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High-dose vitamin D increases fall risk in study of 200 patients
Older adults treated with high-dose vitamin D as part of a double-blind, randomized clinical trial achieved target 25-hydroxyvitamin D levels at 6 and 12 months, but did not achieve the primary endpoint of improved lower extremity function.
In fact, the highest dose used in the study – 60,000 IU of vitamin D3 monthly – was associated with an increased risk of falls, according to Dr. Heike A. Bischoff-Ferrari of University Hospital Zurich, and her colleagues.
In the 200 home-dwelling adults aged older than 70 years who participated in the 1-year study, monthly doses of 60,000 IU of vitamin D3 and 24,000 IU of vitamin D3 plus 300 mcg of calcifediol were significantly more likely than a 24,000 IU dose of vitamin D3 alone to result in 25-hydroxyvitamin D levels of at least 30 ng/mL at 6 and 12 months, but lower extremity function did not differ among the groups, the investigators reported in a study published online Jan. 4 in JAMA Internal Medicine.
For example, the adjusted changes in Short Physical Performance Battery scores – a measure of walking speed, successive chair stands, and balance – were 0.17, 0.16, and 0.16 at 6 months in the 24,000 IU, 60,000 IU, and 24,000 IU plus calcifediol groups, respectively, and 0.38, 0.10, and 0.11 at 12 months (JAMA Intern Med. 2016 Jan 4. doi: 10.1001/jamainternmed.2015.7148).
However, the incidence of falls was 66.9%, 66.1%, and 47.9% in the groups, respectively, and the mean number of falls was higher in the 60,000 IU group (1.47) and 24,000 IU plus calcifediol group (1.24) than in the 24,000 IU group (0.94), they said, noting that a similar pattern was observed during study months 0-6 and months 7-12.
Study subjects had a mean age of 78 years, 58% were vitamin D deficient with levels of less than 20 ng/mL at baseline, and 13% were severely deficient (levels less than 10 ng/mL). All had experienced a low-trauma fall in the previous 12 months and were thus considered a high-risk group for vitamin D deficiency and functional decline. Vitamin D supplementation was given via one 5-mL drink solution each month that provided 24,000 IU of vitamin D3 – equivalent to the current recommendation of 800 IU/day – plus three placebo capsules; a 5-mL drink solution that provided 60,000 IU of vitamin D3 – the equivalent of 2,000 IU/day – plus three placebo capsules; or a 5-mL placebo drink, two capsules containing 12,000 IU of vitamin D3 each, and one capsule containing 300 mcg of calcifediol, which is a potent liver metabolite of vitamin D.
Although vitamin D supplementation has been proposed as a possible strategy for delaying functional decline because of its effects on muscle strength, the current findings, which are consistent with some prior studies, suggest that high-doses of vitamin D confer no benefit with respect to function decline, compared with a standard-of-care dose of 24,000 IU of D3, and that high doses may increase falls in those with a prior fall event. Further research is needed to confirm the findings for daily dosing regimens, as well as to explore the physiology behind a possible detrimental effect of a high monthly bolus dose of vitamin D on muscle function and falls, they concluded.
This study was funded by the Swiss National Science Foundation and the VELUX Foundations, as well as by investigator-initiated funds from Merck Sharp & Dohme AG, WILD, and DSM Nutritional Products. Dr. Bischoff-Ferrari reported receiving speaker fees from and serving on advisory boards for Merck Sharp & Dohme AG, Amgen, WILD, DSM Nutritional Products, Roche Diagnostics, Nestle, Pfizer, and Sanofi.
The vitamin D storyline may be similar to that of antioxidant vitamins, Dr. Steven R. Cummings and his colleagues wrote in an editorial.
“Enthusiasm for the health benefits of vitamin supplements is coupled with the belief that ‘vitamins’ are inherently safe and reinforced by observational studies showing, essentially, that healthy people have higher vitamin levels. Then [randomized, controlled trials] and meta-analyses proved that the supplements in fact increase mortality (beta carotene, vitamin E), or have no health benefits (vitamin A, vitamin C),” they wrote (JAMA Intern Med. 2016 Jan 4. doi: 10.1001/jamainternmed.2015.7568).
The strategy of supplementation with vitamin D to achieve serum levels of at least 30 ng/mL to reduce the risk of falls and fractures has not been established, and according to the findings by Bischoff-Ferrari et al., it may increase the risk of falling.
“Until that approach is supported by randomized trials with updated meta-analyses, it would be prudent to follow recommendation from the Institute of Medicine (IOM) that people 70 years or older have a total daily intake of 800 IU of vitamin D without routine measurement of serum 25(OH)D levels,” they wrote, adding that recommended intakes are best achieved through a balanced diet.
Dr. Cummings is with the California Pacific Medical Center Research Institute, San Francisco, and the University of California, San Francisco. He and his coauthors reported having no disclosures.
The vitamin D storyline may be similar to that of antioxidant vitamins, Dr. Steven R. Cummings and his colleagues wrote in an editorial.
“Enthusiasm for the health benefits of vitamin supplements is coupled with the belief that ‘vitamins’ are inherently safe and reinforced by observational studies showing, essentially, that healthy people have higher vitamin levels. Then [randomized, controlled trials] and meta-analyses proved that the supplements in fact increase mortality (beta carotene, vitamin E), or have no health benefits (vitamin A, vitamin C),” they wrote (JAMA Intern Med. 2016 Jan 4. doi: 10.1001/jamainternmed.2015.7568).
The strategy of supplementation with vitamin D to achieve serum levels of at least 30 ng/mL to reduce the risk of falls and fractures has not been established, and according to the findings by Bischoff-Ferrari et al., it may increase the risk of falling.
“Until that approach is supported by randomized trials with updated meta-analyses, it would be prudent to follow recommendation from the Institute of Medicine (IOM) that people 70 years or older have a total daily intake of 800 IU of vitamin D without routine measurement of serum 25(OH)D levels,” they wrote, adding that recommended intakes are best achieved through a balanced diet.
Dr. Cummings is with the California Pacific Medical Center Research Institute, San Francisco, and the University of California, San Francisco. He and his coauthors reported having no disclosures.
The vitamin D storyline may be similar to that of antioxidant vitamins, Dr. Steven R. Cummings and his colleagues wrote in an editorial.
“Enthusiasm for the health benefits of vitamin supplements is coupled with the belief that ‘vitamins’ are inherently safe and reinforced by observational studies showing, essentially, that healthy people have higher vitamin levels. Then [randomized, controlled trials] and meta-analyses proved that the supplements in fact increase mortality (beta carotene, vitamin E), or have no health benefits (vitamin A, vitamin C),” they wrote (JAMA Intern Med. 2016 Jan 4. doi: 10.1001/jamainternmed.2015.7568).
The strategy of supplementation with vitamin D to achieve serum levels of at least 30 ng/mL to reduce the risk of falls and fractures has not been established, and according to the findings by Bischoff-Ferrari et al., it may increase the risk of falling.
“Until that approach is supported by randomized trials with updated meta-analyses, it would be prudent to follow recommendation from the Institute of Medicine (IOM) that people 70 years or older have a total daily intake of 800 IU of vitamin D without routine measurement of serum 25(OH)D levels,” they wrote, adding that recommended intakes are best achieved through a balanced diet.
Dr. Cummings is with the California Pacific Medical Center Research Institute, San Francisco, and the University of California, San Francisco. He and his coauthors reported having no disclosures.
Older adults treated with high-dose vitamin D as part of a double-blind, randomized clinical trial achieved target 25-hydroxyvitamin D levels at 6 and 12 months, but did not achieve the primary endpoint of improved lower extremity function.
In fact, the highest dose used in the study – 60,000 IU of vitamin D3 monthly – was associated with an increased risk of falls, according to Dr. Heike A. Bischoff-Ferrari of University Hospital Zurich, and her colleagues.
In the 200 home-dwelling adults aged older than 70 years who participated in the 1-year study, monthly doses of 60,000 IU of vitamin D3 and 24,000 IU of vitamin D3 plus 300 mcg of calcifediol were significantly more likely than a 24,000 IU dose of vitamin D3 alone to result in 25-hydroxyvitamin D levels of at least 30 ng/mL at 6 and 12 months, but lower extremity function did not differ among the groups, the investigators reported in a study published online Jan. 4 in JAMA Internal Medicine.
For example, the adjusted changes in Short Physical Performance Battery scores – a measure of walking speed, successive chair stands, and balance – were 0.17, 0.16, and 0.16 at 6 months in the 24,000 IU, 60,000 IU, and 24,000 IU plus calcifediol groups, respectively, and 0.38, 0.10, and 0.11 at 12 months (JAMA Intern Med. 2016 Jan 4. doi: 10.1001/jamainternmed.2015.7148).
However, the incidence of falls was 66.9%, 66.1%, and 47.9% in the groups, respectively, and the mean number of falls was higher in the 60,000 IU group (1.47) and 24,000 IU plus calcifediol group (1.24) than in the 24,000 IU group (0.94), they said, noting that a similar pattern was observed during study months 0-6 and months 7-12.
Study subjects had a mean age of 78 years, 58% were vitamin D deficient with levels of less than 20 ng/mL at baseline, and 13% were severely deficient (levels less than 10 ng/mL). All had experienced a low-trauma fall in the previous 12 months and were thus considered a high-risk group for vitamin D deficiency and functional decline. Vitamin D supplementation was given via one 5-mL drink solution each month that provided 24,000 IU of vitamin D3 – equivalent to the current recommendation of 800 IU/day – plus three placebo capsules; a 5-mL drink solution that provided 60,000 IU of vitamin D3 – the equivalent of 2,000 IU/day – plus three placebo capsules; or a 5-mL placebo drink, two capsules containing 12,000 IU of vitamin D3 each, and one capsule containing 300 mcg of calcifediol, which is a potent liver metabolite of vitamin D.
Although vitamin D supplementation has been proposed as a possible strategy for delaying functional decline because of its effects on muscle strength, the current findings, which are consistent with some prior studies, suggest that high-doses of vitamin D confer no benefit with respect to function decline, compared with a standard-of-care dose of 24,000 IU of D3, and that high doses may increase falls in those with a prior fall event. Further research is needed to confirm the findings for daily dosing regimens, as well as to explore the physiology behind a possible detrimental effect of a high monthly bolus dose of vitamin D on muscle function and falls, they concluded.
This study was funded by the Swiss National Science Foundation and the VELUX Foundations, as well as by investigator-initiated funds from Merck Sharp & Dohme AG, WILD, and DSM Nutritional Products. Dr. Bischoff-Ferrari reported receiving speaker fees from and serving on advisory boards for Merck Sharp & Dohme AG, Amgen, WILD, DSM Nutritional Products, Roche Diagnostics, Nestle, Pfizer, and Sanofi.
Older adults treated with high-dose vitamin D as part of a double-blind, randomized clinical trial achieved target 25-hydroxyvitamin D levels at 6 and 12 months, but did not achieve the primary endpoint of improved lower extremity function.
In fact, the highest dose used in the study – 60,000 IU of vitamin D3 monthly – was associated with an increased risk of falls, according to Dr. Heike A. Bischoff-Ferrari of University Hospital Zurich, and her colleagues.
In the 200 home-dwelling adults aged older than 70 years who participated in the 1-year study, monthly doses of 60,000 IU of vitamin D3 and 24,000 IU of vitamin D3 plus 300 mcg of calcifediol were significantly more likely than a 24,000 IU dose of vitamin D3 alone to result in 25-hydroxyvitamin D levels of at least 30 ng/mL at 6 and 12 months, but lower extremity function did not differ among the groups, the investigators reported in a study published online Jan. 4 in JAMA Internal Medicine.
For example, the adjusted changes in Short Physical Performance Battery scores – a measure of walking speed, successive chair stands, and balance – were 0.17, 0.16, and 0.16 at 6 months in the 24,000 IU, 60,000 IU, and 24,000 IU plus calcifediol groups, respectively, and 0.38, 0.10, and 0.11 at 12 months (JAMA Intern Med. 2016 Jan 4. doi: 10.1001/jamainternmed.2015.7148).
However, the incidence of falls was 66.9%, 66.1%, and 47.9% in the groups, respectively, and the mean number of falls was higher in the 60,000 IU group (1.47) and 24,000 IU plus calcifediol group (1.24) than in the 24,000 IU group (0.94), they said, noting that a similar pattern was observed during study months 0-6 and months 7-12.
Study subjects had a mean age of 78 years, 58% were vitamin D deficient with levels of less than 20 ng/mL at baseline, and 13% were severely deficient (levels less than 10 ng/mL). All had experienced a low-trauma fall in the previous 12 months and were thus considered a high-risk group for vitamin D deficiency and functional decline. Vitamin D supplementation was given via one 5-mL drink solution each month that provided 24,000 IU of vitamin D3 – equivalent to the current recommendation of 800 IU/day – plus three placebo capsules; a 5-mL drink solution that provided 60,000 IU of vitamin D3 – the equivalent of 2,000 IU/day – plus three placebo capsules; or a 5-mL placebo drink, two capsules containing 12,000 IU of vitamin D3 each, and one capsule containing 300 mcg of calcifediol, which is a potent liver metabolite of vitamin D.
Although vitamin D supplementation has been proposed as a possible strategy for delaying functional decline because of its effects on muscle strength, the current findings, which are consistent with some prior studies, suggest that high-doses of vitamin D confer no benefit with respect to function decline, compared with a standard-of-care dose of 24,000 IU of D3, and that high doses may increase falls in those with a prior fall event. Further research is needed to confirm the findings for daily dosing regimens, as well as to explore the physiology behind a possible detrimental effect of a high monthly bolus dose of vitamin D on muscle function and falls, they concluded.
This study was funded by the Swiss National Science Foundation and the VELUX Foundations, as well as by investigator-initiated funds from Merck Sharp & Dohme AG, WILD, and DSM Nutritional Products. Dr. Bischoff-Ferrari reported receiving speaker fees from and serving on advisory boards for Merck Sharp & Dohme AG, Amgen, WILD, DSM Nutritional Products, Roche Diagnostics, Nestle, Pfizer, and Sanofi.
FROM JAMA INTERNAL MEDICINE
Key clinical point: Older adults treated with high-dose vitamin D as part of a double-blind, randomized clinical trial achieved target 25-hydroxyvitamin D levels at 6 and 12 months, but did not achieve the primary endpoint of improved lower extremity function.
Major finding: Fall incidence was 66.9%, 66.1%, and 47.9% with vitamin D3 at doses of 24,000 IU, 60,000 IU, and 24,000 IU, respectively, plus 300 mcg calcifediol.
Data source: A double-blind, randomized trial involving 200 patients.
Disclosures: This study was funded by the Swiss National Science Foundation and the VELUX Foundations, as well as by investigator-initiated funds from Merck Sharp & Dohme AG, WILD, and DSM Nutritional Products. Dr. Bischoff-Ferrari disclosed ties with Merck Sharp & Dohme AG, Amgen, WILD, DSM Nutritional Products, Roche Diagnostics, Nestle, Pfizer, and Sanofi.
Cancer drug discovery database goes 3D
Photo by Rhoda Baer
Researchers have updated the canSAR database, a tool designed to aid cancer drug discovery, by adding 3D structures of faulty proteins and maps of cancer’s communication networks.
The canSAR database brings together biological, chemical, and pharmacological data.
The goal of the database is to make these data accessible to researchers worldwide to help with hypothesis generation and support drug discovery decisions.
Users can search canSAR using text queries, protein/gene name searches, any keyword searches, chemical structure searches, and sequence similarity searches. Users can also explore and filter chemical compound sets, view experimental data, and produce summary plots.
The canSAR database was launched in 2011 with the goal of using Big Data approaches to build a detailed picture of how the majority of known human molecules behave.
The database has already collated billions of experimental measurements, mapping the actions of 1 million drugs and chemicals on human proteins, and it has combined these data with genetic information and results from clinical trials.
The updated version of canSAR uses artificial intelligence to identify nooks and crannies on the surface of faulty cancer-causing molecules as a key step in designing new drugs to block them. It also allows researchers to identify communication lines that can be intercepted within tumor cells, opening up potential new approaches for cancer treatment.
The growing database now holds the 3D structures of almost 3 million cavities on the surface of nearly 110,000 molecules.
“Our database is constantly growing with information and is the largest of its kind, with more than 140,000 users from over 175 countries,” said Bissan Al-Lazikani, PhD, of The Institute of Cancer Research in London, UK.
“And we regularly develop new artificial intelligence technologies that help scientists make predictions and design experiments. Our aim is that cancer scientists will be armed with the data they need to carry out life-saving research into the most exciting drugs of the future.”
“Scientists need to find all the information there is about a faulty gene or protein to understand whether a new drug might work. These data are vast and scattered, but the canSAR database brings them together and adds value by identifying hidden links and presenting the key information easily.”
Details on the updates to canSAR have been published in Nucleic Acid Research. The database is available online at https://cansar.icr.ac.uk/. 
Photo by Rhoda Baer
Researchers have updated the canSAR database, a tool designed to aid cancer drug discovery, by adding 3D structures of faulty proteins and maps of cancer’s communication networks.
The canSAR database brings together biological, chemical, and pharmacological data.
The goal of the database is to make these data accessible to researchers worldwide to help with hypothesis generation and support drug discovery decisions.
Users can search canSAR using text queries, protein/gene name searches, any keyword searches, chemical structure searches, and sequence similarity searches. Users can also explore and filter chemical compound sets, view experimental data, and produce summary plots.
The canSAR database was launched in 2011 with the goal of using Big Data approaches to build a detailed picture of how the majority of known human molecules behave.
The database has already collated billions of experimental measurements, mapping the actions of 1 million drugs and chemicals on human proteins, and it has combined these data with genetic information and results from clinical trials.
The updated version of canSAR uses artificial intelligence to identify nooks and crannies on the surface of faulty cancer-causing molecules as a key step in designing new drugs to block them. It also allows researchers to identify communication lines that can be intercepted within tumor cells, opening up potential new approaches for cancer treatment.
The growing database now holds the 3D structures of almost 3 million cavities on the surface of nearly 110,000 molecules.
“Our database is constantly growing with information and is the largest of its kind, with more than 140,000 users from over 175 countries,” said Bissan Al-Lazikani, PhD, of The Institute of Cancer Research in London, UK.
“And we regularly develop new artificial intelligence technologies that help scientists make predictions and design experiments. Our aim is that cancer scientists will be armed with the data they need to carry out life-saving research into the most exciting drugs of the future.”
“Scientists need to find all the information there is about a faulty gene or protein to understand whether a new drug might work. These data are vast and scattered, but the canSAR database brings them together and adds value by identifying hidden links and presenting the key information easily.”
Details on the updates to canSAR have been published in Nucleic Acid Research. The database is available online at https://cansar.icr.ac.uk/.
Photo by Rhoda Baer
Researchers have updated the canSAR database, a tool designed to aid cancer drug discovery, by adding 3D structures of faulty proteins and maps of cancer’s communication networks.
The canSAR database brings together biological, chemical, and pharmacological data.
The goal of the database is to make these data accessible to researchers worldwide to help with hypothesis generation and support drug discovery decisions.
Users can search canSAR using text queries, protein/gene name searches, any keyword searches, chemical structure searches, and sequence similarity searches. Users can also explore and filter chemical compound sets, view experimental data, and produce summary plots.
The canSAR database was launched in 2011 with the goal of using Big Data approaches to build a detailed picture of how the majority of known human molecules behave.
The database has already collated billions of experimental measurements, mapping the actions of 1 million drugs and chemicals on human proteins, and it has combined these data with genetic information and results from clinical trials.
The updated version of canSAR uses artificial intelligence to identify nooks and crannies on the surface of faulty cancer-causing molecules as a key step in designing new drugs to block them. It also allows researchers to identify communication lines that can be intercepted within tumor cells, opening up potential new approaches for cancer treatment.
The growing database now holds the 3D structures of almost 3 million cavities on the surface of nearly 110,000 molecules.
“Our database is constantly growing with information and is the largest of its kind, with more than 140,000 users from over 175 countries,” said Bissan Al-Lazikani, PhD, of The Institute of Cancer Research in London, UK.
“And we regularly develop new artificial intelligence technologies that help scientists make predictions and design experiments. Our aim is that cancer scientists will be armed with the data they need to carry out life-saving research into the most exciting drugs of the future.”
“Scientists need to find all the information there is about a faulty gene or protein to understand whether a new drug might work. These data are vast and scattered, but the canSAR database brings them together and adds value by identifying hidden links and presenting the key information easily.”
Details on the updates to canSAR have been published in Nucleic Acid Research. The database is available online at https://cansar.icr.ac.uk/.
Nonalcoholic fatty liver disease will keep rising ‘in near term’
Nonalcoholic fatty liver disease (NAFLD) almost tripled among United States veterans in a recent 9-year period, investigators reported in the February issue of Clinical Gastroenterology and Hepatology.
The trend “was evident in all racial groups, across all age groups, and in both genders,” said Dr. Fasiha Kanwal of the Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, both in Houston, and her associates. The increasing prevalence of NAFLD “is likely generalizable to nonveterans,” and will probably persist because of a “fairly steady” 2%-3% overall annual incidence and a steeper rise among younger individuals, they added. “Nonalcoholic fatty liver disease will continue to remain a major public health problem in the United States, at least in the near and intermediate future.”
Although NAFLD is the leading cause of chronic liver failure in the United States, few studies have examined its incidence or prevalence over time, which are key to predicting future disease burden. Therefore, the investigators analyzed data for more than 9.78 million patients who visited the VA at least once between 2003 and 2011. They defined NAFLD as at least two elevated alanine aminotransferase (ALT) values (greater than 40 IU/mL) separated by at least 6 months, with no history of positive serology for hepatitis B surface antigen or hepatitis C virus RNA, and no alcohol-related ICD-9 codes or positive AUDIT-C scores within a year of elevated ALT levels (Clin Gastroenterol Hepatol. 2015 Aug 7. doi: 10.1016/j.cgh.2015.08.010).
During the study period, more than 1.3 million patients, or 13.6%, met the definition of NAFLD, said the researchers. Age-adjusted incidence rates dropped slightly from 3.16% in 2003 to 2.5% in 2011, ranging between 2.3% and 2.7% in most years. Prevalence, however, rose from 6.3% in 2003 (95% confidence interval, 6.26%-6.3%) to 17.6% in 2011 (95% CI, 17.58%-17.65%), a 2.8-fold increase. Moreover, about one in five patients with NAFLD who visited the VA in 2011 was at risk for advanced fibrosis.
Among individuals who were younger than 45 years, the incidence of NAFLD rose from 2.3 to 4.3 cases per 100 persons (annual percentage change, 7.4%; 95% CI, 5.7% to 9.2%), the researchers also found. “Although recent studies show that the rate of increase in both obesity and diabetes, which are both major risk factors for NAFLD, may be slowing down in the U.S., this may not be the case in the VA, where the prevalence of obesity and diabetes is in fact higher than in the U.S. population,” they said.
In general, the findings mirror a recent analysis of the National Health and Nutrition Examination Survey (Aliment Pharmacol Ther. 2015 Jan;41[1]:65-76), according to the investigators. “The VA is the largest integrated health care system in the United States,” they added. “We believe that the sheer size of the veteran cohort, combined with a complete dearth of information regarding the burden of NAFLD in the VA, renders our findings highly significant. Furthermore, the VA is in a unique position to test and implement systemic changes in medical care delivery to improve the health care of NAFLD patients.”
The study was partially supported by the Michael E. DeBakey Veterans Affairs Medical Center. The researchers had no disclosures.
Kanwal and colleagues present an interesting study assessing the trends in the incidence and prevalence of NAFLD in the United States. Findings suggest that the annual incidence of NAFLD has generally been stable (2.2%-3.2%), while the prevalence of NAFLD has increased by 2.8-fold (6.3%-17.6%). These findings are consistent with the literature and provide additional evidence supporting the increasing burden of NAFLD. Although an important study, there are some limitations to the study design. First, the diagnosis of NAFLD was solely based on elevated liver enzymes, which can underestimate the true incidence and prevalence of NAFLD. In fact, in a recent meta-analysis, NAFLD prevalence based on liver enzymes was 13%, while NAFLD prevalence based on radiologic diagnosis was 25% (Hepatology. 2015 Dec 28. doi: 10.1002/hep.28431. [Epub ahead of print]). Second, the study subjects came from the VA system, which may not be representative of the U.S. population (Patrick AFB, FL: Defense Equal Opportunity Management Institute, 2010). This is important because sex-specific differences in the prevalence of NAFLD have been reported (Hepatology. 2015 Dec 28. doi: 10.1002/hep.28431. [Epub ahead of print]). Nevertheless, these limitations do not minimize the important contribution of this study. There appears to be an alarming increase in the burden of NAFLD within all the racial and age groups in the U.S. Further, this increase in the incidence and prevalence of NAFLD is especially significant among the younger age groups (less than 45 years). This finding is in contrast to others who have reported a higher prevalence in older subjects (Presented at AASLD 2015. San Francisco. Abstract #534). If confirmed, this younger cohort of patients with NAFLD can fuel the future burden of liver disease for the next few decades (JAMA. 2012;307:491-7). Given the current lack of an effective treatment for NAFLD, a national strategy to deal with this important and rising cause of chronic liver disease is urgently needed.
Dr. Zobair M. Younossi, MPH, FACG, AGAF, FAASLD, is chairman, department of medicine, Inova Fairfax Hospital; vice president for research, Inova Health System; professor of medicine, VCU-Inova Campus and Beatty Center for Integrated Research, Falls Church, Va. He has consulted for Gilead, AbbVie, Intercept, BMS, and GSK.
Kanwal and colleagues present an interesting study assessing the trends in the incidence and prevalence of NAFLD in the United States. Findings suggest that the annual incidence of NAFLD has generally been stable (2.2%-3.2%), while the prevalence of NAFLD has increased by 2.8-fold (6.3%-17.6%). These findings are consistent with the literature and provide additional evidence supporting the increasing burden of NAFLD. Although an important study, there are some limitations to the study design. First, the diagnosis of NAFLD was solely based on elevated liver enzymes, which can underestimate the true incidence and prevalence of NAFLD. In fact, in a recent meta-analysis, NAFLD prevalence based on liver enzymes was 13%, while NAFLD prevalence based on radiologic diagnosis was 25% (Hepatology. 2015 Dec 28. doi: 10.1002/hep.28431. [Epub ahead of print]). Second, the study subjects came from the VA system, which may not be representative of the U.S. population (Patrick AFB, FL: Defense Equal Opportunity Management Institute, 2010). This is important because sex-specific differences in the prevalence of NAFLD have been reported (Hepatology. 2015 Dec 28. doi: 10.1002/hep.28431. [Epub ahead of print]). Nevertheless, these limitations do not minimize the important contribution of this study. There appears to be an alarming increase in the burden of NAFLD within all the racial and age groups in the U.S. Further, this increase in the incidence and prevalence of NAFLD is especially significant among the younger age groups (less than 45 years). This finding is in contrast to others who have reported a higher prevalence in older subjects (Presented at AASLD 2015. San Francisco. Abstract #534). If confirmed, this younger cohort of patients with NAFLD can fuel the future burden of liver disease for the next few decades (JAMA. 2012;307:491-7). Given the current lack of an effective treatment for NAFLD, a national strategy to deal with this important and rising cause of chronic liver disease is urgently needed.
Dr. Zobair M. Younossi, MPH, FACG, AGAF, FAASLD, is chairman, department of medicine, Inova Fairfax Hospital; vice president for research, Inova Health System; professor of medicine, VCU-Inova Campus and Beatty Center for Integrated Research, Falls Church, Va. He has consulted for Gilead, AbbVie, Intercept, BMS, and GSK.
Kanwal and colleagues present an interesting study assessing the trends in the incidence and prevalence of NAFLD in the United States. Findings suggest that the annual incidence of NAFLD has generally been stable (2.2%-3.2%), while the prevalence of NAFLD has increased by 2.8-fold (6.3%-17.6%). These findings are consistent with the literature and provide additional evidence supporting the increasing burden of NAFLD. Although an important study, there are some limitations to the study design. First, the diagnosis of NAFLD was solely based on elevated liver enzymes, which can underestimate the true incidence and prevalence of NAFLD. In fact, in a recent meta-analysis, NAFLD prevalence based on liver enzymes was 13%, while NAFLD prevalence based on radiologic diagnosis was 25% (Hepatology. 2015 Dec 28. doi: 10.1002/hep.28431. [Epub ahead of print]). Second, the study subjects came from the VA system, which may not be representative of the U.S. population (Patrick AFB, FL: Defense Equal Opportunity Management Institute, 2010). This is important because sex-specific differences in the prevalence of NAFLD have been reported (Hepatology. 2015 Dec 28. doi: 10.1002/hep.28431. [Epub ahead of print]). Nevertheless, these limitations do not minimize the important contribution of this study. There appears to be an alarming increase in the burden of NAFLD within all the racial and age groups in the U.S. Further, this increase in the incidence and prevalence of NAFLD is especially significant among the younger age groups (less than 45 years). This finding is in contrast to others who have reported a higher prevalence in older subjects (Presented at AASLD 2015. San Francisco. Abstract #534). If confirmed, this younger cohort of patients with NAFLD can fuel the future burden of liver disease for the next few decades (JAMA. 2012;307:491-7). Given the current lack of an effective treatment for NAFLD, a national strategy to deal with this important and rising cause of chronic liver disease is urgently needed.
Dr. Zobair M. Younossi, MPH, FACG, AGAF, FAASLD, is chairman, department of medicine, Inova Fairfax Hospital; vice president for research, Inova Health System; professor of medicine, VCU-Inova Campus and Beatty Center for Integrated Research, Falls Church, Va. He has consulted for Gilead, AbbVie, Intercept, BMS, and GSK.
Nonalcoholic fatty liver disease (NAFLD) almost tripled among United States veterans in a recent 9-year period, investigators reported in the February issue of Clinical Gastroenterology and Hepatology.
The trend “was evident in all racial groups, across all age groups, and in both genders,” said Dr. Fasiha Kanwal of the Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, both in Houston, and her associates. The increasing prevalence of NAFLD “is likely generalizable to nonveterans,” and will probably persist because of a “fairly steady” 2%-3% overall annual incidence and a steeper rise among younger individuals, they added. “Nonalcoholic fatty liver disease will continue to remain a major public health problem in the United States, at least in the near and intermediate future.”
Although NAFLD is the leading cause of chronic liver failure in the United States, few studies have examined its incidence or prevalence over time, which are key to predicting future disease burden. Therefore, the investigators analyzed data for more than 9.78 million patients who visited the VA at least once between 2003 and 2011. They defined NAFLD as at least two elevated alanine aminotransferase (ALT) values (greater than 40 IU/mL) separated by at least 6 months, with no history of positive serology for hepatitis B surface antigen or hepatitis C virus RNA, and no alcohol-related ICD-9 codes or positive AUDIT-C scores within a year of elevated ALT levels (Clin Gastroenterol Hepatol. 2015 Aug 7. doi: 10.1016/j.cgh.2015.08.010).
During the study period, more than 1.3 million patients, or 13.6%, met the definition of NAFLD, said the researchers. Age-adjusted incidence rates dropped slightly from 3.16% in 2003 to 2.5% in 2011, ranging between 2.3% and 2.7% in most years. Prevalence, however, rose from 6.3% in 2003 (95% confidence interval, 6.26%-6.3%) to 17.6% in 2011 (95% CI, 17.58%-17.65%), a 2.8-fold increase. Moreover, about one in five patients with NAFLD who visited the VA in 2011 was at risk for advanced fibrosis.
Among individuals who were younger than 45 years, the incidence of NAFLD rose from 2.3 to 4.3 cases per 100 persons (annual percentage change, 7.4%; 95% CI, 5.7% to 9.2%), the researchers also found. “Although recent studies show that the rate of increase in both obesity and diabetes, which are both major risk factors for NAFLD, may be slowing down in the U.S., this may not be the case in the VA, where the prevalence of obesity and diabetes is in fact higher than in the U.S. population,” they said.
In general, the findings mirror a recent analysis of the National Health and Nutrition Examination Survey (Aliment Pharmacol Ther. 2015 Jan;41[1]:65-76), according to the investigators. “The VA is the largest integrated health care system in the United States,” they added. “We believe that the sheer size of the veteran cohort, combined with a complete dearth of information regarding the burden of NAFLD in the VA, renders our findings highly significant. Furthermore, the VA is in a unique position to test and implement systemic changes in medical care delivery to improve the health care of NAFLD patients.”
The study was partially supported by the Michael E. DeBakey Veterans Affairs Medical Center. The researchers had no disclosures.
Nonalcoholic fatty liver disease (NAFLD) almost tripled among United States veterans in a recent 9-year period, investigators reported in the February issue of Clinical Gastroenterology and Hepatology.
The trend “was evident in all racial groups, across all age groups, and in both genders,” said Dr. Fasiha Kanwal of the Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, both in Houston, and her associates. The increasing prevalence of NAFLD “is likely generalizable to nonveterans,” and will probably persist because of a “fairly steady” 2%-3% overall annual incidence and a steeper rise among younger individuals, they added. “Nonalcoholic fatty liver disease will continue to remain a major public health problem in the United States, at least in the near and intermediate future.”
Although NAFLD is the leading cause of chronic liver failure in the United States, few studies have examined its incidence or prevalence over time, which are key to predicting future disease burden. Therefore, the investigators analyzed data for more than 9.78 million patients who visited the VA at least once between 2003 and 2011. They defined NAFLD as at least two elevated alanine aminotransferase (ALT) values (greater than 40 IU/mL) separated by at least 6 months, with no history of positive serology for hepatitis B surface antigen or hepatitis C virus RNA, and no alcohol-related ICD-9 codes or positive AUDIT-C scores within a year of elevated ALT levels (Clin Gastroenterol Hepatol. 2015 Aug 7. doi: 10.1016/j.cgh.2015.08.010).
During the study period, more than 1.3 million patients, or 13.6%, met the definition of NAFLD, said the researchers. Age-adjusted incidence rates dropped slightly from 3.16% in 2003 to 2.5% in 2011, ranging between 2.3% and 2.7% in most years. Prevalence, however, rose from 6.3% in 2003 (95% confidence interval, 6.26%-6.3%) to 17.6% in 2011 (95% CI, 17.58%-17.65%), a 2.8-fold increase. Moreover, about one in five patients with NAFLD who visited the VA in 2011 was at risk for advanced fibrosis.
Among individuals who were younger than 45 years, the incidence of NAFLD rose from 2.3 to 4.3 cases per 100 persons (annual percentage change, 7.4%; 95% CI, 5.7% to 9.2%), the researchers also found. “Although recent studies show that the rate of increase in both obesity and diabetes, which are both major risk factors for NAFLD, may be slowing down in the U.S., this may not be the case in the VA, where the prevalence of obesity and diabetes is in fact higher than in the U.S. population,” they said.
In general, the findings mirror a recent analysis of the National Health and Nutrition Examination Survey (Aliment Pharmacol Ther. 2015 Jan;41[1]:65-76), according to the investigators. “The VA is the largest integrated health care system in the United States,” they added. “We believe that the sheer size of the veteran cohort, combined with a complete dearth of information regarding the burden of NAFLD in the VA, renders our findings highly significant. Furthermore, the VA is in a unique position to test and implement systemic changes in medical care delivery to improve the health care of NAFLD patients.”
The study was partially supported by the Michael E. DeBakey Veterans Affairs Medical Center. The researchers had no disclosures.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: The prevalence of nonalcoholic fatty liver disease has risen substantially since 2003, and will probably keep increasing in the near term.
Major finding: Prevalence among veterans rose about 2.8 times between 2003 and 2011, mirroring trends reported in the general population.
Data source: An analysis of data from 9.78 million Veterans Affairs patients.
Disclosures: The study was partially supported by the Michael E. DeBakey Veterans Affairs Medical Center. The researchers had no disclosures.
Is there an increased risk of GI bleeds with SSRIs?
Yes. Selective serotonin reuptake inhibitors (SSRIs) are likely associated with a moderate increased risk of upper gastrointestinal (UGI) bleeding. Use of a nonsteroidal anti-inflammatory drug (NSAID) in combination with the SSRI appears to amplify the risk (strength of recommendation [SOR]: B, meta-analysis of cohort and case control studies).
The increased risk from SSRIs occurs within the first 7 to 28 days after exposure (SOR: B, retrospective study).
SSRIs raise bleeding risk; concurrent NSAIDs raise it more
A 2014 systematic review and meta-analysis of 19 case-control and cohort studies with a total of 446,949 patients investigated the risk of UGI bleeding in patients using SSRIs and NSAIDs.1 The studies, which included both inpatients and outpatients, were done in Europe and North America. Patients were at least 16 years old, but pooled demographics were not reported. Investigators compared SSRI use with or without concurrent NSAID use to placebo or no treatment.
SSRI use was associated with an increased risk of UGI bleeding in 15 case-control studies (393,268 patients; odds ratio [OR]=1.7; 95% confidence interval [CI], 1.4-1.9) and 4 cohort studies (53,681 patients; OR=1.7; 95% CI, 1.1-2.5). The simultaneous use of SSRIs and NSAIDs compared to nonuse of both medications was associated with a larger increase in bleeding risk (10 case-control studies, 223,336 patients; OR=4.3; 95% CI, 2.8-6.4).
The meta-analysis is limited by statistically significant heterogeneity in all of the pooled results and high risk of bias in 9 of the case-control studies and all of the cohort studies. There was no evidence of publication bias, however.
Bleeding risk rises 7 to 28 days after SSRI exposure
A 2014 case-crossover study of 5377 inpatients in Taiwan with a psychiatric diagnosis evaluated the risk of UGI bleeding within the first 28 days after SSRI exposure (SSRI-mediated inhibition of platelets occurs within the first 7 to 14 days).2 The average age of the patients was 58 years and 75% of the study population was male. Each patient served as his or her own control.
ORs were calculated to compare patients who were exposed to SSRIs only during 7-, 14-, and 21-day windows immediately before a UGI bleed to controls exposed to SSRIs only during the control periods before the 7-, 14-, and 21-day windows. The ORs were adjusted through multivariate analysis to account for 7 potential confounding factors.
SSRI use was associated with an increased risk of UGI bleeding in 7-, 14-, and 21-day windows before the index event (TABLE2). An increased bleeding risk in the 14 days after SSRI initiation was observed in men (OR=2.4; 95% CI, 1.8-3.4) but not women (OR=1.0; 95% CI, 0.6-1.6). Increased bleeding risk in the 14 days after SSRI initiation was also observed in patients younger than 55 years (OR=2.1; 95% CI, 1.5-3.1), patients with a history of upper GI disease (OR=3.1; 95% CI, 1.7-6.0), and patients with no previous exposure to SSRIs (OR=2.6; 95% CI, 1.6-4.2).
This study didn’t account for SSRI indication as a potential confounder, and the study’s inclusion of inpatients, whose illnesses are typically more severe, may limit generalizability.
1. Anglin R, Yuan Y, Moayyedi P, et al. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am J Gastroenterol. 2014;109:811-819.
2. Wang YP, Chen YT, Tsai C, et al. Short-term use of serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding. Am J Psychiatry. 2014;171:54-61.
Yes. Selective serotonin reuptake inhibitors (SSRIs) are likely associated with a moderate increased risk of upper gastrointestinal (UGI) bleeding. Use of a nonsteroidal anti-inflammatory drug (NSAID) in combination with the SSRI appears to amplify the risk (strength of recommendation [SOR]: B, meta-analysis of cohort and case control studies).
The increased risk from SSRIs occurs within the first 7 to 28 days after exposure (SOR: B, retrospective study).
SSRIs raise bleeding risk; concurrent NSAIDs raise it more
A 2014 systematic review and meta-analysis of 19 case-control and cohort studies with a total of 446,949 patients investigated the risk of UGI bleeding in patients using SSRIs and NSAIDs.1 The studies, which included both inpatients and outpatients, were done in Europe and North America. Patients were at least 16 years old, but pooled demographics were not reported. Investigators compared SSRI use with or without concurrent NSAID use to placebo or no treatment.
SSRI use was associated with an increased risk of UGI bleeding in 15 case-control studies (393,268 patients; odds ratio [OR]=1.7; 95% confidence interval [CI], 1.4-1.9) and 4 cohort studies (53,681 patients; OR=1.7; 95% CI, 1.1-2.5). The simultaneous use of SSRIs and NSAIDs compared to nonuse of both medications was associated with a larger increase in bleeding risk (10 case-control studies, 223,336 patients; OR=4.3; 95% CI, 2.8-6.4).
The meta-analysis is limited by statistically significant heterogeneity in all of the pooled results and high risk of bias in 9 of the case-control studies and all of the cohort studies. There was no evidence of publication bias, however.
Bleeding risk rises 7 to 28 days after SSRI exposure
A 2014 case-crossover study of 5377 inpatients in Taiwan with a psychiatric diagnosis evaluated the risk of UGI bleeding within the first 28 days after SSRI exposure (SSRI-mediated inhibition of platelets occurs within the first 7 to 14 days).2 The average age of the patients was 58 years and 75% of the study population was male. Each patient served as his or her own control.
ORs were calculated to compare patients who were exposed to SSRIs only during 7-, 14-, and 21-day windows immediately before a UGI bleed to controls exposed to SSRIs only during the control periods before the 7-, 14-, and 21-day windows. The ORs were adjusted through multivariate analysis to account for 7 potential confounding factors.
SSRI use was associated with an increased risk of UGI bleeding in 7-, 14-, and 21-day windows before the index event (TABLE2). An increased bleeding risk in the 14 days after SSRI initiation was observed in men (OR=2.4; 95% CI, 1.8-3.4) but not women (OR=1.0; 95% CI, 0.6-1.6). Increased bleeding risk in the 14 days after SSRI initiation was also observed in patients younger than 55 years (OR=2.1; 95% CI, 1.5-3.1), patients with a history of upper GI disease (OR=3.1; 95% CI, 1.7-6.0), and patients with no previous exposure to SSRIs (OR=2.6; 95% CI, 1.6-4.2).
This study didn’t account for SSRI indication as a potential confounder, and the study’s inclusion of inpatients, whose illnesses are typically more severe, may limit generalizability.
Yes. Selective serotonin reuptake inhibitors (SSRIs) are likely associated with a moderate increased risk of upper gastrointestinal (UGI) bleeding. Use of a nonsteroidal anti-inflammatory drug (NSAID) in combination with the SSRI appears to amplify the risk (strength of recommendation [SOR]: B, meta-analysis of cohort and case control studies).
The increased risk from SSRIs occurs within the first 7 to 28 days after exposure (SOR: B, retrospective study).
SSRIs raise bleeding risk; concurrent NSAIDs raise it more
A 2014 systematic review and meta-analysis of 19 case-control and cohort studies with a total of 446,949 patients investigated the risk of UGI bleeding in patients using SSRIs and NSAIDs.1 The studies, which included both inpatients and outpatients, were done in Europe and North America. Patients were at least 16 years old, but pooled demographics were not reported. Investigators compared SSRI use with or without concurrent NSAID use to placebo or no treatment.
SSRI use was associated with an increased risk of UGI bleeding in 15 case-control studies (393,268 patients; odds ratio [OR]=1.7; 95% confidence interval [CI], 1.4-1.9) and 4 cohort studies (53,681 patients; OR=1.7; 95% CI, 1.1-2.5). The simultaneous use of SSRIs and NSAIDs compared to nonuse of both medications was associated with a larger increase in bleeding risk (10 case-control studies, 223,336 patients; OR=4.3; 95% CI, 2.8-6.4).
The meta-analysis is limited by statistically significant heterogeneity in all of the pooled results and high risk of bias in 9 of the case-control studies and all of the cohort studies. There was no evidence of publication bias, however.
Bleeding risk rises 7 to 28 days after SSRI exposure
A 2014 case-crossover study of 5377 inpatients in Taiwan with a psychiatric diagnosis evaluated the risk of UGI bleeding within the first 28 days after SSRI exposure (SSRI-mediated inhibition of platelets occurs within the first 7 to 14 days).2 The average age of the patients was 58 years and 75% of the study population was male. Each patient served as his or her own control.
ORs were calculated to compare patients who were exposed to SSRIs only during 7-, 14-, and 21-day windows immediately before a UGI bleed to controls exposed to SSRIs only during the control periods before the 7-, 14-, and 21-day windows. The ORs were adjusted through multivariate analysis to account for 7 potential confounding factors.
SSRI use was associated with an increased risk of UGI bleeding in 7-, 14-, and 21-day windows before the index event (TABLE2). An increased bleeding risk in the 14 days after SSRI initiation was observed in men (OR=2.4; 95% CI, 1.8-3.4) but not women (OR=1.0; 95% CI, 0.6-1.6). Increased bleeding risk in the 14 days after SSRI initiation was also observed in patients younger than 55 years (OR=2.1; 95% CI, 1.5-3.1), patients with a history of upper GI disease (OR=3.1; 95% CI, 1.7-6.0), and patients with no previous exposure to SSRIs (OR=2.6; 95% CI, 1.6-4.2).
This study didn’t account for SSRI indication as a potential confounder, and the study’s inclusion of inpatients, whose illnesses are typically more severe, may limit generalizability.
1. Anglin R, Yuan Y, Moayyedi P, et al. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am J Gastroenterol. 2014;109:811-819.
2. Wang YP, Chen YT, Tsai C, et al. Short-term use of serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding. Am J Psychiatry. 2014;171:54-61.
1. Anglin R, Yuan Y, Moayyedi P, et al. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am J Gastroenterol. 2014;109:811-819.
2. Wang YP, Chen YT, Tsai C, et al. Short-term use of serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding. Am J Psychiatry. 2014;171:54-61.
Evidence-based answers from the Family Physicians Inquiries Network
A new standard of care for rel/ref MM?
Photo courtesy of ASH
ORLANDO, FL—Adding the oral proteasome inhibitor ixazomib to treatment with lenalidomide and dexamethasone can prolong progression-free survival (PFS) in patients with relapsed and/or refractory multiple myeloma (MM), according to interim results of the phase 3 TOURMALINE-MM1 trial.
It is not yet clear if the 3-drug combination can prolong overall survival when compared to treatment with lenalidomide and dexamethasone.
However, researchers believe the triplet shows promise and could become a new standard of care for relapsed/refractory MM.
Philippe Moreau, MD, of the University of Nantes in France, discussed this possibility while presenting results from TOURMALINE-MM1 at the 2015 ASH Annual Meeting (abstract 727*). The study was sponsored by Millennium Pharmaceuticals, Inc.
The trial included 722 MM patients enrolled at 147 centers in 26 countries. Patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).
Baseline patient characteristics were similar between the arms. The median age was 66 in both arms (overall range, 30-91), and nearly 60% of patients in both arms were male.
Fifty percent of patients in the IRd arm and 47% in the Rd arm had an ECOG performance status of 0. Forty-three percent and 45%, respectively, had a status of 1, and 5% and 7%, respectively, had a status of 2.
Eighty-seven percent and 88%, respectively, had an ISS stage of I or II. Fifty-five percent of patients in the IRd arm had standard-risk cytogenetics, as did 60% in the Rd arm.
Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines.
Response and survival
“Ixazomib, when combined with len-dex . . . , was associated with a significant and meaningful improvement in progression-free survival, improved time to progression, and [higher] response rate as well,” Dr Moreau said.
At a median follow-up of about 15 months, the median PFS was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).
Dr Moreau said the PFS benefit was consistent across pre-specified subgroups. So the benefit was present regardless of age, ISS stage, cytogenetic risk, number of prior therapies, prior exposure to a proteasome inhibitor, prior immunomodulatory therapy, whether the patient was refractory to his last therapy, and whether the patient had relapsed or refractory disease.
Dr Moreau also pointed out that, in the IRd arm, the median PFS in high-risk patients was similar to that in the overall patient population and in patients with standard-risk cytogenetics. This suggests ixazomib may overcome the negative impact of cytogenetic alterations.
Whether IRd confers an overall survival benefit is not clear, as those data are not yet mature. At a median follow-up of about 23 months, the median overall survival was not reached in either treatment arm.
The researchers conducted a non-inferential PFS analysis at the same time point (23 months) and found the median PFS was 20 months in the IRd arm and 15.9 months in the Rd arm. The hazard ratio was 0.82.
As for other efficacy endpoints, the overall response rate was 78.3% in the IRd arm and 71.5% in the Rd arm (P=0.035). The rates of complete response were 11.7% and 6.6%, respectively (P=0.019). And the rates of very good partial response or greater were 48.1% and 39%, respectively (P=0.014).
The median time to response was 1.1 months in the IRd arm and 1.9 months in the Rd arm. The median duration of response was 20.5 months and 15 months, respectively. And the median time to progression was 21.4 months and 15.7 months, respectively.
Adverse events
At a median follow-up of about 23 months, patients had received a median of 17 cycles of IRd and a median of 15 cycles of Rd.
The incidence of any adverse event (AE) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.
The incidence of AEs resulting in discontinuation was 17% and 14%, respectively. And the incidence of on-study deaths (occurring within 30 days of the last dose) was 4% and 6%, respectively.
Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%).
“Ixazomib is adding limited toxicity to lenalidomide and dex, with a very low rate of peripheral neuropathy and no cardiovascular or renal adverse signals,” Dr Moreau said.
“This all-oral triplet regimen may become one of the new standards of care in the relapsed setting. [It has] a very safe profile, [is] a very effective combination, [and is] simple and convenient.”
*Data in the abstract differ from the presentation.
Photo courtesy of ASH
ORLANDO, FL—Adding the oral proteasome inhibitor ixazomib to treatment with lenalidomide and dexamethasone can prolong progression-free survival (PFS) in patients with relapsed and/or refractory multiple myeloma (MM), according to interim results of the phase 3 TOURMALINE-MM1 trial.
It is not yet clear if the 3-drug combination can prolong overall survival when compared to treatment with lenalidomide and dexamethasone.
However, researchers believe the triplet shows promise and could become a new standard of care for relapsed/refractory MM.
Philippe Moreau, MD, of the University of Nantes in France, discussed this possibility while presenting results from TOURMALINE-MM1 at the 2015 ASH Annual Meeting (abstract 727*). The study was sponsored by Millennium Pharmaceuticals, Inc.
The trial included 722 MM patients enrolled at 147 centers in 26 countries. Patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).
Baseline patient characteristics were similar between the arms. The median age was 66 in both arms (overall range, 30-91), and nearly 60% of patients in both arms were male.
Fifty percent of patients in the IRd arm and 47% in the Rd arm had an ECOG performance status of 0. Forty-three percent and 45%, respectively, had a status of 1, and 5% and 7%, respectively, had a status of 2.
Eighty-seven percent and 88%, respectively, had an ISS stage of I or II. Fifty-five percent of patients in the IRd arm had standard-risk cytogenetics, as did 60% in the Rd arm.
Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines.
Response and survival
“Ixazomib, when combined with len-dex . . . , was associated with a significant and meaningful improvement in progression-free survival, improved time to progression, and [higher] response rate as well,” Dr Moreau said.
At a median follow-up of about 15 months, the median PFS was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).
Dr Moreau said the PFS benefit was consistent across pre-specified subgroups. So the benefit was present regardless of age, ISS stage, cytogenetic risk, number of prior therapies, prior exposure to a proteasome inhibitor, prior immunomodulatory therapy, whether the patient was refractory to his last therapy, and whether the patient had relapsed or refractory disease.
Dr Moreau also pointed out that, in the IRd arm, the median PFS in high-risk patients was similar to that in the overall patient population and in patients with standard-risk cytogenetics. This suggests ixazomib may overcome the negative impact of cytogenetic alterations.
Whether IRd confers an overall survival benefit is not clear, as those data are not yet mature. At a median follow-up of about 23 months, the median overall survival was not reached in either treatment arm.
The researchers conducted a non-inferential PFS analysis at the same time point (23 months) and found the median PFS was 20 months in the IRd arm and 15.9 months in the Rd arm. The hazard ratio was 0.82.
As for other efficacy endpoints, the overall response rate was 78.3% in the IRd arm and 71.5% in the Rd arm (P=0.035). The rates of complete response were 11.7% and 6.6%, respectively (P=0.019). And the rates of very good partial response or greater were 48.1% and 39%, respectively (P=0.014).
The median time to response was 1.1 months in the IRd arm and 1.9 months in the Rd arm. The median duration of response was 20.5 months and 15 months, respectively. And the median time to progression was 21.4 months and 15.7 months, respectively.
Adverse events
At a median follow-up of about 23 months, patients had received a median of 17 cycles of IRd and a median of 15 cycles of Rd.
The incidence of any adverse event (AE) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.
The incidence of AEs resulting in discontinuation was 17% and 14%, respectively. And the incidence of on-study deaths (occurring within 30 days of the last dose) was 4% and 6%, respectively.
Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%).
“Ixazomib is adding limited toxicity to lenalidomide and dex, with a very low rate of peripheral neuropathy and no cardiovascular or renal adverse signals,” Dr Moreau said.
“This all-oral triplet regimen may become one of the new standards of care in the relapsed setting. [It has] a very safe profile, [is] a very effective combination, [and is] simple and convenient.”
*Data in the abstract differ from the presentation.
Photo courtesy of ASH
ORLANDO, FL—Adding the oral proteasome inhibitor ixazomib to treatment with lenalidomide and dexamethasone can prolong progression-free survival (PFS) in patients with relapsed and/or refractory multiple myeloma (MM), according to interim results of the phase 3 TOURMALINE-MM1 trial.
It is not yet clear if the 3-drug combination can prolong overall survival when compared to treatment with lenalidomide and dexamethasone.
However, researchers believe the triplet shows promise and could become a new standard of care for relapsed/refractory MM.
Philippe Moreau, MD, of the University of Nantes in France, discussed this possibility while presenting results from TOURMALINE-MM1 at the 2015 ASH Annual Meeting (abstract 727*). The study was sponsored by Millennium Pharmaceuticals, Inc.
The trial included 722 MM patients enrolled at 147 centers in 26 countries. Patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).
Baseline patient characteristics were similar between the arms. The median age was 66 in both arms (overall range, 30-91), and nearly 60% of patients in both arms were male.
Fifty percent of patients in the IRd arm and 47% in the Rd arm had an ECOG performance status of 0. Forty-three percent and 45%, respectively, had a status of 1, and 5% and 7%, respectively, had a status of 2.
Eighty-seven percent and 88%, respectively, had an ISS stage of I or II. Fifty-five percent of patients in the IRd arm had standard-risk cytogenetics, as did 60% in the Rd arm.
Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines.
Response and survival
“Ixazomib, when combined with len-dex . . . , was associated with a significant and meaningful improvement in progression-free survival, improved time to progression, and [higher] response rate as well,” Dr Moreau said.
At a median follow-up of about 15 months, the median PFS was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).
Dr Moreau said the PFS benefit was consistent across pre-specified subgroups. So the benefit was present regardless of age, ISS stage, cytogenetic risk, number of prior therapies, prior exposure to a proteasome inhibitor, prior immunomodulatory therapy, whether the patient was refractory to his last therapy, and whether the patient had relapsed or refractory disease.
Dr Moreau also pointed out that, in the IRd arm, the median PFS in high-risk patients was similar to that in the overall patient population and in patients with standard-risk cytogenetics. This suggests ixazomib may overcome the negative impact of cytogenetic alterations.
Whether IRd confers an overall survival benefit is not clear, as those data are not yet mature. At a median follow-up of about 23 months, the median overall survival was not reached in either treatment arm.
The researchers conducted a non-inferential PFS analysis at the same time point (23 months) and found the median PFS was 20 months in the IRd arm and 15.9 months in the Rd arm. The hazard ratio was 0.82.
As for other efficacy endpoints, the overall response rate was 78.3% in the IRd arm and 71.5% in the Rd arm (P=0.035). The rates of complete response were 11.7% and 6.6%, respectively (P=0.019). And the rates of very good partial response or greater were 48.1% and 39%, respectively (P=0.014).
The median time to response was 1.1 months in the IRd arm and 1.9 months in the Rd arm. The median duration of response was 20.5 months and 15 months, respectively. And the median time to progression was 21.4 months and 15.7 months, respectively.
Adverse events
At a median follow-up of about 23 months, patients had received a median of 17 cycles of IRd and a median of 15 cycles of Rd.
The incidence of any adverse event (AE) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.
The incidence of AEs resulting in discontinuation was 17% and 14%, respectively. And the incidence of on-study deaths (occurring within 30 days of the last dose) was 4% and 6%, respectively.
Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%).
“Ixazomib is adding limited toxicity to lenalidomide and dex, with a very low rate of peripheral neuropathy and no cardiovascular or renal adverse signals,” Dr Moreau said.
“This all-oral triplet regimen may become one of the new standards of care in the relapsed setting. [It has] a very safe profile, [is] a very effective combination, [and is] simple and convenient.”
*Data in the abstract differ from the presentation.
Disease Education
Q) The billing consultant who came to our office said we can increase our reimbursements if we also provide education to our patients with chronic kidney disease (CKD). Is she right?
In 2010, under an omnibus bill, kidney disease education (KDE) classes were added as a Medicare benefit. These are for patients with stage 4 CKD (glomerular filtration rate, 15-30 mL/min) and are to be taught by a qualified instructor (MD, PA, NP, or CNS).
The classes can be taught on the same day as an evaluation/management visit (ie, a regular office visit) and are compensated by the hour. (Side note: Medicare defines an hour as 31 minutes—yes, 31 minutes; Medicare takes for granted that you will also need time to chart!) You can teach two classes in the same day. Thus, if you wanted to, you could have a patient arrive for an office visit, then teach two 31-minute classes, and bill all three for the same day. The entire visit could be 75 minutes (although this may be exhausting for this population).
You can conduct the classes in a number of settings, including nursing homes, hospitals, skilled nursing facilities, the office, or even the patient’s home. Many PAs and NPs have taught these classes to hospitalized patients who have lost kidney function due to an acute insult (ie, medications, dehydration, contrast).
Each Medicare recipient has a lifetime benefit of six KDE classes. The CPT billing code is G0420 for an individual class and G0421 for a group class. You must make sure you also code for the stage 4 CKD diagnosis (code: 585.4).
Congress stipulated KDE classes must include information on causes, symptoms, and treatments and comprise a posttest at a specific health literacy level. To make it simple, the National Kidney Foundation Council of Advanced Practitioners (NKF-CAP) has developed two free Power-Point slide decks for clinicians to use in KDE classes (available at www.kidney.org/professionals/CAP/sub_resources#kde). References and updated peer-reviewed guidelines are included. You can print the slides for your patients and/or share the program with your colleagues.
Many nephrology practitioners teach the two slide sets over and over, because patients only retain one-third of the info we provide them on a given day. So if you teach each slide set three times, you have six lifetime classes—and hopefully the patient will have retained everything.
One caveat: Before you initiate KDE classes for a specific patient, check with the patient’s nephrology group (we hope at stage 4 the patient has a nephrologist) to see if they are providing the education. —KZ and JD
Kim Zuber, PA-C, MSPS, DFAAPA
American Academy of Nephrology PAs
Jane S. Davis, CRNP, DNP
Division of Nephrology at the University of Alabama
National Kidney Foundation's Council of Advanced Practitioners
| Clinician Reviews in partnership with |
 |
Renal Consult is edited by Jane S. Davis, CRNP, DNP, a member of the Clinician Reviews editorial board, who is a nurse practitioner in the Division of Nephrology at the University of Alabama at Birmingham and is the communications chairperson for the National Kidney Foundation’s Council of Advanced Practitioners (NKF-CAP); and Kim Zuber, PA-C, MSPS, DFAAPA, a retired physician assistant who works with the American Academy of Nephrology PAs and is also past chair of the NKF-CAP. This month’s responses were authored by Della Connor, PhD, RN, FNP-BC, who is an Assistant Professor at Stephen F. Austin State University in Nacogdoches, Texas, and practices at East Texas Nephrology Associates in Lufkin, and the department editors.
| Clinician Reviews in partnership with |
|
Renal Consult is edited by Jane S. Davis, CRNP, DNP, a member of the Clinician Reviews editorial board, who is a nurse practitioner in the Division of Nephrology at the University of Alabama at Birmingham and is the communications chairperson for the National Kidney Foundation’s Council of Advanced Practitioners (NKF-CAP); and Kim Zuber, PA-C, MSPS, DFAAPA, a retired physician assistant who works with the American Academy of Nephrology PAs and is also past chair of the NKF-CAP. This month’s responses were authored by Della Connor, PhD, RN, FNP-BC, who is an Assistant Professor at Stephen F. Austin State University in Nacogdoches, Texas, and practices at East Texas Nephrology Associates in Lufkin, and the department editors.
| Clinician Reviews in partnership with |
|
Renal Consult is edited by Jane S. Davis, CRNP, DNP, a member of the Clinician Reviews editorial board, who is a nurse practitioner in the Division of Nephrology at the University of Alabama at Birmingham and is the communications chairperson for the National Kidney Foundation’s Council of Advanced Practitioners (NKF-CAP); and Kim Zuber, PA-C, MSPS, DFAAPA, a retired physician assistant who works with the American Academy of Nephrology PAs and is also past chair of the NKF-CAP. This month’s responses were authored by Della Connor, PhD, RN, FNP-BC, who is an Assistant Professor at Stephen F. Austin State University in Nacogdoches, Texas, and practices at East Texas Nephrology Associates in Lufkin, and the department editors.
Q) The billing consultant who came to our office said we can increase our reimbursements if we also provide education to our patients with chronic kidney disease (CKD). Is she right?
In 2010, under an omnibus bill, kidney disease education (KDE) classes were added as a Medicare benefit. These are for patients with stage 4 CKD (glomerular filtration rate, 15-30 mL/min) and are to be taught by a qualified instructor (MD, PA, NP, or CNS).
The classes can be taught on the same day as an evaluation/management visit (ie, a regular office visit) and are compensated by the hour. (Side note: Medicare defines an hour as 31 minutes—yes, 31 minutes; Medicare takes for granted that you will also need time to chart!) You can teach two classes in the same day. Thus, if you wanted to, you could have a patient arrive for an office visit, then teach two 31-minute classes, and bill all three for the same day. The entire visit could be 75 minutes (although this may be exhausting for this population).
You can conduct the classes in a number of settings, including nursing homes, hospitals, skilled nursing facilities, the office, or even the patient’s home. Many PAs and NPs have taught these classes to hospitalized patients who have lost kidney function due to an acute insult (ie, medications, dehydration, contrast).
Each Medicare recipient has a lifetime benefit of six KDE classes. The CPT billing code is G0420 for an individual class and G0421 for a group class. You must make sure you also code for the stage 4 CKD diagnosis (code: 585.4).
Congress stipulated KDE classes must include information on causes, symptoms, and treatments and comprise a posttest at a specific health literacy level. To make it simple, the National Kidney Foundation Council of Advanced Practitioners (NKF-CAP) has developed two free Power-Point slide decks for clinicians to use in KDE classes (available at www.kidney.org/professionals/CAP/sub_resources#kde). References and updated peer-reviewed guidelines are included. You can print the slides for your patients and/or share the program with your colleagues.
Many nephrology practitioners teach the two slide sets over and over, because patients only retain one-third of the info we provide them on a given day. So if you teach each slide set three times, you have six lifetime classes—and hopefully the patient will have retained everything.
One caveat: Before you initiate KDE classes for a specific patient, check with the patient’s nephrology group (we hope at stage 4 the patient has a nephrologist) to see if they are providing the education. —KZ and JD
Kim Zuber, PA-C, MSPS, DFAAPA
American Academy of Nephrology PAs
Jane S. Davis, CRNP, DNP
Division of Nephrology at the University of Alabama
National Kidney Foundation's Council of Advanced Practitioners
Q) The billing consultant who came to our office said we can increase our reimbursements if we also provide education to our patients with chronic kidney disease (CKD). Is she right?
In 2010, under an omnibus bill, kidney disease education (KDE) classes were added as a Medicare benefit. These are for patients with stage 4 CKD (glomerular filtration rate, 15-30 mL/min) and are to be taught by a qualified instructor (MD, PA, NP, or CNS).
The classes can be taught on the same day as an evaluation/management visit (ie, a regular office visit) and are compensated by the hour. (Side note: Medicare defines an hour as 31 minutes—yes, 31 minutes; Medicare takes for granted that you will also need time to chart!) You can teach two classes in the same day. Thus, if you wanted to, you could have a patient arrive for an office visit, then teach two 31-minute classes, and bill all three for the same day. The entire visit could be 75 minutes (although this may be exhausting for this population).
You can conduct the classes in a number of settings, including nursing homes, hospitals, skilled nursing facilities, the office, or even the patient’s home. Many PAs and NPs have taught these classes to hospitalized patients who have lost kidney function due to an acute insult (ie, medications, dehydration, contrast).
Each Medicare recipient has a lifetime benefit of six KDE classes. The CPT billing code is G0420 for an individual class and G0421 for a group class. You must make sure you also code for the stage 4 CKD diagnosis (code: 585.4).
Congress stipulated KDE classes must include information on causes, symptoms, and treatments and comprise a posttest at a specific health literacy level. To make it simple, the National Kidney Foundation Council of Advanced Practitioners (NKF-CAP) has developed two free Power-Point slide decks for clinicians to use in KDE classes (available at www.kidney.org/professionals/CAP/sub_resources#kde). References and updated peer-reviewed guidelines are included. You can print the slides for your patients and/or share the program with your colleagues.
Many nephrology practitioners teach the two slide sets over and over, because patients only retain one-third of the info we provide them on a given day. So if you teach each slide set three times, you have six lifetime classes—and hopefully the patient will have retained everything.
One caveat: Before you initiate KDE classes for a specific patient, check with the patient’s nephrology group (we hope at stage 4 the patient has a nephrologist) to see if they are providing the education. —KZ and JD
Kim Zuber, PA-C, MSPS, DFAAPA
American Academy of Nephrology PAs
Jane S. Davis, CRNP, DNP
Division of Nephrology at the University of Alabama
National Kidney Foundation's Council of Advanced Practitioners
Advances in Hematology and Oncology (May 2014)
High-risk B-ALL subgroup has ‘outstanding outcomes’
Photo courtesy of ASH
ORLANDO, FL—A subgroup of young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) can have “outstanding outcomes” with contemporary therapy, according to researchers.
Results of a large study suggested that patients ages 1 to 30 who have high-risk B-ALL according to National Cancer Institute (NCI) classification can have high rates of event-free survival (EFS) and overall survival (OS) if they have favorable cytogenetic features, have no evidence of CNS disease, and have rapid minimal residual disease (MRD) responses.
The research suggested these patients will not benefit from further chemotherapy intensification.
Elizabeth Raetz, MD, of the University of Utah in Salt Lake City, presented these results at the 2015 ASH Annual Meeting (abstract 807).
She and her colleagues analyzed patients enrolled on the Children’s Oncology Group (COG) AALL03B1 classification study at the time of B-ALL diagnosis. From December 2003 to September 2011, there were 11,144 eligible patients enrolled on this trial.
Eighty-nine percent of these patients were also enrolled on a frontline ALL therapeutic trial, and 96% of these patients were evaluable for post-induction treatment assignment. Sixty-five percent of these patients were treated on a trial for NCI standard-risk B-ALL (COG-AALL0331), and 35% were treated on a trial for high-risk B-ALL (COG-AALL0232).
At the end of induction therapy, patients were classified into low-risk (29%), standard-risk (33%), high-risk (34%), and very-high-risk (4%) groups for further treatment allocation. The variables used for risk classification were age, initial white blood cell count, extramedullary disease status, blast cytogenetics, and early treatment response based on bone marrow morphology and day 29 MRD.
Patients with very-high-risk features (BCR-ABL1, hypodiploidy, induction failure, or poor response at day 43) did not continue on AALL0232/AALL0331 post-induction but did have outcome data captured for analysis.
Response and survival
Rapid early response was defined as M1 (<5% blasts) bone marrow by day 15 plus flow cytometry-based MRD <0.1% on day 29 of induction. Patients with either M2/M3 (≥5% blasts) day 15 marrow or MRD ≥0.1% at day 29 were deemed slow early responders.
Eighty-four percent of patients had a rapid early response to induction, and 16% had a slow early response.
For rapid early responders, the 5-year EFS was 89.3%, and the 5-year OS was 95.2%. For slow early responders, the EFS and OS rates were 67.9% and 84.3%, respectively (P<0.0001 for both EFS and OS comparisons).
Survival according to cytogenetics
Having favorable cytogenetic abnormalities (triple trisomies of chromosomes 4, 10, and 17 or ETV6-RUNX1 fusion) was associated with significantly better EFS and OS than having unfavorable cytogenetics (hypodiploidy [DNA index <0.81 or chromosomes < 44], MLL rearrangements, BCR-ABL1, or iAMP21).
And Dr Raetz pointed out that the 5-year OS exceeded 98% for patients with either standard- or high-risk disease who had favorable cytogenetics.
For patients who were ETV6-RUNX1-positive, the EFS was 93.2% and the OS was 98.3%. For patients who were ETV6-RUNX1 negative, the rates were 83.5% and 92%, respectively (P<0.0001).
For patients with triple trisomy, EFS was 94.7% and OS was 98.7%. For those without triple trisomy, the rates were 83.6% and 92.2%, respectively (P<0.0001).
For patients with MLL rearrangement, the EFS was 73.9% and the OS was 83.1%. For patients without MLL rearrangement, the rates were 85.9% and 93.6%, respectively (P<0.0001).
For patients who were positive for iAMP21, the EFS was 69.5% and the OS was 90.1%. For iAMP21-negative patients, the rates were 86.1% and 93.4%, respectively (P<0.0001 for PFS comparison and P=0.0026 for OS comparison).
Survival according to risk group and MRD
The researchers also assessed EFS and OS among patients with favorable cytogenetics according to NCI risk group and MRD at days 8 and 29.
“One thing to point out is that, regardless of having favorable cytogenetics, those individuals who had end-induction MRD values of greater than 0.01% had inferior outcomes, so that was still a prognostic marker,” Dr Raetz said.
“And one thing that we were pleasantly surprised to see was that, among the NCI high-risk patients, those who had very rapid MRD responses—so less than 1% at day 8 in the blood and less than 0.01% in the marrow on day 29—had a 94.9% 5-year event-free survival and 98.1% overall survival.”
The researchers also divided this group according to age—patients younger than 10 and those 10 years or older. There was no significant difference in EFS or OS between the age groups (P=0.126 and P=0.411).
Standard-risk group
Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 95.7% and the OS was 99.1%.
Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 91.7% and the OS was 99.4%.
Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 88.1% and the OS was 96.8%.
High-risk group
Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 94.9% and the OS was 98.1%.
Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 93.6% and the OS was 95.5%.
Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 75.4% and the OS was 90.4%.
In closing, Dr Raetz said this study showed that real‐time classification incorporating clinical features, blast cytogenetics, and early response was feasible in a large group of patients enrolled on COG ALL trials and identified patients with varying outcomes for risk‐based treatment allocation.
She noted that early response by marrow morphology was not prognostic when MRD response was used and is therefore no longer used in COG studies.
And although favorable cytogenetic features were not prognostic in NCI high-risk B‐ALL patients in prior COG studies, the current study indicates that these patients can have “excellent outcomes” if they have no evidence of CNS leukemia and are rapid MRD responders. So these patients will not benefit from further chemotherapy intensification.
Photo courtesy of ASH
ORLANDO, FL—A subgroup of young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) can have “outstanding outcomes” with contemporary therapy, according to researchers.
Results of a large study suggested that patients ages 1 to 30 who have high-risk B-ALL according to National Cancer Institute (NCI) classification can have high rates of event-free survival (EFS) and overall survival (OS) if they have favorable cytogenetic features, have no evidence of CNS disease, and have rapid minimal residual disease (MRD) responses.
The research suggested these patients will not benefit from further chemotherapy intensification.
Elizabeth Raetz, MD, of the University of Utah in Salt Lake City, presented these results at the 2015 ASH Annual Meeting (abstract 807).
She and her colleagues analyzed patients enrolled on the Children’s Oncology Group (COG) AALL03B1 classification study at the time of B-ALL diagnosis. From December 2003 to September 2011, there were 11,144 eligible patients enrolled on this trial.
Eighty-nine percent of these patients were also enrolled on a frontline ALL therapeutic trial, and 96% of these patients were evaluable for post-induction treatment assignment. Sixty-five percent of these patients were treated on a trial for NCI standard-risk B-ALL (COG-AALL0331), and 35% were treated on a trial for high-risk B-ALL (COG-AALL0232).
At the end of induction therapy, patients were classified into low-risk (29%), standard-risk (33%), high-risk (34%), and very-high-risk (4%) groups for further treatment allocation. The variables used for risk classification were age, initial white blood cell count, extramedullary disease status, blast cytogenetics, and early treatment response based on bone marrow morphology and day 29 MRD.
Patients with very-high-risk features (BCR-ABL1, hypodiploidy, induction failure, or poor response at day 43) did not continue on AALL0232/AALL0331 post-induction but did have outcome data captured for analysis.
Response and survival
Rapid early response was defined as M1 (<5% blasts) bone marrow by day 15 plus flow cytometry-based MRD <0.1% on day 29 of induction. Patients with either M2/M3 (≥5% blasts) day 15 marrow or MRD ≥0.1% at day 29 were deemed slow early responders.
Eighty-four percent of patients had a rapid early response to induction, and 16% had a slow early response.
For rapid early responders, the 5-year EFS was 89.3%, and the 5-year OS was 95.2%. For slow early responders, the EFS and OS rates were 67.9% and 84.3%, respectively (P<0.0001 for both EFS and OS comparisons).
Survival according to cytogenetics
Having favorable cytogenetic abnormalities (triple trisomies of chromosomes 4, 10, and 17 or ETV6-RUNX1 fusion) was associated with significantly better EFS and OS than having unfavorable cytogenetics (hypodiploidy [DNA index <0.81 or chromosomes < 44], MLL rearrangements, BCR-ABL1, or iAMP21).
And Dr Raetz pointed out that the 5-year OS exceeded 98% for patients with either standard- or high-risk disease who had favorable cytogenetics.
For patients who were ETV6-RUNX1-positive, the EFS was 93.2% and the OS was 98.3%. For patients who were ETV6-RUNX1 negative, the rates were 83.5% and 92%, respectively (P<0.0001).
For patients with triple trisomy, EFS was 94.7% and OS was 98.7%. For those without triple trisomy, the rates were 83.6% and 92.2%, respectively (P<0.0001).
For patients with MLL rearrangement, the EFS was 73.9% and the OS was 83.1%. For patients without MLL rearrangement, the rates were 85.9% and 93.6%, respectively (P<0.0001).
For patients who were positive for iAMP21, the EFS was 69.5% and the OS was 90.1%. For iAMP21-negative patients, the rates were 86.1% and 93.4%, respectively (P<0.0001 for PFS comparison and P=0.0026 for OS comparison).
Survival according to risk group and MRD
The researchers also assessed EFS and OS among patients with favorable cytogenetics according to NCI risk group and MRD at days 8 and 29.
“One thing to point out is that, regardless of having favorable cytogenetics, those individuals who had end-induction MRD values of greater than 0.01% had inferior outcomes, so that was still a prognostic marker,” Dr Raetz said.
“And one thing that we were pleasantly surprised to see was that, among the NCI high-risk patients, those who had very rapid MRD responses—so less than 1% at day 8 in the blood and less than 0.01% in the marrow on day 29—had a 94.9% 5-year event-free survival and 98.1% overall survival.”
The researchers also divided this group according to age—patients younger than 10 and those 10 years or older. There was no significant difference in EFS or OS between the age groups (P=0.126 and P=0.411).
Standard-risk group
Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 95.7% and the OS was 99.1%.
Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 91.7% and the OS was 99.4%.
Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 88.1% and the OS was 96.8%.
High-risk group
Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 94.9% and the OS was 98.1%.
Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 93.6% and the OS was 95.5%.
Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 75.4% and the OS was 90.4%.
In closing, Dr Raetz said this study showed that real‐time classification incorporating clinical features, blast cytogenetics, and early response was feasible in a large group of patients enrolled on COG ALL trials and identified patients with varying outcomes for risk‐based treatment allocation.
She noted that early response by marrow morphology was not prognostic when MRD response was used and is therefore no longer used in COG studies.
And although favorable cytogenetic features were not prognostic in NCI high-risk B‐ALL patients in prior COG studies, the current study indicates that these patients can have “excellent outcomes” if they have no evidence of CNS leukemia and are rapid MRD responders. So these patients will not benefit from further chemotherapy intensification.
Photo courtesy of ASH
ORLANDO, FL—A subgroup of young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) can have “outstanding outcomes” with contemporary therapy, according to researchers.
Results of a large study suggested that patients ages 1 to 30 who have high-risk B-ALL according to National Cancer Institute (NCI) classification can have high rates of event-free survival (EFS) and overall survival (OS) if they have favorable cytogenetic features, have no evidence of CNS disease, and have rapid minimal residual disease (MRD) responses.
The research suggested these patients will not benefit from further chemotherapy intensification.
Elizabeth Raetz, MD, of the University of Utah in Salt Lake City, presented these results at the 2015 ASH Annual Meeting (abstract 807).
She and her colleagues analyzed patients enrolled on the Children’s Oncology Group (COG) AALL03B1 classification study at the time of B-ALL diagnosis. From December 2003 to September 2011, there were 11,144 eligible patients enrolled on this trial.
Eighty-nine percent of these patients were also enrolled on a frontline ALL therapeutic trial, and 96% of these patients were evaluable for post-induction treatment assignment. Sixty-five percent of these patients were treated on a trial for NCI standard-risk B-ALL (COG-AALL0331), and 35% were treated on a trial for high-risk B-ALL (COG-AALL0232).
At the end of induction therapy, patients were classified into low-risk (29%), standard-risk (33%), high-risk (34%), and very-high-risk (4%) groups for further treatment allocation. The variables used for risk classification were age, initial white blood cell count, extramedullary disease status, blast cytogenetics, and early treatment response based on bone marrow morphology and day 29 MRD.
Patients with very-high-risk features (BCR-ABL1, hypodiploidy, induction failure, or poor response at day 43) did not continue on AALL0232/AALL0331 post-induction but did have outcome data captured for analysis.
Response and survival
Rapid early response was defined as M1 (<5% blasts) bone marrow by day 15 plus flow cytometry-based MRD <0.1% on day 29 of induction. Patients with either M2/M3 (≥5% blasts) day 15 marrow or MRD ≥0.1% at day 29 were deemed slow early responders.
Eighty-four percent of patients had a rapid early response to induction, and 16% had a slow early response.
For rapid early responders, the 5-year EFS was 89.3%, and the 5-year OS was 95.2%. For slow early responders, the EFS and OS rates were 67.9% and 84.3%, respectively (P<0.0001 for both EFS and OS comparisons).
Survival according to cytogenetics
Having favorable cytogenetic abnormalities (triple trisomies of chromosomes 4, 10, and 17 or ETV6-RUNX1 fusion) was associated with significantly better EFS and OS than having unfavorable cytogenetics (hypodiploidy [DNA index <0.81 or chromosomes < 44], MLL rearrangements, BCR-ABL1, or iAMP21).
And Dr Raetz pointed out that the 5-year OS exceeded 98% for patients with either standard- or high-risk disease who had favorable cytogenetics.
For patients who were ETV6-RUNX1-positive, the EFS was 93.2% and the OS was 98.3%. For patients who were ETV6-RUNX1 negative, the rates were 83.5% and 92%, respectively (P<0.0001).
For patients with triple trisomy, EFS was 94.7% and OS was 98.7%. For those without triple trisomy, the rates were 83.6% and 92.2%, respectively (P<0.0001).
For patients with MLL rearrangement, the EFS was 73.9% and the OS was 83.1%. For patients without MLL rearrangement, the rates were 85.9% and 93.6%, respectively (P<0.0001).
For patients who were positive for iAMP21, the EFS was 69.5% and the OS was 90.1%. For iAMP21-negative patients, the rates were 86.1% and 93.4%, respectively (P<0.0001 for PFS comparison and P=0.0026 for OS comparison).
Survival according to risk group and MRD
The researchers also assessed EFS and OS among patients with favorable cytogenetics according to NCI risk group and MRD at days 8 and 29.
“One thing to point out is that, regardless of having favorable cytogenetics, those individuals who had end-induction MRD values of greater than 0.01% had inferior outcomes, so that was still a prognostic marker,” Dr Raetz said.
“And one thing that we were pleasantly surprised to see was that, among the NCI high-risk patients, those who had very rapid MRD responses—so less than 1% at day 8 in the blood and less than 0.01% in the marrow on day 29—had a 94.9% 5-year event-free survival and 98.1% overall survival.”
The researchers also divided this group according to age—patients younger than 10 and those 10 years or older. There was no significant difference in EFS or OS between the age groups (P=0.126 and P=0.411).
Standard-risk group
Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 95.7% and the OS was 99.1%.
Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 91.7% and the OS was 99.4%.
Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 88.1% and the OS was 96.8%.
High-risk group
Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 94.9% and the OS was 98.1%.
Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 93.6% and the OS was 95.5%.
Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 75.4% and the OS was 90.4%.
In closing, Dr Raetz said this study showed that real‐time classification incorporating clinical features, blast cytogenetics, and early response was feasible in a large group of patients enrolled on COG ALL trials and identified patients with varying outcomes for risk‐based treatment allocation.
She noted that early response by marrow morphology was not prognostic when MRD response was used and is therefore no longer used in COG studies.
And although favorable cytogenetic features were not prognostic in NCI high-risk B‐ALL patients in prior COG studies, the current study indicates that these patients can have “excellent outcomes” if they have no evidence of CNS leukemia and are rapid MRD responders. So these patients will not benefit from further chemotherapy intensification.
Pulmonary nodule on x-ray: An algorithmic approach
› Order a computed tomography chest scan, preferably with thin sections through the nodule, to help characterize an indeterminate pulmonary nodule identified on x-ray. B
› Estimate the pretest probability of malignancy for a patient with a pulmonary nodule using your clinical judgment and/or by using a validated model. B
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
CASE 1 › George D is a 67-year-old patient who has never smoked and who has no history of malignancy. An x-ray of his ribs performed after a fall shows a 13-mm solitary nodule in his right upper lung.
CASE 2 › Cathy B is a healthy 80-year-old with no history of smoking. During a trip to the emergency department for chest pain, she had a computed tomography (CT) scan of her chest. While the chest pain was subsequently attributed to gastroesophageal reflux, the CT revealed a 9-mm part solid nodule that was 75% solid.
How should the physicians caring for each of these patients proceed with their care?
The widespread use of sensitive imaging techniques often leads to the incidental discovery of unrelated—but possibly significant—pulmonary findings. Pulmonary nodules are incidentally discovered on an estimated 0.09% to 0.2% of all chest x-rays, 13% of all chest CT angiograms,1 31% of all cardiac CTs performed for coronary calcium scoring,2 and up to 50% of thin-section chest CT scans.1
The widespread implementation of the US Preventive Services Task Force recommendations on lung cancer screening has further expanded the number of patients in whom asymptomatic pulmonary nodules will be detected. As a result, family physicians (FPs) will frequently encounter this challenging clinical dilemma and will need to:
- assess the patient’s risk profile
- address the patient’s concerns about malignancy while eliciting his or her preference for management
- minimize the risks of surveillance testing
- minimize patient distress while ensuring compliance with a follow-up that may extend up to 4 years
- determine when it’s appropriate to refer the patient to a pulmonologist and/or pulmonary nodule clinic or registry.
Taking these steps, however, can be challenging. In interviews, 15 primary care clinicians who care for patients with pulmonary nodules expressed concerns about limitations in time, knowledge, and resources, as well as a fear about such patients “falling through the cracks.”3 Familiarity with current evidence-based guidelines such as those from the American College of Chest Physicians (ACCP) and knowledge of emerging data on the management of various types of nodules are imperative.
To that end, this review will fill in the information gaps and provide guidance on how best to communicate what is known about a particular type of nodule with the patient who has one. (See “What to say to improve joint decision-making.”4-7) But first, a word about terminology.
What to say to improve joint decision-making4-7
Diagnosis and follow-up of a pulmonary nodule takes an emotional toll on patients, who often have a poor sense of what the presence of a nodule signifies. When caring for a patient with a pulmonary nodule, it’s essential to have an effective communication strategy to ensure that he or she is a well-informed partner in decision-making.
Specifically, you'll need to describe the type of nodule that the patient has, how fast it might grow and its malignancy potential, steps that will need to be taken, and the importance of smoking cessation (if the patient smokes).
Ask the patient about any concerns/fears he or she may have, and provide resources to reduce them. Emphasize shared decision-making and discuss the rationale for various management plans and the limitations of diagnostic tests. Do not minimize the issue; emphasize the need for, and importance of, prolonged follow-up—even for a patient who has a small, low-risk nodule.
Solid vs subsolid pulmonary nodules
Solid pulmonary nodules. Traditionally, the term “solitary pulmonary nodule” has been used to describe a single, well-circumscribed, radiographic opacity that measures up to 3 cm in diameter and is completely surrounded by aerated lung.1,8 The term “solitary” is now less useful because increasingly sensitive imaging techniques often reveal more than one nodule. In the absence of evidence of features that strongly suggest a benign etiology, these are now commonly referred to as indeterminate solid nodules.
Subsolid nodules are pulmonary nodules that have unique characteristics and require separate guidelines for management. Subsolid nodules include pure ground glass nodules (GGNs) and part solid nodules. GGNs are focal nodular areas of increased lung attenuation through which normal parenchymal structures such as airways, vessels, and interlobular septa can be visualized.1,8 Part solid nodules have a solid component. They are usually, but not necessarily, >50% ground glass in appearance.
Lung masses. Focal pulmonary lesions >3 cm in diameter are called lung masses and are presumed to be malignant (bronchogenic carcinoma) unless proven otherwise.1,8
The specific approach to evaluating and monitoring a pulmonary nodule varies depending on whether the nodule is solid or subsolid and other factors, including the nodule’s size.
Monitoring solid nodules
Monitoring of an indeterminate solid nodule is largely determined by the patient’s risk profile and the characteristics of the identified nodule.1 Independent patient predictors of malignancy include older age, smoking status, and history of prior malignancy (>5 years ago). Less established predictors are the presence of moderate or severe obstructive lung disease and exposure to particulate or sulfur oxide-related pollution.9
Patients who have an indeterminate nodule identified on chest x-ray should undergo a chest CT scan, preferably with thin sections through the nodule to help characterize it.1 Nodule characteristics that can help predict a patient’s risk of malignancy include the size (>8 mm confers higher risk), malignant rate of growth, edge characteristics (spiculation or irregular edges), thickness of the wall of a cavitary pulmonary nodule (≥16 mm has a likelihood ratio [LR] 37.97 of malignancy), and the location of the nodule (upper or middle lobe [LR=1.2 to 1.6]). 10 A lack of growth over 2 years and a benign pattern of calcification eliminate the need for further evaluation.
Validated tools to help guide decision-making. Although many physicians estimate pretest probability of malignancy intuitively, validated tools are readily available and can help in clinical decision-making.11 One such tool is the Mayo model, which is available at http://reference.medscape.com/calculator/solitary-pulmonary-nodule-risk. This model takes into account the patient’s age, smoking status, history of cancer, and characteristics of the nodule.
Solid nodules >8 mm to 3 cm
For a patient with a solid nodule >8 mm to 3 cm, ACCP guidelines suggest that physicians estimate the pretest probability of malignancy qualitatively using their clinical judgment and/or quantitatively by using a validated model, such as the Mayo model described above.
Based on the patient’s probability of malignancy, management options include continued CT surveillance, positron emission tomography (PET) imaging, CT-guided needle lung biopsy, bronchoscopy with biopsy, or surgical wedge resection (ALGORITHM 1).1
CT surveillance is recommended for individuals:
- with very low (<5%) probability of malignancy
- with low to moderate (5% to 30%) or moderate to high (31% to 65%) probability of malignancy with negative functional imaging (PET)
- with high probability of malignancy (>65%) when needle biopsy is nondiagnostic and the lesion is not hypermetabolic on PET scan.
Surveillance is also recommended when a fully informed patient prefers nonaggressive management. The intervals for serial CT in this population are at 3 to 6 months, 9 to 12 months, and 18 to 24 months.
In an individual with a solid indeterminate nodule with a high probability of malignancy (>65%), functional imaging should not be performed to characterize the nodule. It may, however, be performed for staging.
Time for biopsy or resection? If a nodule shows evidence of malignant growth on serial imaging, nonsurgical biopsy (CT scan-guided transthoracic needle biopsy, bronchoscopy guided by fluoroscopy, endobronchial ultrasound, electromagnetic navigation bronchoscopy, or virtual bronchoscopy navigation) or surgical resection is recommended.
Nonsurgical biopsy is also recommended when the patient’s pretest probability and imaging test results are discordant, when a benign diagnosis requires specific medical treatment, or if a fully informed patient desires proof of diagnosis prior to surgery.
Thoracoscopy with wedge resection is the gold standard for diagnosis of a malignant nodule. It is recommended:
- when the clinical probability of malignancy is high (>65%)
- when the nodule is intensely hypermetabolic by PET scan or positive by other functional imaging tests
- when nonsurgical biopsy is suggestive of malignancy
- when a fully informed patient prefers a definitive diagnostic procedure.
CASE 1 › The FP contacts Mr. D and advises that he get a chest CT to better characterize his pulmonary nodule. A thin-slice CT of the lung reveals that the 13-mm solid nodule in the right upper lobe has spiculated margins. According to the Mayo risk calculator, Mr. D is at moderate risk of malignancy (32.5%). Mr. D and his physician discuss the findings and possible management options, and Mr. D opts to have a PET scan. The FP gives Mr. D literature on pulmonary nodules and contact information for the provider team. A PET scan shows negative uptake. Mr. D and his physician discuss CT surveillance and nonsurgical biopsy. He opts for CT surveillance. The next CT is scheduled for 3 months.
Solid nodules ≤8 mm
Management of these lesions generally follows the consensus-based guidelines that were first published by the Fleischner Society and subsequently endorsed by the ACCP.1 The 2 main determinants that guide management of nodules ≤8 mm are the patient’s risk factors for cancer and nodule size (ALGORITHM 2).1 The Fleischner guidelines pertain only to patients older than age 35 with no current extra pulmonary malignancy or unexplained fevers. The ACCP guidelines, although similar, do not include these limitations. Patient risk factors include history of smoking, older age, and a history of malignancy.1
Patients with no risk factors for malignancy. The frequency of surveillance CT is determined by the size of the nodule. Nodules ≤4 mm do not need to be followed. For nodules >4 mm to 6 mm, a repeat CT in 12 months is recommended with no follow-up if stable. For nodules >6 to <8 mm, repeat CT is recommended at 6 to 12 months, and again between 18 and 24 months if unchanged.1Patients with one or more risk factors for malignancy. Nodules ≤4 mm should be reevaluated at 12 months in patients with one or more risk factors; no additional follow-up is needed if unchanged. For nodules >4 mm to 6 mm, CT should be repeated between 6 and 12 months and again between 18 and 24 months. Nodules >6 mm to <8 mm should be followed initially between 3 to 6 months, then between 9 and 12 months and again at 24 months if unchanged.1
Subsolid nodules require a different approach
Subsolid nodules have a high prevalence of premalignant and malignant disease (adenocarcinoma in situ, minimally invasive adenocarcinoma, and adenocarcinoma). Studies have reported subsolid nodule malignancy rates ranging from 20% to 75%.11-15 This wide range may be a function of different nodule sizes or rates of biopsy. The prevalence increases even further in nodules with a part solid component.
These factors, plus challenges in measuring serial growth on CT and the uncertain prognosis of untreated premalignant disease, make it necessary to have separate guidelines for managing subsolid nodules. The Fleischner Society, National Comprehensive Cancer Network, and the American College of Radiology (LungRads) each have differing recommendations on the frequency of follow-up for different-sized subsolid nodules. Newer studies favor a more conservative approach.16 Here we describe the current ACCP guidelines for managing subsolid nodules (ALGORITHM 3).1
GGNs. In an individual with a pure GGN ≤5 mm in diameter, no further evaluation is recommended. In an individual with a pure GGN >5 mm in diameter, annual surveillance with chest CT for at least 3 years is recommended.1
Part solid nodules. In an individual with a part solid nodule ≤8 mm, conduct CT surveillance at 3, 12, and 24 months and then annually for an additional one to 3 years. In a patient with a part solid nodule >8 mm to 15 mm, repeat chest CT at 3 months followed by a PET scan, nonsurgical biopsy, and/or surgical resection if the nodule persists. A patient with a part solid nodule >15 mm should undergo a PET scan, nonsurgical biopsy, and/or surgical resection.
CASE 2 › Ms. G is seen in the office by her FP, and they discuss management options. A repeat CT is done in 3 months and shows a persistent, unchanged nodule. Ms. G opts for a transthoracic biopsy, which reveals adenocarcinoma. Following a PET scan, which shows no evidence of metastasis, curative surgical wedge resection is done.
Multiple subsolid nodules. In a patient who has a dominant nodule and one or more additional nodules, each nodule should be evaluated individually, according to recommendations from the Fleischner Society (the ACCP currently does not have guidelines for managing multiple subsolid nodules). An individual with multiple GGNs that all measure ≤5 mm should receive CT exams at 2 and 4 years.13 A patient with multiple GGNs that include at least one nodule >5 mm but no dominant nodule should undergo follow-up CT at 3 months and annual CT surveillance for at least 3 years.13
CORRESPONDENCE
Samina Yunus, MD, MPH, Cleveland Clinic, Family Medicine, 551 East Washington Street, Chagrin Falls, OH 44022; [email protected].
1. Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143:e93S-e120S.
2. Burt JR, Iribarren C, Fair JM, et al; Atherosclerotic Disease, Vascular Function, and Genetic Epidemiology (ADVANCE) Study. Incidental findings on cardiac multidetector row computed tomography among healthy older adults: prevalence and clinical correlates. Arch Intern Med. 2008;168:756-761.
3. Golden SE, Wiener RS, Sullivan D, et al. Primary care providers and a system problem: A qualitative study of clinicians caring for patients with incidental pulmonary nodules. Chest. 2015;148:1422-1429.
4. Sullivan DR, Golden SE, Ganzini L, et al. ‘I still don’t know diddly’: a longitudinal qualitative study of patients’ knowledge and distress while undergoing evaluation of incidental pulmonary nodules. NPJ Prim Care Respir Med. 2015;25:15028.
5. van den Bergh KA, Essink-Bot ML, Borsboom GJ, et al. Long-term effects of lung cancer computed tomography screening on health-related quality of life: the NELSON trial. Eur Respir J. 2011;38:154-161.
6. Wiener RS, Gould MK, Woloshin S, et al. What do you mean, a spot?: A qualitative analysis of patients’ reactions to discussions with their physicians about pulmonary nodules. Chest. 2013;143:672-677.
7. Wiener RS, Gould MK, Woloshin S, et al. ‘The thing is not knowing’: patients’ perspectives on surveillance of an indeterminate pulmonary nodule. Health Expect. 2015;18:355-365.
8. Hansell DM, Bankier AA, MacMahon H, et al. Fleischner Society: glossary of terms for thoracic imaging. Radiology. 2008;246:697-722.
9. Pope CA 3rd, Burnett RT, Thun MJ, et al. Lung cancer, cardiopulmonary mortality, and long-term exposure to fine particulate air pollution. JAMA. 2002;287:1132-1141.
10. Winer-Muram HT. The solitary pulmonary nodule. Radiology. 2006;239:34-49.
11. Gould MK, Ananth L, Barnett PG; Veterans Affairs SNAP Cooperative Study Group. A clinical model to estimate the pretest probability of lung cancer in patients with solitary pulmonary nodules. Chest. 2007;131:383-388.
12. Seidelman JL, Myers JL, Quint LE. Incidental, subsolid pulmonary nodules at CT: etiology and management. Cancer Imaging. 2013;13:365-373.
13. Naidich DP, Bankier AA, MacMahon H, et al. Recommendations for the management of subsolid pulmonary nodules detected at CT: a statement from the Fleischner Society. Radiology. 2013;266:304-317.
14. Oh JY, Kwon SY, Yoon HI, et al. Clinical significance of a solitary ground-glass opacity (GGO) lesion of the lung detected by chest CT. Lung Cancer. 2007;55:67-73.
15. Park CM, Goo JM, Lee HJ, et al. Nodular ground-glass opacity at thin-section CT: histologic correlation and evaluation of change at follow-up. Radiographics. 2007;27:391-408.
16. Heuvelmans MA, Oudkerk M. Management of subsolid pulmonary nodules in CT lung cancer screening. J Thorac Dis. 2015;7:1103-1106.
› Order a computed tomography chest scan, preferably with thin sections through the nodule, to help characterize an indeterminate pulmonary nodule identified on x-ray. B
› Estimate the pretest probability of malignancy for a patient with a pulmonary nodule using your clinical judgment and/or by using a validated model. B
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
CASE 1 › George D is a 67-year-old patient who has never smoked and who has no history of malignancy. An x-ray of his ribs performed after a fall shows a 13-mm solitary nodule in his right upper lung.
CASE 2 › Cathy B is a healthy 80-year-old with no history of smoking. During a trip to the emergency department for chest pain, she had a computed tomography (CT) scan of her chest. While the chest pain was subsequently attributed to gastroesophageal reflux, the CT revealed a 9-mm part solid nodule that was 75% solid.
How should the physicians caring for each of these patients proceed with their care?
The widespread use of sensitive imaging techniques often leads to the incidental discovery of unrelated—but possibly significant—pulmonary findings. Pulmonary nodules are incidentally discovered on an estimated 0.09% to 0.2% of all chest x-rays, 13% of all chest CT angiograms,1 31% of all cardiac CTs performed for coronary calcium scoring,2 and up to 50% of thin-section chest CT scans.1
The widespread implementation of the US Preventive Services Task Force recommendations on lung cancer screening has further expanded the number of patients in whom asymptomatic pulmonary nodules will be detected. As a result, family physicians (FPs) will frequently encounter this challenging clinical dilemma and will need to:
- assess the patient’s risk profile
- address the patient’s concerns about malignancy while eliciting his or her preference for management
- minimize the risks of surveillance testing
- minimize patient distress while ensuring compliance with a follow-up that may extend up to 4 years
- determine when it’s appropriate to refer the patient to a pulmonologist and/or pulmonary nodule clinic or registry.
Taking these steps, however, can be challenging. In interviews, 15 primary care clinicians who care for patients with pulmonary nodules expressed concerns about limitations in time, knowledge, and resources, as well as a fear about such patients “falling through the cracks.”3 Familiarity with current evidence-based guidelines such as those from the American College of Chest Physicians (ACCP) and knowledge of emerging data on the management of various types of nodules are imperative.
To that end, this review will fill in the information gaps and provide guidance on how best to communicate what is known about a particular type of nodule with the patient who has one. (See “What to say to improve joint decision-making.”4-7) But first, a word about terminology.
What to say to improve joint decision-making4-7
Diagnosis and follow-up of a pulmonary nodule takes an emotional toll on patients, who often have a poor sense of what the presence of a nodule signifies. When caring for a patient with a pulmonary nodule, it’s essential to have an effective communication strategy to ensure that he or she is a well-informed partner in decision-making.
Specifically, you'll need to describe the type of nodule that the patient has, how fast it might grow and its malignancy potential, steps that will need to be taken, and the importance of smoking cessation (if the patient smokes).
Ask the patient about any concerns/fears he or she may have, and provide resources to reduce them. Emphasize shared decision-making and discuss the rationale for various management plans and the limitations of diagnostic tests. Do not minimize the issue; emphasize the need for, and importance of, prolonged follow-up—even for a patient who has a small, low-risk nodule.
Solid vs subsolid pulmonary nodules
Solid pulmonary nodules. Traditionally, the term “solitary pulmonary nodule” has been used to describe a single, well-circumscribed, radiographic opacity that measures up to 3 cm in diameter and is completely surrounded by aerated lung.1,8 The term “solitary” is now less useful because increasingly sensitive imaging techniques often reveal more than one nodule. In the absence of evidence of features that strongly suggest a benign etiology, these are now commonly referred to as indeterminate solid nodules.
Subsolid nodules are pulmonary nodules that have unique characteristics and require separate guidelines for management. Subsolid nodules include pure ground glass nodules (GGNs) and part solid nodules. GGNs are focal nodular areas of increased lung attenuation through which normal parenchymal structures such as airways, vessels, and interlobular septa can be visualized.1,8 Part solid nodules have a solid component. They are usually, but not necessarily, >50% ground glass in appearance.
Lung masses. Focal pulmonary lesions >3 cm in diameter are called lung masses and are presumed to be malignant (bronchogenic carcinoma) unless proven otherwise.1,8
The specific approach to evaluating and monitoring a pulmonary nodule varies depending on whether the nodule is solid or subsolid and other factors, including the nodule’s size.
Monitoring solid nodules
Monitoring of an indeterminate solid nodule is largely determined by the patient’s risk profile and the characteristics of the identified nodule.1 Independent patient predictors of malignancy include older age, smoking status, and history of prior malignancy (>5 years ago). Less established predictors are the presence of moderate or severe obstructive lung disease and exposure to particulate or sulfur oxide-related pollution.9
Patients who have an indeterminate nodule identified on chest x-ray should undergo a chest CT scan, preferably with thin sections through the nodule to help characterize it.1 Nodule characteristics that can help predict a patient’s risk of malignancy include the size (>8 mm confers higher risk), malignant rate of growth, edge characteristics (spiculation or irregular edges), thickness of the wall of a cavitary pulmonary nodule (≥16 mm has a likelihood ratio [LR] 37.97 of malignancy), and the location of the nodule (upper or middle lobe [LR=1.2 to 1.6]). 10 A lack of growth over 2 years and a benign pattern of calcification eliminate the need for further evaluation.
Validated tools to help guide decision-making. Although many physicians estimate pretest probability of malignancy intuitively, validated tools are readily available and can help in clinical decision-making.11 One such tool is the Mayo model, which is available at http://reference.medscape.com/calculator/solitary-pulmonary-nodule-risk. This model takes into account the patient’s age, smoking status, history of cancer, and characteristics of the nodule.
Solid nodules >8 mm to 3 cm
For a patient with a solid nodule >8 mm to 3 cm, ACCP guidelines suggest that physicians estimate the pretest probability of malignancy qualitatively using their clinical judgment and/or quantitatively by using a validated model, such as the Mayo model described above.
Based on the patient’s probability of malignancy, management options include continued CT surveillance, positron emission tomography (PET) imaging, CT-guided needle lung biopsy, bronchoscopy with biopsy, or surgical wedge resection (ALGORITHM 1).1
CT surveillance is recommended for individuals:
- with very low (<5%) probability of malignancy
- with low to moderate (5% to 30%) or moderate to high (31% to 65%) probability of malignancy with negative functional imaging (PET)
- with high probability of malignancy (>65%) when needle biopsy is nondiagnostic and the lesion is not hypermetabolic on PET scan.
Surveillance is also recommended when a fully informed patient prefers nonaggressive management. The intervals for serial CT in this population are at 3 to 6 months, 9 to 12 months, and 18 to 24 months.
In an individual with a solid indeterminate nodule with a high probability of malignancy (>65%), functional imaging should not be performed to characterize the nodule. It may, however, be performed for staging.
Time for biopsy or resection? If a nodule shows evidence of malignant growth on serial imaging, nonsurgical biopsy (CT scan-guided transthoracic needle biopsy, bronchoscopy guided by fluoroscopy, endobronchial ultrasound, electromagnetic navigation bronchoscopy, or virtual bronchoscopy navigation) or surgical resection is recommended.
Nonsurgical biopsy is also recommended when the patient’s pretest probability and imaging test results are discordant, when a benign diagnosis requires specific medical treatment, or if a fully informed patient desires proof of diagnosis prior to surgery.
Thoracoscopy with wedge resection is the gold standard for diagnosis of a malignant nodule. It is recommended:
- when the clinical probability of malignancy is high (>65%)
- when the nodule is intensely hypermetabolic by PET scan or positive by other functional imaging tests
- when nonsurgical biopsy is suggestive of malignancy
- when a fully informed patient prefers a definitive diagnostic procedure.
CASE 1 › The FP contacts Mr. D and advises that he get a chest CT to better characterize his pulmonary nodule. A thin-slice CT of the lung reveals that the 13-mm solid nodule in the right upper lobe has spiculated margins. According to the Mayo risk calculator, Mr. D is at moderate risk of malignancy (32.5%). Mr. D and his physician discuss the findings and possible management options, and Mr. D opts to have a PET scan. The FP gives Mr. D literature on pulmonary nodules and contact information for the provider team. A PET scan shows negative uptake. Mr. D and his physician discuss CT surveillance and nonsurgical biopsy. He opts for CT surveillance. The next CT is scheduled for 3 months.
Solid nodules ≤8 mm
Management of these lesions generally follows the consensus-based guidelines that were first published by the Fleischner Society and subsequently endorsed by the ACCP.1 The 2 main determinants that guide management of nodules ≤8 mm are the patient’s risk factors for cancer and nodule size (ALGORITHM 2).1 The Fleischner guidelines pertain only to patients older than age 35 with no current extra pulmonary malignancy or unexplained fevers. The ACCP guidelines, although similar, do not include these limitations. Patient risk factors include history of smoking, older age, and a history of malignancy.1
Patients with no risk factors for malignancy. The frequency of surveillance CT is determined by the size of the nodule. Nodules ≤4 mm do not need to be followed. For nodules >4 mm to 6 mm, a repeat CT in 12 months is recommended with no follow-up if stable. For nodules >6 to <8 mm, repeat CT is recommended at 6 to 12 months, and again between 18 and 24 months if unchanged.1Patients with one or more risk factors for malignancy. Nodules ≤4 mm should be reevaluated at 12 months in patients with one or more risk factors; no additional follow-up is needed if unchanged. For nodules >4 mm to 6 mm, CT should be repeated between 6 and 12 months and again between 18 and 24 months. Nodules >6 mm to <8 mm should be followed initially between 3 to 6 months, then between 9 and 12 months and again at 24 months if unchanged.1
Subsolid nodules require a different approach
Subsolid nodules have a high prevalence of premalignant and malignant disease (adenocarcinoma in situ, minimally invasive adenocarcinoma, and adenocarcinoma). Studies have reported subsolid nodule malignancy rates ranging from 20% to 75%.11-15 This wide range may be a function of different nodule sizes or rates of biopsy. The prevalence increases even further in nodules with a part solid component.
These factors, plus challenges in measuring serial growth on CT and the uncertain prognosis of untreated premalignant disease, make it necessary to have separate guidelines for managing subsolid nodules. The Fleischner Society, National Comprehensive Cancer Network, and the American College of Radiology (LungRads) each have differing recommendations on the frequency of follow-up for different-sized subsolid nodules. Newer studies favor a more conservative approach.16 Here we describe the current ACCP guidelines for managing subsolid nodules (ALGORITHM 3).1
GGNs. In an individual with a pure GGN ≤5 mm in diameter, no further evaluation is recommended. In an individual with a pure GGN >5 mm in diameter, annual surveillance with chest CT for at least 3 years is recommended.1
Part solid nodules. In an individual with a part solid nodule ≤8 mm, conduct CT surveillance at 3, 12, and 24 months and then annually for an additional one to 3 years. In a patient with a part solid nodule >8 mm to 15 mm, repeat chest CT at 3 months followed by a PET scan, nonsurgical biopsy, and/or surgical resection if the nodule persists. A patient with a part solid nodule >15 mm should undergo a PET scan, nonsurgical biopsy, and/or surgical resection.
CASE 2 › Ms. G is seen in the office by her FP, and they discuss management options. A repeat CT is done in 3 months and shows a persistent, unchanged nodule. Ms. G opts for a transthoracic biopsy, which reveals adenocarcinoma. Following a PET scan, which shows no evidence of metastasis, curative surgical wedge resection is done.
Multiple subsolid nodules. In a patient who has a dominant nodule and one or more additional nodules, each nodule should be evaluated individually, according to recommendations from the Fleischner Society (the ACCP currently does not have guidelines for managing multiple subsolid nodules). An individual with multiple GGNs that all measure ≤5 mm should receive CT exams at 2 and 4 years.13 A patient with multiple GGNs that include at least one nodule >5 mm but no dominant nodule should undergo follow-up CT at 3 months and annual CT surveillance for at least 3 years.13
CORRESPONDENCE
Samina Yunus, MD, MPH, Cleveland Clinic, Family Medicine, 551 East Washington Street, Chagrin Falls, OH 44022; [email protected].
› Order a computed tomography chest scan, preferably with thin sections through the nodule, to help characterize an indeterminate pulmonary nodule identified on x-ray. B
› Estimate the pretest probability of malignancy for a patient with a pulmonary nodule using your clinical judgment and/or by using a validated model. B
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
CASE 1 › George D is a 67-year-old patient who has never smoked and who has no history of malignancy. An x-ray of his ribs performed after a fall shows a 13-mm solitary nodule in his right upper lung.
CASE 2 › Cathy B is a healthy 80-year-old with no history of smoking. During a trip to the emergency department for chest pain, she had a computed tomography (CT) scan of her chest. While the chest pain was subsequently attributed to gastroesophageal reflux, the CT revealed a 9-mm part solid nodule that was 75% solid.
How should the physicians caring for each of these patients proceed with their care?
The widespread use of sensitive imaging techniques often leads to the incidental discovery of unrelated—but possibly significant—pulmonary findings. Pulmonary nodules are incidentally discovered on an estimated 0.09% to 0.2% of all chest x-rays, 13% of all chest CT angiograms,1 31% of all cardiac CTs performed for coronary calcium scoring,2 and up to 50% of thin-section chest CT scans.1
The widespread implementation of the US Preventive Services Task Force recommendations on lung cancer screening has further expanded the number of patients in whom asymptomatic pulmonary nodules will be detected. As a result, family physicians (FPs) will frequently encounter this challenging clinical dilemma and will need to:
- assess the patient’s risk profile
- address the patient’s concerns about malignancy while eliciting his or her preference for management
- minimize the risks of surveillance testing
- minimize patient distress while ensuring compliance with a follow-up that may extend up to 4 years
- determine when it’s appropriate to refer the patient to a pulmonologist and/or pulmonary nodule clinic or registry.
Taking these steps, however, can be challenging. In interviews, 15 primary care clinicians who care for patients with pulmonary nodules expressed concerns about limitations in time, knowledge, and resources, as well as a fear about such patients “falling through the cracks.”3 Familiarity with current evidence-based guidelines such as those from the American College of Chest Physicians (ACCP) and knowledge of emerging data on the management of various types of nodules are imperative.
To that end, this review will fill in the information gaps and provide guidance on how best to communicate what is known about a particular type of nodule with the patient who has one. (See “What to say to improve joint decision-making.”4-7) But first, a word about terminology.
What to say to improve joint decision-making4-7
Diagnosis and follow-up of a pulmonary nodule takes an emotional toll on patients, who often have a poor sense of what the presence of a nodule signifies. When caring for a patient with a pulmonary nodule, it’s essential to have an effective communication strategy to ensure that he or she is a well-informed partner in decision-making.
Specifically, you'll need to describe the type of nodule that the patient has, how fast it might grow and its malignancy potential, steps that will need to be taken, and the importance of smoking cessation (if the patient smokes).
Ask the patient about any concerns/fears he or she may have, and provide resources to reduce them. Emphasize shared decision-making and discuss the rationale for various management plans and the limitations of diagnostic tests. Do not minimize the issue; emphasize the need for, and importance of, prolonged follow-up—even for a patient who has a small, low-risk nodule.
Solid vs subsolid pulmonary nodules
Solid pulmonary nodules. Traditionally, the term “solitary pulmonary nodule” has been used to describe a single, well-circumscribed, radiographic opacity that measures up to 3 cm in diameter and is completely surrounded by aerated lung.1,8 The term “solitary” is now less useful because increasingly sensitive imaging techniques often reveal more than one nodule. In the absence of evidence of features that strongly suggest a benign etiology, these are now commonly referred to as indeterminate solid nodules.
Subsolid nodules are pulmonary nodules that have unique characteristics and require separate guidelines for management. Subsolid nodules include pure ground glass nodules (GGNs) and part solid nodules. GGNs are focal nodular areas of increased lung attenuation through which normal parenchymal structures such as airways, vessels, and interlobular septa can be visualized.1,8 Part solid nodules have a solid component. They are usually, but not necessarily, >50% ground glass in appearance.
Lung masses. Focal pulmonary lesions >3 cm in diameter are called lung masses and are presumed to be malignant (bronchogenic carcinoma) unless proven otherwise.1,8
The specific approach to evaluating and monitoring a pulmonary nodule varies depending on whether the nodule is solid or subsolid and other factors, including the nodule’s size.
Monitoring solid nodules
Monitoring of an indeterminate solid nodule is largely determined by the patient’s risk profile and the characteristics of the identified nodule.1 Independent patient predictors of malignancy include older age, smoking status, and history of prior malignancy (>5 years ago). Less established predictors are the presence of moderate or severe obstructive lung disease and exposure to particulate or sulfur oxide-related pollution.9
Patients who have an indeterminate nodule identified on chest x-ray should undergo a chest CT scan, preferably with thin sections through the nodule to help characterize it.1 Nodule characteristics that can help predict a patient’s risk of malignancy include the size (>8 mm confers higher risk), malignant rate of growth, edge characteristics (spiculation or irregular edges), thickness of the wall of a cavitary pulmonary nodule (≥16 mm has a likelihood ratio [LR] 37.97 of malignancy), and the location of the nodule (upper or middle lobe [LR=1.2 to 1.6]). 10 A lack of growth over 2 years and a benign pattern of calcification eliminate the need for further evaluation.
Validated tools to help guide decision-making. Although many physicians estimate pretest probability of malignancy intuitively, validated tools are readily available and can help in clinical decision-making.11 One such tool is the Mayo model, which is available at http://reference.medscape.com/calculator/solitary-pulmonary-nodule-risk. This model takes into account the patient’s age, smoking status, history of cancer, and characteristics of the nodule.
Solid nodules >8 mm to 3 cm
For a patient with a solid nodule >8 mm to 3 cm, ACCP guidelines suggest that physicians estimate the pretest probability of malignancy qualitatively using their clinical judgment and/or quantitatively by using a validated model, such as the Mayo model described above.
Based on the patient’s probability of malignancy, management options include continued CT surveillance, positron emission tomography (PET) imaging, CT-guided needle lung biopsy, bronchoscopy with biopsy, or surgical wedge resection (ALGORITHM 1).1
CT surveillance is recommended for individuals:
- with very low (<5%) probability of malignancy
- with low to moderate (5% to 30%) or moderate to high (31% to 65%) probability of malignancy with negative functional imaging (PET)
- with high probability of malignancy (>65%) when needle biopsy is nondiagnostic and the lesion is not hypermetabolic on PET scan.
Surveillance is also recommended when a fully informed patient prefers nonaggressive management. The intervals for serial CT in this population are at 3 to 6 months, 9 to 12 months, and 18 to 24 months.
In an individual with a solid indeterminate nodule with a high probability of malignancy (>65%), functional imaging should not be performed to characterize the nodule. It may, however, be performed for staging.
Time for biopsy or resection? If a nodule shows evidence of malignant growth on serial imaging, nonsurgical biopsy (CT scan-guided transthoracic needle biopsy, bronchoscopy guided by fluoroscopy, endobronchial ultrasound, electromagnetic navigation bronchoscopy, or virtual bronchoscopy navigation) or surgical resection is recommended.
Nonsurgical biopsy is also recommended when the patient’s pretest probability and imaging test results are discordant, when a benign diagnosis requires specific medical treatment, or if a fully informed patient desires proof of diagnosis prior to surgery.
Thoracoscopy with wedge resection is the gold standard for diagnosis of a malignant nodule. It is recommended:
- when the clinical probability of malignancy is high (>65%)
- when the nodule is intensely hypermetabolic by PET scan or positive by other functional imaging tests
- when nonsurgical biopsy is suggestive of malignancy
- when a fully informed patient prefers a definitive diagnostic procedure.
CASE 1 › The FP contacts Mr. D and advises that he get a chest CT to better characterize his pulmonary nodule. A thin-slice CT of the lung reveals that the 13-mm solid nodule in the right upper lobe has spiculated margins. According to the Mayo risk calculator, Mr. D is at moderate risk of malignancy (32.5%). Mr. D and his physician discuss the findings and possible management options, and Mr. D opts to have a PET scan. The FP gives Mr. D literature on pulmonary nodules and contact information for the provider team. A PET scan shows negative uptake. Mr. D and his physician discuss CT surveillance and nonsurgical biopsy. He opts for CT surveillance. The next CT is scheduled for 3 months.
Solid nodules ≤8 mm
Management of these lesions generally follows the consensus-based guidelines that were first published by the Fleischner Society and subsequently endorsed by the ACCP.1 The 2 main determinants that guide management of nodules ≤8 mm are the patient’s risk factors for cancer and nodule size (ALGORITHM 2).1 The Fleischner guidelines pertain only to patients older than age 35 with no current extra pulmonary malignancy or unexplained fevers. The ACCP guidelines, although similar, do not include these limitations. Patient risk factors include history of smoking, older age, and a history of malignancy.1
Patients with no risk factors for malignancy. The frequency of surveillance CT is determined by the size of the nodule. Nodules ≤4 mm do not need to be followed. For nodules >4 mm to 6 mm, a repeat CT in 12 months is recommended with no follow-up if stable. For nodules >6 to <8 mm, repeat CT is recommended at 6 to 12 months, and again between 18 and 24 months if unchanged.1Patients with one or more risk factors for malignancy. Nodules ≤4 mm should be reevaluated at 12 months in patients with one or more risk factors; no additional follow-up is needed if unchanged. For nodules >4 mm to 6 mm, CT should be repeated between 6 and 12 months and again between 18 and 24 months. Nodules >6 mm to <8 mm should be followed initially between 3 to 6 months, then between 9 and 12 months and again at 24 months if unchanged.1
Subsolid nodules require a different approach
Subsolid nodules have a high prevalence of premalignant and malignant disease (adenocarcinoma in situ, minimally invasive adenocarcinoma, and adenocarcinoma). Studies have reported subsolid nodule malignancy rates ranging from 20% to 75%.11-15 This wide range may be a function of different nodule sizes or rates of biopsy. The prevalence increases even further in nodules with a part solid component.
These factors, plus challenges in measuring serial growth on CT and the uncertain prognosis of untreated premalignant disease, make it necessary to have separate guidelines for managing subsolid nodules. The Fleischner Society, National Comprehensive Cancer Network, and the American College of Radiology (LungRads) each have differing recommendations on the frequency of follow-up for different-sized subsolid nodules. Newer studies favor a more conservative approach.16 Here we describe the current ACCP guidelines for managing subsolid nodules (ALGORITHM 3).1
GGNs. In an individual with a pure GGN ≤5 mm in diameter, no further evaluation is recommended. In an individual with a pure GGN >5 mm in diameter, annual surveillance with chest CT for at least 3 years is recommended.1
Part solid nodules. In an individual with a part solid nodule ≤8 mm, conduct CT surveillance at 3, 12, and 24 months and then annually for an additional one to 3 years. In a patient with a part solid nodule >8 mm to 15 mm, repeat chest CT at 3 months followed by a PET scan, nonsurgical biopsy, and/or surgical resection if the nodule persists. A patient with a part solid nodule >15 mm should undergo a PET scan, nonsurgical biopsy, and/or surgical resection.
CASE 2 › Ms. G is seen in the office by her FP, and they discuss management options. A repeat CT is done in 3 months and shows a persistent, unchanged nodule. Ms. G opts for a transthoracic biopsy, which reveals adenocarcinoma. Following a PET scan, which shows no evidence of metastasis, curative surgical wedge resection is done.
Multiple subsolid nodules. In a patient who has a dominant nodule and one or more additional nodules, each nodule should be evaluated individually, according to recommendations from the Fleischner Society (the ACCP currently does not have guidelines for managing multiple subsolid nodules). An individual with multiple GGNs that all measure ≤5 mm should receive CT exams at 2 and 4 years.13 A patient with multiple GGNs that include at least one nodule >5 mm but no dominant nodule should undergo follow-up CT at 3 months and annual CT surveillance for at least 3 years.13
CORRESPONDENCE
Samina Yunus, MD, MPH, Cleveland Clinic, Family Medicine, 551 East Washington Street, Chagrin Falls, OH 44022; [email protected].
1. Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143:e93S-e120S.
2. Burt JR, Iribarren C, Fair JM, et al; Atherosclerotic Disease, Vascular Function, and Genetic Epidemiology (ADVANCE) Study. Incidental findings on cardiac multidetector row computed tomography among healthy older adults: prevalence and clinical correlates. Arch Intern Med. 2008;168:756-761.
3. Golden SE, Wiener RS, Sullivan D, et al. Primary care providers and a system problem: A qualitative study of clinicians caring for patients with incidental pulmonary nodules. Chest. 2015;148:1422-1429.
4. Sullivan DR, Golden SE, Ganzini L, et al. ‘I still don’t know diddly’: a longitudinal qualitative study of patients’ knowledge and distress while undergoing evaluation of incidental pulmonary nodules. NPJ Prim Care Respir Med. 2015;25:15028.
5. van den Bergh KA, Essink-Bot ML, Borsboom GJ, et al. Long-term effects of lung cancer computed tomography screening on health-related quality of life: the NELSON trial. Eur Respir J. 2011;38:154-161.
6. Wiener RS, Gould MK, Woloshin S, et al. What do you mean, a spot?: A qualitative analysis of patients’ reactions to discussions with their physicians about pulmonary nodules. Chest. 2013;143:672-677.
7. Wiener RS, Gould MK, Woloshin S, et al. ‘The thing is not knowing’: patients’ perspectives on surveillance of an indeterminate pulmonary nodule. Health Expect. 2015;18:355-365.
8. Hansell DM, Bankier AA, MacMahon H, et al. Fleischner Society: glossary of terms for thoracic imaging. Radiology. 2008;246:697-722.
9. Pope CA 3rd, Burnett RT, Thun MJ, et al. Lung cancer, cardiopulmonary mortality, and long-term exposure to fine particulate air pollution. JAMA. 2002;287:1132-1141.
10. Winer-Muram HT. The solitary pulmonary nodule. Radiology. 2006;239:34-49.
11. Gould MK, Ananth L, Barnett PG; Veterans Affairs SNAP Cooperative Study Group. A clinical model to estimate the pretest probability of lung cancer in patients with solitary pulmonary nodules. Chest. 2007;131:383-388.
12. Seidelman JL, Myers JL, Quint LE. Incidental, subsolid pulmonary nodules at CT: etiology and management. Cancer Imaging. 2013;13:365-373.
13. Naidich DP, Bankier AA, MacMahon H, et al. Recommendations for the management of subsolid pulmonary nodules detected at CT: a statement from the Fleischner Society. Radiology. 2013;266:304-317.
14. Oh JY, Kwon SY, Yoon HI, et al. Clinical significance of a solitary ground-glass opacity (GGO) lesion of the lung detected by chest CT. Lung Cancer. 2007;55:67-73.
15. Park CM, Goo JM, Lee HJ, et al. Nodular ground-glass opacity at thin-section CT: histologic correlation and evaluation of change at follow-up. Radiographics. 2007;27:391-408.
16. Heuvelmans MA, Oudkerk M. Management of subsolid pulmonary nodules in CT lung cancer screening. J Thorac Dis. 2015;7:1103-1106.
1. Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143:e93S-e120S.
2. Burt JR, Iribarren C, Fair JM, et al; Atherosclerotic Disease, Vascular Function, and Genetic Epidemiology (ADVANCE) Study. Incidental findings on cardiac multidetector row computed tomography among healthy older adults: prevalence and clinical correlates. Arch Intern Med. 2008;168:756-761.
3. Golden SE, Wiener RS, Sullivan D, et al. Primary care providers and a system problem: A qualitative study of clinicians caring for patients with incidental pulmonary nodules. Chest. 2015;148:1422-1429.
4. Sullivan DR, Golden SE, Ganzini L, et al. ‘I still don’t know diddly’: a longitudinal qualitative study of patients’ knowledge and distress while undergoing evaluation of incidental pulmonary nodules. NPJ Prim Care Respir Med. 2015;25:15028.
5. van den Bergh KA, Essink-Bot ML, Borsboom GJ, et al. Long-term effects of lung cancer computed tomography screening on health-related quality of life: the NELSON trial. Eur Respir J. 2011;38:154-161.
6. Wiener RS, Gould MK, Woloshin S, et al. What do you mean, a spot?: A qualitative analysis of patients’ reactions to discussions with their physicians about pulmonary nodules. Chest. 2013;143:672-677.
7. Wiener RS, Gould MK, Woloshin S, et al. ‘The thing is not knowing’: patients’ perspectives on surveillance of an indeterminate pulmonary nodule. Health Expect. 2015;18:355-365.
8. Hansell DM, Bankier AA, MacMahon H, et al. Fleischner Society: glossary of terms for thoracic imaging. Radiology. 2008;246:697-722.
9. Pope CA 3rd, Burnett RT, Thun MJ, et al. Lung cancer, cardiopulmonary mortality, and long-term exposure to fine particulate air pollution. JAMA. 2002;287:1132-1141.
10. Winer-Muram HT. The solitary pulmonary nodule. Radiology. 2006;239:34-49.
11. Gould MK, Ananth L, Barnett PG; Veterans Affairs SNAP Cooperative Study Group. A clinical model to estimate the pretest probability of lung cancer in patients with solitary pulmonary nodules. Chest. 2007;131:383-388.
12. Seidelman JL, Myers JL, Quint LE. Incidental, subsolid pulmonary nodules at CT: etiology and management. Cancer Imaging. 2013;13:365-373.
13. Naidich DP, Bankier AA, MacMahon H, et al. Recommendations for the management of subsolid pulmonary nodules detected at CT: a statement from the Fleischner Society. Radiology. 2013;266:304-317.
14. Oh JY, Kwon SY, Yoon HI, et al. Clinical significance of a solitary ground-glass opacity (GGO) lesion of the lung detected by chest CT. Lung Cancer. 2007;55:67-73.
15. Park CM, Goo JM, Lee HJ, et al. Nodular ground-glass opacity at thin-section CT: histologic correlation and evaluation of change at follow-up. Radiographics. 2007;27:391-408.
16. Heuvelmans MA, Oudkerk M. Management of subsolid pulmonary nodules in CT lung cancer screening. J Thorac Dis. 2015;7:1103-1106.
Patient Has No Complaints, But Family Is Concerned
ANSWER
The radiograph shows diffuse osteopenia and spondylosis. Of note is a moderate to severe compression deformity of the T8 vertebral body. However, by plain radiograph, it is age indeterminate as to its acuity. For definitive diagnosis, MRI without contrast is required to assess for marrow edema, which then suggests an acute fracture.
This patient was admitted for further workup. MRI was ultimately obtained and revealed marrow edema within that vertebral body. She was treated with a rigid custom-made brace.
ANSWER
The radiograph shows diffuse osteopenia and spondylosis. Of note is a moderate to severe compression deformity of the T8 vertebral body. However, by plain radiograph, it is age indeterminate as to its acuity. For definitive diagnosis, MRI without contrast is required to assess for marrow edema, which then suggests an acute fracture.
This patient was admitted for further workup. MRI was ultimately obtained and revealed marrow edema within that vertebral body. She was treated with a rigid custom-made brace.
ANSWER
The radiograph shows diffuse osteopenia and spondylosis. Of note is a moderate to severe compression deformity of the T8 vertebral body. However, by plain radiograph, it is age indeterminate as to its acuity. For definitive diagnosis, MRI without contrast is required to assess for marrow edema, which then suggests an acute fracture.
This patient was admitted for further workup. MRI was ultimately obtained and revealed marrow edema within that vertebral body. She was treated with a rigid custom-made brace.
An 80-year-old woman presents to the emergency department for evaluation. Her family reports that she has baseline dementia and resides in an assisted living facility. Staff there report that recently the patient has fallen multiple times. The patient herself does not voice any specific complaints, but her family has noticed she is not as active or walking as much as usual. Medical history is significant for mild hypertension. On physical exam, you note that the patient is awake and alert but oriented only to person. Her vital signs are stable. Primary and secondary survey do not demonstrate any obvious injury or trauma. You order some basic blood work, as well as some imaging studies—including thoracic and lumbar radiographs. The lateral thoracic radiograph is shown. What is your impression?
