discordance (1.0 to 7.0 units or more difference between twins), finding that risk of MI or death did not increase among the “heavier” group in these more widely split twin pairs, even when adjusting for smoking status and physical activity.

In contrast to the MI/mortality analyses, “heavier” twins did have significantly greater odds of developing diabetes during follow-up compared to their “leaner” counterparts (OR 1.94, 95% CI 1.51 to 2.48, adjusted for smoking and physical activity). Also unlike the MI/death analyses, this relationship of increased diabetes risk among “heavier” twins was enhanced by increasing BMI dissimilarity between twins, and among twins who had been gaining weight prior to baseline BMI measurement.

Sensitivity analyses excluding twins with less than 1 year of follow-up did not result in changes to the main findings—“heavier” twins still had similar odds of MI/death as “leaner” twins.

Conclusion. The authors conclude that among monozygotic twin pairs, where the possibility for genetic confounding has been eliminated, obesity is not causally associated with increased risk of MI or death, although the results do support an increased risk of developing incident diabetes among individuals with higher BMI.

Commentary

Obesity is a known risk factor for many chronic conditions, including diabetes, osteoarthritis, sleep apnea, and hypertension [1]. However, the relationship between obesity and cardiovascular outcomes, particularly coronary artery disease and death from heart disease, has been more controversial. Some epidemiologic studies have demonstrated reduced mortality risk among patients with obesity and heart failure, and even among those with established coronary artery disease—the so-called “obesity paradox” [2]. Others have observed that overweight older adults may have lower overall mortality compared to their normal weight counterparts [3]. On the other hand, it is known that obesity increases risk for diabetes, which is itself a clear and proven risk factor for CVD and death.

As the authors of the current study point out, genetic confounding may be a potential reason for the conflicting results produced in studies of the obesity–CVD risk relationship. In other words, patients who have genes that promote weight gain may also have genes that promote CVD, through pathways independent of excess adipose tissue, with these hidden pathways acting as confounders of the obesity–CVD relationship. By studying monozygotic twin pairs, who have identical genetic makeup but have developed differential weight status due to different environmental exposures, the investigators designed a study that would eliminate any genetic confounding and allow them to better isolate the relationship between higher BMI and CVD. This is an important topic area because, at a population level, we are faced with an immense number of adults who have obesity. Treatment of this condition is resource intense and it is critical that patients and health care systems understand the potential risk reduction that will be achieved with sustained weight loss.

The strengths of this study include the use of a very unique dataset with longitudinal measures on a large number of monozygotic twin pairs, and the authors’ ability to link this dataset with nationwide comprehensive datasets on health conditions, health care use (pharmacy), sociodemographics, and death. Sweden’s national registries are quite impressive and permit these types of studies in a way that would be very difficult to achieve in the United States, with its innumerable separate health care systems and few data sources that contain information on all citizens. Because of these multiple data sources, the authors were able to adjust for some important lifestyle factors that could easily confound the weight status-MI/death relationship, such as smoking and physical activity. Additionally, their models were able to factor in trajectory of weight on some individuals prior to baseline, rather than viewing baseline weight only as a “snapshot” which could risk missing an important trend of weight gain or loss over time, with important health implications.

There are several limitations of the study that are worth reviewing. First, and most importantly, as pointed out in a commentary associated with the article, the categorization of “leaner” and “heavier” can be somewhat misleading if the true question is whether or not excess adiposity is an independent driver of cardiovascular risk [4]. BMI, at the individual level, is not an ideal measure of adiposity and it does not speak to distribution of fat tissue, which is critically important in evaluating CVD risk [5]. For example, 2 siblings could have identical BMIs, but one might have significantly more lean mass in their legs and buttocks, and the other could have more central adipose tissue, translating to a much higher cardiovascular risk. Measures such as waist circumference are critical factors in addition to BMI to better understand an individual’s adipose tissue volume and distribution.

Although the authors did adjust for some self-reported behaviors that are important predictors of CVD (smoking, exercise), there is still potential for confounding due to unscreened or unreported exposures that differ systematically between “leaner” and “heavier” twins. Of note, smoking status—probably the single most important risk factor for CVD—was missing in 13% of the cohort, and no imputation techniques were used for missing data. Another limitation of this study is that its generalizability to more racial/ethnically diverse populations may be limited. Presumably, the patients in this study were non-Hispanic white Swedes, and whether or not these findings would be replicated in other groups, such as those of African or Asian ancestry, is not known.

Finally, the finding that “heavier” twins had greater odds of developing diabetes during follow-up is certainly consistent with existing literature. However, it is also known that diabetes is a strong risk factor for the development of CVD, including MI, and for death [6]. This raises the question of why the authors observed an increased diabetes risk yet no change in MI/death rates among heavier twins. Most likely the discrepancy is due to inadequate follow-up time of incident diabetes cases. Complications of diabetes can take a number of years to materialize, and, with an average of 12 years’ total follow-up in this study, there simply may not have been time to observe an increased risk of MI/death in heavier twins.

Applications for Clinical Practice

For patients interested in weight loss as a way of reducing CVD risk, this paper does not support the notion that lower body weight alone exerts direct influence on this endpoint. However, it reinforces the link between higher body weight and diabetes, which is a clear risk factor for CVD. Therefore, it still seems reasonable to advise patients who are at risk of diabetes that improving dietary quality, increasing cardiorespiratory fitness, and losing weight can reduce their long-term risk of CVD, even if indirectly so.

—Kristina Lewis, MD, MPH

VIENNA – A grassroots, patient-centric program aimed at encouraging U.S. community hospitals in underserved areas to adopt a comprehensive centers-of-excellence model for treatment of lung cancer has demonstrated that community cancer centers can achieve quality of care comparable to that found in academic medical centers, Raymond Osarogiagbon, MD, declared at the World Congress on Lung Cancer.

One major reason why aggregate lung cancer survival in the United States has barely inched upward during the past 3 decades is there is often a huge gap between the quality of care patients get at academic research centers – including access to clinical trials – and what they can get in community hospitals. Eighty percent of lung cancer patients receive their care in these community cancer centers, where not all physicians and surgeons may be up to speed with guideline-recommended best practices, observed Dr. Osarogiagbon, a medical oncologist and director of the multidisciplinary thoracic oncology program at Baptist Cancer Center in Memphis.

Bruce Jancin/Frontline Medical News

The centers of excellence program, supported by the Bonnie J. Addario Lung Cancer Foundation, is an attempt to address this disparity. In 3 years, 13 hospitals in areas with large underserved patient populations in nine states have qualified. Dr. Osarogiagbon anticipates that the competitive advantage this designation provides will spur more and more community hospitals with cancer centers to get on board.

To qualify, community cancer centers have to commit to following specific best practices as standards of care in accord with guidelines issued by groups including the National Comprehensive Cancer Network and the American Society of Clinical Oncology. Requirements include the use of multidisciplinary teams for treatment decisions, routine use of molecular diagnostics and targeted therapies, patient access to clinical trials, longitudinal institutional data tracking, patient and caregiver education programs, and minimally invasive surgical and staging techniques. A lung cancer screening program is required. So is a systematic program for management of all incidentally detected lung nodules, many of which today fall between the cracks.

In an interview, Dr. Osarogiagbon shared several examples of how achieving the foundation’s center of excellence designation enables community cancer centers to achieve top-quality care on a par with academic medical centers. At Memorial Cancer Institute in Hollywood, Fla., which serves large Hispanic and black populations, implementation of a lung cancer screening program and other measures has resulted in 40% of patients with lung cancer being diagnosed with stage 1 or 2 disease amenable to curative surgery. The overall U.S. rate is significantly lower at 29%.

And in an area composed of western Tennessee, northern Mississippi, and eastern Arkansas, Dr. Osarogiagbon and coinvestigators at the Baptist Cancer Center conducted a study demonstrating that the use of two complementary surgical staging interventions resulted in improved rates of guideline-recommended surgical staging quality.

The observational study, presented elsewhere at the world congress by Nicholas Faris, MD, of the Thoracic Oncology Research Group, Baptist Cancer Center, Memphis, entailed analysis of curative-intent resections in 2,094 patients with non–small-cell lung cancer during 2004-2016. A novel anatomically sound gross dissection protocol was provided to assist pathologists in retrieving the intrapulmonary lymph nodes required for staging in 161 patients undergoing curative resection. A special lymph node specimen collection kit was utilized in 152. Another 289 resections utilized both interventions. And 1,492 patients received neither intervention.

Use of the interventions was associated with higher rates of adherence to various professional organizations’ guidelines for high-quality surgical staging. For example, the American College of Surgeons Commission on Cancer recommends that at least 10 lymph nodes be examined in patients with stage 1a-2b NSCLC. This was achieved in 71% of patients who had both interventions, 56% of those where the lymph node specimen collection kit was utilized but not the pathology intervention, 48% of patients where the pathology intervention but not the kit was employed, and in only 25% of patients where neither was used.

Similarly, more than three mediastinal lymph node stations were sampled in accord with National Comprehensive Cancer Network guidelines in 96% of patients with both interventions, 90% with the lymph node collection kit, 54% with the pathology intervention, and only 44% with neither, Dr. Osarogiagbon said in the interview.

Dr. Osarogiagbon reported serving as a consultant to Eli Lilly, Genentech, and the Association of Community Cancer Centers.

bjancin@frontlinemedcom.com

VIENNA – A grassroots, patient-centric program aimed at encouraging U.S. community hospitals in underserved areas to adopt a comprehensive centers-of-excellence model for treatment of lung cancer has demonstrated that community cancer centers can achieve quality of care comparable to that found in academic medical centers, Raymond Osarogiagbon, MD, declared at the World Congress on Lung Cancer.

One major reason why aggregate lung cancer survival in the United States has barely inched upward during the past 3 decades is there is often a huge gap between the quality of care patients get at academic research centers – including access to clinical trials – and what they can get in community hospitals. Eighty percent of lung cancer patients receive their care in these community cancer centers, where not all physicians and surgeons may be up to speed with guideline-recommended best practices, observed Dr. Osarogiagbon, a medical oncologist and director of the multidisciplinary thoracic oncology program at Baptist Cancer Center in Memphis.

Bruce Jancin/Frontline Medical News

The centers of excellence program, supported by the Bonnie J. Addario Lung Cancer Foundation, is an attempt to address this disparity. In 3 years, 13 hospitals in areas with large underserved patient populations in nine states have qualified. Dr. Osarogiagbon anticipates that the competitive advantage this designation provides will spur more and more community hospitals with cancer centers to get on board.

To qualify, community cancer centers have to commit to following specific best practices as standards of care in accord with guidelines issued by groups including the National Comprehensive Cancer Network and the American Society of Clinical Oncology. Requirements include the use of multidisciplinary teams for treatment decisions, routine use of molecular diagnostics and targeted therapies, patient access to clinical trials, longitudinal institutional data tracking, patient and caregiver education programs, and minimally invasive surgical and staging techniques. A lung cancer screening program is required. So is a systematic program for management of all incidentally detected lung nodules, many of which today fall between the cracks.

In an interview, Dr. Osarogiagbon shared several examples of how achieving the foundation’s center of excellence designation enables community cancer centers to achieve top-quality care on a par with academic medical centers. At Memorial Cancer Institute in Hollywood, Fla., which serves large Hispanic and black populations, implementation of a lung cancer screening program and other measures has resulted in 40% of patients with lung cancer being diagnosed with stage 1 or 2 disease amenable to curative surgery. The overall U.S. rate is significantly lower at 29%.

And in an area composed of western Tennessee, northern Mississippi, and eastern Arkansas, Dr. Osarogiagbon and coinvestigators at the Baptist Cancer Center conducted a study demonstrating that the use of two complementary surgical staging interventions resulted in improved rates of guideline-recommended surgical staging quality.

The observational study, presented elsewhere at the world congress by Nicholas Faris, MD, of the Thoracic Oncology Research Group, Baptist Cancer Center, Memphis, entailed analysis of curative-intent resections in 2,094 patients with non–small-cell lung cancer during 2004-2016. A novel anatomically sound gross dissection protocol was provided to assist pathologists in retrieving the intrapulmonary lymph nodes required for staging in 161 patients undergoing curative resection. A special lymph node specimen collection kit was utilized in 152. Another 289 resections utilized both interventions. And 1,492 patients received neither intervention.

Use of the interventions was associated with higher rates of adherence to various professional organizations’ guidelines for high-quality surgical staging. For example, the American College of Surgeons Commission on Cancer recommends that at least 10 lymph nodes be examined in patients with stage 1a-2b NSCLC. This was achieved in 71% of patients who had both interventions, 56% of those where the lymph node specimen collection kit was utilized but not the pathology intervention, 48% of patients where the pathology intervention but not the kit was employed, and in only 25% of patients where neither was used.

Similarly, more than three mediastinal lymph node stations were sampled in accord with National Comprehensive Cancer Network guidelines in 96% of patients with both interventions, 90% with the lymph node collection kit, 54% with the pathology intervention, and only 44% with neither, Dr. Osarogiagbon said in the interview.

Dr. Osarogiagbon reported serving as a consultant to Eli Lilly, Genentech, and the Association of Community Cancer Centers.

bjancin@frontlinemedcom.com

VIENNA – A grassroots, patient-centric program aimed at encouraging U.S. community hospitals in underserved areas to adopt a comprehensive centers-of-excellence model for treatment of lung cancer has demonstrated that community cancer centers can achieve quality of care comparable to that found in academic medical centers, Raymond Osarogiagbon, MD, declared at the World Congress on Lung Cancer.

One major reason why aggregate lung cancer survival in the United States has barely inched upward during the past 3 decades is there is often a huge gap between the quality of care patients get at academic research centers – including access to clinical trials – and what they can get in community hospitals. Eighty percent of lung cancer patients receive their care in these community cancer centers, where not all physicians and surgeons may be up to speed with guideline-recommended best practices, observed Dr. Osarogiagbon, a medical oncologist and director of the multidisciplinary thoracic oncology program at Baptist Cancer Center in Memphis.

Bruce Jancin/Frontline Medical News

The centers of excellence program, supported by the Bonnie J. Addario Lung Cancer Foundation, is an attempt to address this disparity. In 3 years, 13 hospitals in areas with large underserved patient populations in nine states have qualified. Dr. Osarogiagbon anticipates that the competitive advantage this designation provides will spur more and more community hospitals with cancer centers to get on board.

To qualify, community cancer centers have to commit to following specific best practices as standards of care in accord with guidelines issued by groups including the National Comprehensive Cancer Network and the American Society of Clinical Oncology. Requirements include the use of multidisciplinary teams for treatment decisions, routine use of molecular diagnostics and targeted therapies, patient access to clinical trials, longitudinal institutional data tracking, patient and caregiver education programs, and minimally invasive surgical and staging techniques. A lung cancer screening program is required. So is a systematic program for management of all incidentally detected lung nodules, many of which today fall between the cracks.

In an interview, Dr. Osarogiagbon shared several examples of how achieving the foundation’s center of excellence designation enables community cancer centers to achieve top-quality care on a par with academic medical centers. At Memorial Cancer Institute in Hollywood, Fla., which serves large Hispanic and black populations, implementation of a lung cancer screening program and other measures has resulted in 40% of patients with lung cancer being diagnosed with stage 1 or 2 disease amenable to curative surgery. The overall U.S. rate is significantly lower at 29%.

And in an area composed of western Tennessee, northern Mississippi, and eastern Arkansas, Dr. Osarogiagbon and coinvestigators at the Baptist Cancer Center conducted a study demonstrating that the use of two complementary surgical staging interventions resulted in improved rates of guideline-recommended surgical staging quality.

The observational study, presented elsewhere at the world congress by Nicholas Faris, MD, of the Thoracic Oncology Research Group, Baptist Cancer Center, Memphis, entailed analysis of curative-intent resections in 2,094 patients with non–small-cell lung cancer during 2004-2016. A novel anatomically sound gross dissection protocol was provided to assist pathologists in retrieving the intrapulmonary lymph nodes required for staging in 161 patients undergoing curative resection. A special lymph node specimen collection kit was utilized in 152. Another 289 resections utilized both interventions. And 1,492 patients received neither intervention.

Use of the interventions was associated with higher rates of adherence to various professional organizations’ guidelines for high-quality surgical staging. For example, the American College of Surgeons Commission on Cancer recommends that at least 10 lymph nodes be examined in patients with stage 1a-2b NSCLC. This was achieved in 71% of patients who had both interventions, 56% of those where the lymph node specimen collection kit was utilized but not the pathology intervention, 48% of patients where the pathology intervention but not the kit was employed, and in only 25% of patients where neither was used.

Similarly, more than three mediastinal lymph node stations were sampled in accord with National Comprehensive Cancer Network guidelines in 96% of patients with both interventions, 90% with the lymph node collection kit, 54% with the pathology intervention, and only 44% with neither, Dr. Osarogiagbon said in the interview.

Dr. Osarogiagbon reported serving as a consultant to Eli Lilly, Genentech, and the Association of Community Cancer Centers.

bjancin@frontlinemedcom.com

HOUSTON – Fellowship training in clinical neurophysiology delivered high rates of satisfaction, but recommended areas for improvements include more focus on training in sleep, brain mapping, and evoked potentials, results from a survey of current trainees found.

“There has been no systematic evaluation of neurophysiology fellowships,” Zulfi Haneef, MD, said in an interview in advance of the annual meeting of the American Epilepsy Society. “In fact, there are some studies on neurology residency, but not on any of the neurology fellowships. This study opens a window into what the situation is after residency: what makes the residents decide on a fellowship, and how they feel they have done with the choice of fellowship.”

dbrunk@frontlinemedcom.com

HOUSTON – Fellowship training in clinical neurophysiology delivered high rates of satisfaction, but recommended areas for improvements include more focus on training in sleep, brain mapping, and evoked potentials, results from a survey of current trainees found.

“There has been no systematic evaluation of neurophysiology fellowships,” Zulfi Haneef, MD, said in an interview in advance of the annual meeting of the American Epilepsy Society. “In fact, there are some studies on neurology residency, but not on any of the neurology fellowships. This study opens a window into what the situation is after residency: what makes the residents decide on a fellowship, and how they feel they have done with the choice of fellowship.”

dbrunk@frontlinemedcom.com

HOUSTON – Fellowship training in clinical neurophysiology delivered high rates of satisfaction, but recommended areas for improvements include more focus on training in sleep, brain mapping, and evoked potentials, results from a survey of current trainees found.

“There has been no systematic evaluation of neurophysiology fellowships,” Zulfi Haneef, MD, said in an interview in advance of the annual meeting of the American Epilepsy Society. “In fact, there are some studies on neurology residency, but not on any of the neurology fellowships. This study opens a window into what the situation is after residency: what makes the residents decide on a fellowship, and how they feel they have done with the choice of fellowship.”

dbrunk@frontlinemedcom.com

SAN DIEGO – An artificial red blood cell has come close to emulating the key functions of natural cells and does not appear to be associated with the side effects such as vasospasm and poor response to changes in blood pH that hampered the development of previous artificial blood products, Allan Doctor, MD, reported at the annual meeting of the American Society of Hematology.

The bio-synthetic cells, called ErythroMer, are about 1/50th the size of natural red blood cells. They can be stored at room temperature and reconstituted with water when needed for use.

In a mouse model, the ErythroMer cells were shown to capture oxygen in the lungs and release it to tissue in a pattern that was nearly identical to blood transfusion. In a rat model of shock, ErythroMer was effective for resuscitation.

In a video interview, Dr. Doctor of Washington University in St. Louis discussed the pharmacokinetics of ErythroMer, the need for a readily available blood substitute for treating trauma patients, other potential uses for artificial blood cells, and next steps for testing the product.

Dr. Doctor has equity ownership in KaloCyte, the company developing ErythroMer. He receives research funding from Children’s Discovery Institute and the National Institutes of Health.

mdales@frontlinemedcom.com

SAN DIEGO – An artificial red blood cell has come close to emulating the key functions of natural cells and does not appear to be associated with the side effects such as vasospasm and poor response to changes in blood pH that hampered the development of previous artificial blood products, Allan Doctor, MD, reported at the annual meeting of the American Society of Hematology.

The bio-synthetic cells, called ErythroMer, are about 1/50th the size of natural red blood cells. They can be stored at room temperature and reconstituted with water when needed for use.

In a mouse model, the ErythroMer cells were shown to capture oxygen in the lungs and release it to tissue in a pattern that was nearly identical to blood transfusion. In a rat model of shock, ErythroMer was effective for resuscitation.

In a video interview, Dr. Doctor of Washington University in St. Louis discussed the pharmacokinetics of ErythroMer, the need for a readily available blood substitute for treating trauma patients, other potential uses for artificial blood cells, and next steps for testing the product.

Dr. Doctor has equity ownership in KaloCyte, the company developing ErythroMer. He receives research funding from Children’s Discovery Institute and the National Institutes of Health.

mdales@frontlinemedcom.com

SAN DIEGO – An artificial red blood cell has come close to emulating the key functions of natural cells and does not appear to be associated with the side effects such as vasospasm and poor response to changes in blood pH that hampered the development of previous artificial blood products, Allan Doctor, MD, reported at the annual meeting of the American Society of Hematology.

The bio-synthetic cells, called ErythroMer, are about 1/50th the size of natural red blood cells. They can be stored at room temperature and reconstituted with water when needed for use.

In a mouse model, the ErythroMer cells were shown to capture oxygen in the lungs and release it to tissue in a pattern that was nearly identical to blood transfusion. In a rat model of shock, ErythroMer was effective for resuscitation.

In a video interview, Dr. Doctor of Washington University in St. Louis discussed the pharmacokinetics of ErythroMer, the need for a readily available blood substitute for treating trauma patients, other potential uses for artificial blood cells, and next steps for testing the product.

Dr. Doctor has equity ownership in KaloCyte, the company developing ErythroMer. He receives research funding from Children’s Discovery Institute and the National Institutes of Health.

mdales@frontlinemedcom.com