Topical oxybutynin 3% gel reduced the severity of axillary hyperhidrosis in teens and young adults and improved their quality of life, in a prospective pilot study, Nicholas V. Nguyen, MD, of the division of dermatology, Akron Children’s Hospital, Ohio, and his associates reported.

Ten patients aged 13-24 years with moderate to severe axillary hyperhidrosis started the study and were treated with 1 g of oxybutynin 3% gel applied to each axilla every morning for 4 weeks. Of the seven patients who completed the study, four had a two-point reduction in the Hyperhidrosis Disease Severity Scale (HDSS) at week 1 and all seven achieved that endpoint at week 4. Of the five patients who also had hyperhidrosis of the palms, four had a two-point reduction in the HDSS at weeks 1 and 4; the remaining patient reported no change. Of the five patients who also had plantar hyperhidrosis, two reported a reduction at weeks 1 and 4, two reported no change, and one had no change at week 1 and experienced worse hyperhidrosis at week 4.

Miyuki-3

One patient developed pyelonephritis on the sixth day of treatment, possibly related to the study drug. “This patient had a history of kidney transplantation, immunosuppression, and recurrent urinary tract infections. For these reasons, the drug should be used with caution in patients with a history of urinary retention or recurrent urinary tract infections,” Dr. Nguyen and his colleagues said.

The manufacturer discontinued the 3% formulation during enrollment, because of business reasons. A large, randomized, placebo-controlled, double-blind trial to address unanswered questions is warranted, the researchers noted. Oxybutynin 10% gel, approved for treating overactive bladder, is still commercially available.

The study was supported by a Society for Pediatric Dermatology pilot project grant and a Colorado Clinical and Translational Sciences Institute grant.

SOURCE: Nguyen NV et al. Pediatr Dermatol. 2018 Jan 15. doi: 10.1111/pde.13404.

Topical oxybutynin 3% gel reduced the severity of axillary hyperhidrosis in teens and young adults and improved their quality of life, in a prospective pilot study, Nicholas V. Nguyen, MD, of the division of dermatology, Akron Children’s Hospital, Ohio, and his associates reported.

Ten patients aged 13-24 years with moderate to severe axillary hyperhidrosis started the study and were treated with 1 g of oxybutynin 3% gel applied to each axilla every morning for 4 weeks. Of the seven patients who completed the study, four had a two-point reduction in the Hyperhidrosis Disease Severity Scale (HDSS) at week 1 and all seven achieved that endpoint at week 4. Of the five patients who also had hyperhidrosis of the palms, four had a two-point reduction in the HDSS at weeks 1 and 4; the remaining patient reported no change. Of the five patients who also had plantar hyperhidrosis, two reported a reduction at weeks 1 and 4, two reported no change, and one had no change at week 1 and experienced worse hyperhidrosis at week 4.

Miyuki-3

One patient developed pyelonephritis on the sixth day of treatment, possibly related to the study drug. “This patient had a history of kidney transplantation, immunosuppression, and recurrent urinary tract infections. For these reasons, the drug should be used with caution in patients with a history of urinary retention or recurrent urinary tract infections,” Dr. Nguyen and his colleagues said.

The manufacturer discontinued the 3% formulation during enrollment, because of business reasons. A large, randomized, placebo-controlled, double-blind trial to address unanswered questions is warranted, the researchers noted. Oxybutynin 10% gel, approved for treating overactive bladder, is still commercially available.

The study was supported by a Society for Pediatric Dermatology pilot project grant and a Colorado Clinical and Translational Sciences Institute grant.

SOURCE: Nguyen NV et al. Pediatr Dermatol. 2018 Jan 15. doi: 10.1111/pde.13404.

Topical oxybutynin 3% gel reduced the severity of axillary hyperhidrosis in teens and young adults and improved their quality of life, in a prospective pilot study, Nicholas V. Nguyen, MD, of the division of dermatology, Akron Children’s Hospital, Ohio, and his associates reported.

Ten patients aged 13-24 years with moderate to severe axillary hyperhidrosis started the study and were treated with 1 g of oxybutynin 3% gel applied to each axilla every morning for 4 weeks. Of the seven patients who completed the study, four had a two-point reduction in the Hyperhidrosis Disease Severity Scale (HDSS) at week 1 and all seven achieved that endpoint at week 4. Of the five patients who also had hyperhidrosis of the palms, four had a two-point reduction in the HDSS at weeks 1 and 4; the remaining patient reported no change. Of the five patients who also had plantar hyperhidrosis, two reported a reduction at weeks 1 and 4, two reported no change, and one had no change at week 1 and experienced worse hyperhidrosis at week 4.

Miyuki-3

One patient developed pyelonephritis on the sixth day of treatment, possibly related to the study drug. “This patient had a history of kidney transplantation, immunosuppression, and recurrent urinary tract infections. For these reasons, the drug should be used with caution in patients with a history of urinary retention or recurrent urinary tract infections,” Dr. Nguyen and his colleagues said.

The manufacturer discontinued the 3% formulation during enrollment, because of business reasons. A large, randomized, placebo-controlled, double-blind trial to address unanswered questions is warranted, the researchers noted. Oxybutynin 10% gel, approved for treating overactive bladder, is still commercially available.

The study was supported by a Society for Pediatric Dermatology pilot project grant and a Colorado Clinical and Translational Sciences Institute grant.

SOURCE: Nguyen NV et al. Pediatr Dermatol. 2018 Jan 15. doi: 10.1111/pde.13404.

DR HENRY I am Dr David Henry, the Editor-in-Chief of The Journal of Community and Supportive Oncology (JCSO; JCSO-online.com). I’m with Dr Dan Haller, former Editor-in-Chief of the Journal of Clinical Oncology and currently the Editor-in-Chief of American Society of Clinical Oncology (ASCO) University. He is also my friend and former mentor at University of Pennsylvania Abramson Cancer Center, where he is Professor Emeritus. We’re going to talk about colorectal cancer and a lot of things that came out of the ASCO meeting this year that were practice changing, or certainly interesting and worth further discussion. I thought we’d start talking about the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration, in which for patients with colorectal cancer who were considering adjuvant postoperative therapy, there was a discussion of 3 cycles versus 6 cycles of FOLFOX (fluorouracil [5-FU] plus oxaliplatin) or XELOX (capecitabine plus oxaliplatin, also CAPOX) (Figure 1).¹ Could you comment on what they did, and how that study turned out?

Three of them were individually reported at ASCO this year, and then the totality was presented at the plenary session – the first time in 12 years that a gastrointestinal (GI) cancer trial made the plenary session. The whole point, obviously, is neuropathy. With 6 months of FOLFOX or XELOX, about 13% or more patients will develop grade 3 neuropathy, even if people stop short of the full-cycle length, and that is a big deal for the 50,000 patients or so who get adjuvant therapy. At the plenary session, the data were presented and the next day three individual trials were presented and discussed by Jeff Meyerhardt (of Dana-Farber Cancer Institute, Boston).

There were 6 different trials: a few included rectum, some included stage II, some used CAPOX and FOLFOX-4 or 6. The only trial that used only FOLFOX was the Cancer and Leukemia Group B (CALGB) trial in the United States (US). There was a lot of heterogeneity, but when Dan was around, I asked him whether that was a problem, and he said on the contrary, was a better thing because it allowed for real-life practice.

The primary endpoint of the study was to look for noninferiority of 3 months versus 6 months of treatment. The noninferiority margin was at a hazard ratio of 1.12, so they were willing to barter down a few percentage points from benefit. If you looked at the primary disease-free survival analysis, the hazard ratio was 1.07, which was an absolute difference of 0.9%, favoring 3 months of therapy. But because the hazard ratio crossed the 1.12 boundary, it was considered inconclusive and not proven.

If you looked at the regimens, CAPOX outperformed FOLFOX. That’s a regimen we don’t do much in the US. We tend to use more FOLFOX, but CAPOX looked better. What they then did was look at the different subsets of patients, and the subsets that it was obviously as good in was the group that had T1-3N1 disease, where 3 months of therapy was clearly just as good as 6 months of therapy, with only a 3% risk of grade 3 neuropathy.
 

DR HENRY That would be one to three nodes?

DR HALLER Exactly. That’s about 50% of patients. In the T4N2 patients, neither regimen did very well and the 3-year disease-free survival was in the range of 50%, which is clearly unacceptable. Jeff discussed two things. Why could CAPOX be better? If you do the math, when you do CAPOX, you get more oxaliplatin during the first few months of therapy, because it’s 130 mg every 3 weeks, rather than 85 mg every 2 weeks. His conclusion was, “for my next patient who has T4N2 disease, I’ll offer 6 months of FOLFOX.” The study that really needs to be done in these patients is FOLFOX versus FOLFIRINOX (folinic acid, 5-FU, irinotecan, oxaliplatin) or FOLFOXIRI (folinic acid, 5-FU, oxaliplatin, irinotecan), because we’re clearly not doing well with this population of patients. But for the T1-3N1 disease, discuss the toxicities and logistics of CAPOX or FOLFOX with the patient. They’ll probably offer 3 months of CAPOX.

He discussed the two new trials. One is a study called ARGO, which is being done by the National Surgical Adjuvant Breast and Bowel Project, where people get standard adjuvant chemotherapy, and they’re then randomized to either 24 months of regorafenib 120 mg per day or a placebo. This is an attempt to recreate the transient benefit from bevacizumab in the NSABP C-08 trial. It’s accruing slowly because regorafenib has some toxicity associated with it, but it probably will be completed. Will it continue the benefit as seen in the 12 months of bevacizumab and C-08? We’ll see.

The other, more interesting study is being done in the cooperative groups looking at FOLFOX plus atezolizumab, one of the checkpoint inhibitors. The difficulty here is that only 15% of people with stage III disease have microsatellite instability (MSI)-high tumors, but it’s certainly compelling. This is a straight up comparison. It’s 6 months of FOLFOX in the control arm, or 6 months of FOLFOX plus atezolizumab concurrently for 6 months, and then an additional 6 months of atezolizumab. These are both very fascinating ideas.
 

DR HENRY To go back to one of your original points, this 3 versus 6 months: the neuropathy is significantly less in those getting the 3 months?
 

DR HALLER It went to 3%.
 

DR HENRY We all see that is very bothersome to patients. Before we leave colorectal, I must ask about the right-sided versus left-sided colorectal cancer that we hear a lot about now. Could you comment on how right-sided is worse than left-sided, and do we understand why?

DR HALLER There are two things to consider. If you look back even to simple trials of 5-FU or biochemical modulated 5-FU from 20 years ago, there were clear differences showing worse prognosis in patients with right-sided tumors, so that’s one point to be made. It’s been consistently seen but never acted upon. Then, the explanation for it, possibly, is that the right colon and left colon are two biologically different organs – and they are. Embryologically, the right colon comes from the midgut and the left colon comes from the hindgut, and there were several presentations at ASCO and at prior meetings showing that when you look at different mutations, they differ between the right and left colons. The right-sided tumors are more MSI-high and more BRAF-mutated, left-sided mutations less so.

Then, people started analyzing many of the very large colon cancer trials, including the US trial CALB/SWOG C80405 and the FIRE-3 trials in Europe, where backbone chemotherapy of FOLFIRI or FOLFOX was given with either cetuximab or bevacizumab in RAS wild-type patients. For one study, C80405, they saw that for cetuximab, on the right side, the median survival was 16.7 months and on the left side, it’s 36 months – a 20-month difference. In fact, if you look at the totality of the data, 16.7 almost looks like cetuximab is harming them, as if you were giving it to a RAS-mutated patient, but they were not. They were all RAS wild-type.

For bevacizumab, the right side was 24 months; the left side was 31.4 months. If you look at the left, cetuximab was 36 months and bevacizumab was 31.4 months, so it appears left-sided tumors should get more cetuximab than they are now getting in the US with a 5-month difference, but that decrement is much different on the right, where there’s an 8-month benefit for bevacizumab compared with cetuximab. There is a very good review by Dirk Arnold, who looked at a totality of 6 studies to really examine this more carefully.²

The National Comprehensive Cancer Network has chimed in on this, and is suggesting that for the 25% of people who have right-sided tumors, epidermal growth factor receptor (EGFR) agents not be considered in first-line therapy. NCCN did not go as far to say that EGFR agents should be given on the left side. As I said, the differences are much more impressive in the right, so this is a real sea change for people to consider which side of the tumor affects outcome.

Deb Schrag (Dana-Farber Cancer Institute) presented data at last year’s ASCO not only for stage IV disease showing the same thing, but also stage III disease where there are also right-versus-left differences in terms of recurrence, with a hazard ratio on the right side of about 1.4 compared with the left-sided tumors. Maybe it should be true that 3 months is especially good if you’re treating left-sided tumors, and maybe the right-sided tumor needs to be also calculated with the factors we just talked about. These are two big changes in an area in which we literally haven’t made any change since FOLFOX was introduced a decade ago.

DR HENRY That’s really fascinating, and if not practice changing, then practice challenging. Staying with the mutations idea, in my patients, I’m checking the RAS family and the BRAF mutation, where I’ve learned that’s a particularly bad mutation. I wonder if you might comment on the Kopetz trial, which took a cohort of BRAF mutants and treated them (Figure 2).3 How did that turn out?

DR HALLER It turned out well. We’re turning colon cancer into non–small cell lung cancer in that we’re getting small groups of patients who now have very dedicated care. The backstory here is that there was some thought that you should be treating mutations, not tumor sites. Drugs such as vemurafenib, for example, which is a BRAF inhibitor, worked well in melanoma for the same mutation that’s in colon cancer, V600E. But when vemurafenib was used in the BRAF-mutant patients – these are 10% of the population – median survivorship was one-third that of the rest of the patients, so roughly 12 months. People looked like they were doing worse when vemurafenib was used. They had no benefit.

Scott Kopetz at MD Anderson (Houston, Texas) is a very good bench-to-bed-and-back sort of doc. He looked at this in cell lines and found that when you give a BRAF inhibitor, you upregulate EGFR so you add an EGFR inhibitor. He did a phase 1 and 1B study, and then in the co-operative groups, a study was done – a randomized phase 2 trial for people who had the BRAF-V600E mutation failing first-line therapy, and then went on to receive either irinotecan single agent or irinotecan plus cetuximab or a triple arm of irinotecan, cetuximab, and vemurafenib. There was a crossover, and so the primary endpoint was progression-free survival. It accrued rapidly.

Again, small study, about 100 patients, but for the double-agent arm, or cetuximab–irinotecan, the median survivorship was 2 months. It was 4.4 months for the combination, so more than double. The response rate quadrupled from 4% to 16%, and the people who had disease control tripled, from 22% to 67%. Many of these patients had bulky disease, BRAF mutations. They need response, so this is a very important endpoint.

Overall survival was not different, in part because it was a crossover, and the crossover patients did pretty well. This is going to move more toward first-line therapy, because we don’t talk about fourth- and fifth-line therapies, TAS-102 or regorafenib. These patients don’t make it to even third line. We’re chipping away at what we think is a very homogenous group of peoples’ metastatic disease. They’re obviously not.

DR HENRY In the BRAF-mutant patient, the vemurafenib might drive them toward EGFR, and then the cetuximab could come in and handle that diversion of the pathway. Fascinating.

DR HALLER The preferred regimen in first-line therapy for a BRAF mutant might be FOLFIRI, cetuximab, and vemurafenib, especially on the left side.

DR HENRY Certainly makes sense. We’ll continue the theme at ASCO of “new standard of care.” Let’s move to gastroesophageal junction. There was a so-called FLOT (5-FU, leucovorin, oxaliplatin, Taxotere) presentation in the neoadjuvant/adjuvant setting, 4 cycles preoperatively and 4 cycles postoperatively. Could you comment on that study?

DR HALLER Gastric cancer for metastatic disease has a very large buffet of treatment regimens, and some just become entrenched, like the ECF regimen with epirubicin (epirubicin, cisplatin, 5-FU), where most people don’t exactly know what the contribution of that drug is, and so some people use EOX (epirubicin, oxaliplatin, capecitabine), some people use FOLFOX, some people use FOLFIRI. It gets a little bit confusing as to whether you use taxanes, platinums, or 5-FU or capecitabine.

The Germans came up with a regimen called FLOT – it’s sort of like FOLFOX with Taxotere attached. They did a very large study comparing it with ECF or ECX (epirubicin, cisplatin, capecitabine; Figure 3).⁴ The overall endpoint with over 700 patients was survival. This is an adjuvant regimen. Only 37% of people got ECF or ECX postoperatively, and 50% of the FLOT patients got the regimens postoperatively.

DR HENRY Indeed. Could you comment on the BILCAP study and adjuvant capecitabine for biliary tract cancer?

DR HALLER There are large meta-analyses looking at adjuvant therapy for biliary tract cancers typically from fairly small, fairly old studies that all suggest that in certain stages of resected biliary tumors, either bile duct or gall bladder, adjuvant treatment works, and typically either chemotherapy and radiotherapy, or chemotherapy alone, but not radiotherapy alone.

Capecitabine has been used for metastatic disease for years, mostly by default, and because most GI tumors have some response to fluoropyridines. But we’re finally able now to do large trials in biliary tumors, so this trial was a very large study with almost 450 patients from the United Kingdom over an 8-year period. About 20% were gallbladder, so the R0 surgery was about 60%, R1 at about 40% (Figure 4).⁶

DR HENRY Great data and a small population, but a population in need. That moves us on to pancreatic cancer, and I don’t know if this is happening nationwide, but in my practice, I’m seeing more. These patients tend to present beyond surgery, so they have metastatic or advanced pancreatic cancer. Any comment on where you think this field is going?

DR HALLER We were a bit bereft of new pancreatic cancer studies at ASCO this year. We’re certainly looking more at neoadjuvant therapy for pancreatic cancer, primarily because of ease of administration and the increased ability to tolerate treatments in the preoperative setting. There aren’t many people that get downstaged, but some are. Unfortunately, even in the MSI-high pancreas, which is a small subset, they don’t seem to get as big a bang out of the checkpoint inhibitors as in other tumor sites, so I’m afraid I didn’t come home with much new about this subset of patients.

DR HENRY We’ve covered a nice group of studies and practice-changing new standard-of-care comments from ASCO and other studies. Thank Dr Dan Haller for being with us and commenting. This podcast and discussion are brought to you from The Journal of Community and Supportive Oncology, the JCSO. I’m Dr David Henry, and you can listen to this and other archived articles or podcasts at JCSO-online.com. Thanks for listening.

DR HENRY I am Dr David Henry, the Editor-in-Chief of The Journal of Community and Supportive Oncology (JCSO; JCSO-online.com). I’m with Dr Dan Haller, former Editor-in-Chief of the Journal of Clinical Oncology and currently the Editor-in-Chief of American Society of Clinical Oncology (ASCO) University. He is also my friend and former mentor at University of Pennsylvania Abramson Cancer Center, where he is Professor Emeritus. We’re going to talk about colorectal cancer and a lot of things that came out of the ASCO meeting this year that were practice changing, or certainly interesting and worth further discussion. I thought we’d start talking about the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration, in which for patients with colorectal cancer who were considering adjuvant postoperative therapy, there was a discussion of 3 cycles versus 6 cycles of FOLFOX (fluorouracil [5-FU] plus oxaliplatin) or XELOX (capecitabine plus oxaliplatin, also CAPOX) (Figure 1).¹ Could you comment on what they did, and how that study turned out?

Three of them were individually reported at ASCO this year, and then the totality was presented at the plenary session – the first time in 12 years that a gastrointestinal (GI) cancer trial made the plenary session. The whole point, obviously, is neuropathy. With 6 months of FOLFOX or XELOX, about 13% or more patients will develop grade 3 neuropathy, even if people stop short of the full-cycle length, and that is a big deal for the 50,000 patients or so who get adjuvant therapy. At the plenary session, the data were presented and the next day three individual trials were presented and discussed by Jeff Meyerhardt (of Dana-Farber Cancer Institute, Boston).

There were 6 different trials: a few included rectum, some included stage II, some used CAPOX and FOLFOX-4 or 6. The only trial that used only FOLFOX was the Cancer and Leukemia Group B (CALGB) trial in the United States (US). There was a lot of heterogeneity, but when Dan was around, I asked him whether that was a problem, and he said on the contrary, was a better thing because it allowed for real-life practice.

The primary endpoint of the study was to look for noninferiority of 3 months versus 6 months of treatment. The noninferiority margin was at a hazard ratio of 1.12, so they were willing to barter down a few percentage points from benefit. If you looked at the primary disease-free survival analysis, the hazard ratio was 1.07, which was an absolute difference of 0.9%, favoring 3 months of therapy. But because the hazard ratio crossed the 1.12 boundary, it was considered inconclusive and not proven.

If you looked at the regimens, CAPOX outperformed FOLFOX. That’s a regimen we don’t do much in the US. We tend to use more FOLFOX, but CAPOX looked better. What they then did was look at the different subsets of patients, and the subsets that it was obviously as good in was the group that had T1-3N1 disease, where 3 months of therapy was clearly just as good as 6 months of therapy, with only a 3% risk of grade 3 neuropathy.
 

DR HENRY That would be one to three nodes?

DR HALLER Exactly. That’s about 50% of patients. In the T4N2 patients, neither regimen did very well and the 3-year disease-free survival was in the range of 50%, which is clearly unacceptable. Jeff discussed two things. Why could CAPOX be better? If you do the math, when you do CAPOX, you get more oxaliplatin during the first few months of therapy, because it’s 130 mg every 3 weeks, rather than 85 mg every 2 weeks. His conclusion was, “for my next patient who has T4N2 disease, I’ll offer 6 months of FOLFOX.” The study that really needs to be done in these patients is FOLFOX versus FOLFIRINOX (folinic acid, 5-FU, irinotecan, oxaliplatin) or FOLFOXIRI (folinic acid, 5-FU, oxaliplatin, irinotecan), because we’re clearly not doing well with this population of patients. But for the T1-3N1 disease, discuss the toxicities and logistics of CAPOX or FOLFOX with the patient. They’ll probably offer 3 months of CAPOX.

He discussed the two new trials. One is a study called ARGO, which is being done by the National Surgical Adjuvant Breast and Bowel Project, where people get standard adjuvant chemotherapy, and they’re then randomized to either 24 months of regorafenib 120 mg per day or a placebo. This is an attempt to recreate the transient benefit from bevacizumab in the NSABP C-08 trial. It’s accruing slowly because regorafenib has some toxicity associated with it, but it probably will be completed. Will it continue the benefit as seen in the 12 months of bevacizumab and C-08? We’ll see.

The other, more interesting study is being done in the cooperative groups looking at FOLFOX plus atezolizumab, one of the checkpoint inhibitors. The difficulty here is that only 15% of people with stage III disease have microsatellite instability (MSI)-high tumors, but it’s certainly compelling. This is a straight up comparison. It’s 6 months of FOLFOX in the control arm, or 6 months of FOLFOX plus atezolizumab concurrently for 6 months, and then an additional 6 months of atezolizumab. These are both very fascinating ideas.
 

DR HENRY To go back to one of your original points, this 3 versus 6 months: the neuropathy is significantly less in those getting the 3 months?
 

DR HALLER It went to 3%.
 

DR HENRY We all see that is very bothersome to patients. Before we leave colorectal, I must ask about the right-sided versus left-sided colorectal cancer that we hear a lot about now. Could you comment on how right-sided is worse than left-sided, and do we understand why?

DR HALLER There are two things to consider. If you look back even to simple trials of 5-FU or biochemical modulated 5-FU from 20 years ago, there were clear differences showing worse prognosis in patients with right-sided tumors, so that’s one point to be made. It’s been consistently seen but never acted upon. Then, the explanation for it, possibly, is that the right colon and left colon are two biologically different organs – and they are. Embryologically, the right colon comes from the midgut and the left colon comes from the hindgut, and there were several presentations at ASCO and at prior meetings showing that when you look at different mutations, they differ between the right and left colons. The right-sided tumors are more MSI-high and more BRAF-mutated, left-sided mutations less so.

Then, people started analyzing many of the very large colon cancer trials, including the US trial CALB/SWOG C80405 and the FIRE-3 trials in Europe, where backbone chemotherapy of FOLFIRI or FOLFOX was given with either cetuximab or bevacizumab in RAS wild-type patients. For one study, C80405, they saw that for cetuximab, on the right side, the median survival was 16.7 months and on the left side, it’s 36 months – a 20-month difference. In fact, if you look at the totality of the data, 16.7 almost looks like cetuximab is harming them, as if you were giving it to a RAS-mutated patient, but they were not. They were all RAS wild-type.

For bevacizumab, the right side was 24 months; the left side was 31.4 months. If you look at the left, cetuximab was 36 months and bevacizumab was 31.4 months, so it appears left-sided tumors should get more cetuximab than they are now getting in the US with a 5-month difference, but that decrement is much different on the right, where there’s an 8-month benefit for bevacizumab compared with cetuximab. There is a very good review by Dirk Arnold, who looked at a totality of 6 studies to really examine this more carefully.²

The National Comprehensive Cancer Network has chimed in on this, and is suggesting that for the 25% of people who have right-sided tumors, epidermal growth factor receptor (EGFR) agents not be considered in first-line therapy. NCCN did not go as far to say that EGFR agents should be given on the left side. As I said, the differences are much more impressive in the right, so this is a real sea change for people to consider which side of the tumor affects outcome.

Deb Schrag (Dana-Farber Cancer Institute) presented data at last year’s ASCO not only for stage IV disease showing the same thing, but also stage III disease where there are also right-versus-left differences in terms of recurrence, with a hazard ratio on the right side of about 1.4 compared with the left-sided tumors. Maybe it should be true that 3 months is especially good if you’re treating left-sided tumors, and maybe the right-sided tumor needs to be also calculated with the factors we just talked about. These are two big changes in an area in which we literally haven’t made any change since FOLFOX was introduced a decade ago.

DR HENRY That’s really fascinating, and if not practice changing, then practice challenging. Staying with the mutations idea, in my patients, I’m checking the RAS family and the BRAF mutation, where I’ve learned that’s a particularly bad mutation. I wonder if you might comment on the Kopetz trial, which took a cohort of BRAF mutants and treated them (Figure 2).3 How did that turn out?

DR HALLER It turned out well. We’re turning colon cancer into non–small cell lung cancer in that we’re getting small groups of patients who now have very dedicated care. The backstory here is that there was some thought that you should be treating mutations, not tumor sites. Drugs such as vemurafenib, for example, which is a BRAF inhibitor, worked well in melanoma for the same mutation that’s in colon cancer, V600E. But when vemurafenib was used in the BRAF-mutant patients – these are 10% of the population – median survivorship was one-third that of the rest of the patients, so roughly 12 months. People looked like they were doing worse when vemurafenib was used. They had no benefit.

Scott Kopetz at MD Anderson (Houston, Texas) is a very good bench-to-bed-and-back sort of doc. He looked at this in cell lines and found that when you give a BRAF inhibitor, you upregulate EGFR so you add an EGFR inhibitor. He did a phase 1 and 1B study, and then in the co-operative groups, a study was done – a randomized phase 2 trial for people who had the BRAF-V600E mutation failing first-line therapy, and then went on to receive either irinotecan single agent or irinotecan plus cetuximab or a triple arm of irinotecan, cetuximab, and vemurafenib. There was a crossover, and so the primary endpoint was progression-free survival. It accrued rapidly.

Again, small study, about 100 patients, but for the double-agent arm, or cetuximab–irinotecan, the median survivorship was 2 months. It was 4.4 months for the combination, so more than double. The response rate quadrupled from 4% to 16%, and the people who had disease control tripled, from 22% to 67%. Many of these patients had bulky disease, BRAF mutations. They need response, so this is a very important endpoint.

Overall survival was not different, in part because it was a crossover, and the crossover patients did pretty well. This is going to move more toward first-line therapy, because we don’t talk about fourth- and fifth-line therapies, TAS-102 or regorafenib. These patients don’t make it to even third line. We’re chipping away at what we think is a very homogenous group of peoples’ metastatic disease. They’re obviously not.

DR HENRY In the BRAF-mutant patient, the vemurafenib might drive them toward EGFR, and then the cetuximab could come in and handle that diversion of the pathway. Fascinating.

DR HALLER The preferred regimen in first-line therapy for a BRAF mutant might be FOLFIRI, cetuximab, and vemurafenib, especially on the left side.

DR HENRY Certainly makes sense. We’ll continue the theme at ASCO of “new standard of care.” Let’s move to gastroesophageal junction. There was a so-called FLOT (5-FU, leucovorin, oxaliplatin, Taxotere) presentation in the neoadjuvant/adjuvant setting, 4 cycles preoperatively and 4 cycles postoperatively. Could you comment on that study?

DR HALLER Gastric cancer for metastatic disease has a very large buffet of treatment regimens, and some just become entrenched, like the ECF regimen with epirubicin (epirubicin, cisplatin, 5-FU), where most people don’t exactly know what the contribution of that drug is, and so some people use EOX (epirubicin, oxaliplatin, capecitabine), some people use FOLFOX, some people use FOLFIRI. It gets a little bit confusing as to whether you use taxanes, platinums, or 5-FU or capecitabine.

The Germans came up with a regimen called FLOT – it’s sort of like FOLFOX with Taxotere attached. They did a very large study comparing it with ECF or ECX (epirubicin, cisplatin, capecitabine; Figure 3).⁴ The overall endpoint with over 700 patients was survival. This is an adjuvant regimen. Only 37% of people got ECF or ECX postoperatively, and 50% of the FLOT patients got the regimens postoperatively.

DR HENRY Indeed. Could you comment on the BILCAP study and adjuvant capecitabine for biliary tract cancer?

DR HALLER There are large meta-analyses looking at adjuvant therapy for biliary tract cancers typically from fairly small, fairly old studies that all suggest that in certain stages of resected biliary tumors, either bile duct or gall bladder, adjuvant treatment works, and typically either chemotherapy and radiotherapy, or chemotherapy alone, but not radiotherapy alone.

Capecitabine has been used for metastatic disease for years, mostly by default, and because most GI tumors have some response to fluoropyridines. But we’re finally able now to do large trials in biliary tumors, so this trial was a very large study with almost 450 patients from the United Kingdom over an 8-year period. About 20% were gallbladder, so the R0 surgery was about 60%, R1 at about 40% (Figure 4).⁶

DR HENRY Great data and a small population, but a population in need. That moves us on to pancreatic cancer, and I don’t know if this is happening nationwide, but in my practice, I’m seeing more. These patients tend to present beyond surgery, so they have metastatic or advanced pancreatic cancer. Any comment on where you think this field is going?

DR HALLER We were a bit bereft of new pancreatic cancer studies at ASCO this year. We’re certainly looking more at neoadjuvant therapy for pancreatic cancer, primarily because of ease of administration and the increased ability to tolerate treatments in the preoperative setting. There aren’t many people that get downstaged, but some are. Unfortunately, even in the MSI-high pancreas, which is a small subset, they don’t seem to get as big a bang out of the checkpoint inhibitors as in other tumor sites, so I’m afraid I didn’t come home with much new about this subset of patients.

DR HENRY We’ve covered a nice group of studies and practice-changing new standard-of-care comments from ASCO and other studies. Thank Dr Dan Haller for being with us and commenting. This podcast and discussion are brought to you from The Journal of Community and Supportive Oncology, the JCSO. I’m Dr David Henry, and you can listen to this and other archived articles or podcasts at JCSO-online.com. Thanks for listening.

DR HENRY I am Dr David Henry, the Editor-in-Chief of The Journal of Community and Supportive Oncology (JCSO; JCSO-online.com). I’m with Dr Dan Haller, former Editor-in-Chief of the Journal of Clinical Oncology and currently the Editor-in-Chief of American Society of Clinical Oncology (ASCO) University. He is also my friend and former mentor at University of Pennsylvania Abramson Cancer Center, where he is Professor Emeritus. We’re going to talk about colorectal cancer and a lot of things that came out of the ASCO meeting this year that were practice changing, or certainly interesting and worth further discussion. I thought we’d start talking about the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration, in which for patients with colorectal cancer who were considering adjuvant postoperative therapy, there was a discussion of 3 cycles versus 6 cycles of FOLFOX (fluorouracil [5-FU] plus oxaliplatin) or XELOX (capecitabine plus oxaliplatin, also CAPOX) (Figure 1).¹ Could you comment on what they did, and how that study turned out?

Three of them were individually reported at ASCO this year, and then the totality was presented at the plenary session – the first time in 12 years that a gastrointestinal (GI) cancer trial made the plenary session. The whole point, obviously, is neuropathy. With 6 months of FOLFOX or XELOX, about 13% or more patients will develop grade 3 neuropathy, even if people stop short of the full-cycle length, and that is a big deal for the 50,000 patients or so who get adjuvant therapy. At the plenary session, the data were presented and the next day three individual trials were presented and discussed by Jeff Meyerhardt (of Dana-Farber Cancer Institute, Boston).

There were 6 different trials: a few included rectum, some included stage II, some used CAPOX and FOLFOX-4 or 6. The only trial that used only FOLFOX was the Cancer and Leukemia Group B (CALGB) trial in the United States (US). There was a lot of heterogeneity, but when Dan was around, I asked him whether that was a problem, and he said on the contrary, was a better thing because it allowed for real-life practice.

The primary endpoint of the study was to look for noninferiority of 3 months versus 6 months of treatment. The noninferiority margin was at a hazard ratio of 1.12, so they were willing to barter down a few percentage points from benefit. If you looked at the primary disease-free survival analysis, the hazard ratio was 1.07, which was an absolute difference of 0.9%, favoring 3 months of therapy. But because the hazard ratio crossed the 1.12 boundary, it was considered inconclusive and not proven.

If you looked at the regimens, CAPOX outperformed FOLFOX. That’s a regimen we don’t do much in the US. We tend to use more FOLFOX, but CAPOX looked better. What they then did was look at the different subsets of patients, and the subsets that it was obviously as good in was the group that had T1-3N1 disease, where 3 months of therapy was clearly just as good as 6 months of therapy, with only a 3% risk of grade 3 neuropathy.
 

DR HENRY That would be one to three nodes?

DR HALLER Exactly. That’s about 50% of patients. In the T4N2 patients, neither regimen did very well and the 3-year disease-free survival was in the range of 50%, which is clearly unacceptable. Jeff discussed two things. Why could CAPOX be better? If you do the math, when you do CAPOX, you get more oxaliplatin during the first few months of therapy, because it’s 130 mg every 3 weeks, rather than 85 mg every 2 weeks. His conclusion was, “for my next patient who has T4N2 disease, I’ll offer 6 months of FOLFOX.” The study that really needs to be done in these patients is FOLFOX versus FOLFIRINOX (folinic acid, 5-FU, irinotecan, oxaliplatin) or FOLFOXIRI (folinic acid, 5-FU, oxaliplatin, irinotecan), because we’re clearly not doing well with this population of patients. But for the T1-3N1 disease, discuss the toxicities and logistics of CAPOX or FOLFOX with the patient. They’ll probably offer 3 months of CAPOX.

He discussed the two new trials. One is a study called ARGO, which is being done by the National Surgical Adjuvant Breast and Bowel Project, where people get standard adjuvant chemotherapy, and they’re then randomized to either 24 months of regorafenib 120 mg per day or a placebo. This is an attempt to recreate the transient benefit from bevacizumab in the NSABP C-08 trial. It’s accruing slowly because regorafenib has some toxicity associated with it, but it probably will be completed. Will it continue the benefit as seen in the 12 months of bevacizumab and C-08? We’ll see.

The other, more interesting study is being done in the cooperative groups looking at FOLFOX plus atezolizumab, one of the checkpoint inhibitors. The difficulty here is that only 15% of people with stage III disease have microsatellite instability (MSI)-high tumors, but it’s certainly compelling. This is a straight up comparison. It’s 6 months of FOLFOX in the control arm, or 6 months of FOLFOX plus atezolizumab concurrently for 6 months, and then an additional 6 months of atezolizumab. These are both very fascinating ideas.
 

DR HENRY To go back to one of your original points, this 3 versus 6 months: the neuropathy is significantly less in those getting the 3 months?
 

DR HALLER It went to 3%.
 

DR HENRY We all see that is very bothersome to patients. Before we leave colorectal, I must ask about the right-sided versus left-sided colorectal cancer that we hear a lot about now. Could you comment on how right-sided is worse than left-sided, and do we understand why?

DR HALLER There are two things to consider. If you look back even to simple trials of 5-FU or biochemical modulated 5-FU from 20 years ago, there were clear differences showing worse prognosis in patients with right-sided tumors, so that’s one point to be made. It’s been consistently seen but never acted upon. Then, the explanation for it, possibly, is that the right colon and left colon are two biologically different organs – and they are. Embryologically, the right colon comes from the midgut and the left colon comes from the hindgut, and there were several presentations at ASCO and at prior meetings showing that when you look at different mutations, they differ between the right and left colons. The right-sided tumors are more MSI-high and more BRAF-mutated, left-sided mutations less so.

Then, people started analyzing many of the very large colon cancer trials, including the US trial CALB/SWOG C80405 and the FIRE-3 trials in Europe, where backbone chemotherapy of FOLFIRI or FOLFOX was given with either cetuximab or bevacizumab in RAS wild-type patients. For one study, C80405, they saw that for cetuximab, on the right side, the median survival was 16.7 months and on the left side, it’s 36 months – a 20-month difference. In fact, if you look at the totality of the data, 16.7 almost looks like cetuximab is harming them, as if you were giving it to a RAS-mutated patient, but they were not. They were all RAS wild-type.

For bevacizumab, the right side was 24 months; the left side was 31.4 months. If you look at the left, cetuximab was 36 months and bevacizumab was 31.4 months, so it appears left-sided tumors should get more cetuximab than they are now getting in the US with a 5-month difference, but that decrement is much different on the right, where there’s an 8-month benefit for bevacizumab compared with cetuximab. There is a very good review by Dirk Arnold, who looked at a totality of 6 studies to really examine this more carefully.²

The National Comprehensive Cancer Network has chimed in on this, and is suggesting that for the 25% of people who have right-sided tumors, epidermal growth factor receptor (EGFR) agents not be considered in first-line therapy. NCCN did not go as far to say that EGFR agents should be given on the left side. As I said, the differences are much more impressive in the right, so this is a real sea change for people to consider which side of the tumor affects outcome.

Deb Schrag (Dana-Farber Cancer Institute) presented data at last year’s ASCO not only for stage IV disease showing the same thing, but also stage III disease where there are also right-versus-left differences in terms of recurrence, with a hazard ratio on the right side of about 1.4 compared with the left-sided tumors. Maybe it should be true that 3 months is especially good if you’re treating left-sided tumors, and maybe the right-sided tumor needs to be also calculated with the factors we just talked about. These are two big changes in an area in which we literally haven’t made any change since FOLFOX was introduced a decade ago.

DR HENRY That’s really fascinating, and if not practice changing, then practice challenging. Staying with the mutations idea, in my patients, I’m checking the RAS family and the BRAF mutation, where I’ve learned that’s a particularly bad mutation. I wonder if you might comment on the Kopetz trial, which took a cohort of BRAF mutants and treated them (Figure 2).3 How did that turn out?

DR HALLER It turned out well. We’re turning colon cancer into non–small cell lung cancer in that we’re getting small groups of patients who now have very dedicated care. The backstory here is that there was some thought that you should be treating mutations, not tumor sites. Drugs such as vemurafenib, for example, which is a BRAF inhibitor, worked well in melanoma for the same mutation that’s in colon cancer, V600E. But when vemurafenib was used in the BRAF-mutant patients – these are 10% of the population – median survivorship was one-third that of the rest of the patients, so roughly 12 months. People looked like they were doing worse when vemurafenib was used. They had no benefit.

Scott Kopetz at MD Anderson (Houston, Texas) is a very good bench-to-bed-and-back sort of doc. He looked at this in cell lines and found that when you give a BRAF inhibitor, you upregulate EGFR so you add an EGFR inhibitor. He did a phase 1 and 1B study, and then in the co-operative groups, a study was done – a randomized phase 2 trial for people who had the BRAF-V600E mutation failing first-line therapy, and then went on to receive either irinotecan single agent or irinotecan plus cetuximab or a triple arm of irinotecan, cetuximab, and vemurafenib. There was a crossover, and so the primary endpoint was progression-free survival. It accrued rapidly.

Again, small study, about 100 patients, but for the double-agent arm, or cetuximab–irinotecan, the median survivorship was 2 months. It was 4.4 months for the combination, so more than double. The response rate quadrupled from 4% to 16%, and the people who had disease control tripled, from 22% to 67%. Many of these patients had bulky disease, BRAF mutations. They need response, so this is a very important endpoint.

Overall survival was not different, in part because it was a crossover, and the crossover patients did pretty well. This is going to move more toward first-line therapy, because we don’t talk about fourth- and fifth-line therapies, TAS-102 or regorafenib. These patients don’t make it to even third line. We’re chipping away at what we think is a very homogenous group of peoples’ metastatic disease. They’re obviously not.

DR HENRY In the BRAF-mutant patient, the vemurafenib might drive them toward EGFR, and then the cetuximab could come in and handle that diversion of the pathway. Fascinating.

DR HALLER The preferred regimen in first-line therapy for a BRAF mutant might be FOLFIRI, cetuximab, and vemurafenib, especially on the left side.

DR HENRY Certainly makes sense. We’ll continue the theme at ASCO of “new standard of care.” Let’s move to gastroesophageal junction. There was a so-called FLOT (5-FU, leucovorin, oxaliplatin, Taxotere) presentation in the neoadjuvant/adjuvant setting, 4 cycles preoperatively and 4 cycles postoperatively. Could you comment on that study?

DR HALLER Gastric cancer for metastatic disease has a very large buffet of treatment regimens, and some just become entrenched, like the ECF regimen with epirubicin (epirubicin, cisplatin, 5-FU), where most people don’t exactly know what the contribution of that drug is, and so some people use EOX (epirubicin, oxaliplatin, capecitabine), some people use FOLFOX, some people use FOLFIRI. It gets a little bit confusing as to whether you use taxanes, platinums, or 5-FU or capecitabine.

The Germans came up with a regimen called FLOT – it’s sort of like FOLFOX with Taxotere attached. They did a very large study comparing it with ECF or ECX (epirubicin, cisplatin, capecitabine; Figure 3).⁴ The overall endpoint with over 700 patients was survival. This is an adjuvant regimen. Only 37% of people got ECF or ECX postoperatively, and 50% of the FLOT patients got the regimens postoperatively.

DR HENRY Indeed. Could you comment on the BILCAP study and adjuvant capecitabine for biliary tract cancer?

DR HALLER There are large meta-analyses looking at adjuvant therapy for biliary tract cancers typically from fairly small, fairly old studies that all suggest that in certain stages of resected biliary tumors, either bile duct or gall bladder, adjuvant treatment works, and typically either chemotherapy and radiotherapy, or chemotherapy alone, but not radiotherapy alone.

Capecitabine has been used for metastatic disease for years, mostly by default, and because most GI tumors have some response to fluoropyridines. But we’re finally able now to do large trials in biliary tumors, so this trial was a very large study with almost 450 patients from the United Kingdom over an 8-year period. About 20% were gallbladder, so the R0 surgery was about 60%, R1 at about 40% (Figure 4).⁶

DR HENRY Great data and a small population, but a population in need. That moves us on to pancreatic cancer, and I don’t know if this is happening nationwide, but in my practice, I’m seeing more. These patients tend to present beyond surgery, so they have metastatic or advanced pancreatic cancer. Any comment on where you think this field is going?

DR HALLER We were a bit bereft of new pancreatic cancer studies at ASCO this year. We’re certainly looking more at neoadjuvant therapy for pancreatic cancer, primarily because of ease of administration and the increased ability to tolerate treatments in the preoperative setting. There aren’t many people that get downstaged, but some are. Unfortunately, even in the MSI-high pancreas, which is a small subset, they don’t seem to get as big a bang out of the checkpoint inhibitors as in other tumor sites, so I’m afraid I didn’t come home with much new about this subset of patients.

DR HENRY We’ve covered a nice group of studies and practice-changing new standard-of-care comments from ASCO and other studies. Thank Dr Dan Haller for being with us and commenting. This podcast and discussion are brought to you from The Journal of Community and Supportive Oncology, the JCSO. I’m Dr David Henry, and you can listen to this and other archived articles or podcasts at JCSO-online.com. Thanks for listening.

Women with relapsing-remitting multiple sclerosis (MS) who discontinue natalizumab treatment before pregnancy may have increased disease activity, according to a study published March 6 in Neurology. In addition, taking natalizumab during the first trimester of pregnancy increases the risk of miscarriage, although the risk remains similar to that of the general population, according to an accompanying study.

An Analysis of Pregnancy Data

Emilio Portaccio, MD, of the Don Carlo Gnocchi Foundation in Florence, Italy, and colleagues analyzed data for all pregnancies between 2009 and 2015 in patients with MS who presented to 19 Italian sites. They compared data for 83 patients receiving natalizumab with those for 350 control patients who were receiving injectable immunomodulatory agents or no treatment. The investigators followed up with the women every six months, at each relapse, and at one year after birth.

The patients receiving natalizumab had 92 pregnancies. Approximately 37% of women receiving natalizumab had at least one relapse during pregnancy, compared with 10% of controls. Relapse rate during pregnancy was higher among patients whose last infusion occurred before the last menstrual period (55.9%) than among patients whose last infusion occurred after the last menstrual period (20%) or controls (10%). Receiving the last natalizumab infusion before the last menstrual period was the only predictor of relapse during pregnancy. In the first trimester after delivery, the rate of relapse was 21.7% in natalizumab-treated patients and 13.7% in controls.

Twelve patients had disability worsening at the end of the one-year follow-up. In 11 of these patients, disability accumulation resulted from relapses during pregnancy or after delivery. Disease progression was reduced in patients for whom medication was reintroduced earlier after delivery.

About 75% of pregnancies in women receiving natalizumab had treatment exposure, and the mean duration of exposure was 1.2 weeks. The odds ratio of spontaneous abortion was 3.9 among patients receiving natalizumab, compared with controls. The rate of spontaneous abortion among natalizumab-treated patients (17.4%) was similar to that observed for the general Italian population (14%), however. The rate of major congenital anomalies was 3.7% in patients exposed to natalizumab, 1.3% in patients exposed to interferon beta, and 0.9% in untreated patients. The differences between groups were not significant. Exposure to natalizumab and exposure to interferon beta were associated with a lower length of the newborn.

Relapse Severity Was Not Measured

One limitation of the studies is that the women treated with natalizumab may have been different from women not treated with natalizumab in ways that the investigators did not measure. In addition, the researchers did not measure relapse severity.

“Our findings suggest that if women who take natalizumab for MS want to become pregnant, it may be best to continue treatment up until a pregnancy test is positive and then at that point discontinue use,” said Dr. Portaccio. “While there is still a risk of increased disease activity, this course of action may lower that risk.”

—Erik Greb

Suggested Reading

Portaccio E, Annovazzi P, Ghezzi A, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: I: Fetal risks. Neurology. 2018;90(10):e823-e831.

Portaccio E, Moiola L, Martinelli V, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: II: Maternal risks. Neurology. 2018;90(10):e832-e839.

Women with relapsing-remitting multiple sclerosis (MS) who discontinue natalizumab treatment before pregnancy may have increased disease activity, according to a study published March 6 in Neurology. In addition, taking natalizumab during the first trimester of pregnancy increases the risk of miscarriage, although the risk remains similar to that of the general population, according to an accompanying study.

An Analysis of Pregnancy Data

Emilio Portaccio, MD, of the Don Carlo Gnocchi Foundation in Florence, Italy, and colleagues analyzed data for all pregnancies between 2009 and 2015 in patients with MS who presented to 19 Italian sites. They compared data for 83 patients receiving natalizumab with those for 350 control patients who were receiving injectable immunomodulatory agents or no treatment. The investigators followed up with the women every six months, at each relapse, and at one year after birth.

The patients receiving natalizumab had 92 pregnancies. Approximately 37% of women receiving natalizumab had at least one relapse during pregnancy, compared with 10% of controls. Relapse rate during pregnancy was higher among patients whose last infusion occurred before the last menstrual period (55.9%) than among patients whose last infusion occurred after the last menstrual period (20%) or controls (10%). Receiving the last natalizumab infusion before the last menstrual period was the only predictor of relapse during pregnancy. In the first trimester after delivery, the rate of relapse was 21.7% in natalizumab-treated patients and 13.7% in controls.

Twelve patients had disability worsening at the end of the one-year follow-up. In 11 of these patients, disability accumulation resulted from relapses during pregnancy or after delivery. Disease progression was reduced in patients for whom medication was reintroduced earlier after delivery.

About 75% of pregnancies in women receiving natalizumab had treatment exposure, and the mean duration of exposure was 1.2 weeks. The odds ratio of spontaneous abortion was 3.9 among patients receiving natalizumab, compared with controls. The rate of spontaneous abortion among natalizumab-treated patients (17.4%) was similar to that observed for the general Italian population (14%), however. The rate of major congenital anomalies was 3.7% in patients exposed to natalizumab, 1.3% in patients exposed to interferon beta, and 0.9% in untreated patients. The differences between groups were not significant. Exposure to natalizumab and exposure to interferon beta were associated with a lower length of the newborn.

Relapse Severity Was Not Measured

One limitation of the studies is that the women treated with natalizumab may have been different from women not treated with natalizumab in ways that the investigators did not measure. In addition, the researchers did not measure relapse severity.

“Our findings suggest that if women who take natalizumab for MS want to become pregnant, it may be best to continue treatment up until a pregnancy test is positive and then at that point discontinue use,” said Dr. Portaccio. “While there is still a risk of increased disease activity, this course of action may lower that risk.”

—Erik Greb

Suggested Reading

Portaccio E, Annovazzi P, Ghezzi A, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: I: Fetal risks. Neurology. 2018;90(10):e823-e831.

Portaccio E, Moiola L, Martinelli V, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: II: Maternal risks. Neurology. 2018;90(10):e832-e839.

Women with relapsing-remitting multiple sclerosis (MS) who discontinue natalizumab treatment before pregnancy may have increased disease activity, according to a study published March 6 in Neurology. In addition, taking natalizumab during the first trimester of pregnancy increases the risk of miscarriage, although the risk remains similar to that of the general population, according to an accompanying study.

An Analysis of Pregnancy Data

Emilio Portaccio, MD, of the Don Carlo Gnocchi Foundation in Florence, Italy, and colleagues analyzed data for all pregnancies between 2009 and 2015 in patients with MS who presented to 19 Italian sites. They compared data for 83 patients receiving natalizumab with those for 350 control patients who were receiving injectable immunomodulatory agents or no treatment. The investigators followed up with the women every six months, at each relapse, and at one year after birth.

The patients receiving natalizumab had 92 pregnancies. Approximately 37% of women receiving natalizumab had at least one relapse during pregnancy, compared with 10% of controls. Relapse rate during pregnancy was higher among patients whose last infusion occurred before the last menstrual period (55.9%) than among patients whose last infusion occurred after the last menstrual period (20%) or controls (10%). Receiving the last natalizumab infusion before the last menstrual period was the only predictor of relapse during pregnancy. In the first trimester after delivery, the rate of relapse was 21.7% in natalizumab-treated patients and 13.7% in controls.

Twelve patients had disability worsening at the end of the one-year follow-up. In 11 of these patients, disability accumulation resulted from relapses during pregnancy or after delivery. Disease progression was reduced in patients for whom medication was reintroduced earlier after delivery.

About 75% of pregnancies in women receiving natalizumab had treatment exposure, and the mean duration of exposure was 1.2 weeks. The odds ratio of spontaneous abortion was 3.9 among patients receiving natalizumab, compared with controls. The rate of spontaneous abortion among natalizumab-treated patients (17.4%) was similar to that observed for the general Italian population (14%), however. The rate of major congenital anomalies was 3.7% in patients exposed to natalizumab, 1.3% in patients exposed to interferon beta, and 0.9% in untreated patients. The differences between groups were not significant. Exposure to natalizumab and exposure to interferon beta were associated with a lower length of the newborn.

Relapse Severity Was Not Measured

One limitation of the studies is that the women treated with natalizumab may have been different from women not treated with natalizumab in ways that the investigators did not measure. In addition, the researchers did not measure relapse severity.

“Our findings suggest that if women who take natalizumab for MS want to become pregnant, it may be best to continue treatment up until a pregnancy test is positive and then at that point discontinue use,” said Dr. Portaccio. “While there is still a risk of increased disease activity, this course of action may lower that risk.”

—Erik Greb

Suggested Reading

Portaccio E, Annovazzi P, Ghezzi A, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: I: Fetal risks. Neurology. 2018;90(10):e823-e831.

Portaccio E, Moiola L, Martinelli V, et al. Pregnancy decision-making in women with multiple sclerosis treated with natalizumab: II: Maternal risks. Neurology. 2018;90(10):e832-e839.

Prophylactic haloperidol did not prevent delirium or improve survival in a placebo-controlled trial of 1,789 critically ill adults at 21 ICUs in the Netherlands, according to research published in the February 20 issue of JAMA.

“These findings do not support the use of prophylactic haloperidol in critically ill adults,” said Mark van den Boogaard, PhD, Assistant Professor of Intensive Care Medicine at Radboud University Medical Center in Nijmegen, the Netherlands.

Haloperidol is used routinely in ICUs to treat and prevent delirium, which affects as many as half of ICU patients and is associated with prolonged mechanical ventilation, longer ICU and hospital stays, and increased mortality. Results of past studies of haloperidol in the ICU have been mixed.

For this study, eligible participants were expected to be in the ICU for at least two days and were not delirious at baseline. Patients were randomized to receive 1 mg of haloperidol (n = 350), 2 mg of haloperidol (n = 732), or placebo (n = 707) three times daily. The 1-mg haloperidol arm was stopped early because of futility. The ICUs also used nonpharmacologic interventions to prevent delirium, including early mobilization and noise reduction.

Patients had a mean age of 66.6; 61.4% were men. Most of the ICU admissions were urgent and for medical or surgical reasons. There was no statistically significant difference in survival at 28 days following entrance into the study, which was the study’s primary end point. At that point, 83.3% of the patients who received 2-mg doses of haloperidol and 82.7% of the subjects who received placebo had survived.

Prophylactic haloperidol had no effect on reducing the incidence of delirium, which was diagnosed in 33.3% of patients who received haloperidol and 33.0% of patients who received placebo. Likewise, there were no significant differences between the groups in the number of delirium-free and coma-free days, duration of mechanical ventilation, and ICU and hospital length of stay.

“The study population included severely ill ICU adults whose brains may have been too seriously affected for haloperidol to exert a prophylactic effect, since in non-ICU adults, prophylactic haloperidol may have beneficial effects. But the subgroup of patients with a low severity of illness score also demonstrated no beneficial effects,” the investigators said.

—M. Alexander Otto

Suggested Reading

van den Boogaard M, Slooter AJC, Brüggemann RJM, et al. Effect of haloperidol on survival among critically ill adults with a high risk of delirium: The REDUCE randomized clinical trial. JAMA. 2018;319(7):680-690.

Prophylactic haloperidol did not prevent delirium or improve survival in a placebo-controlled trial of 1,789 critically ill adults at 21 ICUs in the Netherlands, according to research published in the February 20 issue of JAMA.

“These findings do not support the use of prophylactic haloperidol in critically ill adults,” said Mark van den Boogaard, PhD, Assistant Professor of Intensive Care Medicine at Radboud University Medical Center in Nijmegen, the Netherlands.

Haloperidol is used routinely in ICUs to treat and prevent delirium, which affects as many as half of ICU patients and is associated with prolonged mechanical ventilation, longer ICU and hospital stays, and increased mortality. Results of past studies of haloperidol in the ICU have been mixed.

For this study, eligible participants were expected to be in the ICU for at least two days and were not delirious at baseline. Patients were randomized to receive 1 mg of haloperidol (n = 350), 2 mg of haloperidol (n = 732), or placebo (n = 707) three times daily. The 1-mg haloperidol arm was stopped early because of futility. The ICUs also used nonpharmacologic interventions to prevent delirium, including early mobilization and noise reduction.

Patients had a mean age of 66.6; 61.4% were men. Most of the ICU admissions were urgent and for medical or surgical reasons. There was no statistically significant difference in survival at 28 days following entrance into the study, which was the study’s primary end point. At that point, 83.3% of the patients who received 2-mg doses of haloperidol and 82.7% of the subjects who received placebo had survived.

Prophylactic haloperidol had no effect on reducing the incidence of delirium, which was diagnosed in 33.3% of patients who received haloperidol and 33.0% of patients who received placebo. Likewise, there were no significant differences between the groups in the number of delirium-free and coma-free days, duration of mechanical ventilation, and ICU and hospital length of stay.

“The study population included severely ill ICU adults whose brains may have been too seriously affected for haloperidol to exert a prophylactic effect, since in non-ICU adults, prophylactic haloperidol may have beneficial effects. But the subgroup of patients with a low severity of illness score also demonstrated no beneficial effects,” the investigators said.

—M. Alexander Otto

Suggested Reading

van den Boogaard M, Slooter AJC, Brüggemann RJM, et al. Effect of haloperidol on survival among critically ill adults with a high risk of delirium: The REDUCE randomized clinical trial. JAMA. 2018;319(7):680-690.

Prophylactic haloperidol did not prevent delirium or improve survival in a placebo-controlled trial of 1,789 critically ill adults at 21 ICUs in the Netherlands, according to research published in the February 20 issue of JAMA.

“These findings do not support the use of prophylactic haloperidol in critically ill adults,” said Mark van den Boogaard, PhD, Assistant Professor of Intensive Care Medicine at Radboud University Medical Center in Nijmegen, the Netherlands.

Haloperidol is used routinely in ICUs to treat and prevent delirium, which affects as many as half of ICU patients and is associated with prolonged mechanical ventilation, longer ICU and hospital stays, and increased mortality. Results of past studies of haloperidol in the ICU have been mixed.

For this study, eligible participants were expected to be in the ICU for at least two days and were not delirious at baseline. Patients were randomized to receive 1 mg of haloperidol (n = 350), 2 mg of haloperidol (n = 732), or placebo (n = 707) three times daily. The 1-mg haloperidol arm was stopped early because of futility. The ICUs also used nonpharmacologic interventions to prevent delirium, including early mobilization and noise reduction.

Patients had a mean age of 66.6; 61.4% were men. Most of the ICU admissions were urgent and for medical or surgical reasons. There was no statistically significant difference in survival at 28 days following entrance into the study, which was the study’s primary end point. At that point, 83.3% of the patients who received 2-mg doses of haloperidol and 82.7% of the subjects who received placebo had survived.

Prophylactic haloperidol had no effect on reducing the incidence of delirium, which was diagnosed in 33.3% of patients who received haloperidol and 33.0% of patients who received placebo. Likewise, there were no significant differences between the groups in the number of delirium-free and coma-free days, duration of mechanical ventilation, and ICU and hospital length of stay.

“The study population included severely ill ICU adults whose brains may have been too seriously affected for haloperidol to exert a prophylactic effect, since in non-ICU adults, prophylactic haloperidol may have beneficial effects. But the subgroup of patients with a low severity of illness score also demonstrated no beneficial effects,” the investigators said.

—M. Alexander Otto

Suggested Reading

van den Boogaard M, Slooter AJC, Brüggemann RJM, et al. Effect of haloperidol on survival among critically ill adults with a high risk of delirium: The REDUCE randomized clinical trial. JAMA. 2018;319(7):680-690.

Elderly individuals who have excessive daytime sleepiness may be more susceptible to accumulation of an Alzheimer’s disease biomarker, according to a study published online ahead of print March 12 in JAMA Neurology.

Excessive daytime sleepiness (EDS) was associated with increased accumulation of beta-amyloid, an important biomarker of Alzheimer’s disease that manifests in early preclinical stages, said Diego Z. Carvalho, MD, a senior neurology resident at the Mayo Clinic in Rochester, Minnesota, and colleagues.

This finding corroborates previous studies showing that EDS is a risk factor for dementia or cognitive decline, the authors noted.

“It remains unclear whether EDS is a result of greater sleep instability, synaptic or network overload, or neurodegeneration of wakefulness-promoting centers,” said Dr. Carvalho and colleagues. “However, participants with EDS were more vulnerable to Alzheimer’s disease pathologic processes.”

The researchers conducted a prospective, longitudinal cohort analysis that included 283 participants age 70 or older without a diagnosis of dementia who filled out a sleepiness assessment survey and underwent baseline and follow-up imaging studies as part of the Mayo Clinic Study of Aging. All participants included in the analysis underwent at least two consecutive carbon 11–labeled Pittsburgh compound B PET (PiB-PET) scans.

EDS, defined as a score of at least 10 on the Epworth Sleepiness Scale (ESS), was observed in 63 participants (22.3%). At baseline, EDS was significantly associated with increased beta-amyloid accumulation in the anterior cingulate, posterior cingulate-precuneus, and parietal regions. The association between EDS and longitudinal beta-amyloid accumulation was most pronounced in participants who had global PiB positivity at baseline in anterior cingulate and cingulate-precuneus regions. Findings of the study are consistent with a previous investigation of middle-aged participants without dementia, said Dr. Carvalho and colleagues. In that study, increased daytime somnolence was associated with increased beta-amyloid burden in regions including the precuneus and anterior cingulate. Daytime sleepiness in that study was measured using the Sleep Scale.

Further investigation of the link between EDS and beta-amyloid accumulation is warranted. In particular, the researchers suggested that future studies might evaluate whether amyloid accumulation can be avoided through early recognition of EDS and subsequent treatment of underlying sleep disorders.

Poor Sleep Quality May Be an Early Warning Sign of Alzheimer’s Disease

The study advances the understanding of sleep disturbance as a risk factor for Alzheimer’s disease, said Joseph R. Winer, of the Department of Psychology at the University of California, Berkeley, and Bryce A. Mander, PhD, Assistant Professor of Psychiatry and Human Behavior at the University of California, Irvine School of Medicine, in an accompanying editorial.

Findings from the study suggest that poor sleep quality may be an early warning sign of Alzheimer’s disease-related processes. The results should be interpreted with caution, however, because daytime sleepiness was assessed subjectively using the Epworth Sleepiness Scale (ESS), they said. ESS score may reflect declining sleep quality, but it is not necessarily a warning sign for impending amyloidosis because of the low specificity of subjective sleepiness and the many underlying causes that could contribute to ESS scores.

The results suggest that in the future sleep dysfunction might be managed with sleep-based interventions at the optimal time to intervene in the beta-amyloid cascade, Mr. Winer and Dr. Mander said.

Future studies would ideally include other markers of Alzheimer’s disease progression, such as cortical atrophy, tau deposition, or cardiovascular changes, and better explain a physiologic link between subjective daytime sleepiness and longitudinal change in beta-amyloid, said Mr. Winer and Dr. Mander.

—Andrew D. Bowser

Suggested Reading

Carvalho DZ, St Louis EK, Knopman DS, et al. Association of excessive daytime sleepiness with β-amyloid accumulation in elderly persons without dementia. JAMA Neurol. 2018 March 12 [Epub ahead of print].

Winer JR, Mander BA. Waking up to the importance of sleep in the pathogenesis of Alzheimer disease. JAMA Neurol. 2018 Mar 12 [Epub ahead of print].

Elderly individuals who have excessive daytime sleepiness may be more susceptible to accumulation of an Alzheimer’s disease biomarker, according to a study published online ahead of print March 12 in JAMA Neurology.

Excessive daytime sleepiness (EDS) was associated with increased accumulation of beta-amyloid, an important biomarker of Alzheimer’s disease that manifests in early preclinical stages, said Diego Z. Carvalho, MD, a senior neurology resident at the Mayo Clinic in Rochester, Minnesota, and colleagues.

This finding corroborates previous studies showing that EDS is a risk factor for dementia or cognitive decline, the authors noted.

“It remains unclear whether EDS is a result of greater sleep instability, synaptic or network overload, or neurodegeneration of wakefulness-promoting centers,” said Dr. Carvalho and colleagues. “However, participants with EDS were more vulnerable to Alzheimer’s disease pathologic processes.”

The researchers conducted a prospective, longitudinal cohort analysis that included 283 participants age 70 or older without a diagnosis of dementia who filled out a sleepiness assessment survey and underwent baseline and follow-up imaging studies as part of the Mayo Clinic Study of Aging. All participants included in the analysis underwent at least two consecutive carbon 11–labeled Pittsburgh compound B PET (PiB-PET) scans.

EDS, defined as a score of at least 10 on the Epworth Sleepiness Scale (ESS), was observed in 63 participants (22.3%). At baseline, EDS was significantly associated with increased beta-amyloid accumulation in the anterior cingulate, posterior cingulate-precuneus, and parietal regions. The association between EDS and longitudinal beta-amyloid accumulation was most pronounced in participants who had global PiB positivity at baseline in anterior cingulate and cingulate-precuneus regions. Findings of the study are consistent with a previous investigation of middle-aged participants without dementia, said Dr. Carvalho and colleagues. In that study, increased daytime somnolence was associated with increased beta-amyloid burden in regions including the precuneus and anterior cingulate. Daytime sleepiness in that study was measured using the Sleep Scale.

Further investigation of the link between EDS and beta-amyloid accumulation is warranted. In particular, the researchers suggested that future studies might evaluate whether amyloid accumulation can be avoided through early recognition of EDS and subsequent treatment of underlying sleep disorders.

Poor Sleep Quality May Be an Early Warning Sign of Alzheimer’s Disease

The study advances the understanding of sleep disturbance as a risk factor for Alzheimer’s disease, said Joseph R. Winer, of the Department of Psychology at the University of California, Berkeley, and Bryce A. Mander, PhD, Assistant Professor of Psychiatry and Human Behavior at the University of California, Irvine School of Medicine, in an accompanying editorial.

Findings from the study suggest that poor sleep quality may be an early warning sign of Alzheimer’s disease-related processes. The results should be interpreted with caution, however, because daytime sleepiness was assessed subjectively using the Epworth Sleepiness Scale (ESS), they said. ESS score may reflect declining sleep quality, but it is not necessarily a warning sign for impending amyloidosis because of the low specificity of subjective sleepiness and the many underlying causes that could contribute to ESS scores.

The results suggest that in the future sleep dysfunction might be managed with sleep-based interventions at the optimal time to intervene in the beta-amyloid cascade, Mr. Winer and Dr. Mander said.

Future studies would ideally include other markers of Alzheimer’s disease progression, such as cortical atrophy, tau deposition, or cardiovascular changes, and better explain a physiologic link between subjective daytime sleepiness and longitudinal change in beta-amyloid, said Mr. Winer and Dr. Mander.

—Andrew D. Bowser

Suggested Reading

Carvalho DZ, St Louis EK, Knopman DS, et al. Association of excessive daytime sleepiness with β-amyloid accumulation in elderly persons without dementia. JAMA Neurol. 2018 March 12 [Epub ahead of print].

Winer JR, Mander BA. Waking up to the importance of sleep in the pathogenesis of Alzheimer disease. JAMA Neurol. 2018 Mar 12 [Epub ahead of print].

Elderly individuals who have excessive daytime sleepiness may be more susceptible to accumulation of an Alzheimer’s disease biomarker, according to a study published online ahead of print March 12 in JAMA Neurology.

Excessive daytime sleepiness (EDS) was associated with increased accumulation of beta-amyloid, an important biomarker of Alzheimer’s disease that manifests in early preclinical stages, said Diego Z. Carvalho, MD, a senior neurology resident at the Mayo Clinic in Rochester, Minnesota, and colleagues.

This finding corroborates previous studies showing that EDS is a risk factor for dementia or cognitive decline, the authors noted.

“It remains unclear whether EDS is a result of greater sleep instability, synaptic or network overload, or neurodegeneration of wakefulness-promoting centers,” said Dr. Carvalho and colleagues. “However, participants with EDS were more vulnerable to Alzheimer’s disease pathologic processes.”

The researchers conducted a prospective, longitudinal cohort analysis that included 283 participants age 70 or older without a diagnosis of dementia who filled out a sleepiness assessment survey and underwent baseline and follow-up imaging studies as part of the Mayo Clinic Study of Aging. All participants included in the analysis underwent at least two consecutive carbon 11–labeled Pittsburgh compound B PET (PiB-PET) scans.

EDS, defined as a score of at least 10 on the Epworth Sleepiness Scale (ESS), was observed in 63 participants (22.3%). At baseline, EDS was significantly associated with increased beta-amyloid accumulation in the anterior cingulate, posterior cingulate-precuneus, and parietal regions. The association between EDS and longitudinal beta-amyloid accumulation was most pronounced in participants who had global PiB positivity at baseline in anterior cingulate and cingulate-precuneus regions. Findings of the study are consistent with a previous investigation of middle-aged participants without dementia, said Dr. Carvalho and colleagues. In that study, increased daytime somnolence was associated with increased beta-amyloid burden in regions including the precuneus and anterior cingulate. Daytime sleepiness in that study was measured using the Sleep Scale.

Further investigation of the link between EDS and beta-amyloid accumulation is warranted. In particular, the researchers suggested that future studies might evaluate whether amyloid accumulation can be avoided through early recognition of EDS and subsequent treatment of underlying sleep disorders.

Poor Sleep Quality May Be an Early Warning Sign of Alzheimer’s Disease

The study advances the understanding of sleep disturbance as a risk factor for Alzheimer’s disease, said Joseph R. Winer, of the Department of Psychology at the University of California, Berkeley, and Bryce A. Mander, PhD, Assistant Professor of Psychiatry and Human Behavior at the University of California, Irvine School of Medicine, in an accompanying editorial.

Findings from the study suggest that poor sleep quality may be an early warning sign of Alzheimer’s disease-related processes. The results should be interpreted with caution, however, because daytime sleepiness was assessed subjectively using the Epworth Sleepiness Scale (ESS), they said. ESS score may reflect declining sleep quality, but it is not necessarily a warning sign for impending amyloidosis because of the low specificity of subjective sleepiness and the many underlying causes that could contribute to ESS scores.

The results suggest that in the future sleep dysfunction might be managed with sleep-based interventions at the optimal time to intervene in the beta-amyloid cascade, Mr. Winer and Dr. Mander said.

Future studies would ideally include other markers of Alzheimer’s disease progression, such as cortical atrophy, tau deposition, or cardiovascular changes, and better explain a physiologic link between subjective daytime sleepiness and longitudinal change in beta-amyloid, said Mr. Winer and Dr. Mander.

—Andrew D. Bowser

Suggested Reading

Carvalho DZ, St Louis EK, Knopman DS, et al. Association of excessive daytime sleepiness with β-amyloid accumulation in elderly persons without dementia. JAMA Neurol. 2018 March 12 [Epub ahead of print].

Winer JR, Mander BA. Waking up to the importance of sleep in the pathogenesis of Alzheimer disease. JAMA Neurol. 2018 Mar 12 [Epub ahead of print].

Cannabis extract, physical activity, and cognitive behavioral therapy are complementary and alternative medicines (CAMs) with the strongest evidence of efficacy for multiple sclerosis (MS), according to a systematic review published in the January issue of Journal of Neurology, Neurosurgery and Psychiatry. However, there is little class I and class II evidence to support the effect of CAMs.

“We found little evidence for CAM treatments of MS, and class I evidence was almost universally lacking,” said Suzi B. Claflin, PhD, a postdoctoral research fellow at Menzies Institute for Medical Research at the University of Tasmania in Hobart, Australia, and colleagues. Some CAM treatments were evaluated in a single study, and when treatments were evaluated in more than one study, the studies “had different designs and methodologies, and in some cases, contradictory results.”

A Systematic Review

There is an in interest in CAM treatments among the MS community, possibly due to perceived and actual shortcomings of available pharmacologic treatments, said the researchers. Cross-sectional studies have found that 37% to 100% of patients with MS have used CAMs at some point in their lives, and up to 51.8% of these patients have used CAMs in the past year. Despite the common use of CAMs, there is a lack of understanding of their efficacy, the authors noted.

The World Health Organization has defined CAM as “a broad set of health care practices that are not part of [a] country’s own tradition and are not integrated into the dominant health care system.” For the present review, however, the researchers defined CAM broadly as a noninvasive therapy used in addition to or in lieu of the standard pharmacologic treatment of MS.

To provide an overview of the modern evidence for CAM use in patients with MS and to highlight future directions for research, Dr. Claflin and colleagues conducted a systematic review of full research articles published between January 1, 2001, and January 18, 2017, that were written in English, had only human participants, and tested the effect of a CAM treatment on health outcomes in patients with MS only. The researchers included in their review studies with at least 50 participants that provided class I or class II evidence of efficacy. In all, they included 38 studies and divided them into the following five CAM types: cannabis, diet, exercise, psychologic approaches, and other.

Best-Supported Evidence

Five studies found significant beneficial effects of cannabis extract for incontinence, pain, spasticity, and muscle stiffness, whereas two studies found no effect of cannabis extract on primary outcomes. A single study found a positive effect of tetrahydrocannabinol extract on incontinence, and one study found no effect for this treatment on spasticity.

Psychologic approaches such as cognitive behavioral therapy (CBT) appear to be effective in treating MS-related psychologic symptoms. Seven class II studies found that CBT significantly improved depression, fatigue, distress, and general health. In one study, there was no effect of CBT on functional impairment. In a single study, there was no effect of cognitive rehabilitation on function. In another study, mindfulness significantly improved health-related quality of life, depression, and fatigue.

Among exercise treatments, some balance and gait training techniques significantly improved fatigue, balance, walking, and endurance, while other techniques did not. Exercise generally was found to improve muscle strength and mobility-related health outcomes in several studies, and may have some effect on psychologic symptoms. In several studies, however, primary outcomes were not significantly affected. In a single study, yoga had no effect on attention and alertness. In another study, group yoga was not effective in improving MS Impact Scale scores, but some effects on secondary outcomes were observed.

Least-Supported Evidence

Among dietary treatments, biotin had a significant effect on disability progression in one study. In another single study, there was no effect of gingko biloba on cognitive function. Two studies of polyunsaturated fatty acid supplementation for disability had contradictory results: one study found that the treatment reduced relapse rate, and another study found no effect on gadolinium-enhancing lesions. In addition, three studies found no effect of vitamin D supplementation after MS onset on primary outcomes, but one of the studies found some suggestion of benefit of vitamin D as an add-on treatment.

Among other CAMs, acupressure significantly reduced fatigue in a single study. In another single study, amphetamine salts improved processing speed. Two studies found contradictory results for the efficacy of reflexology for pain. Finally, one study found a positive effect of relaxation on stress and depression, and one study found a positive effect of relaxation on pain.

“In order to improve our understanding of the effects of CAM on MS health outcomes, future work should cultivate methodological consistency by establishing standard control or comparator groups and outcome measures,” said Dr. Claflin and colleagues. “This field would also be well served by establishing outcomes of interest, which would allow for greater replication and the accrual of a depth of evidence about an outcome.”

—Erica Tricarico

Suggested Reading

Claflin SB, van der Mei IAF, Taylor BV. Complementary and alternative treatments of multiple sclerosis: a review of the evidence from 2001 to 2016. J Neurol Neurosurg Psychiatry. 2018;89(1):34-41.

Cannabis extract, physical activity, and cognitive behavioral therapy are complementary and alternative medicines (CAMs) with the strongest evidence of efficacy for multiple sclerosis (MS), according to a systematic review published in the January issue of Journal of Neurology, Neurosurgery and Psychiatry. However, there is little class I and class II evidence to support the effect of CAMs.

“We found little evidence for CAM treatments of MS, and class I evidence was almost universally lacking,” said Suzi B. Claflin, PhD, a postdoctoral research fellow at Menzies Institute for Medical Research at the University of Tasmania in Hobart, Australia, and colleagues. Some CAM treatments were evaluated in a single study, and when treatments were evaluated in more than one study, the studies “had different designs and methodologies, and in some cases, contradictory results.”

A Systematic Review

There is an in interest in CAM treatments among the MS community, possibly due to perceived and actual shortcomings of available pharmacologic treatments, said the researchers. Cross-sectional studies have found that 37% to 100% of patients with MS have used CAMs at some point in their lives, and up to 51.8% of these patients have used CAMs in the past year. Despite the common use of CAMs, there is a lack of understanding of their efficacy, the authors noted.

The World Health Organization has defined CAM as “a broad set of health care practices that are not part of [a] country’s own tradition and are not integrated into the dominant health care system.” For the present review, however, the researchers defined CAM broadly as a noninvasive therapy used in addition to or in lieu of the standard pharmacologic treatment of MS.

To provide an overview of the modern evidence for CAM use in patients with MS and to highlight future directions for research, Dr. Claflin and colleagues conducted a systematic review of full research articles published between January 1, 2001, and January 18, 2017, that were written in English, had only human participants, and tested the effect of a CAM treatment on health outcomes in patients with MS only. The researchers included in their review studies with at least 50 participants that provided class I or class II evidence of efficacy. In all, they included 38 studies and divided them into the following five CAM types: cannabis, diet, exercise, psychologic approaches, and other.

Best-Supported Evidence

Five studies found significant beneficial effects of cannabis extract for incontinence, pain, spasticity, and muscle stiffness, whereas two studies found no effect of cannabis extract on primary outcomes. A single study found a positive effect of tetrahydrocannabinol extract on incontinence, and one study found no effect for this treatment on spasticity.

Psychologic approaches such as cognitive behavioral therapy (CBT) appear to be effective in treating MS-related psychologic symptoms. Seven class II studies found that CBT significantly improved depression, fatigue, distress, and general health. In one study, there was no effect of CBT on functional impairment. In a single study, there was no effect of cognitive rehabilitation on function. In another study, mindfulness significantly improved health-related quality of life, depression, and fatigue.

Among exercise treatments, some balance and gait training techniques significantly improved fatigue, balance, walking, and endurance, while other techniques did not. Exercise generally was found to improve muscle strength and mobility-related health outcomes in several studies, and may have some effect on psychologic symptoms. In several studies, however, primary outcomes were not significantly affected. In a single study, yoga had no effect on attention and alertness. In another study, group yoga was not effective in improving MS Impact Scale scores, but some effects on secondary outcomes were observed.

Least-Supported Evidence

Among dietary treatments, biotin had a significant effect on disability progression in one study. In another single study, there was no effect of gingko biloba on cognitive function. Two studies of polyunsaturated fatty acid supplementation for disability had contradictory results: one study found that the treatment reduced relapse rate, and another study found no effect on gadolinium-enhancing lesions. In addition, three studies found no effect of vitamin D supplementation after MS onset on primary outcomes, but one of the studies found some suggestion of benefit of vitamin D as an add-on treatment.

Among other CAMs, acupressure significantly reduced fatigue in a single study. In another single study, amphetamine salts improved processing speed. Two studies found contradictory results for the efficacy of reflexology for pain. Finally, one study found a positive effect of relaxation on stress and depression, and one study found a positive effect of relaxation on pain.

“In order to improve our understanding of the effects of CAM on MS health outcomes, future work should cultivate methodological consistency by establishing standard control or comparator groups and outcome measures,” said Dr. Claflin and colleagues. “This field would also be well served by establishing outcomes of interest, which would allow for greater replication and the accrual of a depth of evidence about an outcome.”

—Erica Tricarico

Suggested Reading

Claflin SB, van der Mei IAF, Taylor BV. Complementary and alternative treatments of multiple sclerosis: a review of the evidence from 2001 to 2016. J Neurol Neurosurg Psychiatry. 2018;89(1):34-41.

Cannabis extract, physical activity, and cognitive behavioral therapy are complementary and alternative medicines (CAMs) with the strongest evidence of efficacy for multiple sclerosis (MS), according to a systematic review published in the January issue of Journal of Neurology, Neurosurgery and Psychiatry. However, there is little class I and class II evidence to support the effect of CAMs.

“We found little evidence for CAM treatments of MS, and class I evidence was almost universally lacking,” said Suzi B. Claflin, PhD, a postdoctoral research fellow at Menzies Institute for Medical Research at the University of Tasmania in Hobart, Australia, and colleagues. Some CAM treatments were evaluated in a single study, and when treatments were evaluated in more than one study, the studies “had different designs and methodologies, and in some cases, contradictory results.”

A Systematic Review

There is an in interest in CAM treatments among the MS community, possibly due to perceived and actual shortcomings of available pharmacologic treatments, said the researchers. Cross-sectional studies have found that 37% to 100% of patients with MS have used CAMs at some point in their lives, and up to 51.8% of these patients have used CAMs in the past year. Despite the common use of CAMs, there is a lack of understanding of their efficacy, the authors noted.

The World Health Organization has defined CAM as “a broad set of health care practices that are not part of [a] country’s own tradition and are not integrated into the dominant health care system.” For the present review, however, the researchers defined CAM broadly as a noninvasive therapy used in addition to or in lieu of the standard pharmacologic treatment of MS.

To provide an overview of the modern evidence for CAM use in patients with MS and to highlight future directions for research, Dr. Claflin and colleagues conducted a systematic review of full research articles published between January 1, 2001, and January 18, 2017, that were written in English, had only human participants, and tested the effect of a CAM treatment on health outcomes in patients with MS only. The researchers included in their review studies with at least 50 participants that provided class I or class II evidence of efficacy. In all, they included 38 studies and divided them into the following five CAM types: cannabis, diet, exercise, psychologic approaches, and other.

Best-Supported Evidence

Five studies found significant beneficial effects of cannabis extract for incontinence, pain, spasticity, and muscle stiffness, whereas two studies found no effect of cannabis extract on primary outcomes. A single study found a positive effect of tetrahydrocannabinol extract on incontinence, and one study found no effect for this treatment on spasticity.

Psychologic approaches such as cognitive behavioral therapy (CBT) appear to be effective in treating MS-related psychologic symptoms. Seven class II studies found that CBT significantly improved depression, fatigue, distress, and general health. In one study, there was no effect of CBT on functional impairment. In a single study, there was no effect of cognitive rehabilitation on function. In another study, mindfulness significantly improved health-related quality of life, depression, and fatigue.

Among exercise treatments, some balance and gait training techniques significantly improved fatigue, balance, walking, and endurance, while other techniques did not. Exercise generally was found to improve muscle strength and mobility-related health outcomes in several studies, and may have some effect on psychologic symptoms. In several studies, however, primary outcomes were not significantly affected. In a single study, yoga had no effect on attention and alertness. In another study, group yoga was not effective in improving MS Impact Scale scores, but some effects on secondary outcomes were observed.

Least-Supported Evidence

Among dietary treatments, biotin had a significant effect on disability progression in one study. In another single study, there was no effect of gingko biloba on cognitive function. Two studies of polyunsaturated fatty acid supplementation for disability had contradictory results: one study found that the treatment reduced relapse rate, and another study found no effect on gadolinium-enhancing lesions. In addition, three studies found no effect of vitamin D supplementation after MS onset on primary outcomes, but one of the studies found some suggestion of benefit of vitamin D as an add-on treatment.

Among other CAMs, acupressure significantly reduced fatigue in a single study. In another single study, amphetamine salts improved processing speed. Two studies found contradictory results for the efficacy of reflexology for pain. Finally, one study found a positive effect of relaxation on stress and depression, and one study found a positive effect of relaxation on pain.

“In order to improve our understanding of the effects of CAM on MS health outcomes, future work should cultivate methodological consistency by establishing standard control or comparator groups and outcome measures,” said Dr. Claflin and colleagues. “This field would also be well served by establishing outcomes of interest, which would allow for greater replication and the accrual of a depth of evidence about an outcome.”

—Erica Tricarico

Suggested Reading

Claflin SB, van der Mei IAF, Taylor BV. Complementary and alternative treatments of multiple sclerosis: a review of the evidence from 2001 to 2016. J Neurol Neurosurg Psychiatry. 2018;89(1):34-41.

Prenatal care has long included carrier screening for genetic diseases, such as cystic fibrosis and Tay-Sachs disease. Recently, advances in genetics technologies led to the development of multiplex panels that can be used to test for hundreds of genetic disorders simultaneously, and can be used to assess carrier status for expectant couples or those planning a pregnancy. Although such screening covers many more conditions than those recommended in traditional guidelines, the benefit of expanded carrier screening (ECS) over standard gene-by-gene testing is not clear.

In this Update, I review recent ECS research that can be helpful to those who practice reproductive endocrinology and infertility medicine, maternal–fetal medicine, and general ObGyn. This research considered some of the many complexities of ECS:

• number and type of severe autosomal recessive conditions identified by an ECS panel, or by panethnic screening for 3 common conditions (cystic fibrosis, fragile X syndrome, spinal muscular atrophy)
• whether the disorders covered by ECS panels meet recommended criteria regarding severity, prevalence, and test accuracy
• women’s thoughts and perspectives on ECS
• whether the marketing materials disseminated by commercial providers of ECS are accurate and balanced.

Genetic diseases identified by expanded carrier screening

Haque IS, Lazarin GA, Kang HP, Evans EA, Goldberg JD, Wapner RJ. Modeled fetal risk of genetic diseases identified by expanded carrier screening. JAMA. 2016;316(7):734-742.

Screening during pregnancy to determine if one or both parents are carriers of genetic disorders historically has involved testing for a limited number of conditions, such as cystic fibrosis, hemoglobinopathies, and Tay-Sachs disease. Patients usually are offered testing for 1 or 2 disorders, with test choices primarily based on patient race and ethnicity. Unfortunately, ancestry-based screening may result in inequitable distribution of genetic testing and resources, as it has significant limitations in our increasingly multicultural society, which includes many people of uncertain or mixed race and ethnicity.

Advantages of expanded carrier screening

Several commercial laboratories now offer ECS. Haque and colleagues used data from one of these laboratories and modeled the predicted number of potentially affected fetuses that would be identified with traditional, ethnicity-based screening as compared with ECS. In one of their hypothetical cohorts, of Northern European couples, traditional screening would identify 55 affected fetuses per 100,000 (1 in 1,800), and ECS would identify 159 per 100,000 (almost 3 times more). The numbers identified with ECS varied with race or ethnicity and ranged from 94 per 100,000 (about 1 in 1,000) for Hispanic couples to 392 per 100,000 (about 1 in 250) for Ashkenazi Jewish couples.

In Australia, Archibald and colleagues conducted a similar study, of panethnic screening of 12,000 women for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy.¹ The number of affected fetuses identified was about 1 per 1,000 screened couples--not much different from the ECS number, though comparison is difficult given the likely very different racial and ethnic backgrounds of the 2 cohorts.

Although these data suggest ECS increases detection of genetic disorders, and it seems almost self-evident that more screening is better, there are concerns about ECS.² Traditional carrier screening methods focus on conditions that significantly affect quality of life--owing to cognitive or physical disabilities or required lifelong medical therapies--and that have a fetal, neonatal, or early-childhood onset and well-defined phenotype. In ECS panels, additional conditions may vary significantly in severity or age of onset. Although some genetic variants on ECS panels have a consistent phenotype, the natural history of others is less well understood. Panels often include conditions for which carrier screening of the general population is not recommended by current guidelines--for example, hemochromatosis and factor V Leiden. Moreover, almost by definition, ECS panels include rare conditions for which the natural history may not be well understood, and the carrier frequency as well as the proportion of condition-causing variants that can be detected may be unclear, leaving the residual risk unknown.

Read about the ideal expanded carrier screening panel.

The ideal expanded carrier screening panel

Stevens B, Krstic N, Jones M, Murphy L, Hoskovec J. Finding middle ground in constructing a clinically useful expanded carrier screening panel. Obstet Gynecol. 2017;130(2):279-284.

Both the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG) have proposed criteria for including specific disorders on ECS panels.^3,4 These criteria consider disorder characteristics, such as carrier prevalence, which should be at least 1 in 100; severity; early-childhood onset; and complete penetrance. In addition, they consider test characteristics, such as sensitivity, which should be at least 70%.

Details of the study

Stevens and colleagues evaluated the ECS panels offered by 6 commercial laboratories in the United States. They found that only 27% of included conditions met the recommended criteria, and concluded that these panels are putting patients at risk for undue anxiety, and that time and money are being spent on follow-up testing for rare and mild conditions for which the benefits of testing are unclear or unlikely. The potential benefits of the extra screening should be weighed against the significant resulting harms.

Across the 6 ECS panels, 96 conditions met the criteria. As some laboratories allow providers to customize their panels, members of my practice, after reviewing this thought-provoking article, agreed we should create a custom panel that includes only these 96 conditions. Unfortunately, no commercial laboratory includes all 96 conditions, so it is not feasible to create an "ideal" panel at this time.

Arguments favoring ECS include its low cost and the efficiency of screening with multigene panels. In a 2013 study, however, 24% of patients were identified as carriers, and in most cases this finding led to screening for the reproductive partner as well.⁵ If the rate of detection of the disorder is low, the utility of screening with the same panel may be limited, and couples may require more extensive testing, such as gene sequencing, which is far more expensive. These findings and the additional testing also will increase the need for genetic counseling, and may lead to invasive prenatal diagnostic testing with further increases in costs. If counseling and prenatal testing yield improved outcomes--increased detection of important findings--the benefit will justify the higher costs. However, if the increased costs are largely generated chasing down and explaining findings that are not important to patients or providers, the costs may be incurred without benefit.

Read about the pregnant women’s perspectives on ECS.

Pregnant women's perspectives on expanded carrier screening

Propst L, Connor G, Hinton M, Poorvu T, Dungan J. Pregnant women's perspectives on expanded carrier screening [published online February 23, 2018]. J Genet Couns. doi:10.1007/s10897-018-0232-x.

Although several authors have discussed ECS detection rates, less has been reported on how women perceive ECS or how they elect or decline screening. Studies have found that the decision to undergo screening for cystic fibrosis is influenced by factors that include age, sex, ethnicity, socioeconomic status, lack of family history, cost, fear of a blood test, lack of knowledge about the condition, already having children, wanting to avoid having a disabled child, abortion preferences, and feeling pressured by health care providers.^6,7 Propst and colleagues asked women for their perspectives on ECS, on electing or declining screening, and on any anxiety associated with their decision.

Details of the study

Women who declined ECS said they did so because they:

• had no family history
• knew there was a very small chance their partner carried the same condition  
• would not change the course of their pregnancy on the basis of the test results.

Women who elected ECS said they did so because they wanted to:

• know their risk of having a child with a genetic condition
• have all available information about their genetic risks
• be able to make decisions about continuing or terminating their pregnancy.

Women also were asked what they would do if they discovered their fetus had a genetic disorder. About 42% said they were unsure what they would do, 34% said they would continue their pregnancy and prepare for the birth of an affected child, and 24% said they likely would terminate their pregnancy.

The most common reason women gave for declining ECS was that they had no family history. However, ECS is not a good option for women with a positive family history, as they need genetic counseling and specific consideration of their own risks and what testing should be done. The majority of couples who have a child with a genetic disease have no other family history of the disorder. In a study of reproductive carrier screening in Australia, 88% of carriers had no family history.¹ Careful pretest counseling is needed to explain the distinction between, on one hand, genetic counseling and testing for those with a family history of genetic disease and, on the other hand, population screening performed to identify unsuspecting individuals who are healthy carriers of genetic disorders.

Another crucial point about carrier screening is the need to consider how its results will be used, and what options the carrier couple will have. For women who are pregnant when a risk is identified, options include expectant management, with diagnosis after birth, or prenatal diagnosis with termination of an affected fetus, out-adoption of an affected fetus, or expectant management with preparation for caring for an affected child. For women who are not pregnant when they have ECS, additional options include use of a gamete (ovum or sperm) donor to achieve pregnancy, or preimplantation genetic diagnosis with implantation of only unaffected embryos.

Read about the marketing of ECS.

Marketing of expanded carrier screening

Chokoshvili D, Borry P, Vears DF. A systematic analysis of online marketing materials used by providers of expanded carrier screening [published online December 14, 2017]. Genet Med. doi:10.1038/gim.2017.222.

Prenatal carrier screening can be helpful to women and their families, but it is also a high-volume, lucrative business, with many commercial laboratories competing for the growing ECS market. Professional medical societies recommend making all screening candidates aware of the purpose, characteristics, and limitations of the tests, and of the potential significance of their results. As becoming familiar and comfortable with the tests and explaining them to each patient can be time-consuming, and daunting, many busy clinicians have started relying on marketing materials and other information from the commercial laboratories. Therefore analysis of the accuracy of such materials is in order.

Details of the study

Chokoshvili and colleagues performed a systematic analysis of the quality and accuracy of online marketing materials for ECS. They identified 18 providers: 16 commercial laboratories and 2 medical services providers. All described ECS as a useful tool for family planning, and some were very directive in stating that this testing is "one of the most important steps in preparing for parenthood." In their materials, most of the companies cover some limitations, such as residual risk, but none of the commercial laboratories indicate that ECS can overestimate risk (many variants have incomplete penetrance, meaning that some individuals with a positive test result may in fact be asymptomatic throughout their lifetime).

In addition, whereas a large amount of the marketing materials implies the test was developed in line with professional recommendations, none in fact complies with ACOG and ACMG guidance. Finally, though some of the online information provided by laboratories can be helpful, it is important for clinicians to remember that reproductive genetic counseling should be nondirective and balanced. Carrier testing should be based on patient (not provider) values regarding reproductive autonomy.

Summary

ECS increasingly is being adopted into clinical practice. According to ACOG, traditional ethnicity-based screening, panethnic screening (the same limited panel of tests for all patients), and ECS are all acceptable alternatives for prenatal carrier screening.³ For providers who offer ECS, it is important to have a good understanding of each selected test and its limitations. Providers should have a plan for following up patients who have positive test results; this plan may include having genetic counseling and prenatal genetic diagnostic testing in place. Although treatment is available for a few genetic conditions, for the large majority, prenatal screening has not been proved to lead to improved therapeutic options. Providers should try to make sure that patients do not have unrealistic expectations of the outcomes of carrier screening.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Prenatal care has long included carrier screening for genetic diseases, such as cystic fibrosis and Tay-Sachs disease. Recently, advances in genetics technologies led to the development of multiplex panels that can be used to test for hundreds of genetic disorders simultaneously, and can be used to assess carrier status for expectant couples or those planning a pregnancy. Although such screening covers many more conditions than those recommended in traditional guidelines, the benefit of expanded carrier screening (ECS) over standard gene-by-gene testing is not clear.

In this Update, I review recent ECS research that can be helpful to those who practice reproductive endocrinology and infertility medicine, maternal–fetal medicine, and general ObGyn. This research considered some of the many complexities of ECS:

• number and type of severe autosomal recessive conditions identified by an ECS panel, or by panethnic screening for 3 common conditions (cystic fibrosis, fragile X syndrome, spinal muscular atrophy)
• whether the disorders covered by ECS panels meet recommended criteria regarding severity, prevalence, and test accuracy
• women’s thoughts and perspectives on ECS
• whether the marketing materials disseminated by commercial providers of ECS are accurate and balanced.

Genetic diseases identified by expanded carrier screening

Haque IS, Lazarin GA, Kang HP, Evans EA, Goldberg JD, Wapner RJ. Modeled fetal risk of genetic diseases identified by expanded carrier screening. JAMA. 2016;316(7):734-742.

Screening during pregnancy to determine if one or both parents are carriers of genetic disorders historically has involved testing for a limited number of conditions, such as cystic fibrosis, hemoglobinopathies, and Tay-Sachs disease. Patients usually are offered testing for 1 or 2 disorders, with test choices primarily based on patient race and ethnicity. Unfortunately, ancestry-based screening may result in inequitable distribution of genetic testing and resources, as it has significant limitations in our increasingly multicultural society, which includes many people of uncertain or mixed race and ethnicity.

Advantages of expanded carrier screening

Several commercial laboratories now offer ECS. Haque and colleagues used data from one of these laboratories and modeled the predicted number of potentially affected fetuses that would be identified with traditional, ethnicity-based screening as compared with ECS. In one of their hypothetical cohorts, of Northern European couples, traditional screening would identify 55 affected fetuses per 100,000 (1 in 1,800), and ECS would identify 159 per 100,000 (almost 3 times more). The numbers identified with ECS varied with race or ethnicity and ranged from 94 per 100,000 (about 1 in 1,000) for Hispanic couples to 392 per 100,000 (about 1 in 250) for Ashkenazi Jewish couples.

In Australia, Archibald and colleagues conducted a similar study, of panethnic screening of 12,000 women for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy.¹ The number of affected fetuses identified was about 1 per 1,000 screened couples--not much different from the ECS number, though comparison is difficult given the likely very different racial and ethnic backgrounds of the 2 cohorts.

Although these data suggest ECS increases detection of genetic disorders, and it seems almost self-evident that more screening is better, there are concerns about ECS.² Traditional carrier screening methods focus on conditions that significantly affect quality of life--owing to cognitive or physical disabilities or required lifelong medical therapies--and that have a fetal, neonatal, or early-childhood onset and well-defined phenotype. In ECS panels, additional conditions may vary significantly in severity or age of onset. Although some genetic variants on ECS panels have a consistent phenotype, the natural history of others is less well understood. Panels often include conditions for which carrier screening of the general population is not recommended by current guidelines--for example, hemochromatosis and factor V Leiden. Moreover, almost by definition, ECS panels include rare conditions for which the natural history may not be well understood, and the carrier frequency as well as the proportion of condition-causing variants that can be detected may be unclear, leaving the residual risk unknown.

Read about the ideal expanded carrier screening panel.

The ideal expanded carrier screening panel

Stevens B, Krstic N, Jones M, Murphy L, Hoskovec J. Finding middle ground in constructing a clinically useful expanded carrier screening panel. Obstet Gynecol. 2017;130(2):279-284.

Both the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG) have proposed criteria for including specific disorders on ECS panels.^3,4 These criteria consider disorder characteristics, such as carrier prevalence, which should be at least 1 in 100; severity; early-childhood onset; and complete penetrance. In addition, they consider test characteristics, such as sensitivity, which should be at least 70%.

Details of the study

Stevens and colleagues evaluated the ECS panels offered by 6 commercial laboratories in the United States. They found that only 27% of included conditions met the recommended criteria, and concluded that these panels are putting patients at risk for undue anxiety, and that time and money are being spent on follow-up testing for rare and mild conditions for which the benefits of testing are unclear or unlikely. The potential benefits of the extra screening should be weighed against the significant resulting harms.

Across the 6 ECS panels, 96 conditions met the criteria. As some laboratories allow providers to customize their panels, members of my practice, after reviewing this thought-provoking article, agreed we should create a custom panel that includes only these 96 conditions. Unfortunately, no commercial laboratory includes all 96 conditions, so it is not feasible to create an "ideal" panel at this time.

Arguments favoring ECS include its low cost and the efficiency of screening with multigene panels. In a 2013 study, however, 24% of patients were identified as carriers, and in most cases this finding led to screening for the reproductive partner as well.⁵ If the rate of detection of the disorder is low, the utility of screening with the same panel may be limited, and couples may require more extensive testing, such as gene sequencing, which is far more expensive. These findings and the additional testing also will increase the need for genetic counseling, and may lead to invasive prenatal diagnostic testing with further increases in costs. If counseling and prenatal testing yield improved outcomes--increased detection of important findings--the benefit will justify the higher costs. However, if the increased costs are largely generated chasing down and explaining findings that are not important to patients or providers, the costs may be incurred without benefit.

Read about the pregnant women’s perspectives on ECS.

Pregnant women's perspectives on expanded carrier screening

Propst L, Connor G, Hinton M, Poorvu T, Dungan J. Pregnant women's perspectives on expanded carrier screening [published online February 23, 2018]. J Genet Couns. doi:10.1007/s10897-018-0232-x.

Although several authors have discussed ECS detection rates, less has been reported on how women perceive ECS or how they elect or decline screening. Studies have found that the decision to undergo screening for cystic fibrosis is influenced by factors that include age, sex, ethnicity, socioeconomic status, lack of family history, cost, fear of a blood test, lack of knowledge about the condition, already having children, wanting to avoid having a disabled child, abortion preferences, and feeling pressured by health care providers.^6,7 Propst and colleagues asked women for their perspectives on ECS, on electing or declining screening, and on any anxiety associated with their decision.

Details of the study

Women who declined ECS said they did so because they:

• had no family history
• knew there was a very small chance their partner carried the same condition  
• would not change the course of their pregnancy on the basis of the test results.

Women who elected ECS said they did so because they wanted to:

• know their risk of having a child with a genetic condition
• have all available information about their genetic risks
• be able to make decisions about continuing or terminating their pregnancy.

Women also were asked what they would do if they discovered their fetus had a genetic disorder. About 42% said they were unsure what they would do, 34% said they would continue their pregnancy and prepare for the birth of an affected child, and 24% said they likely would terminate their pregnancy.

The most common reason women gave for declining ECS was that they had no family history. However, ECS is not a good option for women with a positive family history, as they need genetic counseling and specific consideration of their own risks and what testing should be done. The majority of couples who have a child with a genetic disease have no other family history of the disorder. In a study of reproductive carrier screening in Australia, 88% of carriers had no family history.¹ Careful pretest counseling is needed to explain the distinction between, on one hand, genetic counseling and testing for those with a family history of genetic disease and, on the other hand, population screening performed to identify unsuspecting individuals who are healthy carriers of genetic disorders.

Another crucial point about carrier screening is the need to consider how its results will be used, and what options the carrier couple will have. For women who are pregnant when a risk is identified, options include expectant management, with diagnosis after birth, or prenatal diagnosis with termination of an affected fetus, out-adoption of an affected fetus, or expectant management with preparation for caring for an affected child. For women who are not pregnant when they have ECS, additional options include use of a gamete (ovum or sperm) donor to achieve pregnancy, or preimplantation genetic diagnosis with implantation of only unaffected embryos.

Read about the marketing of ECS.

Marketing of expanded carrier screening

Chokoshvili D, Borry P, Vears DF. A systematic analysis of online marketing materials used by providers of expanded carrier screening [published online December 14, 2017]. Genet Med. doi:10.1038/gim.2017.222.

Prenatal carrier screening can be helpful to women and their families, but it is also a high-volume, lucrative business, with many commercial laboratories competing for the growing ECS market. Professional medical societies recommend making all screening candidates aware of the purpose, characteristics, and limitations of the tests, and of the potential significance of their results. As becoming familiar and comfortable with the tests and explaining them to each patient can be time-consuming, and daunting, many busy clinicians have started relying on marketing materials and other information from the commercial laboratories. Therefore analysis of the accuracy of such materials is in order.

Details of the study

Chokoshvili and colleagues performed a systematic analysis of the quality and accuracy of online marketing materials for ECS. They identified 18 providers: 16 commercial laboratories and 2 medical services providers. All described ECS as a useful tool for family planning, and some were very directive in stating that this testing is "one of the most important steps in preparing for parenthood." In their materials, most of the companies cover some limitations, such as residual risk, but none of the commercial laboratories indicate that ECS can overestimate risk (many variants have incomplete penetrance, meaning that some individuals with a positive test result may in fact be asymptomatic throughout their lifetime).

In addition, whereas a large amount of the marketing materials implies the test was developed in line with professional recommendations, none in fact complies with ACOG and ACMG guidance. Finally, though some of the online information provided by laboratories can be helpful, it is important for clinicians to remember that reproductive genetic counseling should be nondirective and balanced. Carrier testing should be based on patient (not provider) values regarding reproductive autonomy.

Summary

ECS increasingly is being adopted into clinical practice. According to ACOG, traditional ethnicity-based screening, panethnic screening (the same limited panel of tests for all patients), and ECS are all acceptable alternatives for prenatal carrier screening.³ For providers who offer ECS, it is important to have a good understanding of each selected test and its limitations. Providers should have a plan for following up patients who have positive test results; this plan may include having genetic counseling and prenatal genetic diagnostic testing in place. Although treatment is available for a few genetic conditions, for the large majority, prenatal screening has not been proved to lead to improved therapeutic options. Providers should try to make sure that patients do not have unrealistic expectations of the outcomes of carrier screening.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Prenatal care has long included carrier screening for genetic diseases, such as cystic fibrosis and Tay-Sachs disease. Recently, advances in genetics technologies led to the development of multiplex panels that can be used to test for hundreds of genetic disorders simultaneously, and can be used to assess carrier status for expectant couples or those planning a pregnancy. Although such screening covers many more conditions than those recommended in traditional guidelines, the benefit of expanded carrier screening (ECS) over standard gene-by-gene testing is not clear.

In this Update, I review recent ECS research that can be helpful to those who practice reproductive endocrinology and infertility medicine, maternal–fetal medicine, and general ObGyn. This research considered some of the many complexities of ECS:

• number and type of severe autosomal recessive conditions identified by an ECS panel, or by panethnic screening for 3 common conditions (cystic fibrosis, fragile X syndrome, spinal muscular atrophy)
• whether the disorders covered by ECS panels meet recommended criteria regarding severity, prevalence, and test accuracy
• women’s thoughts and perspectives on ECS
• whether the marketing materials disseminated by commercial providers of ECS are accurate and balanced.

Genetic diseases identified by expanded carrier screening

Haque IS, Lazarin GA, Kang HP, Evans EA, Goldberg JD, Wapner RJ. Modeled fetal risk of genetic diseases identified by expanded carrier screening. JAMA. 2016;316(7):734-742.

Screening during pregnancy to determine if one or both parents are carriers of genetic disorders historically has involved testing for a limited number of conditions, such as cystic fibrosis, hemoglobinopathies, and Tay-Sachs disease. Patients usually are offered testing for 1 or 2 disorders, with test choices primarily based on patient race and ethnicity. Unfortunately, ancestry-based screening may result in inequitable distribution of genetic testing and resources, as it has significant limitations in our increasingly multicultural society, which includes many people of uncertain or mixed race and ethnicity.

Advantages of expanded carrier screening

Several commercial laboratories now offer ECS. Haque and colleagues used data from one of these laboratories and modeled the predicted number of potentially affected fetuses that would be identified with traditional, ethnicity-based screening as compared with ECS. In one of their hypothetical cohorts, of Northern European couples, traditional screening would identify 55 affected fetuses per 100,000 (1 in 1,800), and ECS would identify 159 per 100,000 (almost 3 times more). The numbers identified with ECS varied with race or ethnicity and ranged from 94 per 100,000 (about 1 in 1,000) for Hispanic couples to 392 per 100,000 (about 1 in 250) for Ashkenazi Jewish couples.

In Australia, Archibald and colleagues conducted a similar study, of panethnic screening of 12,000 women for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy.¹ The number of affected fetuses identified was about 1 per 1,000 screened couples--not much different from the ECS number, though comparison is difficult given the likely very different racial and ethnic backgrounds of the 2 cohorts.

Although these data suggest ECS increases detection of genetic disorders, and it seems almost self-evident that more screening is better, there are concerns about ECS.² Traditional carrier screening methods focus on conditions that significantly affect quality of life--owing to cognitive or physical disabilities or required lifelong medical therapies--and that have a fetal, neonatal, or early-childhood onset and well-defined phenotype. In ECS panels, additional conditions may vary significantly in severity or age of onset. Although some genetic variants on ECS panels have a consistent phenotype, the natural history of others is less well understood. Panels often include conditions for which carrier screening of the general population is not recommended by current guidelines--for example, hemochromatosis and factor V Leiden. Moreover, almost by definition, ECS panels include rare conditions for which the natural history may not be well understood, and the carrier frequency as well as the proportion of condition-causing variants that can be detected may be unclear, leaving the residual risk unknown.

Read about the ideal expanded carrier screening panel.

The ideal expanded carrier screening panel

Stevens B, Krstic N, Jones M, Murphy L, Hoskovec J. Finding middle ground in constructing a clinically useful expanded carrier screening panel. Obstet Gynecol. 2017;130(2):279-284.

Both the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG) have proposed criteria for including specific disorders on ECS panels.^3,4 These criteria consider disorder characteristics, such as carrier prevalence, which should be at least 1 in 100; severity; early-childhood onset; and complete penetrance. In addition, they consider test characteristics, such as sensitivity, which should be at least 70%.

Details of the study

Stevens and colleagues evaluated the ECS panels offered by 6 commercial laboratories in the United States. They found that only 27% of included conditions met the recommended criteria, and concluded that these panels are putting patients at risk for undue anxiety, and that time and money are being spent on follow-up testing for rare and mild conditions for which the benefits of testing are unclear or unlikely. The potential benefits of the extra screening should be weighed against the significant resulting harms.

Across the 6 ECS panels, 96 conditions met the criteria. As some laboratories allow providers to customize their panels, members of my practice, after reviewing this thought-provoking article, agreed we should create a custom panel that includes only these 96 conditions. Unfortunately, no commercial laboratory includes all 96 conditions, so it is not feasible to create an "ideal" panel at this time.

Arguments favoring ECS include its low cost and the efficiency of screening with multigene panels. In a 2013 study, however, 24% of patients were identified as carriers, and in most cases this finding led to screening for the reproductive partner as well.⁵ If the rate of detection of the disorder is low, the utility of screening with the same panel may be limited, and couples may require more extensive testing, such as gene sequencing, which is far more expensive. These findings and the additional testing also will increase the need for genetic counseling, and may lead to invasive prenatal diagnostic testing with further increases in costs. If counseling and prenatal testing yield improved outcomes--increased detection of important findings--the benefit will justify the higher costs. However, if the increased costs are largely generated chasing down and explaining findings that are not important to patients or providers, the costs may be incurred without benefit.

Read about the pregnant women’s perspectives on ECS.

Pregnant women's perspectives on expanded carrier screening

Propst L, Connor G, Hinton M, Poorvu T, Dungan J. Pregnant women's perspectives on expanded carrier screening [published online February 23, 2018]. J Genet Couns. doi:10.1007/s10897-018-0232-x.

Although several authors have discussed ECS detection rates, less has been reported on how women perceive ECS or how they elect or decline screening. Studies have found that the decision to undergo screening for cystic fibrosis is influenced by factors that include age, sex, ethnicity, socioeconomic status, lack of family history, cost, fear of a blood test, lack of knowledge about the condition, already having children, wanting to avoid having a disabled child, abortion preferences, and feeling pressured by health care providers.^6,7 Propst and colleagues asked women for their perspectives on ECS, on electing or declining screening, and on any anxiety associated with their decision.

Details of the study

Women who declined ECS said they did so because they:

• had no family history
• knew there was a very small chance their partner carried the same condition  
• would not change the course of their pregnancy on the basis of the test results.

Women who elected ECS said they did so because they wanted to:

• know their risk of having a child with a genetic condition
• have all available information about their genetic risks
• be able to make decisions about continuing or terminating their pregnancy.

Women also were asked what they would do if they discovered their fetus had a genetic disorder. About 42% said they were unsure what they would do, 34% said they would continue their pregnancy and prepare for the birth of an affected child, and 24% said they likely would terminate their pregnancy.

The most common reason women gave for declining ECS was that they had no family history. However, ECS is not a good option for women with a positive family history, as they need genetic counseling and specific consideration of their own risks and what testing should be done. The majority of couples who have a child with a genetic disease have no other family history of the disorder. In a study of reproductive carrier screening in Australia, 88% of carriers had no family history.¹ Careful pretest counseling is needed to explain the distinction between, on one hand, genetic counseling and testing for those with a family history of genetic disease and, on the other hand, population screening performed to identify unsuspecting individuals who are healthy carriers of genetic disorders.

Another crucial point about carrier screening is the need to consider how its results will be used, and what options the carrier couple will have. For women who are pregnant when a risk is identified, options include expectant management, with diagnosis after birth, or prenatal diagnosis with termination of an affected fetus, out-adoption of an affected fetus, or expectant management with preparation for caring for an affected child. For women who are not pregnant when they have ECS, additional options include use of a gamete (ovum or sperm) donor to achieve pregnancy, or preimplantation genetic diagnosis with implantation of only unaffected embryos.

Read about the marketing of ECS.

Marketing of expanded carrier screening

Chokoshvili D, Borry P, Vears DF. A systematic analysis of online marketing materials used by providers of expanded carrier screening [published online December 14, 2017]. Genet Med. doi:10.1038/gim.2017.222.

Prenatal carrier screening can be helpful to women and their families, but it is also a high-volume, lucrative business, with many commercial laboratories competing for the growing ECS market. Professional medical societies recommend making all screening candidates aware of the purpose, characteristics, and limitations of the tests, and of the potential significance of their results. As becoming familiar and comfortable with the tests and explaining them to each patient can be time-consuming, and daunting, many busy clinicians have started relying on marketing materials and other information from the commercial laboratories. Therefore analysis of the accuracy of such materials is in order.

Details of the study

Chokoshvili and colleagues performed a systematic analysis of the quality and accuracy of online marketing materials for ECS. They identified 18 providers: 16 commercial laboratories and 2 medical services providers. All described ECS as a useful tool for family planning, and some were very directive in stating that this testing is "one of the most important steps in preparing for parenthood." In their materials, most of the companies cover some limitations, such as residual risk, but none of the commercial laboratories indicate that ECS can overestimate risk (many variants have incomplete penetrance, meaning that some individuals with a positive test result may in fact be asymptomatic throughout their lifetime).

In addition, whereas a large amount of the marketing materials implies the test was developed in line with professional recommendations, none in fact complies with ACOG and ACMG guidance. Finally, though some of the online information provided by laboratories can be helpful, it is important for clinicians to remember that reproductive genetic counseling should be nondirective and balanced. Carrier testing should be based on patient (not provider) values regarding reproductive autonomy.

Summary

ECS increasingly is being adopted into clinical practice. According to ACOG, traditional ethnicity-based screening, panethnic screening (the same limited panel of tests for all patients), and ECS are all acceptable alternatives for prenatal carrier screening.³ For providers who offer ECS, it is important to have a good understanding of each selected test and its limitations. Providers should have a plan for following up patients who have positive test results; this plan may include having genetic counseling and prenatal genetic diagnostic testing in place. Although treatment is available for a few genetic conditions, for the large majority, prenatal screening has not been proved to lead to improved therapeutic options. Providers should try to make sure that patients do not have unrealistic expectations of the outcomes of carrier screening.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The Third Annual "UCLA / SVS Symposium: A Comprehensive Review and Update of What's New in Vascular and Endovascular Surgery," is set for Aug. 25 to 27 in California. This course is offered by the Division of Vascular and Endovascular Surgery at UCLA and the Society for Vascular Surgery. It provides an in-depth review of our specialty for those preparing to take the vascular board examinations as well as providing the basic didactic education for vascular residents and fellows in training.

The Third Annual "UCLA / SVS Symposium: A Comprehensive Review and Update of What's New in Vascular and Endovascular Surgery," is set for Aug. 25 to 27 in California. This course is offered by the Division of Vascular and Endovascular Surgery at UCLA and the Society for Vascular Surgery. It provides an in-depth review of our specialty for those preparing to take the vascular board examinations as well as providing the basic didactic education for vascular residents and fellows in training.

The Third Annual "UCLA / SVS Symposium: A Comprehensive Review and Update of What's New in Vascular and Endovascular Surgery," is set for Aug. 25 to 27 in California. This course is offered by the Division of Vascular and Endovascular Surgery at UCLA and the Society for Vascular Surgery. It provides an in-depth review of our specialty for those preparing to take the vascular board examinations as well as providing the basic didactic education for vascular residents and fellows in training.

Want to make a billion dollars? Here’s a hot tip: Invent wearable technology that detects diabetes, measures glucose levels, and determines how much insulin is needed – all without the need for a single drop of blood.

If you accept this mission, there’s a catch: You’ll have a whole bunch of company. When it comes to using technology to free patients with diabetes from the dreaded finger stick, “hope springs eternal in the hearts of scientists, entrepreneurs, opportunists, and charlatans alike,” writes electrochemical specialist and consultant John L. Smith, PhD, in his book “The Pursuit of Noninvasive Glucose.”

Google and Apple have been in the hunt, along with countless makers of devices and software. A noninvasive glucose monitoring system is the prime target, but there’s also plenty of interest in software that puts data from such devices as heartbeat sensors to work.

Early failure has a lasting impact

In the beginning, there was Glucowatch. And it was not good.

The GlucoWatch G2 Biographer product received approval from the Food and Drug Administration back in 2001 and touted as a high-tech tool to monitor glucose levels via interstitial concentrations every 10 minutes. The device promised to draw glucose to the skin surface for measurement via electric shocks, and alarms were to go off when hypoglycemia or hyperglycemia was detected.

But numerous problems cropped up. There was a time lag, with the device estimating glucose levels that actually occurred 15-20 minutes earlier. Some patients couldn’t tolerate wearing the watch, and some were burned by the electric current.

And perhaps worst of all, the measurements often weren’t accurate, with one study finding that more than half of 240 nighttime alarms incorrectly warned children with diabetes of dangerously high or low glucose. (Diabetes Technol Ther. 2005 June; 7[3]:440-7).

As a result of the Glucowatch debacle, the FDA “become a little gun shy about approving anything. It made it even harder to approve something,” said Mark J. Rice, MD, of Vanderbilt University, Nashville, Tenn., who has tried to develop glucose-measuring technology.

On tech front, promises and more promises

So far, there have been more promises than actual products.

If you don’t look too closely at the website of a device called GlucoWise, you might assume a noninvasive glucose monitor already exists. Under a photo of a smiling woman, the site promises a “100% pain-free device that makes traditional blood sampling a thing of the past.”

The “simple yet highly reliable” device, which looks a bit like a large clip for a potato chip bag, promises to measure glucose through high-frequency radio waves that penetrate thin body tissue in the earlobe or the area between the thumb and forefinger.

But the GlucoWise device is neither approved nor available, and the company’s predictions that it would take preorders by late 2016 didn’t come true.

Another product called SugarBEAT missed its planned 2016 release and now hopes to be available in the Britain later this year. It promises to measure glucose levels every 5 minutes via a small disposable patch that draws interstitial fluid from the skin.

Meanwhile, Apple has enlisted biomedical engineers to work on a secret project to measure glucose continuously and noninvasively, CNBC reported last year. And Google announced in 2014 that it was working on a glucose-detecting contact lens that could alert patients via tiny LED lights – yes, apparently in the lenses themselves – if levels go too high or low. But neither of these technologies is ready for prime time.

Sneaky glucose molecules elude scientists

According to Dr. Rice, no truly noninvasive glucose-measuring technique has worked so far.

The challenge, he said, is that it’s difficult to measure tiny glucose molecules, which have no color and share many characteristics with H₂O.

“The real problem is trying to measure a colorless molecule in a sea of water,” Dr. Rice said.

Glucose lab tests rely on indicators from reactions with other substances, he said, “but you can’t do that in the body.” Measuring glucose in tears or urine is one possibility, he said, but the scarcity in those liquids poses a challenge: “Your body doesn’t want to spill glucose and lose energy.”

Dr. Rice himself explored a glucose-measuring technique that aimed to correlate glucose levels to the speed of the retina’s reaction to light. The idea was that patients would wear special glasses that would shine a light in the eye at the press of a button. The project ultimately failed.

There are other challenges, said Dr. Baers, the technology adviser. “Glucose concentrations in sweat or tears are not reflective of blood glucose concentrations. To make things even more challenging, glucose levels in these fluids are orders of magnitude smaller than that found in blood.”

And, she said, there’s a time lag between glucose levels in blood and in other body fluids. “This means that a sweat glucose level is really giving information from an hour previous, which can be dangerous if you’re operating machinery or driving.”

Wearable diabetes tech targets more than glucose

There’s more to wearable, noninvasive diabetes technology than glucose-monitoring. One of the new frontiers is diagnostics.

Earlier this year, researchers from the University of California at San Francisco and the digital startup Cardiogram reported that they were able to use data from digital heart rate sensors (like those found in Apple Watches, Fitbits and other devices) to correctly detect diabetes in patients.

In a study presented at the 2018 meeting of the Association for the Advancement of Artificial Intelligence, the researchers said they detected diabetes in 85% of 462 participants (out of a pool of 14,011) who’d previously been diagnosed with the condition (AAAAI abstract arXiv:1802.02511v1 [cs.LG]).

As tech advances, questions remain

San Diego’s Scripps Whittier Diabetes Institute is another player in the diabetes/digital health world. It’s currently working on several clinical trials of diabetes technology, including a study into whether older adults with type 1 diabetes will benefit from a continuous glucose monitoring device with a wireless connection.

[email protected]

Want to make a billion dollars? Here’s a hot tip: Invent wearable technology that detects diabetes, measures glucose levels, and determines how much insulin is needed – all without the need for a single drop of blood.

If you accept this mission, there’s a catch: You’ll have a whole bunch of company. When it comes to using technology to free patients with diabetes from the dreaded finger stick, “hope springs eternal in the hearts of scientists, entrepreneurs, opportunists, and charlatans alike,” writes electrochemical specialist and consultant John L. Smith, PhD, in his book “The Pursuit of Noninvasive Glucose.”

Google and Apple have been in the hunt, along with countless makers of devices and software. A noninvasive glucose monitoring system is the prime target, but there’s also plenty of interest in software that puts data from such devices as heartbeat sensors to work.

Early failure has a lasting impact

In the beginning, there was Glucowatch. And it was not good.

The GlucoWatch G2 Biographer product received approval from the Food and Drug Administration back in 2001 and touted as a high-tech tool to monitor glucose levels via interstitial concentrations every 10 minutes. The device promised to draw glucose to the skin surface for measurement via electric shocks, and alarms were to go off when hypoglycemia or hyperglycemia was detected.

But numerous problems cropped up. There was a time lag, with the device estimating glucose levels that actually occurred 15-20 minutes earlier. Some patients couldn’t tolerate wearing the watch, and some were burned by the electric current.

And perhaps worst of all, the measurements often weren’t accurate, with one study finding that more than half of 240 nighttime alarms incorrectly warned children with diabetes of dangerously high or low glucose. (Diabetes Technol Ther. 2005 June; 7[3]:440-7).

As a result of the Glucowatch debacle, the FDA “become a little gun shy about approving anything. It made it even harder to approve something,” said Mark J. Rice, MD, of Vanderbilt University, Nashville, Tenn., who has tried to develop glucose-measuring technology.

On tech front, promises and more promises

So far, there have been more promises than actual products.

If you don’t look too closely at the website of a device called GlucoWise, you might assume a noninvasive glucose monitor already exists. Under a photo of a smiling woman, the site promises a “100% pain-free device that makes traditional blood sampling a thing of the past.”

The “simple yet highly reliable” device, which looks a bit like a large clip for a potato chip bag, promises to measure glucose through high-frequency radio waves that penetrate thin body tissue in the earlobe or the area between the thumb and forefinger.

But the GlucoWise device is neither approved nor available, and the company’s predictions that it would take preorders by late 2016 didn’t come true.

Another product called SugarBEAT missed its planned 2016 release and now hopes to be available in the Britain later this year. It promises to measure glucose levels every 5 minutes via a small disposable patch that draws interstitial fluid from the skin.

Meanwhile, Apple has enlisted biomedical engineers to work on a secret project to measure glucose continuously and noninvasively, CNBC reported last year. And Google announced in 2014 that it was working on a glucose-detecting contact lens that could alert patients via tiny LED lights – yes, apparently in the lenses themselves – if levels go too high or low. But neither of these technologies is ready for prime time.

Sneaky glucose molecules elude scientists

According to Dr. Rice, no truly noninvasive glucose-measuring technique has worked so far.

The challenge, he said, is that it’s difficult to measure tiny glucose molecules, which have no color and share many characteristics with H₂O.

“The real problem is trying to measure a colorless molecule in a sea of water,” Dr. Rice said.

Glucose lab tests rely on indicators from reactions with other substances, he said, “but you can’t do that in the body.” Measuring glucose in tears or urine is one possibility, he said, but the scarcity in those liquids poses a challenge: “Your body doesn’t want to spill glucose and lose energy.”

Dr. Rice himself explored a glucose-measuring technique that aimed to correlate glucose levels to the speed of the retina’s reaction to light. The idea was that patients would wear special glasses that would shine a light in the eye at the press of a button. The project ultimately failed.

There are other challenges, said Dr. Baers, the technology adviser. “Glucose concentrations in sweat or tears are not reflective of blood glucose concentrations. To make things even more challenging, glucose levels in these fluids are orders of magnitude smaller than that found in blood.”

And, she said, there’s a time lag between glucose levels in blood and in other body fluids. “This means that a sweat glucose level is really giving information from an hour previous, which can be dangerous if you’re operating machinery or driving.”

Wearable diabetes tech targets more than glucose

There’s more to wearable, noninvasive diabetes technology than glucose-monitoring. One of the new frontiers is diagnostics.

Earlier this year, researchers from the University of California at San Francisco and the digital startup Cardiogram reported that they were able to use data from digital heart rate sensors (like those found in Apple Watches, Fitbits and other devices) to correctly detect diabetes in patients.

In a study presented at the 2018 meeting of the Association for the Advancement of Artificial Intelligence, the researchers said they detected diabetes in 85% of 462 participants (out of a pool of 14,011) who’d previously been diagnosed with the condition (AAAAI abstract arXiv:1802.02511v1 [cs.LG]).

As tech advances, questions remain

San Diego’s Scripps Whittier Diabetes Institute is another player in the diabetes/digital health world. It’s currently working on several clinical trials of diabetes technology, including a study into whether older adults with type 1 diabetes will benefit from a continuous glucose monitoring device with a wireless connection.

[email protected]

Want to make a billion dollars? Here’s a hot tip: Invent wearable technology that detects diabetes, measures glucose levels, and determines how much insulin is needed – all without the need for a single drop of blood.

If you accept this mission, there’s a catch: You’ll have a whole bunch of company. When it comes to using technology to free patients with diabetes from the dreaded finger stick, “hope springs eternal in the hearts of scientists, entrepreneurs, opportunists, and charlatans alike,” writes electrochemical specialist and consultant John L. Smith, PhD, in his book “The Pursuit of Noninvasive Glucose.”

Google and Apple have been in the hunt, along with countless makers of devices and software. A noninvasive glucose monitoring system is the prime target, but there’s also plenty of interest in software that puts data from such devices as heartbeat sensors to work.

Early failure has a lasting impact

In the beginning, there was Glucowatch. And it was not good.

The GlucoWatch G2 Biographer product received approval from the Food and Drug Administration back in 2001 and touted as a high-tech tool to monitor glucose levels via interstitial concentrations every 10 minutes. The device promised to draw glucose to the skin surface for measurement via electric shocks, and alarms were to go off when hypoglycemia or hyperglycemia was detected.

But numerous problems cropped up. There was a time lag, with the device estimating glucose levels that actually occurred 15-20 minutes earlier. Some patients couldn’t tolerate wearing the watch, and some were burned by the electric current.

And perhaps worst of all, the measurements often weren’t accurate, with one study finding that more than half of 240 nighttime alarms incorrectly warned children with diabetes of dangerously high or low glucose. (Diabetes Technol Ther. 2005 June; 7[3]:440-7).

As a result of the Glucowatch debacle, the FDA “become a little gun shy about approving anything. It made it even harder to approve something,” said Mark J. Rice, MD, of Vanderbilt University, Nashville, Tenn., who has tried to develop glucose-measuring technology.

On tech front, promises and more promises

So far, there have been more promises than actual products.

If you don’t look too closely at the website of a device called GlucoWise, you might assume a noninvasive glucose monitor already exists. Under a photo of a smiling woman, the site promises a “100% pain-free device that makes traditional blood sampling a thing of the past.”

The “simple yet highly reliable” device, which looks a bit like a large clip for a potato chip bag, promises to measure glucose through high-frequency radio waves that penetrate thin body tissue in the earlobe or the area between the thumb and forefinger.

But the GlucoWise device is neither approved nor available, and the company’s predictions that it would take preorders by late 2016 didn’t come true.

Another product called SugarBEAT missed its planned 2016 release and now hopes to be available in the Britain later this year. It promises to measure glucose levels every 5 minutes via a small disposable patch that draws interstitial fluid from the skin.

Meanwhile, Apple has enlisted biomedical engineers to work on a secret project to measure glucose continuously and noninvasively, CNBC reported last year. And Google announced in 2014 that it was working on a glucose-detecting contact lens that could alert patients via tiny LED lights – yes, apparently in the lenses themselves – if levels go too high or low. But neither of these technologies is ready for prime time.

Sneaky glucose molecules elude scientists

According to Dr. Rice, no truly noninvasive glucose-measuring technique has worked so far.

The challenge, he said, is that it’s difficult to measure tiny glucose molecules, which have no color and share many characteristics with H₂O.

“The real problem is trying to measure a colorless molecule in a sea of water,” Dr. Rice said.

Glucose lab tests rely on indicators from reactions with other substances, he said, “but you can’t do that in the body.” Measuring glucose in tears or urine is one possibility, he said, but the scarcity in those liquids poses a challenge: “Your body doesn’t want to spill glucose and lose energy.”

Dr. Rice himself explored a glucose-measuring technique that aimed to correlate glucose levels to the speed of the retina’s reaction to light. The idea was that patients would wear special glasses that would shine a light in the eye at the press of a button. The project ultimately failed.

There are other challenges, said Dr. Baers, the technology adviser. “Glucose concentrations in sweat or tears are not reflective of blood glucose concentrations. To make things even more challenging, glucose levels in these fluids are orders of magnitude smaller than that found in blood.”

And, she said, there’s a time lag between glucose levels in blood and in other body fluids. “This means that a sweat glucose level is really giving information from an hour previous, which can be dangerous if you’re operating machinery or driving.”

Wearable diabetes tech targets more than glucose

There’s more to wearable, noninvasive diabetes technology than glucose-monitoring. One of the new frontiers is diagnostics.

Earlier this year, researchers from the University of California at San Francisco and the digital startup Cardiogram reported that they were able to use data from digital heart rate sensors (like those found in Apple Watches, Fitbits and other devices) to correctly detect diabetes in patients.

In a study presented at the 2018 meeting of the Association for the Advancement of Artificial Intelligence, the researchers said they detected diabetes in 85% of 462 participants (out of a pool of 14,011) who’d previously been diagnosed with the condition (AAAAI abstract arXiv:1802.02511v1 [cs.LG]).

As tech advances, questions remain

San Diego’s Scripps Whittier Diabetes Institute is another player in the diabetes/digital health world. It’s currently working on several clinical trials of diabetes technology, including a study into whether older adults with type 1 diabetes will benefit from a continuous glucose monitoring device with a wireless connection.

[email protected]

SVS is accepting applications for Medical Editor of "Vascular Specialist," the monthly news periodical produced by SVS. The editor can expect to spend approximately 10-20 hours each month in the three weeks leading up to publication. A modest annual honorarium is provided. Previous editorial experience will be helpful. Please send letters of interest by April 15 to Kenneth M. Slaw, Ph.D., at [email protected]. He will forward your interest to the SVS Publications Committee for consideration. More information is in the March 29 issue of Pulse.

SVS is accepting applications for Medical Editor of "Vascular Specialist," the monthly news periodical produced by SVS. The editor can expect to spend approximately 10-20 hours each month in the three weeks leading up to publication. A modest annual honorarium is provided. Previous editorial experience will be helpful. Please send letters of interest by April 15 to Kenneth M. Slaw, Ph.D., at [email protected]. He will forward your interest to the SVS Publications Committee for consideration. More information is in the March 29 issue of Pulse.

SVS is accepting applications for Medical Editor of "Vascular Specialist," the monthly news periodical produced by SVS. The editor can expect to spend approximately 10-20 hours each month in the three weeks leading up to publication. A modest annual honorarium is provided. Previous editorial experience will be helpful. Please send letters of interest by April 15 to Kenneth M. Slaw, Ph.D., at [email protected]. He will forward your interest to the SVS Publications Committee for consideration. More information is in the March 29 issue of Pulse.