A suspicion from retrospective data has now been confirmed by a prospective clinical trial: Adding panitumumab (Vectibix) to standard chemotherapy in left-sided RAS wild-type metastatic colorectal cancer (mCRC) is more effective than adding bevacizumab (Avastin).

Patients treated with panitumumab alongside chemotherapy saw a 16% improvement in overall survival versus those given bevacizumab after a median follow-up of over 5 years.

The overall survival benefit rose to 18% in those with left-sided tumors.

However, there was no difference in overall survival between the two treatment groups in the small subgroup of patients with right-sided primary tumors.

These findings come from the PARADIGM trial conducted in Japan.

The results were presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.

“If gene testing shows that a tumor is RAS wild-type, the choice of initial treatment with panitumumab plus mFOLFOX6 chemotherapy is superior ... for those people with left-sided tumors,” said lead researcher Takayuki Yoshino, MD, PhD, department of gastrointestinal oncology, National Cancer Center Hospital East, Chiba, Japan, in an ASCO press release.

“It has long been believed that the sequence of metastatic colorectal cancer treatment does not matter as long as patients had access to the drugs at some point, which has now been disproven,” he noted.

Dr. Yoshino added in a press conference about the trial that the results establish “a standard first-line combination regimen for patients with RAS wild-type, left-sided mCRC.”

This is the “longest survival ever reported in a first-line unresectable metastatic colorectal cancer prospective phase 3 trial,” commented Cathy Eng, MD, ASCO Expert in gastrointestinal cancers.

The findings “emphasize the importance of taking into account sidedness, as well as including comprehensive biomarker testing,” she said.

Dr. Eng underlined that this is especially the case for RAS gene status testing, “which is critical for all colorectal cancer patients at the time of diagnosis of metastatic disease.”

These results are of particular relevance in the United States, where the choice between an anti-EGFR or anti-VEGF antibody for the treatment of mCRC has been an area of “controversy” because of the lack of supporting data.

Panitumumab is a human monoclonal antibody that targets EGFR. It was approved in 2006 for use in mCRC by the U.S. Food and Drug Administration and also approved in 2014 for use in combination with FOLFOX for the first-line treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) mCRC, having previously been shown to be equally effective as cetuximab (another EGFR inhibitor) in this population.

In contrast, bevacizumab is a monoclonal antibody that targets the VEGF receptor. It was approved by the FDA for use in mCRC in 2004 in combination with intravenous 5-fluorouracil–based chemotherapy.

Dr. Yoshino explained that around 36% of patients with CRC have metastatic tumors at diagnosis and that adding an anti-EGFR or anti-VEGF antibody to chemotherapy improves overall survival in these patients by up to 30 months.

There has been “accumulating” evidence from retrospective studies suggesting that patients with RAS wild-type mCRC whose primary tumor is on the left side, which accounts for approximately 35% of mCRC cases, have a longer survival benefit with an anti-EGFR antibody, he commented.

Despite this, both antibody types continue to be used in these patients, he added.

PARADIGM was the first prospective trial to compare the two antibody types. Patients were randomized to receive either panitumumab or bevacizumab plus the combination chemotherapy regimen modified FOLFOX6 (mFOLFOX6).

The trial involved 823 Japanese patients with previously untreated wild-type mCRC with unresectable disease. Most patients had left-sided primary tumors (312 of 400 patients in the panitumumab group, and 292 of 402 patients in the bevacizumab group).  

After a median follow-up of 61 months, panitumumab was associated with a significant improvement in overall survival in the overall study population, at a hazard ratio of 0.84 (P = .030, with the boundary of significance set at P < .05).

In addition, panitumumab was associated with a significant improvement in overall survival in the large subgroup of patients with left-sided primary tumors, at 37.9 versus 34.3 months, or a hazard ratio of 0.82 (P = .031).

However, there was no significant difference in overall survival between the two treatment groups in the smaller subgroup of patients with right-sided tumors, at a hazard ratio of 1.09.

Median progression-free survival was no different between the panitumumab and bevacizumab groups, at 13.7 versus 13.2 months in patients with a left-sided tumor and 12.9 versus 12.0 months in the overall cohort.

There was, however, a difference in response rates in left-sided patients between those receiving the two antibodies, at 80.2% with panitumumab versus 68.6% with bevacizumab, and in curative resection rates, at 18.3% and 11.6%, respectively.

These results demonstrate the “superiority of first-line panitumumab versus bevacizumab in combination with mFOLFOX6 in the left-sided and overall populations,” Dr. Yoshino concluded.

He also highlighted that the team has undertaken a large-scale biomarker analysis of pre- and posttreatment plasma and tissue samples from patients in the PARADIGM study to identify potential biomarkers of treatment response.

At the plenary session, discussant for this abstract Chiara Cremolini, MD, PhD, professor of medical oncology, Pisa (Italy) University Hospital, commented that “location matters” when it comes to mCRC tumors.

Dr. Cremolini pointed out that the separation of the survival curves at 28 months suggests that the 40% of patients with left-sided tumors who survived only up until that time point receive an equal benefit from panitumumab and bevacizumab.

In contrast, the remainder who survived for longer showed better outcomes with panitumumab.

Overall, she said, in her opinion and based on the findings from other studies, the current results support the use of panitumumab plus mFOLFOX6 as first-line therapy in patients with microsatellite stable RAS wild-type and with BRAF wild-type left-sided mCRC.

Dr. Cremolini emphasized that patients should be warned that, if they opt for doublet chemotherapy plus bevacizumab, they could face a median 3.6-month loss in overall survival, as well as poorer treatment activity.

However, patients with high microsatellite instability should receive immunotherapy up front, she added, while those with BRAF mutations should be given FOLFOX upfront plus bevacizumab, followed by encorafenib plus cetuximab in the case of progression.

Dr. Cremolini ended by noting that there has, as yet, been no prospective comparison of doublet chemotherapy plus an anti-EGFR antibody with triplet chemotherapy plus bevacizumab in this population.

The study was funded by Takeda. Dr. Yoshino has reported relationships with Bayer Yakuhin, Chugai Pharmaceutical, Merck, and MSD. Dr. Eng has reported relationships with Bayer Health, Gilead/Forty Seven, GlaxoSmithKline, Hookipa Biotech, Mirati Therapeutics, Natera, Pfizer, Elevar, Fruquitinib, Merck, and Pfizer.

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

A suspicion from retrospective data has now been confirmed by a prospective clinical trial: Adding panitumumab (Vectibix) to standard chemotherapy in left-sided RAS wild-type metastatic colorectal cancer (mCRC) is more effective than adding bevacizumab (Avastin).

Patients treated with panitumumab alongside chemotherapy saw a 16% improvement in overall survival versus those given bevacizumab after a median follow-up of over 5 years.

The overall survival benefit rose to 18% in those with left-sided tumors.

However, there was no difference in overall survival between the two treatment groups in the small subgroup of patients with right-sided primary tumors.

These findings come from the PARADIGM trial conducted in Japan.

The results were presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.

“If gene testing shows that a tumor is RAS wild-type, the choice of initial treatment with panitumumab plus mFOLFOX6 chemotherapy is superior ... for those people with left-sided tumors,” said lead researcher Takayuki Yoshino, MD, PhD, department of gastrointestinal oncology, National Cancer Center Hospital East, Chiba, Japan, in an ASCO press release.

“It has long been believed that the sequence of metastatic colorectal cancer treatment does not matter as long as patients had access to the drugs at some point, which has now been disproven,” he noted.

Dr. Yoshino added in a press conference about the trial that the results establish “a standard first-line combination regimen for patients with RAS wild-type, left-sided mCRC.”

This is the “longest survival ever reported in a first-line unresectable metastatic colorectal cancer prospective phase 3 trial,” commented Cathy Eng, MD, ASCO Expert in gastrointestinal cancers.

The findings “emphasize the importance of taking into account sidedness, as well as including comprehensive biomarker testing,” she said.

Dr. Eng underlined that this is especially the case for RAS gene status testing, “which is critical for all colorectal cancer patients at the time of diagnosis of metastatic disease.”

These results are of particular relevance in the United States, where the choice between an anti-EGFR or anti-VEGF antibody for the treatment of mCRC has been an area of “controversy” because of the lack of supporting data.

Panitumumab is a human monoclonal antibody that targets EGFR. It was approved in 2006 for use in mCRC by the U.S. Food and Drug Administration and also approved in 2014 for use in combination with FOLFOX for the first-line treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) mCRC, having previously been shown to be equally effective as cetuximab (another EGFR inhibitor) in this population.

In contrast, bevacizumab is a monoclonal antibody that targets the VEGF receptor. It was approved by the FDA for use in mCRC in 2004 in combination with intravenous 5-fluorouracil–based chemotherapy.

Dr. Yoshino explained that around 36% of patients with CRC have metastatic tumors at diagnosis and that adding an anti-EGFR or anti-VEGF antibody to chemotherapy improves overall survival in these patients by up to 30 months.

There has been “accumulating” evidence from retrospective studies suggesting that patients with RAS wild-type mCRC whose primary tumor is on the left side, which accounts for approximately 35% of mCRC cases, have a longer survival benefit with an anti-EGFR antibody, he commented.

Despite this, both antibody types continue to be used in these patients, he added.

PARADIGM was the first prospective trial to compare the two antibody types. Patients were randomized to receive either panitumumab or bevacizumab plus the combination chemotherapy regimen modified FOLFOX6 (mFOLFOX6).

The trial involved 823 Japanese patients with previously untreated wild-type mCRC with unresectable disease. Most patients had left-sided primary tumors (312 of 400 patients in the panitumumab group, and 292 of 402 patients in the bevacizumab group).  

After a median follow-up of 61 months, panitumumab was associated with a significant improvement in overall survival in the overall study population, at a hazard ratio of 0.84 (P = .030, with the boundary of significance set at P < .05).

In addition, panitumumab was associated with a significant improvement in overall survival in the large subgroup of patients with left-sided primary tumors, at 37.9 versus 34.3 months, or a hazard ratio of 0.82 (P = .031).

However, there was no significant difference in overall survival between the two treatment groups in the smaller subgroup of patients with right-sided tumors, at a hazard ratio of 1.09.

Median progression-free survival was no different between the panitumumab and bevacizumab groups, at 13.7 versus 13.2 months in patients with a left-sided tumor and 12.9 versus 12.0 months in the overall cohort.

There was, however, a difference in response rates in left-sided patients between those receiving the two antibodies, at 80.2% with panitumumab versus 68.6% with bevacizumab, and in curative resection rates, at 18.3% and 11.6%, respectively.

These results demonstrate the “superiority of first-line panitumumab versus bevacizumab in combination with mFOLFOX6 in the left-sided and overall populations,” Dr. Yoshino concluded.

He also highlighted that the team has undertaken a large-scale biomarker analysis of pre- and posttreatment plasma and tissue samples from patients in the PARADIGM study to identify potential biomarkers of treatment response.

At the plenary session, discussant for this abstract Chiara Cremolini, MD, PhD, professor of medical oncology, Pisa (Italy) University Hospital, commented that “location matters” when it comes to mCRC tumors.

Dr. Cremolini pointed out that the separation of the survival curves at 28 months suggests that the 40% of patients with left-sided tumors who survived only up until that time point receive an equal benefit from panitumumab and bevacizumab.

In contrast, the remainder who survived for longer showed better outcomes with panitumumab.

Overall, she said, in her opinion and based on the findings from other studies, the current results support the use of panitumumab plus mFOLFOX6 as first-line therapy in patients with microsatellite stable RAS wild-type and with BRAF wild-type left-sided mCRC.

Dr. Cremolini emphasized that patients should be warned that, if they opt for doublet chemotherapy plus bevacizumab, they could face a median 3.6-month loss in overall survival, as well as poorer treatment activity.

However, patients with high microsatellite instability should receive immunotherapy up front, she added, while those with BRAF mutations should be given FOLFOX upfront plus bevacizumab, followed by encorafenib plus cetuximab in the case of progression.

Dr. Cremolini ended by noting that there has, as yet, been no prospective comparison of doublet chemotherapy plus an anti-EGFR antibody with triplet chemotherapy plus bevacizumab in this population.

The study was funded by Takeda. Dr. Yoshino has reported relationships with Bayer Yakuhin, Chugai Pharmaceutical, Merck, and MSD. Dr. Eng has reported relationships with Bayer Health, Gilead/Forty Seven, GlaxoSmithKline, Hookipa Biotech, Mirati Therapeutics, Natera, Pfizer, Elevar, Fruquitinib, Merck, and Pfizer.

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

A suspicion from retrospective data has now been confirmed by a prospective clinical trial: Adding panitumumab (Vectibix) to standard chemotherapy in left-sided RAS wild-type metastatic colorectal cancer (mCRC) is more effective than adding bevacizumab (Avastin).

Patients treated with panitumumab alongside chemotherapy saw a 16% improvement in overall survival versus those given bevacizumab after a median follow-up of over 5 years.

The overall survival benefit rose to 18% in those with left-sided tumors.

However, there was no difference in overall survival between the two treatment groups in the small subgroup of patients with right-sided primary tumors.

These findings come from the PARADIGM trial conducted in Japan.

The results were presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.

“If gene testing shows that a tumor is RAS wild-type, the choice of initial treatment with panitumumab plus mFOLFOX6 chemotherapy is superior ... for those people with left-sided tumors,” said lead researcher Takayuki Yoshino, MD, PhD, department of gastrointestinal oncology, National Cancer Center Hospital East, Chiba, Japan, in an ASCO press release.

“It has long been believed that the sequence of metastatic colorectal cancer treatment does not matter as long as patients had access to the drugs at some point, which has now been disproven,” he noted.

Dr. Yoshino added in a press conference about the trial that the results establish “a standard first-line combination regimen for patients with RAS wild-type, left-sided mCRC.”

This is the “longest survival ever reported in a first-line unresectable metastatic colorectal cancer prospective phase 3 trial,” commented Cathy Eng, MD, ASCO Expert in gastrointestinal cancers.

The findings “emphasize the importance of taking into account sidedness, as well as including comprehensive biomarker testing,” she said.

Dr. Eng underlined that this is especially the case for RAS gene status testing, “which is critical for all colorectal cancer patients at the time of diagnosis of metastatic disease.”

These results are of particular relevance in the United States, where the choice between an anti-EGFR or anti-VEGF antibody for the treatment of mCRC has been an area of “controversy” because of the lack of supporting data.

Panitumumab is a human monoclonal antibody that targets EGFR. It was approved in 2006 for use in mCRC by the U.S. Food and Drug Administration and also approved in 2014 for use in combination with FOLFOX for the first-line treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) mCRC, having previously been shown to be equally effective as cetuximab (another EGFR inhibitor) in this population.

In contrast, bevacizumab is a monoclonal antibody that targets the VEGF receptor. It was approved by the FDA for use in mCRC in 2004 in combination with intravenous 5-fluorouracil–based chemotherapy.

Dr. Yoshino explained that around 36% of patients with CRC have metastatic tumors at diagnosis and that adding an anti-EGFR or anti-VEGF antibody to chemotherapy improves overall survival in these patients by up to 30 months.

There has been “accumulating” evidence from retrospective studies suggesting that patients with RAS wild-type mCRC whose primary tumor is on the left side, which accounts for approximately 35% of mCRC cases, have a longer survival benefit with an anti-EGFR antibody, he commented.

Despite this, both antibody types continue to be used in these patients, he added.

PARADIGM was the first prospective trial to compare the two antibody types. Patients were randomized to receive either panitumumab or bevacizumab plus the combination chemotherapy regimen modified FOLFOX6 (mFOLFOX6).

The trial involved 823 Japanese patients with previously untreated wild-type mCRC with unresectable disease. Most patients had left-sided primary tumors (312 of 400 patients in the panitumumab group, and 292 of 402 patients in the bevacizumab group).  

After a median follow-up of 61 months, panitumumab was associated with a significant improvement in overall survival in the overall study population, at a hazard ratio of 0.84 (P = .030, with the boundary of significance set at P < .05).

In addition, panitumumab was associated with a significant improvement in overall survival in the large subgroup of patients with left-sided primary tumors, at 37.9 versus 34.3 months, or a hazard ratio of 0.82 (P = .031).

However, there was no significant difference in overall survival between the two treatment groups in the smaller subgroup of patients with right-sided tumors, at a hazard ratio of 1.09.

Median progression-free survival was no different between the panitumumab and bevacizumab groups, at 13.7 versus 13.2 months in patients with a left-sided tumor and 12.9 versus 12.0 months in the overall cohort.

There was, however, a difference in response rates in left-sided patients between those receiving the two antibodies, at 80.2% with panitumumab versus 68.6% with bevacizumab, and in curative resection rates, at 18.3% and 11.6%, respectively.

These results demonstrate the “superiority of first-line panitumumab versus bevacizumab in combination with mFOLFOX6 in the left-sided and overall populations,” Dr. Yoshino concluded.

He also highlighted that the team has undertaken a large-scale biomarker analysis of pre- and posttreatment plasma and tissue samples from patients in the PARADIGM study to identify potential biomarkers of treatment response.

At the plenary session, discussant for this abstract Chiara Cremolini, MD, PhD, professor of medical oncology, Pisa (Italy) University Hospital, commented that “location matters” when it comes to mCRC tumors.

Dr. Cremolini pointed out that the separation of the survival curves at 28 months suggests that the 40% of patients with left-sided tumors who survived only up until that time point receive an equal benefit from panitumumab and bevacizumab.

In contrast, the remainder who survived for longer showed better outcomes with panitumumab.

Overall, she said, in her opinion and based on the findings from other studies, the current results support the use of panitumumab plus mFOLFOX6 as first-line therapy in patients with microsatellite stable RAS wild-type and with BRAF wild-type left-sided mCRC.

Dr. Cremolini emphasized that patients should be warned that, if they opt for doublet chemotherapy plus bevacizumab, they could face a median 3.6-month loss in overall survival, as well as poorer treatment activity.

However, patients with high microsatellite instability should receive immunotherapy up front, she added, while those with BRAF mutations should be given FOLFOX upfront plus bevacizumab, followed by encorafenib plus cetuximab in the case of progression.

Dr. Cremolini ended by noting that there has, as yet, been no prospective comparison of doublet chemotherapy plus an anti-EGFR antibody with triplet chemotherapy plus bevacizumab in this population.

The study was funded by Takeda. Dr. Yoshino has reported relationships with Bayer Yakuhin, Chugai Pharmaceutical, Merck, and MSD. Dr. Eng has reported relationships with Bayer Health, Gilead/Forty Seven, GlaxoSmithKline, Hookipa Biotech, Mirati Therapeutics, Natera, Pfizer, Elevar, Fruquitinib, Merck, and Pfizer.

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

Cannabis-based products may control chronic pain as effectively as opioids, but adverse effects are common, and long-term safety remains unknown, according to a new study.

Several other systematic reviews have recently evaluated cannabinoids for treating chronic pain, but the new study’s methodology was “distinct” in “important ways,” leading to “conclusions that differ from other reviews,” according to the authors of the paper published in the Annals of Internal Medicine.

In the new systematic review, synthetic products with high THC:CBD ratios were associated with moderate improvements in pain, whereas plant-based products with comparable THC:CBD ratios offered less relief, said study author Marian S. McDonagh, PharmD, professor of medical informatics and clinical epidemiology, and codirector of the Evidence-based Practice Center at Oregon Health & Science University, Portland, and colleagues.

Specifically, the investigators stratified cannabis-based interventions according to relative content of two key cannabinoids: THC and CBD. Products were sorted into five categories: high THC:CBD ratio (at least 2:1), comparable THC:CBD ratio (less than 2:1 but more than 1:2), low THC:CBD ratio (no more than 1:2), whole-plant cannabis products, and other cannabinoids.

“In preclinical studies, THC and related compounds have demonstrated analgesic properties, although its psychoactive effects and addiction potential may limit its suitability as an analgesic,” the investigators wrote. “CBD and other cannabinoids may also have some analgesic or anti-inflammatory properties and are not believed to be psychoactive or addictive. Given the variation in analgesic effect with THC and CBD, response may differ according to the ratio of THC to CBD in products used to treat pain.”

The final analysis included 18 randomized placebo-controlled trials involving 1,740 individuals and 7 cohort studies involving 13,095 individuals. Most of the studies were short-term, lasting 1-6 months.

Pain was scored on a ten-point scale, with improvements reported as the mean difference from baseline to post treatment. A mean difference in pain score of 0.5-1.0 was considered a “small effect,” an improvement of 1-2 points was considered a “moderate effect,” and an improvement greater than 2 points was considered a “large effect.”
 

Cannabis-based products with relatively high THC:CBD ratios showed efficacy

Synthetic products with high THC:CBD ratios offered moderate pain relief, based on a mean difference in pain score of –1.15 (95% confidence interval, –1.99 to –0.54), whereas products with comparable THC:CBD ratios were associated with a small effect on pain, with a mean difference of –0.52 (95% CI, –0.95 to –0.19).

According to Dr. McDonagh, treatment response rates were on par with response rates for more conventional treatments, “such as opioids or specific antidepressant drugs,” but data for the cannabis-based products are weaker.

“The amount of evidence available for cannabis-related products is very limited for [response rates], and therefore less certain,” Dr. McDonagh said in an interview. “The average reduction in pain severity is also similar to some other treatments, but we do not have studies directly comparing these treatments to draw conclusions.”

Although the cannabis-based products with relatively high and comparable THC:CBD ratios showed efficacy, they were also associated with “moderate to large increased risk for dizziness, sedation, and nausea,” the investigators wrote, noting that evidence was insufficient to characterize other “key adverse event outcomes” that may occur with long-term use, such as “psychosis, cannabis use disorder, and cognitive deficits.”

For products with low THC:CBD ratios, or without reported THC:CBD ratios, data were too scarce to reach any conclusions at all about safety or efficacy, highlighting the sizable knowledge gaps that remain in the area, the authors said.

“The current evidence on cannabis-related products for chronic pain is quite limited,” Dr. McDonagh said in an interview. “Patients with chronic pain should consult with their doctor to discuss which of the many options for treating chronic pain is best for them to start with.”
 

Patients may face resistance when asking about cannabis

According to Kevin F. Boehnke, PhD, and Daniel J. Clauw, MD, of the anesthesiology department and Chronic Pain and Fatigue Research Center at the University of Michigan, Ann Arbor, patients with chronic pain may face resistance, or even risk of being reported, when asking about cannabis-based products.

“Some physicians cite lack of data as rationale for not engaging with patients who wish to use or currently use cannabis,” Dr. Boehnke and Dr. Clauw wrote in an accompanying editorial. “Such practices may reflect consideration of cannabis solely as a drug of misuse (even in the 37 states where medical cannabis is legal) and requirements to refer patients who disclose or test positive for cannabis use to addiction services or decline to refill opioid prescriptions.”

Instead of shutting patients out, Dr. Boehnke and Dr. Clauw suggested clinicians engage in an “open information exchange” with their patients that focuses on “pragmatism, patient experience, known cannabinoid effects, and harm reduction.” In these conversations, the editorialists recommend noting that, “as with other analgesics, some persons will benefit, and others will not.”

They also offered some practical guidance: “Clinicians could suggest using tinctures (effect onset, 15-45 minutes) for breakthrough pain and edibles or capsules (which last about 6-8 hours) for extended relief. ... The scientific literature suggests that CBD doses could start at 5-10 mg twice daily and increase to 40-50 mg daily, whereas THC doses could start at 0.5-3 mg (initially at night) and increase to 30-40 mg/day.”

David Copenhaver, MD, MPH, clinical professor and chief of the division of pain medicine at UC Davis Health, Sacramento, shared a similar clinical mindset for patients choosing between opioids and cannabis-based products, specifically, CBD.

Compared with opioids, “the side-effect profile for CBD is less and the risk of mortality is less,” Dr. Copenhaver said in an interview, pointing out that nobody, to his knowledge, has ever died from an overdose of cannabis alone, and that CBD doses up to 1,000 mg/kg have been safely tolerated in people. “You present that, and most patients will say, ‘You know, I’d like to give this a try.’”

If so, Dr. Copenhaver makes sure patients know about a nonmedical risk: “The risk to the pocketbook.” Unlike opioids, which are covered under most insurance policies, most cannabis-based therapies are self-pay.

Buyers may get what they pay for, Dr. Copenhaver said, since products vary in quality, as do the dispensaries, from “very modest,” to highly sophisticated, with some even using chromatographic datasets to support the purity of their products.

Dr. Copenhaver steers his patients toward these more sophisticated retailers. Their expertise appears to be paying off, he said, not only in relief for patients, but also in market share. “Survival of the most fit will occur in the marketplace based on the results,” he said. “Unfortunately, some of that information doesn’t get percolated out into the literature.”

For investigators to fully uncover what cannabis-based products can do for chronic pain, Dr. Copenhaver said they need to get as “granular” as the leading dispensaries, which may first require recognition of the “very expansive opportunity” that less-studied cannabinoids may provide.

The study was supported by the Agency for Healthcare Research and Quality, U.S. Department of Health & Human Services. The investigators, Dr. Boehnke, Dr. Clauw, and Dr. Copenhaver, disclosed no conflicts of interest.

Cannabis-based products may control chronic pain as effectively as opioids, but adverse effects are common, and long-term safety remains unknown, according to a new study.

Several other systematic reviews have recently evaluated cannabinoids for treating chronic pain, but the new study’s methodology was “distinct” in “important ways,” leading to “conclusions that differ from other reviews,” according to the authors of the paper published in the Annals of Internal Medicine.

In the new systematic review, synthetic products with high THC:CBD ratios were associated with moderate improvements in pain, whereas plant-based products with comparable THC:CBD ratios offered less relief, said study author Marian S. McDonagh, PharmD, professor of medical informatics and clinical epidemiology, and codirector of the Evidence-based Practice Center at Oregon Health & Science University, Portland, and colleagues.

Specifically, the investigators stratified cannabis-based interventions according to relative content of two key cannabinoids: THC and CBD. Products were sorted into five categories: high THC:CBD ratio (at least 2:1), comparable THC:CBD ratio (less than 2:1 but more than 1:2), low THC:CBD ratio (no more than 1:2), whole-plant cannabis products, and other cannabinoids.

“In preclinical studies, THC and related compounds have demonstrated analgesic properties, although its psychoactive effects and addiction potential may limit its suitability as an analgesic,” the investigators wrote. “CBD and other cannabinoids may also have some analgesic or anti-inflammatory properties and are not believed to be psychoactive or addictive. Given the variation in analgesic effect with THC and CBD, response may differ according to the ratio of THC to CBD in products used to treat pain.”

The final analysis included 18 randomized placebo-controlled trials involving 1,740 individuals and 7 cohort studies involving 13,095 individuals. Most of the studies were short-term, lasting 1-6 months.

Pain was scored on a ten-point scale, with improvements reported as the mean difference from baseline to post treatment. A mean difference in pain score of 0.5-1.0 was considered a “small effect,” an improvement of 1-2 points was considered a “moderate effect,” and an improvement greater than 2 points was considered a “large effect.”
 

Cannabis-based products with relatively high THC:CBD ratios showed efficacy

Synthetic products with high THC:CBD ratios offered moderate pain relief, based on a mean difference in pain score of –1.15 (95% confidence interval, –1.99 to –0.54), whereas products with comparable THC:CBD ratios were associated with a small effect on pain, with a mean difference of –0.52 (95% CI, –0.95 to –0.19).

According to Dr. McDonagh, treatment response rates were on par with response rates for more conventional treatments, “such as opioids or specific antidepressant drugs,” but data for the cannabis-based products are weaker.

“The amount of evidence available for cannabis-related products is very limited for [response rates], and therefore less certain,” Dr. McDonagh said in an interview. “The average reduction in pain severity is also similar to some other treatments, but we do not have studies directly comparing these treatments to draw conclusions.”

Although the cannabis-based products with relatively high and comparable THC:CBD ratios showed efficacy, they were also associated with “moderate to large increased risk for dizziness, sedation, and nausea,” the investigators wrote, noting that evidence was insufficient to characterize other “key adverse event outcomes” that may occur with long-term use, such as “psychosis, cannabis use disorder, and cognitive deficits.”

For products with low THC:CBD ratios, or without reported THC:CBD ratios, data were too scarce to reach any conclusions at all about safety or efficacy, highlighting the sizable knowledge gaps that remain in the area, the authors said.

“The current evidence on cannabis-related products for chronic pain is quite limited,” Dr. McDonagh said in an interview. “Patients with chronic pain should consult with their doctor to discuss which of the many options for treating chronic pain is best for them to start with.”
 

Patients may face resistance when asking about cannabis

According to Kevin F. Boehnke, PhD, and Daniel J. Clauw, MD, of the anesthesiology department and Chronic Pain and Fatigue Research Center at the University of Michigan, Ann Arbor, patients with chronic pain may face resistance, or even risk of being reported, when asking about cannabis-based products.

“Some physicians cite lack of data as rationale for not engaging with patients who wish to use or currently use cannabis,” Dr. Boehnke and Dr. Clauw wrote in an accompanying editorial. “Such practices may reflect consideration of cannabis solely as a drug of misuse (even in the 37 states where medical cannabis is legal) and requirements to refer patients who disclose or test positive for cannabis use to addiction services or decline to refill opioid prescriptions.”

Instead of shutting patients out, Dr. Boehnke and Dr. Clauw suggested clinicians engage in an “open information exchange” with their patients that focuses on “pragmatism, patient experience, known cannabinoid effects, and harm reduction.” In these conversations, the editorialists recommend noting that, “as with other analgesics, some persons will benefit, and others will not.”

They also offered some practical guidance: “Clinicians could suggest using tinctures (effect onset, 15-45 minutes) for breakthrough pain and edibles or capsules (which last about 6-8 hours) for extended relief. ... The scientific literature suggests that CBD doses could start at 5-10 mg twice daily and increase to 40-50 mg daily, whereas THC doses could start at 0.5-3 mg (initially at night) and increase to 30-40 mg/day.”

David Copenhaver, MD, MPH, clinical professor and chief of the division of pain medicine at UC Davis Health, Sacramento, shared a similar clinical mindset for patients choosing between opioids and cannabis-based products, specifically, CBD.

Compared with opioids, “the side-effect profile for CBD is less and the risk of mortality is less,” Dr. Copenhaver said in an interview, pointing out that nobody, to his knowledge, has ever died from an overdose of cannabis alone, and that CBD doses up to 1,000 mg/kg have been safely tolerated in people. “You present that, and most patients will say, ‘You know, I’d like to give this a try.’”

If so, Dr. Copenhaver makes sure patients know about a nonmedical risk: “The risk to the pocketbook.” Unlike opioids, which are covered under most insurance policies, most cannabis-based therapies are self-pay.

Buyers may get what they pay for, Dr. Copenhaver said, since products vary in quality, as do the dispensaries, from “very modest,” to highly sophisticated, with some even using chromatographic datasets to support the purity of their products.

Dr. Copenhaver steers his patients toward these more sophisticated retailers. Their expertise appears to be paying off, he said, not only in relief for patients, but also in market share. “Survival of the most fit will occur in the marketplace based on the results,” he said. “Unfortunately, some of that information doesn’t get percolated out into the literature.”

For investigators to fully uncover what cannabis-based products can do for chronic pain, Dr. Copenhaver said they need to get as “granular” as the leading dispensaries, which may first require recognition of the “very expansive opportunity” that less-studied cannabinoids may provide.

The study was supported by the Agency for Healthcare Research and Quality, U.S. Department of Health & Human Services. The investigators, Dr. Boehnke, Dr. Clauw, and Dr. Copenhaver, disclosed no conflicts of interest.

Cannabis-based products may control chronic pain as effectively as opioids, but adverse effects are common, and long-term safety remains unknown, according to a new study.

Several other systematic reviews have recently evaluated cannabinoids for treating chronic pain, but the new study’s methodology was “distinct” in “important ways,” leading to “conclusions that differ from other reviews,” according to the authors of the paper published in the Annals of Internal Medicine.

In the new systematic review, synthetic products with high THC:CBD ratios were associated with moderate improvements in pain, whereas plant-based products with comparable THC:CBD ratios offered less relief, said study author Marian S. McDonagh, PharmD, professor of medical informatics and clinical epidemiology, and codirector of the Evidence-based Practice Center at Oregon Health & Science University, Portland, and colleagues.

Specifically, the investigators stratified cannabis-based interventions according to relative content of two key cannabinoids: THC and CBD. Products were sorted into five categories: high THC:CBD ratio (at least 2:1), comparable THC:CBD ratio (less than 2:1 but more than 1:2), low THC:CBD ratio (no more than 1:2), whole-plant cannabis products, and other cannabinoids.

“In preclinical studies, THC and related compounds have demonstrated analgesic properties, although its psychoactive effects and addiction potential may limit its suitability as an analgesic,” the investigators wrote. “CBD and other cannabinoids may also have some analgesic or anti-inflammatory properties and are not believed to be psychoactive or addictive. Given the variation in analgesic effect with THC and CBD, response may differ according to the ratio of THC to CBD in products used to treat pain.”

The final analysis included 18 randomized placebo-controlled trials involving 1,740 individuals and 7 cohort studies involving 13,095 individuals. Most of the studies were short-term, lasting 1-6 months.

Pain was scored on a ten-point scale, with improvements reported as the mean difference from baseline to post treatment. A mean difference in pain score of 0.5-1.0 was considered a “small effect,” an improvement of 1-2 points was considered a “moderate effect,” and an improvement greater than 2 points was considered a “large effect.”
 

Cannabis-based products with relatively high THC:CBD ratios showed efficacy

Synthetic products with high THC:CBD ratios offered moderate pain relief, based on a mean difference in pain score of –1.15 (95% confidence interval, –1.99 to –0.54), whereas products with comparable THC:CBD ratios were associated with a small effect on pain, with a mean difference of –0.52 (95% CI, –0.95 to –0.19).

According to Dr. McDonagh, treatment response rates were on par with response rates for more conventional treatments, “such as opioids or specific antidepressant drugs,” but data for the cannabis-based products are weaker.

“The amount of evidence available for cannabis-related products is very limited for [response rates], and therefore less certain,” Dr. McDonagh said in an interview. “The average reduction in pain severity is also similar to some other treatments, but we do not have studies directly comparing these treatments to draw conclusions.”

Although the cannabis-based products with relatively high and comparable THC:CBD ratios showed efficacy, they were also associated with “moderate to large increased risk for dizziness, sedation, and nausea,” the investigators wrote, noting that evidence was insufficient to characterize other “key adverse event outcomes” that may occur with long-term use, such as “psychosis, cannabis use disorder, and cognitive deficits.”

For products with low THC:CBD ratios, or without reported THC:CBD ratios, data were too scarce to reach any conclusions at all about safety or efficacy, highlighting the sizable knowledge gaps that remain in the area, the authors said.

“The current evidence on cannabis-related products for chronic pain is quite limited,” Dr. McDonagh said in an interview. “Patients with chronic pain should consult with their doctor to discuss which of the many options for treating chronic pain is best for them to start with.”
 

Patients may face resistance when asking about cannabis

According to Kevin F. Boehnke, PhD, and Daniel J. Clauw, MD, of the anesthesiology department and Chronic Pain and Fatigue Research Center at the University of Michigan, Ann Arbor, patients with chronic pain may face resistance, or even risk of being reported, when asking about cannabis-based products.

“Some physicians cite lack of data as rationale for not engaging with patients who wish to use or currently use cannabis,” Dr. Boehnke and Dr. Clauw wrote in an accompanying editorial. “Such practices may reflect consideration of cannabis solely as a drug of misuse (even in the 37 states where medical cannabis is legal) and requirements to refer patients who disclose or test positive for cannabis use to addiction services or decline to refill opioid prescriptions.”

Instead of shutting patients out, Dr. Boehnke and Dr. Clauw suggested clinicians engage in an “open information exchange” with their patients that focuses on “pragmatism, patient experience, known cannabinoid effects, and harm reduction.” In these conversations, the editorialists recommend noting that, “as with other analgesics, some persons will benefit, and others will not.”

They also offered some practical guidance: “Clinicians could suggest using tinctures (effect onset, 15-45 minutes) for breakthrough pain and edibles or capsules (which last about 6-8 hours) for extended relief. ... The scientific literature suggests that CBD doses could start at 5-10 mg twice daily and increase to 40-50 mg daily, whereas THC doses could start at 0.5-3 mg (initially at night) and increase to 30-40 mg/day.”

David Copenhaver, MD, MPH, clinical professor and chief of the division of pain medicine at UC Davis Health, Sacramento, shared a similar clinical mindset for patients choosing between opioids and cannabis-based products, specifically, CBD.

Compared with opioids, “the side-effect profile for CBD is less and the risk of mortality is less,” Dr. Copenhaver said in an interview, pointing out that nobody, to his knowledge, has ever died from an overdose of cannabis alone, and that CBD doses up to 1,000 mg/kg have been safely tolerated in people. “You present that, and most patients will say, ‘You know, I’d like to give this a try.’”

If so, Dr. Copenhaver makes sure patients know about a nonmedical risk: “The risk to the pocketbook.” Unlike opioids, which are covered under most insurance policies, most cannabis-based therapies are self-pay.

Buyers may get what they pay for, Dr. Copenhaver said, since products vary in quality, as do the dispensaries, from “very modest,” to highly sophisticated, with some even using chromatographic datasets to support the purity of their products.

Dr. Copenhaver steers his patients toward these more sophisticated retailers. Their expertise appears to be paying off, he said, not only in relief for patients, but also in market share. “Survival of the most fit will occur in the marketplace based on the results,” he said. “Unfortunately, some of that information doesn’t get percolated out into the literature.”

For investigators to fully uncover what cannabis-based products can do for chronic pain, Dr. Copenhaver said they need to get as “granular” as the leading dispensaries, which may first require recognition of the “very expansive opportunity” that less-studied cannabinoids may provide.

The study was supported by the Agency for Healthcare Research and Quality, U.S. Department of Health & Human Services. The investigators, Dr. Boehnke, Dr. Clauw, and Dr. Copenhaver, disclosed no conflicts of interest.

NATIONAL HARBOR, MD. -- Over 25 years of clinical research, phase 3 trials of approved disease-modifying therapies (DMTs) for multiple sclerosis (MS) were overwhelmingly made up of White subjects, a new analysis finds, and many studies failed to report percentages of non-White subjects at all. Researchers also found that the websites of multiple major drug manufacturers don’t include any trial data about how medications may affect people of different races and ethnicities.

It’s clear that “non-White participants are significantly underreported and unrepresented,” said study corresponding author and Dell Medical School/The University of Texas at Austin neurologist Leorah Freeman, MD, PhD, in an interview. “Despite the globalization of MS trials over time, we do not see that trials are enrolling more diverse populations.”

The study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers and published in Neurology.

“The lack of diversity in MS research is something that has been sporadically discussed in the past. By conducting this systematic review of MS phase 3 trials, we wanted to put numbers on this issue and review the evidence systematically,” Dr. Freeman said. “By doing so, we hoped to raise awareness about the problem of underreporting and underrepresentation of non-White participants in trials so that we, as a community involved in MS research, can start having the difficult conversations needed for change to occur.”
 

25 years of clinical research

The researchers reviewed 44 phase 3 studies from 1995-2020 that represented 45 trials. “We wanted to capture data from the very first global trials being conducted for the approval of MS DMTs, and the first was published in 1995,” Dr. Freeman said. “We were interested in understanding the impact of trial globalization over a long period of time on diversity of enrollment.”

The studies include trials of mainstays of MS treatment such as interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, diroximel fumarate, fingolimod, natalizumab, and others.

The researchers found that 17 (37.8%) of the trials did not report race or ethnicity, 14 (31.1%) reported race and ethnicity as proportion of White participants only, and 14 (31.1%) reported 2 or more races/ethnicities.

Of the 28 trials with racial breakdowns, the median percentage of White participants was 93.8% (range 78.5-99.6% across 28 studies), 1.9% for Black participants (range 0.1-8.1% across 14 studies), and 0.5% for Asian participants (range 0.1-14.5% across 11 studies).

The studies often failed to account for non-White subjects even though “Black people, in particular, have been shown to have a more severe disease course,” Dr. Freeman said.

A 2022 study of more than 2.6 million Southern California adults finds that prevalence of MS was similar among White and Black people at about 230 per 100,000. “Taken together with previous studies, these findings indicate that the burden of MS in the United States Black community has long been underrecognized,” the researchers wrote.

According to Dr. Freeman, it’s unclear why the studies were so dominated by White subjects. “Lack of awareness about the importance of this information likely explains why this information often goes unreported.”

She highlighted the TOWER (teriflunomide) and DEFINE and CONFIRM (dimethyl fumarate) studies as positive examples. “We noted the inclusion of trial sites in Asia and consequently a higher representation of Asian people with MS in those trials. We felt these studies were examples of how trial globalization can support better representation of underrepresented groups.”

And she noted that the ongoing CHIMES trial is examining the use of ocrelizumab in Black and Hispanic people with MS. “This study was designed in partnership with MS patients and advocacy groups to bridge gaps in clinical trial participation in these communities,” she said. “Innovative strategies were developed to increase participation of Black and Hispanic patients in this trial.”
 

What should happen next?

Going forward, Dr. Freeman said, “MS researchers, DMT manufacturers, sponsors, and publishers need to set better standards for racial and ethnic representation and reporting in trial publications.”

In an interview, epidemiologist Luisa N. Borrell, DDS, PhD, a professor who studies race and medicine at City University of New York, said the new study is valid and useful. She noted that it reflects the findings of a 2022 analysis of more than 20,500 clinical trials in the U.S. from 2000-2020: Only 43% reported racial/ethnic breakdowns, and the subjects were much more White than the population at large.

Possible reasons for the disparity include distrust among possible participants and lack of health literacy, she said, which are both “modifiable issues.”

Dr. Borrell added: “Clinical trials should aim to recruit populations affected by the outcome of interest. That would allow for the intervention to effectively treat those who need it the most. Moreover, the lack of diversity of trials brings issues of generalizability and transportability of the findings.”

No funding is reported. Dr. Freeman and some of the other study authors report various disclosures.

NATIONAL HARBOR, MD. -- Over 25 years of clinical research, phase 3 trials of approved disease-modifying therapies (DMTs) for multiple sclerosis (MS) were overwhelmingly made up of White subjects, a new analysis finds, and many studies failed to report percentages of non-White subjects at all. Researchers also found that the websites of multiple major drug manufacturers don’t include any trial data about how medications may affect people of different races and ethnicities.

It’s clear that “non-White participants are significantly underreported and unrepresented,” said study corresponding author and Dell Medical School/The University of Texas at Austin neurologist Leorah Freeman, MD, PhD, in an interview. “Despite the globalization of MS trials over time, we do not see that trials are enrolling more diverse populations.”

The study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers and published in Neurology.

“The lack of diversity in MS research is something that has been sporadically discussed in the past. By conducting this systematic review of MS phase 3 trials, we wanted to put numbers on this issue and review the evidence systematically,” Dr. Freeman said. “By doing so, we hoped to raise awareness about the problem of underreporting and underrepresentation of non-White participants in trials so that we, as a community involved in MS research, can start having the difficult conversations needed for change to occur.”
 

25 years of clinical research

The researchers reviewed 44 phase 3 studies from 1995-2020 that represented 45 trials. “We wanted to capture data from the very first global trials being conducted for the approval of MS DMTs, and the first was published in 1995,” Dr. Freeman said. “We were interested in understanding the impact of trial globalization over a long period of time on diversity of enrollment.”

The studies include trials of mainstays of MS treatment such as interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, diroximel fumarate, fingolimod, natalizumab, and others.

The researchers found that 17 (37.8%) of the trials did not report race or ethnicity, 14 (31.1%) reported race and ethnicity as proportion of White participants only, and 14 (31.1%) reported 2 or more races/ethnicities.

Of the 28 trials with racial breakdowns, the median percentage of White participants was 93.8% (range 78.5-99.6% across 28 studies), 1.9% for Black participants (range 0.1-8.1% across 14 studies), and 0.5% for Asian participants (range 0.1-14.5% across 11 studies).

The studies often failed to account for non-White subjects even though “Black people, in particular, have been shown to have a more severe disease course,” Dr. Freeman said.

A 2022 study of more than 2.6 million Southern California adults finds that prevalence of MS was similar among White and Black people at about 230 per 100,000. “Taken together with previous studies, these findings indicate that the burden of MS in the United States Black community has long been underrecognized,” the researchers wrote.

According to Dr. Freeman, it’s unclear why the studies were so dominated by White subjects. “Lack of awareness about the importance of this information likely explains why this information often goes unreported.”

She highlighted the TOWER (teriflunomide) and DEFINE and CONFIRM (dimethyl fumarate) studies as positive examples. “We noted the inclusion of trial sites in Asia and consequently a higher representation of Asian people with MS in those trials. We felt these studies were examples of how trial globalization can support better representation of underrepresented groups.”

And she noted that the ongoing CHIMES trial is examining the use of ocrelizumab in Black and Hispanic people with MS. “This study was designed in partnership with MS patients and advocacy groups to bridge gaps in clinical trial participation in these communities,” she said. “Innovative strategies were developed to increase participation of Black and Hispanic patients in this trial.”
 

What should happen next?

Going forward, Dr. Freeman said, “MS researchers, DMT manufacturers, sponsors, and publishers need to set better standards for racial and ethnic representation and reporting in trial publications.”

In an interview, epidemiologist Luisa N. Borrell, DDS, PhD, a professor who studies race and medicine at City University of New York, said the new study is valid and useful. She noted that it reflects the findings of a 2022 analysis of more than 20,500 clinical trials in the U.S. from 2000-2020: Only 43% reported racial/ethnic breakdowns, and the subjects were much more White than the population at large.

Possible reasons for the disparity include distrust among possible participants and lack of health literacy, she said, which are both “modifiable issues.”

Dr. Borrell added: “Clinical trials should aim to recruit populations affected by the outcome of interest. That would allow for the intervention to effectively treat those who need it the most. Moreover, the lack of diversity of trials brings issues of generalizability and transportability of the findings.”

No funding is reported. Dr. Freeman and some of the other study authors report various disclosures.

NATIONAL HARBOR, MD. -- Over 25 years of clinical research, phase 3 trials of approved disease-modifying therapies (DMTs) for multiple sclerosis (MS) were overwhelmingly made up of White subjects, a new analysis finds, and many studies failed to report percentages of non-White subjects at all. Researchers also found that the websites of multiple major drug manufacturers don’t include any trial data about how medications may affect people of different races and ethnicities.

It’s clear that “non-White participants are significantly underreported and unrepresented,” said study corresponding author and Dell Medical School/The University of Texas at Austin neurologist Leorah Freeman, MD, PhD, in an interview. “Despite the globalization of MS trials over time, we do not see that trials are enrolling more diverse populations.”

The study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers and published in Neurology.

“The lack of diversity in MS research is something that has been sporadically discussed in the past. By conducting this systematic review of MS phase 3 trials, we wanted to put numbers on this issue and review the evidence systematically,” Dr. Freeman said. “By doing so, we hoped to raise awareness about the problem of underreporting and underrepresentation of non-White participants in trials so that we, as a community involved in MS research, can start having the difficult conversations needed for change to occur.”
 

25 years of clinical research

The researchers reviewed 44 phase 3 studies from 1995-2020 that represented 45 trials. “We wanted to capture data from the very first global trials being conducted for the approval of MS DMTs, and the first was published in 1995,” Dr. Freeman said. “We were interested in understanding the impact of trial globalization over a long period of time on diversity of enrollment.”

The studies include trials of mainstays of MS treatment such as interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, diroximel fumarate, fingolimod, natalizumab, and others.

The researchers found that 17 (37.8%) of the trials did not report race or ethnicity, 14 (31.1%) reported race and ethnicity as proportion of White participants only, and 14 (31.1%) reported 2 or more races/ethnicities.

Of the 28 trials with racial breakdowns, the median percentage of White participants was 93.8% (range 78.5-99.6% across 28 studies), 1.9% for Black participants (range 0.1-8.1% across 14 studies), and 0.5% for Asian participants (range 0.1-14.5% across 11 studies).

The studies often failed to account for non-White subjects even though “Black people, in particular, have been shown to have a more severe disease course,” Dr. Freeman said.

A 2022 study of more than 2.6 million Southern California adults finds that prevalence of MS was similar among White and Black people at about 230 per 100,000. “Taken together with previous studies, these findings indicate that the burden of MS in the United States Black community has long been underrecognized,” the researchers wrote.

According to Dr. Freeman, it’s unclear why the studies were so dominated by White subjects. “Lack of awareness about the importance of this information likely explains why this information often goes unreported.”

She highlighted the TOWER (teriflunomide) and DEFINE and CONFIRM (dimethyl fumarate) studies as positive examples. “We noted the inclusion of trial sites in Asia and consequently a higher representation of Asian people with MS in those trials. We felt these studies were examples of how trial globalization can support better representation of underrepresented groups.”

And she noted that the ongoing CHIMES trial is examining the use of ocrelizumab in Black and Hispanic people with MS. “This study was designed in partnership with MS patients and advocacy groups to bridge gaps in clinical trial participation in these communities,” she said. “Innovative strategies were developed to increase participation of Black and Hispanic patients in this trial.”
 

What should happen next?

Going forward, Dr. Freeman said, “MS researchers, DMT manufacturers, sponsors, and publishers need to set better standards for racial and ethnic representation and reporting in trial publications.”

In an interview, epidemiologist Luisa N. Borrell, DDS, PhD, a professor who studies race and medicine at City University of New York, said the new study is valid and useful. She noted that it reflects the findings of a 2022 analysis of more than 20,500 clinical trials in the U.S. from 2000-2020: Only 43% reported racial/ethnic breakdowns, and the subjects were much more White than the population at large.

Possible reasons for the disparity include distrust among possible participants and lack of health literacy, she said, which are both “modifiable issues.”

Dr. Borrell added: “Clinical trials should aim to recruit populations affected by the outcome of interest. That would allow for the intervention to effectively treat those who need it the most. Moreover, the lack of diversity of trials brings issues of generalizability and transportability of the findings.”

No funding is reported. Dr. Freeman and some of the other study authors report various disclosures.

CHICAGO -- High-dose ifosfamide has shown superior survival benefit over three other chemotherapy regimens for patients with recurring or refractory primary Ewing sarcoma (RR-ES) in the practice-changing rEECur trial.

This international trial is the first randomized head-to-head comparison of commonly used chemotherapy regimens in patients with the rare and deadly disease.

The study results are expected to change the standard of care and be practice-changing on a global scale, commented Julie Gralow, MD, chief medical officer at the annual meeting of the American Society of Clinical Oncology, where the results were presented June 5 during a plenary session.

Ewing sarcoma is a very rare cancer of the bone and soft tissue that mainly affects children and young adults, particularly in the second decade of life, explained lead author Martin McCabe, MD, clinical senior lecturer in pediatric, teenage, and young adult cancer at the University of Manchester (England). The incidence rate is 3.2 per million people under age 25 years, he said.

Dr. Gralow explained in an interview that treatment of Ewing sarcoma differs from one cancer center to another. Several different chemotherapy regimens are being used, all based on single-arm trials, with no consensus on which is best.

This international trial set out to answer that question and compared four different regimens. Participating centers were “able to solve a question by partnering, coming together, and even in a very rare population get enough patients to define the winner,” she said.

Earlier findings from this trial had shown that ifosfamide had improved survival, compared with gemcitabine and docetaxel and compared with irinotecan and temozolomide.

At the meeting, results of the comparison of ifosfamide versus a combination of topotecan and cyclophosphamide (TC) were presented.

Median overall survival was 15.4 versus 10.5 months with ifosfamide versus TC, and 1-year overall survival was 55% versus 45%, respectively, for a 94% probability that ifosfamide is better than TC for overall survival, Dr. McCabe reported.  

Median event-free survival was 16.8 months in 73 patients in the ifosfamide group versus 10.4 months for 73 patients in the TC group. Six-month event-free survival was 47% versus 37%, respectively. “Given the observed data, there is a 96% probability that ifosfamide is better than TC for event-free survival,” he said.   

High-dose ifosfamide prolonged median event-free survival by 5.7 months, compared with 3.7 months for TC.

Notably, greater event-free survival and overall survival differences were observed for patients under age 14 years, compared with those aged 14 and older, Dr. McCabe noted.

As for toxicity, similar rates of neutropenic infections were seen in the two groups, but more severe renal and brain toxicity were observed with ifosfamide, with both occurring in less than 10% of patients, he said.

Despite the practice-changing results, Dr. McCabe stressed that the “differences [between treatments] are quite small, and what we actually need is better drugs to cure more patients.”

The rEEcur trial is continuing to recruit patients to the ifosfamide group, and a fifth chemotherapy group of carboplatin and etoposide has been added.

Later this year, investigators also plan to add a new group with a molecular targeted therapeutic.
 

Important global collaboration

Dr. Gralow emphasized the global collaboration that was behind this trial, which set out to answer important questions about how best to treat a rare disease. “In this really terrific collaboration ... there was an agreement to test all these regimens that are commonly used, and so we now have data on efficacy and toxicity.”

“It’s a really important concept in rare diseases: If we all work together, we actually can study them and get answers,” she said.

“I think pediatricians and oncologists are [now] better able to talk about the risks and benefits [of the regimens],” she added.

Vicki L. Keedy, MD, an ASCO Expert in sarcoma, concurred. The findings from the rEECur trial “could help physicians talk with patients and their families about the likelihood of response, survival, and toxicity for each regimen available for relapsed Ewing sarcoma based on objective, randomized data,” she commented in an ASCO press release. 

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

CHICAGO -- High-dose ifosfamide has shown superior survival benefit over three other chemotherapy regimens for patients with recurring or refractory primary Ewing sarcoma (RR-ES) in the practice-changing rEECur trial.

This international trial is the first randomized head-to-head comparison of commonly used chemotherapy regimens in patients with the rare and deadly disease.

The study results are expected to change the standard of care and be practice-changing on a global scale, commented Julie Gralow, MD, chief medical officer at the annual meeting of the American Society of Clinical Oncology, where the results were presented June 5 during a plenary session.

Ewing sarcoma is a very rare cancer of the bone and soft tissue that mainly affects children and young adults, particularly in the second decade of life, explained lead author Martin McCabe, MD, clinical senior lecturer in pediatric, teenage, and young adult cancer at the University of Manchester (England). The incidence rate is 3.2 per million people under age 25 years, he said.

Dr. Gralow explained in an interview that treatment of Ewing sarcoma differs from one cancer center to another. Several different chemotherapy regimens are being used, all based on single-arm trials, with no consensus on which is best.

This international trial set out to answer that question and compared four different regimens. Participating centers were “able to solve a question by partnering, coming together, and even in a very rare population get enough patients to define the winner,” she said.

Earlier findings from this trial had shown that ifosfamide had improved survival, compared with gemcitabine and docetaxel and compared with irinotecan and temozolomide.

At the meeting, results of the comparison of ifosfamide versus a combination of topotecan and cyclophosphamide (TC) were presented.

Median overall survival was 15.4 versus 10.5 months with ifosfamide versus TC, and 1-year overall survival was 55% versus 45%, respectively, for a 94% probability that ifosfamide is better than TC for overall survival, Dr. McCabe reported.  

Median event-free survival was 16.8 months in 73 patients in the ifosfamide group versus 10.4 months for 73 patients in the TC group. Six-month event-free survival was 47% versus 37%, respectively. “Given the observed data, there is a 96% probability that ifosfamide is better than TC for event-free survival,” he said.   

High-dose ifosfamide prolonged median event-free survival by 5.7 months, compared with 3.7 months for TC.

Notably, greater event-free survival and overall survival differences were observed for patients under age 14 years, compared with those aged 14 and older, Dr. McCabe noted.

As for toxicity, similar rates of neutropenic infections were seen in the two groups, but more severe renal and brain toxicity were observed with ifosfamide, with both occurring in less than 10% of patients, he said.

Despite the practice-changing results, Dr. McCabe stressed that the “differences [between treatments] are quite small, and what we actually need is better drugs to cure more patients.”

The rEEcur trial is continuing to recruit patients to the ifosfamide group, and a fifth chemotherapy group of carboplatin and etoposide has been added.

Later this year, investigators also plan to add a new group with a molecular targeted therapeutic.
 

Important global collaboration

Dr. Gralow emphasized the global collaboration that was behind this trial, which set out to answer important questions about how best to treat a rare disease. “In this really terrific collaboration ... there was an agreement to test all these regimens that are commonly used, and so we now have data on efficacy and toxicity.”

“It’s a really important concept in rare diseases: If we all work together, we actually can study them and get answers,” she said.

“I think pediatricians and oncologists are [now] better able to talk about the risks and benefits [of the regimens],” she added.

Vicki L. Keedy, MD, an ASCO Expert in sarcoma, concurred. The findings from the rEECur trial “could help physicians talk with patients and their families about the likelihood of response, survival, and toxicity for each regimen available for relapsed Ewing sarcoma based on objective, randomized data,” she commented in an ASCO press release. 

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

CHICAGO -- High-dose ifosfamide has shown superior survival benefit over three other chemotherapy regimens for patients with recurring or refractory primary Ewing sarcoma (RR-ES) in the practice-changing rEECur trial.

This international trial is the first randomized head-to-head comparison of commonly used chemotherapy regimens in patients with the rare and deadly disease.

The study results are expected to change the standard of care and be practice-changing on a global scale, commented Julie Gralow, MD, chief medical officer at the annual meeting of the American Society of Clinical Oncology, where the results were presented June 5 during a plenary session.

Ewing sarcoma is a very rare cancer of the bone and soft tissue that mainly affects children and young adults, particularly in the second decade of life, explained lead author Martin McCabe, MD, clinical senior lecturer in pediatric, teenage, and young adult cancer at the University of Manchester (England). The incidence rate is 3.2 per million people under age 25 years, he said.

Dr. Gralow explained in an interview that treatment of Ewing sarcoma differs from one cancer center to another. Several different chemotherapy regimens are being used, all based on single-arm trials, with no consensus on which is best.

This international trial set out to answer that question and compared four different regimens. Participating centers were “able to solve a question by partnering, coming together, and even in a very rare population get enough patients to define the winner,” she said.

Earlier findings from this trial had shown that ifosfamide had improved survival, compared with gemcitabine and docetaxel and compared with irinotecan and temozolomide.

At the meeting, results of the comparison of ifosfamide versus a combination of topotecan and cyclophosphamide (TC) were presented.

Median overall survival was 15.4 versus 10.5 months with ifosfamide versus TC, and 1-year overall survival was 55% versus 45%, respectively, for a 94% probability that ifosfamide is better than TC for overall survival, Dr. McCabe reported.  

Median event-free survival was 16.8 months in 73 patients in the ifosfamide group versus 10.4 months for 73 patients in the TC group. Six-month event-free survival was 47% versus 37%, respectively. “Given the observed data, there is a 96% probability that ifosfamide is better than TC for event-free survival,” he said.   

High-dose ifosfamide prolonged median event-free survival by 5.7 months, compared with 3.7 months for TC.

Notably, greater event-free survival and overall survival differences were observed for patients under age 14 years, compared with those aged 14 and older, Dr. McCabe noted.

As for toxicity, similar rates of neutropenic infections were seen in the two groups, but more severe renal and brain toxicity were observed with ifosfamide, with both occurring in less than 10% of patients, he said.

Despite the practice-changing results, Dr. McCabe stressed that the “differences [between treatments] are quite small, and what we actually need is better drugs to cure more patients.”

The rEEcur trial is continuing to recruit patients to the ifosfamide group, and a fifth chemotherapy group of carboplatin and etoposide has been added.

Later this year, investigators also plan to add a new group with a molecular targeted therapeutic.
 

Important global collaboration

Dr. Gralow emphasized the global collaboration that was behind this trial, which set out to answer important questions about how best to treat a rare disease. “In this really terrific collaboration ... there was an agreement to test all these regimens that are commonly used, and so we now have data on efficacy and toxicity.”

“It’s a really important concept in rare diseases: If we all work together, we actually can study them and get answers,” she said.

“I think pediatricians and oncologists are [now] better able to talk about the risks and benefits [of the regimens],” she added.

Vicki L. Keedy, MD, an ASCO Expert in sarcoma, concurred. The findings from the rEECur trial “could help physicians talk with patients and their families about the likelihood of response, survival, and toxicity for each regimen available for relapsed Ewing sarcoma based on objective, randomized data,” she commented in an ASCO press release. 

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

It happens quickly: A child on the autism spectrum bolts from supervision and disappears – an emergency called “autism elopement.” While any child can wander off, children on the autism spectrum face particular risks. These include the lure of water and the risk of drowning.

Some youngsters on the spectrum will follow this strong attraction to water and head for a nearby pond, river, or swimming pool. Such circumstances have made drowning a leading cause of death for these missing youths.

Autism elopement can happen any time. Summer can be especially dangerous. When the weather warms, the risk of drowning death rises, says Lori McIlwain, cofounder of the National Autism Association.

“The fatality risk is higher in May, June, July for that child to exit the setting unnoticed, especially if there’s an outdoor gathering and then they go directly to water,” Ms. McIlwain says. For instance, she says children can dart away during outdoor play, barbecues, gatherings, and other activities. Or they might wander off while vacationing near a beach or hotel pool.
 

Autism elopement

Many people don’t know about this risk, including some families with youngsters on the autism spectrum. The National Center for Missing and Exploited Children is working to change that – and find solutions.

About 12 years ago, “we started noticing a very disturbing trend that children with autism were going missing and they were having grave results,” says John Bischoff, vice president of the Center’s Missing Children Division.

The Center analyzed a decade of data on accidental deaths of children on the autism spectrum. Drowning was the #1 cause, accounting for 84% of those deaths.

In 2012, researchers reported on autism and wandering in the journal Pediatrics. They analyzed answers from about 1,000 families to an online survey on the topic. Parents who had children on the spectrum and children not on the spectrum responded. Nearly half of the parents said their child with autism had tried to wander off after age 4, and 26% had gone missing long enough to cause concern.

“Of those who went missing, 24% were in danger of drowning and 65% were in danger of traffic injury,” the researchers wrote. Children on the spectrum might also be drawn to traffic signs, highways, fire trucks, and trains.

In comparison, brothers and sisters of all ages who were not on the spectrum were much less likely to have wandered off.
 

Seeking a quiet place

It’s not entirely clear why children with autism are so drawn to water, Ms. McIlwain says. But there are some clues.

“What we see is that these children exit settings that are usually bothersome,” Ms. McIlwain says. “[Those settings are] loud, with a high amount of stimuli or stress or commotion, and they go to a quiet place, usually water in a quiet area. It’s calm. It’s peaceful.”

Water isn’t the only dangerous draw. When autism elopement happens, “they also go to the woods, they go to abandoned vehicles,” she says. “So any quiet thing is usually where they will head.”
 

A family’s loss

Beth Dilg, a mother in Maryland, lost her 7-year-old daughter, Savannah Martin, who was on the autism spectrum, to drowning in 2011. Ms. Dilg had been living in Oklahoma and raising her three children alone after separating from her husband. On a chilly February day, Savannah and her 2-year-old brother left their house after Ms. Dilg had asked her 11-year-old son to keep watch while she went into the bathroom for a few minutes.

When Ms. Dilg realized the two younger kids had left, she searched the property frantically. She shouted Savannah’s name repeatedly, but the child, who had limited language, didn’t come when called. “I feel like she knew what her name was,” Ms. Dilg says, “but it wasn’t like you’d call her name and she’d come to you.”

Ms. Dilg ran to a pond near her property after her 11-year-old son said that the two siblings were in the water. Ms. Dilg entered the water and grabbed her toddler, who had survived after having been kept afloat by his bicycle helmet. But when Ms. Dilg reached Savannah, she was already unresponsive. A neighbor helped pull the children out.

It can happen in any family. Even when a parent takes precautions, a child can slip out in a moment, perhaps while the parent is asleep or taking care of personal needs or if the child is at school or elsewhere.

“It’s unrealistic to say that you’d never take your eyes off your kid,” Ms. Dilg says.

She had tried to protect Savannah by starting her on swimming lessons, installing high locks on the doors, and trying to teach her about how to stay safe.

Still, children can be skillful in finding ways to escape, Ms. Dilg says. “These kids with autism are so smart. They may not be verbal, but they have this level of intelligence,” she says. “You always have to stay a step ahead of them.”

Ms. Dilg has been a longtime volunteer with Team HOPE, a peer support group with the National Center for Missing and Exploited Children. She offers emotional support to parents whose children are missing or who have died, including the parents of youngsters with autism who have drowned.
 

Teaching first responders

If a child on the autism spectrum goes missing, searching for them can be complicated by their condition. For instance, some children cannot speak or aren’t able to respond to searchers calling their name. The National Center for Missing and Exploited Children offers training to law enforcement and provides search protocols for first responders.

The center has drawn on expertise from Laurie Reyes, an officer with Maryland’s Montgomery County Police Department. In 2005, Ms. Reyes created a special unit within the department to focus on safety for people at risk for wandering. They have conditions that include autism/intellectual and developmental disabilities, as well as Alzheimer’s and other forms of dementia.

“We have a culture of awareness here,” Ms. Reyes says. All Montgomery County recruits and officers receive training in how to interact with those on the autism spectrum, who may not respond to police commands. Police also learn how to search, including immediately checking bodies of water. “We’ve had many times where we’ve located individuals in bodies of water,” Ms. Reyes says.

Don’t wait to call 911. When a child goes missing, time matters. Ms. Reyes advises families not to search on their own. “Call 911 right away,” she says.
 

Top safety tips to help prevent autism elopement

Use these tips to help keep kids on the autism spectrum safe and prevent drownings.

Secure your home. Use window and door alarms to alert you if a door or window becomes ajar. “Those door alarms are essential,” Ms. McIlwain says.

You can buy alarms online or get them free from the National Autism Association through its Big Red Safety Box program.

You can also buy portable door alarms for travel and arrange to have door alarms at your child’s school.

Ms. McIlwain advises securing the home with adequate locks and using baby monitors. Installing visual prompts, such as a stop sign on the door, might also cue a child not to leave.

Use personal identification. Ms. McIlwain says that children with autism must wear identification, such as a wristband, that includes their name, autism diagnosis, and the name and phone number of a contact person.

If children won’t wear a wristband, IDs on shoelaces are an option, she says. But parents should be aware that kids might leave without shoes or take them off before entering water.

Parents can also weigh the pros and cons of using tracking and locater devices, Ms. McIlwain says.

Identify triggers. “What’s going to make the child want to leave the setting? Is it noise? Is it a certain thing that they fear?” Ms. McIlwain says. “There’s always a reason.”

If parents can identify particular triggers, they can use calming techniques, for example, or provide headphones to counteract bothersome noises.

Teach safety skills, such as swimming lessons. Swimming lessons are important, Ms. McIlwain says. However, children with autism are often bothered by noise and commotion. So a regular swim class might not work for them.

Instead, Ms. McIlwain encourages parents to ask their local YMCA about special-needs swimming lessons or to search for such lessons online. What usually turns out to be best is to give the child a few private swimming lessons “with somebody who understands autism.”

For the child’s final lesson, they should swim fully clothed and with shoes on, Ms. McIlwain says. “A lot of our kids go straight into water fully clothed, and they just need to be able to be familiar with how that feels and the weight of that and be able to swim like that as well.”

If a child is drawn to water, discuss a scheduled time to go so that the youngster can wait, Ms. McIlwain says. “They can see that they’re going to get that water time. They’re going to be able to go to that place. They’re going to wait instead of trying to go on their own.”

Keep a close watch and team up. “When there is a family gathering or an outdoor barbecue, a lot of times, we all think, there are more adults here, so there are going to be more eyes on all the kids. And that always ends up being opposite, right?” Ms. McIlwain says.

Be specific about who is monitoring the child’s safety.

“We encourage parents to do the ‘Tag, you’re it’ game with one another. So you basically tag an adult who is responsible for keeping an eye on that child for a period of time so that there’s always supervision.”
 

Be prepared

There are a few things you can do now to be ready in case your child slips away. These measures may help find the child quickly.

Take photos today. Keep a full-length shot and a head shot of your child and store them electronically. If your child wanders away, you can immediately send the images to law enforcement to help them search.

Write a 911 script. Have this document ready in case your child wanders. It describes, among other things, points of interest that might draw your child, as well as locations of nearby bodies of water. By having it all written down, you’ll be able to share the information quickly with first responders. The Montgomery County Police Department has a “Wandering 911 Script” that you can download and use.

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

It happens quickly: A child on the autism spectrum bolts from supervision and disappears – an emergency called “autism elopement.” While any child can wander off, children on the autism spectrum face particular risks. These include the lure of water and the risk of drowning.

Some youngsters on the spectrum will follow this strong attraction to water and head for a nearby pond, river, or swimming pool. Such circumstances have made drowning a leading cause of death for these missing youths.

Autism elopement can happen any time. Summer can be especially dangerous. When the weather warms, the risk of drowning death rises, says Lori McIlwain, cofounder of the National Autism Association.

“The fatality risk is higher in May, June, July for that child to exit the setting unnoticed, especially if there’s an outdoor gathering and then they go directly to water,” Ms. McIlwain says. For instance, she says children can dart away during outdoor play, barbecues, gatherings, and other activities. Or they might wander off while vacationing near a beach or hotel pool.
 

Autism elopement

Many people don’t know about this risk, including some families with youngsters on the autism spectrum. The National Center for Missing and Exploited Children is working to change that – and find solutions.

About 12 years ago, “we started noticing a very disturbing trend that children with autism were going missing and they were having grave results,” says John Bischoff, vice president of the Center’s Missing Children Division.

The Center analyzed a decade of data on accidental deaths of children on the autism spectrum. Drowning was the #1 cause, accounting for 84% of those deaths.

In 2012, researchers reported on autism and wandering in the journal Pediatrics. They analyzed answers from about 1,000 families to an online survey on the topic. Parents who had children on the spectrum and children not on the spectrum responded. Nearly half of the parents said their child with autism had tried to wander off after age 4, and 26% had gone missing long enough to cause concern.

“Of those who went missing, 24% were in danger of drowning and 65% were in danger of traffic injury,” the researchers wrote. Children on the spectrum might also be drawn to traffic signs, highways, fire trucks, and trains.

In comparison, brothers and sisters of all ages who were not on the spectrum were much less likely to have wandered off.
 

Seeking a quiet place

It’s not entirely clear why children with autism are so drawn to water, Ms. McIlwain says. But there are some clues.

“What we see is that these children exit settings that are usually bothersome,” Ms. McIlwain says. “[Those settings are] loud, with a high amount of stimuli or stress or commotion, and they go to a quiet place, usually water in a quiet area. It’s calm. It’s peaceful.”

Water isn’t the only dangerous draw. When autism elopement happens, “they also go to the woods, they go to abandoned vehicles,” she says. “So any quiet thing is usually where they will head.”
 

A family’s loss

Beth Dilg, a mother in Maryland, lost her 7-year-old daughter, Savannah Martin, who was on the autism spectrum, to drowning in 2011. Ms. Dilg had been living in Oklahoma and raising her three children alone after separating from her husband. On a chilly February day, Savannah and her 2-year-old brother left their house after Ms. Dilg had asked her 11-year-old son to keep watch while she went into the bathroom for a few minutes.

When Ms. Dilg realized the two younger kids had left, she searched the property frantically. She shouted Savannah’s name repeatedly, but the child, who had limited language, didn’t come when called. “I feel like she knew what her name was,” Ms. Dilg says, “but it wasn’t like you’d call her name and she’d come to you.”

Ms. Dilg ran to a pond near her property after her 11-year-old son said that the two siblings were in the water. Ms. Dilg entered the water and grabbed her toddler, who had survived after having been kept afloat by his bicycle helmet. But when Ms. Dilg reached Savannah, she was already unresponsive. A neighbor helped pull the children out.

It can happen in any family. Even when a parent takes precautions, a child can slip out in a moment, perhaps while the parent is asleep or taking care of personal needs or if the child is at school or elsewhere.

“It’s unrealistic to say that you’d never take your eyes off your kid,” Ms. Dilg says.

She had tried to protect Savannah by starting her on swimming lessons, installing high locks on the doors, and trying to teach her about how to stay safe.

Still, children can be skillful in finding ways to escape, Ms. Dilg says. “These kids with autism are so smart. They may not be verbal, but they have this level of intelligence,” she says. “You always have to stay a step ahead of them.”

Ms. Dilg has been a longtime volunteer with Team HOPE, a peer support group with the National Center for Missing and Exploited Children. She offers emotional support to parents whose children are missing or who have died, including the parents of youngsters with autism who have drowned.
 

Teaching first responders

If a child on the autism spectrum goes missing, searching for them can be complicated by their condition. For instance, some children cannot speak or aren’t able to respond to searchers calling their name. The National Center for Missing and Exploited Children offers training to law enforcement and provides search protocols for first responders.

The center has drawn on expertise from Laurie Reyes, an officer with Maryland’s Montgomery County Police Department. In 2005, Ms. Reyes created a special unit within the department to focus on safety for people at risk for wandering. They have conditions that include autism/intellectual and developmental disabilities, as well as Alzheimer’s and other forms of dementia.

“We have a culture of awareness here,” Ms. Reyes says. All Montgomery County recruits and officers receive training in how to interact with those on the autism spectrum, who may not respond to police commands. Police also learn how to search, including immediately checking bodies of water. “We’ve had many times where we’ve located individuals in bodies of water,” Ms. Reyes says.

Don’t wait to call 911. When a child goes missing, time matters. Ms. Reyes advises families not to search on their own. “Call 911 right away,” she says.
 

Top safety tips to help prevent autism elopement

Use these tips to help keep kids on the autism spectrum safe and prevent drownings.

Secure your home. Use window and door alarms to alert you if a door or window becomes ajar. “Those door alarms are essential,” Ms. McIlwain says.

You can buy alarms online or get them free from the National Autism Association through its Big Red Safety Box program.

You can also buy portable door alarms for travel and arrange to have door alarms at your child’s school.

Ms. McIlwain advises securing the home with adequate locks and using baby monitors. Installing visual prompts, such as a stop sign on the door, might also cue a child not to leave.

Use personal identification. Ms. McIlwain says that children with autism must wear identification, such as a wristband, that includes their name, autism diagnosis, and the name and phone number of a contact person.

If children won’t wear a wristband, IDs on shoelaces are an option, she says. But parents should be aware that kids might leave without shoes or take them off before entering water.

Parents can also weigh the pros and cons of using tracking and locater devices, Ms. McIlwain says.

Identify triggers. “What’s going to make the child want to leave the setting? Is it noise? Is it a certain thing that they fear?” Ms. McIlwain says. “There’s always a reason.”

If parents can identify particular triggers, they can use calming techniques, for example, or provide headphones to counteract bothersome noises.

Teach safety skills, such as swimming lessons. Swimming lessons are important, Ms. McIlwain says. However, children with autism are often bothered by noise and commotion. So a regular swim class might not work for them.

Instead, Ms. McIlwain encourages parents to ask their local YMCA about special-needs swimming lessons or to search for such lessons online. What usually turns out to be best is to give the child a few private swimming lessons “with somebody who understands autism.”

For the child’s final lesson, they should swim fully clothed and with shoes on, Ms. McIlwain says. “A lot of our kids go straight into water fully clothed, and they just need to be able to be familiar with how that feels and the weight of that and be able to swim like that as well.”

If a child is drawn to water, discuss a scheduled time to go so that the youngster can wait, Ms. McIlwain says. “They can see that they’re going to get that water time. They’re going to be able to go to that place. They’re going to wait instead of trying to go on their own.”

Keep a close watch and team up. “When there is a family gathering or an outdoor barbecue, a lot of times, we all think, there are more adults here, so there are going to be more eyes on all the kids. And that always ends up being opposite, right?” Ms. McIlwain says.

Be specific about who is monitoring the child’s safety.

“We encourage parents to do the ‘Tag, you’re it’ game with one another. So you basically tag an adult who is responsible for keeping an eye on that child for a period of time so that there’s always supervision.”
 

Be prepared

There are a few things you can do now to be ready in case your child slips away. These measures may help find the child quickly.

Take photos today. Keep a full-length shot and a head shot of your child and store them electronically. If your child wanders away, you can immediately send the images to law enforcement to help them search.

Write a 911 script. Have this document ready in case your child wanders. It describes, among other things, points of interest that might draw your child, as well as locations of nearby bodies of water. By having it all written down, you’ll be able to share the information quickly with first responders. The Montgomery County Police Department has a “Wandering 911 Script” that you can download and use.

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

It happens quickly: A child on the autism spectrum bolts from supervision and disappears – an emergency called “autism elopement.” While any child can wander off, children on the autism spectrum face particular risks. These include the lure of water and the risk of drowning.

Some youngsters on the spectrum will follow this strong attraction to water and head for a nearby pond, river, or swimming pool. Such circumstances have made drowning a leading cause of death for these missing youths.

Autism elopement can happen any time. Summer can be especially dangerous. When the weather warms, the risk of drowning death rises, says Lori McIlwain, cofounder of the National Autism Association.

“The fatality risk is higher in May, June, July for that child to exit the setting unnoticed, especially if there’s an outdoor gathering and then they go directly to water,” Ms. McIlwain says. For instance, she says children can dart away during outdoor play, barbecues, gatherings, and other activities. Or they might wander off while vacationing near a beach or hotel pool.
 

Autism elopement

Many people don’t know about this risk, including some families with youngsters on the autism spectrum. The National Center for Missing and Exploited Children is working to change that – and find solutions.

About 12 years ago, “we started noticing a very disturbing trend that children with autism were going missing and they were having grave results,” says John Bischoff, vice president of the Center’s Missing Children Division.

The Center analyzed a decade of data on accidental deaths of children on the autism spectrum. Drowning was the #1 cause, accounting for 84% of those deaths.

In 2012, researchers reported on autism and wandering in the journal Pediatrics. They analyzed answers from about 1,000 families to an online survey on the topic. Parents who had children on the spectrum and children not on the spectrum responded. Nearly half of the parents said their child with autism had tried to wander off after age 4, and 26% had gone missing long enough to cause concern.

“Of those who went missing, 24% were in danger of drowning and 65% were in danger of traffic injury,” the researchers wrote. Children on the spectrum might also be drawn to traffic signs, highways, fire trucks, and trains.

In comparison, brothers and sisters of all ages who were not on the spectrum were much less likely to have wandered off.
 

Seeking a quiet place

It’s not entirely clear why children with autism are so drawn to water, Ms. McIlwain says. But there are some clues.

“What we see is that these children exit settings that are usually bothersome,” Ms. McIlwain says. “[Those settings are] loud, with a high amount of stimuli or stress or commotion, and they go to a quiet place, usually water in a quiet area. It’s calm. It’s peaceful.”

Water isn’t the only dangerous draw. When autism elopement happens, “they also go to the woods, they go to abandoned vehicles,” she says. “So any quiet thing is usually where they will head.”
 

A family’s loss

Beth Dilg, a mother in Maryland, lost her 7-year-old daughter, Savannah Martin, who was on the autism spectrum, to drowning in 2011. Ms. Dilg had been living in Oklahoma and raising her three children alone after separating from her husband. On a chilly February day, Savannah and her 2-year-old brother left their house after Ms. Dilg had asked her 11-year-old son to keep watch while she went into the bathroom for a few minutes.

When Ms. Dilg realized the two younger kids had left, she searched the property frantically. She shouted Savannah’s name repeatedly, but the child, who had limited language, didn’t come when called. “I feel like she knew what her name was,” Ms. Dilg says, “but it wasn’t like you’d call her name and she’d come to you.”

Ms. Dilg ran to a pond near her property after her 11-year-old son said that the two siblings were in the water. Ms. Dilg entered the water and grabbed her toddler, who had survived after having been kept afloat by his bicycle helmet. But when Ms. Dilg reached Savannah, she was already unresponsive. A neighbor helped pull the children out.

It can happen in any family. Even when a parent takes precautions, a child can slip out in a moment, perhaps while the parent is asleep or taking care of personal needs or if the child is at school or elsewhere.

“It’s unrealistic to say that you’d never take your eyes off your kid,” Ms. Dilg says.

She had tried to protect Savannah by starting her on swimming lessons, installing high locks on the doors, and trying to teach her about how to stay safe.

Still, children can be skillful in finding ways to escape, Ms. Dilg says. “These kids with autism are so smart. They may not be verbal, but they have this level of intelligence,” she says. “You always have to stay a step ahead of them.”

Ms. Dilg has been a longtime volunteer with Team HOPE, a peer support group with the National Center for Missing and Exploited Children. She offers emotional support to parents whose children are missing or who have died, including the parents of youngsters with autism who have drowned.
 

Teaching first responders

If a child on the autism spectrum goes missing, searching for them can be complicated by their condition. For instance, some children cannot speak or aren’t able to respond to searchers calling their name. The National Center for Missing and Exploited Children offers training to law enforcement and provides search protocols for first responders.

The center has drawn on expertise from Laurie Reyes, an officer with Maryland’s Montgomery County Police Department. In 2005, Ms. Reyes created a special unit within the department to focus on safety for people at risk for wandering. They have conditions that include autism/intellectual and developmental disabilities, as well as Alzheimer’s and other forms of dementia.

“We have a culture of awareness here,” Ms. Reyes says. All Montgomery County recruits and officers receive training in how to interact with those on the autism spectrum, who may not respond to police commands. Police also learn how to search, including immediately checking bodies of water. “We’ve had many times where we’ve located individuals in bodies of water,” Ms. Reyes says.

Don’t wait to call 911. When a child goes missing, time matters. Ms. Reyes advises families not to search on their own. “Call 911 right away,” she says.
 

Top safety tips to help prevent autism elopement

Use these tips to help keep kids on the autism spectrum safe and prevent drownings.

Secure your home. Use window and door alarms to alert you if a door or window becomes ajar. “Those door alarms are essential,” Ms. McIlwain says.

You can buy alarms online or get them free from the National Autism Association through its Big Red Safety Box program.

You can also buy portable door alarms for travel and arrange to have door alarms at your child’s school.

Ms. McIlwain advises securing the home with adequate locks and using baby monitors. Installing visual prompts, such as a stop sign on the door, might also cue a child not to leave.

Use personal identification. Ms. McIlwain says that children with autism must wear identification, such as a wristband, that includes their name, autism diagnosis, and the name and phone number of a contact person.

If children won’t wear a wristband, IDs on shoelaces are an option, she says. But parents should be aware that kids might leave without shoes or take them off before entering water.

Parents can also weigh the pros and cons of using tracking and locater devices, Ms. McIlwain says.

Identify triggers. “What’s going to make the child want to leave the setting? Is it noise? Is it a certain thing that they fear?” Ms. McIlwain says. “There’s always a reason.”

If parents can identify particular triggers, they can use calming techniques, for example, or provide headphones to counteract bothersome noises.

Teach safety skills, such as swimming lessons. Swimming lessons are important, Ms. McIlwain says. However, children with autism are often bothered by noise and commotion. So a regular swim class might not work for them.

Instead, Ms. McIlwain encourages parents to ask their local YMCA about special-needs swimming lessons or to search for such lessons online. What usually turns out to be best is to give the child a few private swimming lessons “with somebody who understands autism.”

For the child’s final lesson, they should swim fully clothed and with shoes on, Ms. McIlwain says. “A lot of our kids go straight into water fully clothed, and they just need to be able to be familiar with how that feels and the weight of that and be able to swim like that as well.”

If a child is drawn to water, discuss a scheduled time to go so that the youngster can wait, Ms. McIlwain says. “They can see that they’re going to get that water time. They’re going to be able to go to that place. They’re going to wait instead of trying to go on their own.”

Keep a close watch and team up. “When there is a family gathering or an outdoor barbecue, a lot of times, we all think, there are more adults here, so there are going to be more eyes on all the kids. And that always ends up being opposite, right?” Ms. McIlwain says.

Be specific about who is monitoring the child’s safety.

“We encourage parents to do the ‘Tag, you’re it’ game with one another. So you basically tag an adult who is responsible for keeping an eye on that child for a period of time so that there’s always supervision.”
 

Be prepared

There are a few things you can do now to be ready in case your child slips away. These measures may help find the child quickly.

Take photos today. Keep a full-length shot and a head shot of your child and store them electronically. If your child wanders away, you can immediately send the images to law enforcement to help them search.

Write a 911 script. Have this document ready in case your child wanders. It describes, among other things, points of interest that might draw your child, as well as locations of nearby bodies of water. By having it all written down, you’ll be able to share the information quickly with first responders. The Montgomery County Police Department has a “Wandering 911 Script” that you can download and use.

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

With monkeypox now circulating in the United States, expecting mothers may worry about what might happen if they contract the infection while pregnant.

As of today, 25 cases of monkeypox have been confirmed in the United States since the outbreak began in early May, according to the U.S. Centers for Disease Control and Prevention. Although none of those cases has involved a pregnant person, the World Health Organization says monkeypox can pass from mother to fetus before delivery or to newborns by close contact during and after birth.

The case count could grow as the agency continues to investigate potential infections of the virus. In a conference call Friday, health officials stressed the importance of contact tracing, testing, and vaccine treatment.

As physicians in the United States are scrambling for information on ways to treat patients, a new study, published in Ultrasound in Obstetrics & Gynecology, could help clinicians better care for pregnant people infected with monkeypox. The authors advise consistently monitoring the fetus for infection and conducting regular ultrasounds, among other precautions. 

Asma Khalil, MBBCh, MD, a professor of obstetrics and fetal medicine at St. George’s University, London, and lead author of the new study, said the monkeypox outbreak outside Africa caught many clinicians by surprise.

“We quickly realized very few physicians caring for pregnant women knew anything at all about monkeypox and how it affects pregnancy,” Dr. Khalil told this news organization. “Clinicians caring for pregnant women are likely to be faced soon with pregnant women concerned they may have the infection – because they have a rash, for example – or indeed pregnant women who do have the infection.”

According to the CDC, monkeypox can be transmitted through direct contact with the rash, sores, or scabs caused by the virus, as well as contact with clothing, bedding, towels, or other surfaces used by an infected person. Respiratory droplets and oral fluids from a person with monkeypox have also been linked to spread of the virus, as has sexual activity.

Although the condition is rarely fatal, infants and young children are at the greatest risk of developing severe symptoms, health officials said. 

The U.S. Food and Drug Administration has approved a monkeypox vaccine, Jynneos (Bavarian Nordic A/S), for general use, but it has not been specifically approved for pregnant people. However, a study of 300 pregnant women who received the vaccine reported no adverse reactions or failed pregnancies linked to the shots.

The new review suggests that women who have a confirmed infection during pregnancy should have a doctor closely monitor the fetus until birth.

If the fetus is over 26 weeks or if the mother is unwell, the fetus should be cared for with heart monitoring, either by a doctor or remotely every 2-3 days. Ultrasounds should be performed regularly to confirm that the fetus is still growing well and that the placenta is functioning properly.

Further into the pregnancy, monitoring should include measurements of the fetus and detailed assessment of the fetal organs and the amniotic fluid. Once the infection is resolved, the risk to the fetus is small, according to Dr. Khalil. However, since data are limited, she recommended an ultrasound scan every 2-4 weeks. At birth, for the protection of the infant and the mother, the baby should be isolated until infection is no longer a risk.

The Royal College of Obstetricians & Gynaecologists is preparing guidance on the management of monkeypox in pregnant people, Dr. Khalil said. The American College of Obstetricians and Gynecologists said it is “relying on the CDC for the time being,” according to a spokesperson for ACOG. 

“There is a clear need for further research in this area,” Dr. Khalil said. “The current outbreak is an ideal opportunity to make this happen.”

Dr. Khalil has disclosed no relevant financial relationships.

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

With monkeypox now circulating in the United States, expecting mothers may worry about what might happen if they contract the infection while pregnant.

As of today, 25 cases of monkeypox have been confirmed in the United States since the outbreak began in early May, according to the U.S. Centers for Disease Control and Prevention. Although none of those cases has involved a pregnant person, the World Health Organization says monkeypox can pass from mother to fetus before delivery or to newborns by close contact during and after birth.

The case count could grow as the agency continues to investigate potential infections of the virus. In a conference call Friday, health officials stressed the importance of contact tracing, testing, and vaccine treatment.

As physicians in the United States are scrambling for information on ways to treat patients, a new study, published in Ultrasound in Obstetrics & Gynecology, could help clinicians better care for pregnant people infected with monkeypox. The authors advise consistently monitoring the fetus for infection and conducting regular ultrasounds, among other precautions. 

Asma Khalil, MBBCh, MD, a professor of obstetrics and fetal medicine at St. George’s University, London, and lead author of the new study, said the monkeypox outbreak outside Africa caught many clinicians by surprise.

“We quickly realized very few physicians caring for pregnant women knew anything at all about monkeypox and how it affects pregnancy,” Dr. Khalil told this news organization. “Clinicians caring for pregnant women are likely to be faced soon with pregnant women concerned they may have the infection – because they have a rash, for example – or indeed pregnant women who do have the infection.”

According to the CDC, monkeypox can be transmitted through direct contact with the rash, sores, or scabs caused by the virus, as well as contact with clothing, bedding, towels, or other surfaces used by an infected person. Respiratory droplets and oral fluids from a person with monkeypox have also been linked to spread of the virus, as has sexual activity.

Although the condition is rarely fatal, infants and young children are at the greatest risk of developing severe symptoms, health officials said. 

The U.S. Food and Drug Administration has approved a monkeypox vaccine, Jynneos (Bavarian Nordic A/S), for general use, but it has not been specifically approved for pregnant people. However, a study of 300 pregnant women who received the vaccine reported no adverse reactions or failed pregnancies linked to the shots.

The new review suggests that women who have a confirmed infection during pregnancy should have a doctor closely monitor the fetus until birth.

If the fetus is over 26 weeks or if the mother is unwell, the fetus should be cared for with heart monitoring, either by a doctor or remotely every 2-3 days. Ultrasounds should be performed regularly to confirm that the fetus is still growing well and that the placenta is functioning properly.

Further into the pregnancy, monitoring should include measurements of the fetus and detailed assessment of the fetal organs and the amniotic fluid. Once the infection is resolved, the risk to the fetus is small, according to Dr. Khalil. However, since data are limited, she recommended an ultrasound scan every 2-4 weeks. At birth, for the protection of the infant and the mother, the baby should be isolated until infection is no longer a risk.

The Royal College of Obstetricians & Gynaecologists is preparing guidance on the management of monkeypox in pregnant people, Dr. Khalil said. The American College of Obstetricians and Gynecologists said it is “relying on the CDC for the time being,” according to a spokesperson for ACOG. 

“There is a clear need for further research in this area,” Dr. Khalil said. “The current outbreak is an ideal opportunity to make this happen.”

Dr. Khalil has disclosed no relevant financial relationships.

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

With monkeypox now circulating in the United States, expecting mothers may worry about what might happen if they contract the infection while pregnant.

As of today, 25 cases of monkeypox have been confirmed in the United States since the outbreak began in early May, according to the U.S. Centers for Disease Control and Prevention. Although none of those cases has involved a pregnant person, the World Health Organization says monkeypox can pass from mother to fetus before delivery or to newborns by close contact during and after birth.

The case count could grow as the agency continues to investigate potential infections of the virus. In a conference call Friday, health officials stressed the importance of contact tracing, testing, and vaccine treatment.

As physicians in the United States are scrambling for information on ways to treat patients, a new study, published in Ultrasound in Obstetrics & Gynecology, could help clinicians better care for pregnant people infected with monkeypox. The authors advise consistently monitoring the fetus for infection and conducting regular ultrasounds, among other precautions. 

Asma Khalil, MBBCh, MD, a professor of obstetrics and fetal medicine at St. George’s University, London, and lead author of the new study, said the monkeypox outbreak outside Africa caught many clinicians by surprise.

“We quickly realized very few physicians caring for pregnant women knew anything at all about monkeypox and how it affects pregnancy,” Dr. Khalil told this news organization. “Clinicians caring for pregnant women are likely to be faced soon with pregnant women concerned they may have the infection – because they have a rash, for example – or indeed pregnant women who do have the infection.”

According to the CDC, monkeypox can be transmitted through direct contact with the rash, sores, or scabs caused by the virus, as well as contact with clothing, bedding, towels, or other surfaces used by an infected person. Respiratory droplets and oral fluids from a person with monkeypox have also been linked to spread of the virus, as has sexual activity.

Although the condition is rarely fatal, infants and young children are at the greatest risk of developing severe symptoms, health officials said. 

The U.S. Food and Drug Administration has approved a monkeypox vaccine, Jynneos (Bavarian Nordic A/S), for general use, but it has not been specifically approved for pregnant people. However, a study of 300 pregnant women who received the vaccine reported no adverse reactions or failed pregnancies linked to the shots.

The new review suggests that women who have a confirmed infection during pregnancy should have a doctor closely monitor the fetus until birth.

If the fetus is over 26 weeks or if the mother is unwell, the fetus should be cared for with heart monitoring, either by a doctor or remotely every 2-3 days. Ultrasounds should be performed regularly to confirm that the fetus is still growing well and that the placenta is functioning properly.

Further into the pregnancy, monitoring should include measurements of the fetus and detailed assessment of the fetal organs and the amniotic fluid. Once the infection is resolved, the risk to the fetus is small, according to Dr. Khalil. However, since data are limited, she recommended an ultrasound scan every 2-4 weeks. At birth, for the protection of the infant and the mother, the baby should be isolated until infection is no longer a risk.

The Royal College of Obstetricians & Gynaecologists is preparing guidance on the management of monkeypox in pregnant people, Dr. Khalil said. The American College of Obstetricians and Gynecologists said it is “relying on the CDC for the time being,” according to a spokesperson for ACOG. 

“There is a clear need for further research in this area,” Dr. Khalil said. “The current outbreak is an ideal opportunity to make this happen.”

Dr. Khalil has disclosed no relevant financial relationships.

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

As a physician who has had a career-long obsession with the underappreciated value of sleep, a recent study published in the journal Child Development caught my eye. The findings presented by a group of Australian-based psychologists and educators suggest a positive association between napping and learning by preschool children. While the study itself relied on a very small sample and may not prove to be repeatable, the authors included in their introduction an excellent discussion of a large collection of recent studies supporting the educational benefit of sleep in general and napping in particular.

Although sleep seems to finally be receiving some of the attention it deserves, I am still concerned that as a profession we are failing to give it the appropriate weight at our health maintenance visits. This is particularly true of napping. Understandably, napping doesn’t feel urgent to parents in those turbulent first 4 or 5 months of night wakings and erratic settling. However, as a child approaches the 6-month milestone, napping is a topic ripe for well-considered anticipatory guidance.

When the recurrent cycles of awake-eat-sleep begin to develop into a somewhat predictable pattern and solid food is introduced, it’s time to suggest to parents a strategy that will encourage a napping pattern that will hopefully habituate into toddlerhood and beyond.

It can begin simply as a matter of defining the feeding in the middle of the day as lunch and then programming the period immediately following that meal as a siesta – a segment of the day completely reserved for rest. Many warm-weather countries have been using this strategy for centuries. Try to go to the pharmacy to pick up a prescription at 2 o’clock in the afternoon in rural Spain. It just ain’t gonna happen.

Most adults and children I know seem to be sleepy during this midday postprandial period. It makes more than a little sense to harness this natural drowsiness into creating a napping habit. However, the challenge for many young families is controlling their schedule to create a period of time when nothing else is going on in the child’s environment, leaving sleep as the only option. For some parents this requires the discipline to pause their own lives long enough so that the children realize that they aren’t missing out on something fun. This means no TV, no phone conversations, no visitors. Obviously, it also means not scheduling any appointments during this siesta period. Skilled day care providers have been doing this for years. But the message hasn’t seeped into the general population and sadly I occasionally see mothers with toddlers in the grocery store at 1 in the afternoon.

Once the nap/siesta is firmly welded to lunch, this gives the parent the ability to make minor adjustments that reflect the child’s stamina. If the child seems to be tiring/getting grumpy, serve up lunch a bit early and the restorative nap follows. As the child gets older and his or her stamina improves he or she may not be sleepy but the siesta remains as a quiet time. Some days it may be a nap, some days just a rest for an hour. By counseling parents to define the period after lunch as a siesta you will be helping them avoid that dreaded transition period called “giving up the nap.”

You may already be including this strategy in your anticipatory guidance. It may help to add to your advice the accumulating evidence that napping may play an important role in the child’s development and education.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

As a physician who has had a career-long obsession with the underappreciated value of sleep, a recent study published in the journal Child Development caught my eye. The findings presented by a group of Australian-based psychologists and educators suggest a positive association between napping and learning by preschool children. While the study itself relied on a very small sample and may not prove to be repeatable, the authors included in their introduction an excellent discussion of a large collection of recent studies supporting the educational benefit of sleep in general and napping in particular.

Although sleep seems to finally be receiving some of the attention it deserves, I am still concerned that as a profession we are failing to give it the appropriate weight at our health maintenance visits. This is particularly true of napping. Understandably, napping doesn’t feel urgent to parents in those turbulent first 4 or 5 months of night wakings and erratic settling. However, as a child approaches the 6-month milestone, napping is a topic ripe for well-considered anticipatory guidance.

When the recurrent cycles of awake-eat-sleep begin to develop into a somewhat predictable pattern and solid food is introduced, it’s time to suggest to parents a strategy that will encourage a napping pattern that will hopefully habituate into toddlerhood and beyond.

It can begin simply as a matter of defining the feeding in the middle of the day as lunch and then programming the period immediately following that meal as a siesta – a segment of the day completely reserved for rest. Many warm-weather countries have been using this strategy for centuries. Try to go to the pharmacy to pick up a prescription at 2 o’clock in the afternoon in rural Spain. It just ain’t gonna happen.

Most adults and children I know seem to be sleepy during this midday postprandial period. It makes more than a little sense to harness this natural drowsiness into creating a napping habit. However, the challenge for many young families is controlling their schedule to create a period of time when nothing else is going on in the child’s environment, leaving sleep as the only option. For some parents this requires the discipline to pause their own lives long enough so that the children realize that they aren’t missing out on something fun. This means no TV, no phone conversations, no visitors. Obviously, it also means not scheduling any appointments during this siesta period. Skilled day care providers have been doing this for years. But the message hasn’t seeped into the general population and sadly I occasionally see mothers with toddlers in the grocery store at 1 in the afternoon.

Once the nap/siesta is firmly welded to lunch, this gives the parent the ability to make minor adjustments that reflect the child’s stamina. If the child seems to be tiring/getting grumpy, serve up lunch a bit early and the restorative nap follows. As the child gets older and his or her stamina improves he or she may not be sleepy but the siesta remains as a quiet time. Some days it may be a nap, some days just a rest for an hour. By counseling parents to define the period after lunch as a siesta you will be helping them avoid that dreaded transition period called “giving up the nap.”

You may already be including this strategy in your anticipatory guidance. It may help to add to your advice the accumulating evidence that napping may play an important role in the child’s development and education.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

As a physician who has had a career-long obsession with the underappreciated value of sleep, a recent study published in the journal Child Development caught my eye. The findings presented by a group of Australian-based psychologists and educators suggest a positive association between napping and learning by preschool children. While the study itself relied on a very small sample and may not prove to be repeatable, the authors included in their introduction an excellent discussion of a large collection of recent studies supporting the educational benefit of sleep in general and napping in particular.

Although sleep seems to finally be receiving some of the attention it deserves, I am still concerned that as a profession we are failing to give it the appropriate weight at our health maintenance visits. This is particularly true of napping. Understandably, napping doesn’t feel urgent to parents in those turbulent first 4 or 5 months of night wakings and erratic settling. However, as a child approaches the 6-month milestone, napping is a topic ripe for well-considered anticipatory guidance.

When the recurrent cycles of awake-eat-sleep begin to develop into a somewhat predictable pattern and solid food is introduced, it’s time to suggest to parents a strategy that will encourage a napping pattern that will hopefully habituate into toddlerhood and beyond.

It can begin simply as a matter of defining the feeding in the middle of the day as lunch and then programming the period immediately following that meal as a siesta – a segment of the day completely reserved for rest. Many warm-weather countries have been using this strategy for centuries. Try to go to the pharmacy to pick up a prescription at 2 o’clock in the afternoon in rural Spain. It just ain’t gonna happen.

Most adults and children I know seem to be sleepy during this midday postprandial period. It makes more than a little sense to harness this natural drowsiness into creating a napping habit. However, the challenge for many young families is controlling their schedule to create a period of time when nothing else is going on in the child’s environment, leaving sleep as the only option. For some parents this requires the discipline to pause their own lives long enough so that the children realize that they aren’t missing out on something fun. This means no TV, no phone conversations, no visitors. Obviously, it also means not scheduling any appointments during this siesta period. Skilled day care providers have been doing this for years. But the message hasn’t seeped into the general population and sadly I occasionally see mothers with toddlers in the grocery store at 1 in the afternoon.

Once the nap/siesta is firmly welded to lunch, this gives the parent the ability to make minor adjustments that reflect the child’s stamina. If the child seems to be tiring/getting grumpy, serve up lunch a bit early and the restorative nap follows. As the child gets older and his or her stamina improves he or she may not be sleepy but the siesta remains as a quiet time. Some days it may be a nap, some days just a rest for an hour. By counseling parents to define the period after lunch as a siesta you will be helping them avoid that dreaded transition period called “giving up the nap.”

You may already be including this strategy in your anticipatory guidance. It may help to add to your advice the accumulating evidence that napping may play an important role in the child’s development and education.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Now hot off the press from the “always-guessed-it-was-true-but-now-you-know-it” department comes a multinational study that looked at childhood cardiovascular risk factors and longevity.

Using data collected from individuals in Finland, Australia, and the United States the International Childhood Cardiovascular Cohorts Consortium Outcomes Study investigators sought links between subjects’ body mass index, systolic blood pressure, total cholesterol, blood triglyceride level, and smoking in childhood with cardiovascular disease and outcomes as they aged into adulthood.

The children were initially enrolled in the 1970s and 1980s. The adult evaluations were done in 2015-2019 when the subjects’ average age was 46. Of the 40,000 individuals who originally entered the study, 800 were found to have cardiovascular events of which over 300 had resulted in death. I found these numbers a bit surprising given the relatively young age at which the follow-up data were collected.

What was less surprising is that people with higher than normal values for all five risk factors as children had nearly three times the risk of cardiovascular disease as adults. Researchers found that smoking at a young age was biggest risk factor with body mass index, systolic blood pressure, blood triglycerides, and cholesterol following in descending order. They also found that adults who were obese as children had triple the risk of cardiovascular disease as adults. High blood pressure in childhood doubled the risk.

It will be interesting to see if and how these trends change as the study population ages. It could be that the effect of these childhood risk factors is blunted as the those segments at the highest risk die off and/or risk- associated behaviors adopted in adulthood become more prominent. But, it feels more likely that the childhood risk factors will remain as major contributors.

Is this just another ho-hum-told-you-so study or does it have some special relevance for us as pediatricians? At a minimum these findings should inspire us to stick with our calling to commit ourselves to the health of children. A healthy adult population is clearly our legacy.

Of course the two individual risk factors in childhood that appear to be the most potent in adulthood, obesity and smoking, are also the most frustrating for pediatricians to address. However, the study suggests that we should rejoice in those few successes when we achieve them. Childhood obesity has been a tough nut to crack. On the other hand, the societal change that has made great strides in adult smoking over the last half century should encourage us that our work with the pediatric population will eventually bring rewards.

Smoking and obesity can include components of both patient and parental behavior. Monitoring cholesterol, triglycerides, and blood pressure hinges on our behavior as providers. Although there have been recent recommendations that we be more attentive, we don’t have a strong history when it comes to detecting and addressing high blood pressure in children. This study should serve as an another reminder to take blood pressure more seriously.

I was surprised and somewhat disappointed that I first learned about the results of this study in an email newsletter from the medical school I attended. I would have hoped that a paper like this from a well known peer-reviewed journal with a clear message about the relationship of childhood health and longevity should have been picked up quickly by the lay press. Again, this leaves it to us to promote the message that the health of children is important in and of itself but plays a critical role in the health of adults.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Now hot off the press from the “always-guessed-it-was-true-but-now-you-know-it” department comes a multinational study that looked at childhood cardiovascular risk factors and longevity.

Using data collected from individuals in Finland, Australia, and the United States the International Childhood Cardiovascular Cohorts Consortium Outcomes Study investigators sought links between subjects’ body mass index, systolic blood pressure, total cholesterol, blood triglyceride level, and smoking in childhood with cardiovascular disease and outcomes as they aged into adulthood.

The children were initially enrolled in the 1970s and 1980s. The adult evaluations were done in 2015-2019 when the subjects’ average age was 46. Of the 40,000 individuals who originally entered the study, 800 were found to have cardiovascular events of which over 300 had resulted in death. I found these numbers a bit surprising given the relatively young age at which the follow-up data were collected.

What was less surprising is that people with higher than normal values for all five risk factors as children had nearly three times the risk of cardiovascular disease as adults. Researchers found that smoking at a young age was biggest risk factor with body mass index, systolic blood pressure, blood triglycerides, and cholesterol following in descending order. They also found that adults who were obese as children had triple the risk of cardiovascular disease as adults. High blood pressure in childhood doubled the risk.

It will be interesting to see if and how these trends change as the study population ages. It could be that the effect of these childhood risk factors is blunted as the those segments at the highest risk die off and/or risk- associated behaviors adopted in adulthood become more prominent. But, it feels more likely that the childhood risk factors will remain as major contributors.

Is this just another ho-hum-told-you-so study or does it have some special relevance for us as pediatricians? At a minimum these findings should inspire us to stick with our calling to commit ourselves to the health of children. A healthy adult population is clearly our legacy.

Of course the two individual risk factors in childhood that appear to be the most potent in adulthood, obesity and smoking, are also the most frustrating for pediatricians to address. However, the study suggests that we should rejoice in those few successes when we achieve them. Childhood obesity has been a tough nut to crack. On the other hand, the societal change that has made great strides in adult smoking over the last half century should encourage us that our work with the pediatric population will eventually bring rewards.

Smoking and obesity can include components of both patient and parental behavior. Monitoring cholesterol, triglycerides, and blood pressure hinges on our behavior as providers. Although there have been recent recommendations that we be more attentive, we don’t have a strong history when it comes to detecting and addressing high blood pressure in children. This study should serve as an another reminder to take blood pressure more seriously.

I was surprised and somewhat disappointed that I first learned about the results of this study in an email newsletter from the medical school I attended. I would have hoped that a paper like this from a well known peer-reviewed journal with a clear message about the relationship of childhood health and longevity should have been picked up quickly by the lay press. Again, this leaves it to us to promote the message that the health of children is important in and of itself but plays a critical role in the health of adults.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Now hot off the press from the “always-guessed-it-was-true-but-now-you-know-it” department comes a multinational study that looked at childhood cardiovascular risk factors and longevity.

Using data collected from individuals in Finland, Australia, and the United States the International Childhood Cardiovascular Cohorts Consortium Outcomes Study investigators sought links between subjects’ body mass index, systolic blood pressure, total cholesterol, blood triglyceride level, and smoking in childhood with cardiovascular disease and outcomes as they aged into adulthood.

The children were initially enrolled in the 1970s and 1980s. The adult evaluations were done in 2015-2019 when the subjects’ average age was 46. Of the 40,000 individuals who originally entered the study, 800 were found to have cardiovascular events of which over 300 had resulted in death. I found these numbers a bit surprising given the relatively young age at which the follow-up data were collected.

What was less surprising is that people with higher than normal values for all five risk factors as children had nearly three times the risk of cardiovascular disease as adults. Researchers found that smoking at a young age was biggest risk factor with body mass index, systolic blood pressure, blood triglycerides, and cholesterol following in descending order. They also found that adults who were obese as children had triple the risk of cardiovascular disease as adults. High blood pressure in childhood doubled the risk.

It will be interesting to see if and how these trends change as the study population ages. It could be that the effect of these childhood risk factors is blunted as the those segments at the highest risk die off and/or risk- associated behaviors adopted in adulthood become more prominent. But, it feels more likely that the childhood risk factors will remain as major contributors.

Is this just another ho-hum-told-you-so study or does it have some special relevance for us as pediatricians? At a minimum these findings should inspire us to stick with our calling to commit ourselves to the health of children. A healthy adult population is clearly our legacy.

Of course the two individual risk factors in childhood that appear to be the most potent in adulthood, obesity and smoking, are also the most frustrating for pediatricians to address. However, the study suggests that we should rejoice in those few successes when we achieve them. Childhood obesity has been a tough nut to crack. On the other hand, the societal change that has made great strides in adult smoking over the last half century should encourage us that our work with the pediatric population will eventually bring rewards.

Smoking and obesity can include components of both patient and parental behavior. Monitoring cholesterol, triglycerides, and blood pressure hinges on our behavior as providers. Although there have been recent recommendations that we be more attentive, we don’t have a strong history when it comes to detecting and addressing high blood pressure in children. This study should serve as an another reminder to take blood pressure more seriously.

I was surprised and somewhat disappointed that I first learned about the results of this study in an email newsletter from the medical school I attended. I would have hoped that a paper like this from a well known peer-reviewed journal with a clear message about the relationship of childhood health and longevity should have been picked up quickly by the lay press. Again, this leaves it to us to promote the message that the health of children is important in and of itself but plays a critical role in the health of adults.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.

The trial, known as DETERMINATION, found that newly diagnosed patients treated with a triplet of drugs had longer progression-free survival (PFS) if they received an autologous stem cell transplant (ASCT) soon after the drug therapy than if they simply had their stem cells collected for a possible future transplant.

Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.

However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.

In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.  

The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.

“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.

Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.

“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
 

Study details

In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.

At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.

The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).

The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.

“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.

Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.

“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.

When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).

However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.

“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”

He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.

“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
 

Lack of difference in overall survival

These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.

“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.” 

Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.

The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.” 

Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.

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

CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.

The trial, known as DETERMINATION, found that newly diagnosed patients treated with a triplet of drugs had longer progression-free survival (PFS) if they received an autologous stem cell transplant (ASCT) soon after the drug therapy than if they simply had their stem cells collected for a possible future transplant.

Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.

However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.

In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.  

The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.

“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.

Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.

“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
 

Study details

In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.

At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.

The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).

The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.

“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.

Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.

“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.

When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).

However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.

“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”

He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.

“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
 

Lack of difference in overall survival

These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.

“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.” 

Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.

The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.” 

Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.

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

CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.

The trial, known as DETERMINATION, found that newly diagnosed patients treated with a triplet of drugs had longer progression-free survival (PFS) if they received an autologous stem cell transplant (ASCT) soon after the drug therapy than if they simply had their stem cells collected for a possible future transplant.

Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.

However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.

In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.  

The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.

“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.

Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.

“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
 

Study details

In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.

At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.

The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).

The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.

“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.

Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.

“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.

When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).

However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.

“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”

He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.

“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
 

Lack of difference in overall survival

These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.

“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.” 

Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.

The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.” 

Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.

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

SAN DIEGO – The risk of laser or intense-pulsed light–induced vitiligo from treating vitiligo with either modality appears to be low, but caution is recommended until further studies are carried out.

Those are the preliminary conclusions from a systematic review and survey of experts that Albert Wolkerstorfer, MD, presented during a clinical abstract session at the annual conference of the American Society for Laser Medicine and Surgery.

According to Dr. Wolkerstorfer, a dermatologist at Amsterdam University Medical Center, clinicians are reluctant to perform laser/intense pulsed light (IPL) treatments in patients with vitiligo because of the absence of clear guidelines, so he and his colleagues set out to investigate the risks of laser/IPL-induced vitiligo in patients with vitiligo and to seek out international consensus on recommendations from experts. “There is hardly any literature about it and certainly no guidelines,” he pointed out.

Dr. Wolkerstorfer and his colleagues designed three consecutive studies: A systematic review of laser/IPL-induced vitiligo; an international survey among 14 vitiligo experts from 10 countries about the occurrence of laser‐induced vitiligo, and a Delphi technique aimed at establishing a broad consensus about recommendations for safe use of lasers in vitiligo patients. At the time of the meeting, the Delphi process was still being carried out, so he did not discuss that study.

For the systematic review, the researchers found 11,073 unique hits on PubMed, Embase, and CINAHL using the terms “vitiligo,” “depigmentation,” “hypopigmentation,” and “leukoderma.” Only six case reports of laser/IPL-induced vitiligo were included in the final analysis. Of these, three had de novo vitiligo and three had vitiligo/halo nevi. These cases included two that occurred following treatment of port wine stains with the 585-nm laser; one that occurred following treatment of dyspigmentation with IPL; one that occurred following treatment of hypertrichosis with the 1,064-nm laser, one that occurred following treatment of hypertrichosis with the 755-nm laser, and one case that occurred following treatment of melasma with the ablative laser.

For the international survey of 14 experts from 10 countries, respondents said they had 10,670 new face-to-face vitiligo consultations in the past year. They reported that 30 of the vitiligo cases (0.3%) were likely caused by laser/IPL. Of these 30 cases, 18 (60%) had de novo vitiligo.

Of these cases, vitiligo occurred most frequently after laser hair reduction (47%), followed by use of the fractional laser (17%), and the ablative laser (13%). The interval between laser/IPL treatment and onset of vitiligo was 0-4 weeks in 27% of cases and 4-12 weeks in 57% of cases. Direct complications such as blistering, crusting, and erosions occurred in 57% of cases.

“Our conclusion is that laser and IPL-induced vitiligo is a rare phenomenon, and it often affects patients without prior vitiligo, which was really a surprise to us,” Dr. Wolkerstorfer said. “Complications seem to increase the risk,” he added.

“Despite the apparently low risk, we recommend caution [in patients with vitiligo], especially with aggressive laser procedures,” he said. “We recommend using conservative settings, not to treat active vitiligo patients ... and to perform test spots prior to treating large areas.” But he characterized this recommendation as “totally preliminary” pending results of the Delphi technique aimed at building consensus about laser/IPL treatments in vitiligo.

In an interview at the meeting, one of the session moderators, Oge Onwudiwe, MD, a dermatologist who practices in Alexandria, Va., said that as clinicians await results of the study’s Delphi consensus, current use of lasers and IPL in patients with vitiligo “is based on your clinical judgment and whether the vitiligo is active or inactive. If the patient has vitiligo and you’re doing laser hair removal in the armpit, they may get active lesions in that area, but they can cover it. So, they may take that as a ‘win’ with the risk. But if it can erupt in other areas, that’s a risk they must be willing to take.”

Dr. Wolkerstorfer disclosed that he has received grant or research funding from Lumenis, Novartis, and Avita Medical. He is an advisory board member for Incyte. Dr. Onwudiwe reported having no disclosures.

SAN DIEGO – The risk of laser or intense-pulsed light–induced vitiligo from treating vitiligo with either modality appears to be low, but caution is recommended until further studies are carried out.

Those are the preliminary conclusions from a systematic review and survey of experts that Albert Wolkerstorfer, MD, presented during a clinical abstract session at the annual conference of the American Society for Laser Medicine and Surgery.

According to Dr. Wolkerstorfer, a dermatologist at Amsterdam University Medical Center, clinicians are reluctant to perform laser/intense pulsed light (IPL) treatments in patients with vitiligo because of the absence of clear guidelines, so he and his colleagues set out to investigate the risks of laser/IPL-induced vitiligo in patients with vitiligo and to seek out international consensus on recommendations from experts. “There is hardly any literature about it and certainly no guidelines,” he pointed out.

Dr. Wolkerstorfer and his colleagues designed three consecutive studies: A systematic review of laser/IPL-induced vitiligo; an international survey among 14 vitiligo experts from 10 countries about the occurrence of laser‐induced vitiligo, and a Delphi technique aimed at establishing a broad consensus about recommendations for safe use of lasers in vitiligo patients. At the time of the meeting, the Delphi process was still being carried out, so he did not discuss that study.

For the systematic review, the researchers found 11,073 unique hits on PubMed, Embase, and CINAHL using the terms “vitiligo,” “depigmentation,” “hypopigmentation,” and “leukoderma.” Only six case reports of laser/IPL-induced vitiligo were included in the final analysis. Of these, three had de novo vitiligo and three had vitiligo/halo nevi. These cases included two that occurred following treatment of port wine stains with the 585-nm laser; one that occurred following treatment of dyspigmentation with IPL; one that occurred following treatment of hypertrichosis with the 1,064-nm laser, one that occurred following treatment of hypertrichosis with the 755-nm laser, and one case that occurred following treatment of melasma with the ablative laser.

For the international survey of 14 experts from 10 countries, respondents said they had 10,670 new face-to-face vitiligo consultations in the past year. They reported that 30 of the vitiligo cases (0.3%) were likely caused by laser/IPL. Of these 30 cases, 18 (60%) had de novo vitiligo.

Of these cases, vitiligo occurred most frequently after laser hair reduction (47%), followed by use of the fractional laser (17%), and the ablative laser (13%). The interval between laser/IPL treatment and onset of vitiligo was 0-4 weeks in 27% of cases and 4-12 weeks in 57% of cases. Direct complications such as blistering, crusting, and erosions occurred in 57% of cases.

“Our conclusion is that laser and IPL-induced vitiligo is a rare phenomenon, and it often affects patients without prior vitiligo, which was really a surprise to us,” Dr. Wolkerstorfer said. “Complications seem to increase the risk,” he added.

“Despite the apparently low risk, we recommend caution [in patients with vitiligo], especially with aggressive laser procedures,” he said. “We recommend using conservative settings, not to treat active vitiligo patients ... and to perform test spots prior to treating large areas.” But he characterized this recommendation as “totally preliminary” pending results of the Delphi technique aimed at building consensus about laser/IPL treatments in vitiligo.

In an interview at the meeting, one of the session moderators, Oge Onwudiwe, MD, a dermatologist who practices in Alexandria, Va., said that as clinicians await results of the study’s Delphi consensus, current use of lasers and IPL in patients with vitiligo “is based on your clinical judgment and whether the vitiligo is active or inactive. If the patient has vitiligo and you’re doing laser hair removal in the armpit, they may get active lesions in that area, but they can cover it. So, they may take that as a ‘win’ with the risk. But if it can erupt in other areas, that’s a risk they must be willing to take.”

Dr. Wolkerstorfer disclosed that he has received grant or research funding from Lumenis, Novartis, and Avita Medical. He is an advisory board member for Incyte. Dr. Onwudiwe reported having no disclosures.

SAN DIEGO – The risk of laser or intense-pulsed light–induced vitiligo from treating vitiligo with either modality appears to be low, but caution is recommended until further studies are carried out.

Those are the preliminary conclusions from a systematic review and survey of experts that Albert Wolkerstorfer, MD, presented during a clinical abstract session at the annual conference of the American Society for Laser Medicine and Surgery.

According to Dr. Wolkerstorfer, a dermatologist at Amsterdam University Medical Center, clinicians are reluctant to perform laser/intense pulsed light (IPL) treatments in patients with vitiligo because of the absence of clear guidelines, so he and his colleagues set out to investigate the risks of laser/IPL-induced vitiligo in patients with vitiligo and to seek out international consensus on recommendations from experts. “There is hardly any literature about it and certainly no guidelines,” he pointed out.

Dr. Wolkerstorfer and his colleagues designed three consecutive studies: A systematic review of laser/IPL-induced vitiligo; an international survey among 14 vitiligo experts from 10 countries about the occurrence of laser‐induced vitiligo, and a Delphi technique aimed at establishing a broad consensus about recommendations for safe use of lasers in vitiligo patients. At the time of the meeting, the Delphi process was still being carried out, so he did not discuss that study.

For the systematic review, the researchers found 11,073 unique hits on PubMed, Embase, and CINAHL using the terms “vitiligo,” “depigmentation,” “hypopigmentation,” and “leukoderma.” Only six case reports of laser/IPL-induced vitiligo were included in the final analysis. Of these, three had de novo vitiligo and three had vitiligo/halo nevi. These cases included two that occurred following treatment of port wine stains with the 585-nm laser; one that occurred following treatment of dyspigmentation with IPL; one that occurred following treatment of hypertrichosis with the 1,064-nm laser, one that occurred following treatment of hypertrichosis with the 755-nm laser, and one case that occurred following treatment of melasma with the ablative laser.

For the international survey of 14 experts from 10 countries, respondents said they had 10,670 new face-to-face vitiligo consultations in the past year. They reported that 30 of the vitiligo cases (0.3%) were likely caused by laser/IPL. Of these 30 cases, 18 (60%) had de novo vitiligo.

Of these cases, vitiligo occurred most frequently after laser hair reduction (47%), followed by use of the fractional laser (17%), and the ablative laser (13%). The interval between laser/IPL treatment and onset of vitiligo was 0-4 weeks in 27% of cases and 4-12 weeks in 57% of cases. Direct complications such as blistering, crusting, and erosions occurred in 57% of cases.

“Our conclusion is that laser and IPL-induced vitiligo is a rare phenomenon, and it often affects patients without prior vitiligo, which was really a surprise to us,” Dr. Wolkerstorfer said. “Complications seem to increase the risk,” he added.

“Despite the apparently low risk, we recommend caution [in patients with vitiligo], especially with aggressive laser procedures,” he said. “We recommend using conservative settings, not to treat active vitiligo patients ... and to perform test spots prior to treating large areas.” But he characterized this recommendation as “totally preliminary” pending results of the Delphi technique aimed at building consensus about laser/IPL treatments in vitiligo.

In an interview at the meeting, one of the session moderators, Oge Onwudiwe, MD, a dermatologist who practices in Alexandria, Va., said that as clinicians await results of the study’s Delphi consensus, current use of lasers and IPL in patients with vitiligo “is based on your clinical judgment and whether the vitiligo is active or inactive. If the patient has vitiligo and you’re doing laser hair removal in the armpit, they may get active lesions in that area, but they can cover it. So, they may take that as a ‘win’ with the risk. But if it can erupt in other areas, that’s a risk they must be willing to take.”

Dr. Wolkerstorfer disclosed that he has received grant or research funding from Lumenis, Novartis, and Avita Medical. He is an advisory board member for Incyte. Dr. Onwudiwe reported having no disclosures.