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MDedge conference coverage features onsite reporting of the latest study results and expert perspectives from leading researchers.
‘Superior’ CLL regimen cuts chemo in half
“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.
Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress.
The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.
For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.
All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.
After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.
At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.
By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.
One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.
Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.
“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.
She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.
Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.
And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.
The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.
Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”
“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.
Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.
“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”
“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said.
Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.
“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.
Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress.
The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.
For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.
All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.
After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.
At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.
By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.
One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.
Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.
“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.
She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.
Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.
And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.
The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.
Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”
“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.
Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.
“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”
“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said.
Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.
“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.
Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress.
The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.
For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.
All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.
After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.
At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.
By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.
One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.
Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.
“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.
She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.
Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.
And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.
The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.
Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”
“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.
Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.
“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”
“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said.
Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.
FROM EHA 2022
Obesity linked to smaller testes and possible infertility
new data suggest.
Testicular volume is a fertility marker directly related to sperm count that has halved in the past 40 years worldwide for unknown reasons. At the same time, childhood obesity has risen dramatically and infertility appears to have risen as well, Rossella Cannarella, MD, of the department of endocrinology and andrology, University of Catania (Italy), said at the annual meeting of the Endocrine Society.
According to recent Italian studies, between 14% and 23% of young men aged 18-19 had testicular hypotrophy. “Worryingly, we don’t know the reason for this hypotrophy. And therefore, they are at risk for future infertility,” Dr. Cannarella said during a press briefing.
Her study, which included a total of 264 male children and adolescents, also linked lower testicular volume to hyperinsulinemia and insulin resistance. “The testis is not quiescent in childhood and is sensitive to the hormone insulin. Obesity and metabolic impairment actually can have an effect and negative impact on Sertoli cell proliferation,” Dr. Cannarella said.
Screen testicular volume at all visits
If other studies confirm these results, she said that pediatricians should begin routinely assessing testicular volume at all visits as is now done with height and weight to identify early deflection of the testicular growth curve.
In addition, “include male infertility as a possible consequence of obesity in counseling of male obese children,” she advised.
Asked to comment, Amin Sedaghat Herati, MD, director of male infertility and men’s health at Johns Hopkins Hospital, and assistant professor of urology at Johns Hopkins Medicine, both in Baltimore, said in an interview: “I think what’s really interesting about this study is the association that they’ve made between testicular volume and obesity.”
But, he noted, “it does not implicate necessarily the development of infertility. It’s an extrapolation. So it’s a step towards the link between obesity and infertility, and it’s an important study to establish the association, but changes in testicular volume and even changes in semen panel don’t necessarily indicate fertility or infertility.”
The findings are “consistent with what we know as far as what obesity can potentially do to the activity of the cells in the testes. The authors are postulating that it’s more the support cells, called Sertoli cells, but I would say it’s probably all of the cells that are being affected by obesity and specifically elevated leptin levels,” Dr. Herati said.
He agrees with the recommendation that pediatricians screen all boys for testicular volume. “I agree it’s a good idea so they don’t miss any cases in which the testes don’t develop the way they should or any other conditions,” Dr. Herati said. “I think in general it’s a good practice, especially in the peripubertal stage, to make sure that kids are on the same growth curve and that they’re meeting their Tanner staging. [Pediatricians] should be looking at the size of the testes and tracking, maybe not at every visit, but at least on an annual basis.”
And, he noted, “I think any study that establishes a link that we can point to when we’re educating patients and parents is important.”
Links found between overweight/obesity, testicular hypotrophy
The study population included 61 male children and adolescents with normal weight, 53 with overweight, and 150 with obesity. Insulin resistance (Homeostatic Model Assessment for Insulin Resistance index ≥ 2.5) was present in 97 participants, 22 had prediabetes, and 3 had type 2 diabetes. Clinical data were collected retrospectively.
Among the boys aged 9-14 years, those with overweight and obesity had significantly lower testicular volume, compared with those of normal weight.
Those who were in Tanner Stage 1 were more likely to have overweight and obesity than those with normal weight, suggesting that “overweight and obese adolescents start puberty later than those of normal weight,” Dr. Cannarella said.
In the 14- to 16-year-old age group, those with insulin resistance had lower testicular volume, compared with those without insulin resistance (HOMA index < 2.5). The number of insulin-resistant adolescents was greater than that of controls in the Tanner stage 2 group.
In both the prepubertal (< 9 years) and pubertal (14-16 years) groups, hyperinsulinemia was associated with lower levels of testicular volume.
Hyperinsulinemia did not influence the timing of puberty onset.
No way to quantify the effect of obesity on fertility just yet
During a press briefing, Dr. Cannarella commented that obesity is likely just one of several factors influencing what appears to be an increase in male infertility over time. “It isn’t of course the only reason, but many factors in our environment have drastically changed, compared to 40 years ago, including the prevalence of heavy metals and endocrine disruptors, and of course, the change in habits and higher prevalence of metabolic disease. All of this has an impact on the proliferation of Sertoli cells in childhood and this may explain the trend toward the decline of sperm concentration and count.”
Longitudinal data are needed to establish cause and effect, she noted. “We need longitudinal studies that link the degrees of testicular volume with the degree of the sperm concentration and count starting from childhood and ending with the adult age. This is the missing link so far.”
Dr. Cannarella has reported no relevant financial relationships. Dr. Herati has reported being an advisor for Dadi, LiNA Medical, and Teleflex.
A version of this article first appeared on Medscape.com.
new data suggest.
Testicular volume is a fertility marker directly related to sperm count that has halved in the past 40 years worldwide for unknown reasons. At the same time, childhood obesity has risen dramatically and infertility appears to have risen as well, Rossella Cannarella, MD, of the department of endocrinology and andrology, University of Catania (Italy), said at the annual meeting of the Endocrine Society.
According to recent Italian studies, between 14% and 23% of young men aged 18-19 had testicular hypotrophy. “Worryingly, we don’t know the reason for this hypotrophy. And therefore, they are at risk for future infertility,” Dr. Cannarella said during a press briefing.
Her study, which included a total of 264 male children and adolescents, also linked lower testicular volume to hyperinsulinemia and insulin resistance. “The testis is not quiescent in childhood and is sensitive to the hormone insulin. Obesity and metabolic impairment actually can have an effect and negative impact on Sertoli cell proliferation,” Dr. Cannarella said.
Screen testicular volume at all visits
If other studies confirm these results, she said that pediatricians should begin routinely assessing testicular volume at all visits as is now done with height and weight to identify early deflection of the testicular growth curve.
In addition, “include male infertility as a possible consequence of obesity in counseling of male obese children,” she advised.
Asked to comment, Amin Sedaghat Herati, MD, director of male infertility and men’s health at Johns Hopkins Hospital, and assistant professor of urology at Johns Hopkins Medicine, both in Baltimore, said in an interview: “I think what’s really interesting about this study is the association that they’ve made between testicular volume and obesity.”
But, he noted, “it does not implicate necessarily the development of infertility. It’s an extrapolation. So it’s a step towards the link between obesity and infertility, and it’s an important study to establish the association, but changes in testicular volume and even changes in semen panel don’t necessarily indicate fertility or infertility.”
The findings are “consistent with what we know as far as what obesity can potentially do to the activity of the cells in the testes. The authors are postulating that it’s more the support cells, called Sertoli cells, but I would say it’s probably all of the cells that are being affected by obesity and specifically elevated leptin levels,” Dr. Herati said.
He agrees with the recommendation that pediatricians screen all boys for testicular volume. “I agree it’s a good idea so they don’t miss any cases in which the testes don’t develop the way they should or any other conditions,” Dr. Herati said. “I think in general it’s a good practice, especially in the peripubertal stage, to make sure that kids are on the same growth curve and that they’re meeting their Tanner staging. [Pediatricians] should be looking at the size of the testes and tracking, maybe not at every visit, but at least on an annual basis.”
And, he noted, “I think any study that establishes a link that we can point to when we’re educating patients and parents is important.”
Links found between overweight/obesity, testicular hypotrophy
The study population included 61 male children and adolescents with normal weight, 53 with overweight, and 150 with obesity. Insulin resistance (Homeostatic Model Assessment for Insulin Resistance index ≥ 2.5) was present in 97 participants, 22 had prediabetes, and 3 had type 2 diabetes. Clinical data were collected retrospectively.
Among the boys aged 9-14 years, those with overweight and obesity had significantly lower testicular volume, compared with those of normal weight.
Those who were in Tanner Stage 1 were more likely to have overweight and obesity than those with normal weight, suggesting that “overweight and obese adolescents start puberty later than those of normal weight,” Dr. Cannarella said.
In the 14- to 16-year-old age group, those with insulin resistance had lower testicular volume, compared with those without insulin resistance (HOMA index < 2.5). The number of insulin-resistant adolescents was greater than that of controls in the Tanner stage 2 group.
In both the prepubertal (< 9 years) and pubertal (14-16 years) groups, hyperinsulinemia was associated with lower levels of testicular volume.
Hyperinsulinemia did not influence the timing of puberty onset.
No way to quantify the effect of obesity on fertility just yet
During a press briefing, Dr. Cannarella commented that obesity is likely just one of several factors influencing what appears to be an increase in male infertility over time. “It isn’t of course the only reason, but many factors in our environment have drastically changed, compared to 40 years ago, including the prevalence of heavy metals and endocrine disruptors, and of course, the change in habits and higher prevalence of metabolic disease. All of this has an impact on the proliferation of Sertoli cells in childhood and this may explain the trend toward the decline of sperm concentration and count.”
Longitudinal data are needed to establish cause and effect, she noted. “We need longitudinal studies that link the degrees of testicular volume with the degree of the sperm concentration and count starting from childhood and ending with the adult age. This is the missing link so far.”
Dr. Cannarella has reported no relevant financial relationships. Dr. Herati has reported being an advisor for Dadi, LiNA Medical, and Teleflex.
A version of this article first appeared on Medscape.com.
new data suggest.
Testicular volume is a fertility marker directly related to sperm count that has halved in the past 40 years worldwide for unknown reasons. At the same time, childhood obesity has risen dramatically and infertility appears to have risen as well, Rossella Cannarella, MD, of the department of endocrinology and andrology, University of Catania (Italy), said at the annual meeting of the Endocrine Society.
According to recent Italian studies, between 14% and 23% of young men aged 18-19 had testicular hypotrophy. “Worryingly, we don’t know the reason for this hypotrophy. And therefore, they are at risk for future infertility,” Dr. Cannarella said during a press briefing.
Her study, which included a total of 264 male children and adolescents, also linked lower testicular volume to hyperinsulinemia and insulin resistance. “The testis is not quiescent in childhood and is sensitive to the hormone insulin. Obesity and metabolic impairment actually can have an effect and negative impact on Sertoli cell proliferation,” Dr. Cannarella said.
Screen testicular volume at all visits
If other studies confirm these results, she said that pediatricians should begin routinely assessing testicular volume at all visits as is now done with height and weight to identify early deflection of the testicular growth curve.
In addition, “include male infertility as a possible consequence of obesity in counseling of male obese children,” she advised.
Asked to comment, Amin Sedaghat Herati, MD, director of male infertility and men’s health at Johns Hopkins Hospital, and assistant professor of urology at Johns Hopkins Medicine, both in Baltimore, said in an interview: “I think what’s really interesting about this study is the association that they’ve made between testicular volume and obesity.”
But, he noted, “it does not implicate necessarily the development of infertility. It’s an extrapolation. So it’s a step towards the link between obesity and infertility, and it’s an important study to establish the association, but changes in testicular volume and even changes in semen panel don’t necessarily indicate fertility or infertility.”
The findings are “consistent with what we know as far as what obesity can potentially do to the activity of the cells in the testes. The authors are postulating that it’s more the support cells, called Sertoli cells, but I would say it’s probably all of the cells that are being affected by obesity and specifically elevated leptin levels,” Dr. Herati said.
He agrees with the recommendation that pediatricians screen all boys for testicular volume. “I agree it’s a good idea so they don’t miss any cases in which the testes don’t develop the way they should or any other conditions,” Dr. Herati said. “I think in general it’s a good practice, especially in the peripubertal stage, to make sure that kids are on the same growth curve and that they’re meeting their Tanner staging. [Pediatricians] should be looking at the size of the testes and tracking, maybe not at every visit, but at least on an annual basis.”
And, he noted, “I think any study that establishes a link that we can point to when we’re educating patients and parents is important.”
Links found between overweight/obesity, testicular hypotrophy
The study population included 61 male children and adolescents with normal weight, 53 with overweight, and 150 with obesity. Insulin resistance (Homeostatic Model Assessment for Insulin Resistance index ≥ 2.5) was present in 97 participants, 22 had prediabetes, and 3 had type 2 diabetes. Clinical data were collected retrospectively.
Among the boys aged 9-14 years, those with overweight and obesity had significantly lower testicular volume, compared with those of normal weight.
Those who were in Tanner Stage 1 were more likely to have overweight and obesity than those with normal weight, suggesting that “overweight and obese adolescents start puberty later than those of normal weight,” Dr. Cannarella said.
In the 14- to 16-year-old age group, those with insulin resistance had lower testicular volume, compared with those without insulin resistance (HOMA index < 2.5). The number of insulin-resistant adolescents was greater than that of controls in the Tanner stage 2 group.
In both the prepubertal (< 9 years) and pubertal (14-16 years) groups, hyperinsulinemia was associated with lower levels of testicular volume.
Hyperinsulinemia did not influence the timing of puberty onset.
No way to quantify the effect of obesity on fertility just yet
During a press briefing, Dr. Cannarella commented that obesity is likely just one of several factors influencing what appears to be an increase in male infertility over time. “It isn’t of course the only reason, but many factors in our environment have drastically changed, compared to 40 years ago, including the prevalence of heavy metals and endocrine disruptors, and of course, the change in habits and higher prevalence of metabolic disease. All of this has an impact on the proliferation of Sertoli cells in childhood and this may explain the trend toward the decline of sperm concentration and count.”
Longitudinal data are needed to establish cause and effect, she noted. “We need longitudinal studies that link the degrees of testicular volume with the degree of the sperm concentration and count starting from childhood and ending with the adult age. This is the missing link so far.”
Dr. Cannarella has reported no relevant financial relationships. Dr. Herati has reported being an advisor for Dadi, LiNA Medical, and Teleflex.
A version of this article first appeared on Medscape.com.
FROM ENDO 2022
Fatty liver disease drives rise in liver cancer deaths
LONDON – Around the world, nonalcoholic fatty liver disease (NAFLD) has driven an increase in deaths from liver cancer over the past decade, overtaking alcoholic liver disease, hepatitis B, and hepatitis C, according to an analysis of the Global Burden of Disease Study 2019.
A global rise in liver cancer deaths and chronic liver disease reflects changes in underlying health patterns, said Zobair Younossi, MD, MPH, professor and chair, department of medicine, Inova Fairfax Medical Campus, Falls Church, Va., who presented the analysis at the meeting sponsored by the European Association for the Study of the Liver.
Dr. Younossi told this news organization. “We have known about the increasing prevalence for some time, but now the outcomes in terms of mortality are catching up,” he said.
“The bottom line of this study is that the burden of this disease [NAFLD] is going up, and it will be the most important disease of the next decade or so,” he said, adding that “the largest annual percentage increase in rates of mortality from liver cancer or chronic liver disease cirrhosis is related to NAFLD.”
Specifically, during the decade of 2009–2019, the annual percent change of +1.33% in the global liver cancer death rate was driven by the fact that the APC for NAFLD was +2.47%. By comparison, the APC for alcoholic liver disease was +1.91%; for hepatitis B, the APC was +0.21%; and for hepatitis C, the APC was +1.12%.
Aleksander Krag, MD, PhD, professor and senior consultant of hepatology and director of Odense (Denmark) Liver Research Centre at SDU and Odense University Hospital, who chaired the session in which this presentation was a part, acknowledged the importance of recognizing the contribution of NAFLD to liver cancer mortality.
“Liver diseases are on the rise. They are the fastest rising cause of death in the United Kingdom, faster than heart disease and other cancers. NAFLD in particular is the fastest growing cause of liver cancer, and the leading cause in France and the United States,” he remarked.
Dr. Krag also highlighted the costs of disease management.
“Managing fatty liver disease in Europe is estimated at €35 billion in direct health care, so we need to do something now,” he stressed.
“The global burden of NAFLD is so high that we need both prevention and treatment tools,” Dr. Krag said. “Change to lifestyle is a ‘no-brainer’ and costs governments very little. For the sake of our young people, we need to take this very seriously. At a political level, we can easily implement this, for example, by banning junk food advertisements, but also educating young people and their families. Good drugs will also help.”
NAFLD: The liver manifestation of type 2 diabetes
About 25%-30% of the global population have NAFLD, and 3%-5% have NASH. Dr. Younossi highlighted that the U.S. transplant database shows that NAFLD was the second indication for all liver transplants in the country. NAFLD also was a leading cause of liver transplants for patients with hepatocellular carcinoma.
There are around 2 billion cases of chronic liver disease globally, he said. He noted that, over time, there has been an increase in all kinds of liver diseases, as reflected in the annual percent change.
“The global epidemic of obesity and type 2 diabetes is driving the rise in NAFLD, but even among lean people, the prevalence of NAFLD is around 9%,” Dr. Younossi said. “Alongside the eye and kidney complications of diabetes, this is the liver manifestation of type 2 diabetes.”
To assess global liver disease and death, Dr. Younossi and his colleagues turned to the Global Burden of Disease Study, which gathered data from around 7,000 investigators located across 22 different regions of the world, comprising 156 countries.
They calculated the incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) in relation to liver cancer and chronic liver disease, including the APC. They linked the data to changes in four liver diseases: NAFLD, alcoholic liver disease, hepatitis B infection, and hepatitis C infection.
The cases of NAFLD reported in the study had been diagnosed by ultrasound or other imaging. Importantly, the prevalence of NAFLD was adjusted for alcohol use in the various national populations, explained Dr. Younossi.
In 2019, they reported that the overall global prevalence of liver disease reached 1.69 billion (liver cancer, 0.04%; chronic liver disease, 99.96%), with an incidence of 2.59 million (liver cancer, 20.7%; chronic liver disease, 79.3%), mortality of 1.95 million (liver cancer, 24.8%; chronic liver disease, 75.3%), and DALYs of 58.7 million (liver cancer, 21.3%; chronic liver disease, 78.7%).
Between 2009 and 2019, deaths from liver cancer rose by 27.2%, and deaths from chronic liver disease rose by 10.6%. DALYs from liver cancer rose by 21.9%, and DALYs from chronic liver disease were up by 5.1%.
In contrast to the increase in liver cancer deaths, deaths from chronic liver disease decreased (APC, –0.18%). The decrease was driven by a decrease in hepatitis B (APC, –1.83%). APCs for hepatitis C (+0.37%), alcoholic liver disease (+0.45%), and NAFLD (+1.33%) increased.
“The burden of hepatitis B–related mortality has decreased because we have been so good at vaccinating people,” Dr. Younossi remarked.
NAFLD ‘exploding’ in Middle East, North Africa, and East Asia
The increase in NAFLD has been seen in all regions of the world, but a breakdown by region shows that NAFLD is primarily “exploding” with highest prevalence and mortality in the Middle East (mostly Egypt, Iran, and Turkey), North Africa, and East Asia, said Dr. Younossi. In addition, there are large increases in the West and South America.
“We knew that the prevalence was high in the Middle East, but we now know that mortality is also high, so we are connecting these data,” said Dr. Younossi.
Awareness lacking
Dr. Younossi pressed the fact that awareness among the general population, primary care providers, and policy makers is very low. “From my perspective, raising awareness of NAFLD is the No. 1 priority, and that is the value of this study.”
He added that more people will become aware as testing becomes more manageable.
“There are some noninvasive tests being developed, so in the future, we won’t have to do liver biopsies to diagnose these patients,” he said. “Currently, there are some excellent treatments being developed.”
“The [World Health Organization] does not mention NAFLD as an important noncommunicable disease, and this too has to change,” Dr. Younossi added.
Dr. Younossi has received research funds and/or has consulted for Abbott, Allergan, Bristol-Myers Squibb, Echosens, Genfit, Gilead Sciences, Intercept, Madrigal, Merck, and Novo Nordisk. Dr. Karg disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
LONDON – Around the world, nonalcoholic fatty liver disease (NAFLD) has driven an increase in deaths from liver cancer over the past decade, overtaking alcoholic liver disease, hepatitis B, and hepatitis C, according to an analysis of the Global Burden of Disease Study 2019.
A global rise in liver cancer deaths and chronic liver disease reflects changes in underlying health patterns, said Zobair Younossi, MD, MPH, professor and chair, department of medicine, Inova Fairfax Medical Campus, Falls Church, Va., who presented the analysis at the meeting sponsored by the European Association for the Study of the Liver.
Dr. Younossi told this news organization. “We have known about the increasing prevalence for some time, but now the outcomes in terms of mortality are catching up,” he said.
“The bottom line of this study is that the burden of this disease [NAFLD] is going up, and it will be the most important disease of the next decade or so,” he said, adding that “the largest annual percentage increase in rates of mortality from liver cancer or chronic liver disease cirrhosis is related to NAFLD.”
Specifically, during the decade of 2009–2019, the annual percent change of +1.33% in the global liver cancer death rate was driven by the fact that the APC for NAFLD was +2.47%. By comparison, the APC for alcoholic liver disease was +1.91%; for hepatitis B, the APC was +0.21%; and for hepatitis C, the APC was +1.12%.
Aleksander Krag, MD, PhD, professor and senior consultant of hepatology and director of Odense (Denmark) Liver Research Centre at SDU and Odense University Hospital, who chaired the session in which this presentation was a part, acknowledged the importance of recognizing the contribution of NAFLD to liver cancer mortality.
“Liver diseases are on the rise. They are the fastest rising cause of death in the United Kingdom, faster than heart disease and other cancers. NAFLD in particular is the fastest growing cause of liver cancer, and the leading cause in France and the United States,” he remarked.
Dr. Krag also highlighted the costs of disease management.
“Managing fatty liver disease in Europe is estimated at €35 billion in direct health care, so we need to do something now,” he stressed.
“The global burden of NAFLD is so high that we need both prevention and treatment tools,” Dr. Krag said. “Change to lifestyle is a ‘no-brainer’ and costs governments very little. For the sake of our young people, we need to take this very seriously. At a political level, we can easily implement this, for example, by banning junk food advertisements, but also educating young people and their families. Good drugs will also help.”
NAFLD: The liver manifestation of type 2 diabetes
About 25%-30% of the global population have NAFLD, and 3%-5% have NASH. Dr. Younossi highlighted that the U.S. transplant database shows that NAFLD was the second indication for all liver transplants in the country. NAFLD also was a leading cause of liver transplants for patients with hepatocellular carcinoma.
There are around 2 billion cases of chronic liver disease globally, he said. He noted that, over time, there has been an increase in all kinds of liver diseases, as reflected in the annual percent change.
“The global epidemic of obesity and type 2 diabetes is driving the rise in NAFLD, but even among lean people, the prevalence of NAFLD is around 9%,” Dr. Younossi said. “Alongside the eye and kidney complications of diabetes, this is the liver manifestation of type 2 diabetes.”
To assess global liver disease and death, Dr. Younossi and his colleagues turned to the Global Burden of Disease Study, which gathered data from around 7,000 investigators located across 22 different regions of the world, comprising 156 countries.
They calculated the incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) in relation to liver cancer and chronic liver disease, including the APC. They linked the data to changes in four liver diseases: NAFLD, alcoholic liver disease, hepatitis B infection, and hepatitis C infection.
The cases of NAFLD reported in the study had been diagnosed by ultrasound or other imaging. Importantly, the prevalence of NAFLD was adjusted for alcohol use in the various national populations, explained Dr. Younossi.
In 2019, they reported that the overall global prevalence of liver disease reached 1.69 billion (liver cancer, 0.04%; chronic liver disease, 99.96%), with an incidence of 2.59 million (liver cancer, 20.7%; chronic liver disease, 79.3%), mortality of 1.95 million (liver cancer, 24.8%; chronic liver disease, 75.3%), and DALYs of 58.7 million (liver cancer, 21.3%; chronic liver disease, 78.7%).
Between 2009 and 2019, deaths from liver cancer rose by 27.2%, and deaths from chronic liver disease rose by 10.6%. DALYs from liver cancer rose by 21.9%, and DALYs from chronic liver disease were up by 5.1%.
In contrast to the increase in liver cancer deaths, deaths from chronic liver disease decreased (APC, –0.18%). The decrease was driven by a decrease in hepatitis B (APC, –1.83%). APCs for hepatitis C (+0.37%), alcoholic liver disease (+0.45%), and NAFLD (+1.33%) increased.
“The burden of hepatitis B–related mortality has decreased because we have been so good at vaccinating people,” Dr. Younossi remarked.
NAFLD ‘exploding’ in Middle East, North Africa, and East Asia
The increase in NAFLD has been seen in all regions of the world, but a breakdown by region shows that NAFLD is primarily “exploding” with highest prevalence and mortality in the Middle East (mostly Egypt, Iran, and Turkey), North Africa, and East Asia, said Dr. Younossi. In addition, there are large increases in the West and South America.
“We knew that the prevalence was high in the Middle East, but we now know that mortality is also high, so we are connecting these data,” said Dr. Younossi.
Awareness lacking
Dr. Younossi pressed the fact that awareness among the general population, primary care providers, and policy makers is very low. “From my perspective, raising awareness of NAFLD is the No. 1 priority, and that is the value of this study.”
He added that more people will become aware as testing becomes more manageable.
“There are some noninvasive tests being developed, so in the future, we won’t have to do liver biopsies to diagnose these patients,” he said. “Currently, there are some excellent treatments being developed.”
“The [World Health Organization] does not mention NAFLD as an important noncommunicable disease, and this too has to change,” Dr. Younossi added.
Dr. Younossi has received research funds and/or has consulted for Abbott, Allergan, Bristol-Myers Squibb, Echosens, Genfit, Gilead Sciences, Intercept, Madrigal, Merck, and Novo Nordisk. Dr. Karg disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
LONDON – Around the world, nonalcoholic fatty liver disease (NAFLD) has driven an increase in deaths from liver cancer over the past decade, overtaking alcoholic liver disease, hepatitis B, and hepatitis C, according to an analysis of the Global Burden of Disease Study 2019.
A global rise in liver cancer deaths and chronic liver disease reflects changes in underlying health patterns, said Zobair Younossi, MD, MPH, professor and chair, department of medicine, Inova Fairfax Medical Campus, Falls Church, Va., who presented the analysis at the meeting sponsored by the European Association for the Study of the Liver.
Dr. Younossi told this news organization. “We have known about the increasing prevalence for some time, but now the outcomes in terms of mortality are catching up,” he said.
“The bottom line of this study is that the burden of this disease [NAFLD] is going up, and it will be the most important disease of the next decade or so,” he said, adding that “the largest annual percentage increase in rates of mortality from liver cancer or chronic liver disease cirrhosis is related to NAFLD.”
Specifically, during the decade of 2009–2019, the annual percent change of +1.33% in the global liver cancer death rate was driven by the fact that the APC for NAFLD was +2.47%. By comparison, the APC for alcoholic liver disease was +1.91%; for hepatitis B, the APC was +0.21%; and for hepatitis C, the APC was +1.12%.
Aleksander Krag, MD, PhD, professor and senior consultant of hepatology and director of Odense (Denmark) Liver Research Centre at SDU and Odense University Hospital, who chaired the session in which this presentation was a part, acknowledged the importance of recognizing the contribution of NAFLD to liver cancer mortality.
“Liver diseases are on the rise. They are the fastest rising cause of death in the United Kingdom, faster than heart disease and other cancers. NAFLD in particular is the fastest growing cause of liver cancer, and the leading cause in France and the United States,” he remarked.
Dr. Krag also highlighted the costs of disease management.
“Managing fatty liver disease in Europe is estimated at €35 billion in direct health care, so we need to do something now,” he stressed.
“The global burden of NAFLD is so high that we need both prevention and treatment tools,” Dr. Krag said. “Change to lifestyle is a ‘no-brainer’ and costs governments very little. For the sake of our young people, we need to take this very seriously. At a political level, we can easily implement this, for example, by banning junk food advertisements, but also educating young people and their families. Good drugs will also help.”
NAFLD: The liver manifestation of type 2 diabetes
About 25%-30% of the global population have NAFLD, and 3%-5% have NASH. Dr. Younossi highlighted that the U.S. transplant database shows that NAFLD was the second indication for all liver transplants in the country. NAFLD also was a leading cause of liver transplants for patients with hepatocellular carcinoma.
There are around 2 billion cases of chronic liver disease globally, he said. He noted that, over time, there has been an increase in all kinds of liver diseases, as reflected in the annual percent change.
“The global epidemic of obesity and type 2 diabetes is driving the rise in NAFLD, but even among lean people, the prevalence of NAFLD is around 9%,” Dr. Younossi said. “Alongside the eye and kidney complications of diabetes, this is the liver manifestation of type 2 diabetes.”
To assess global liver disease and death, Dr. Younossi and his colleagues turned to the Global Burden of Disease Study, which gathered data from around 7,000 investigators located across 22 different regions of the world, comprising 156 countries.
They calculated the incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) in relation to liver cancer and chronic liver disease, including the APC. They linked the data to changes in four liver diseases: NAFLD, alcoholic liver disease, hepatitis B infection, and hepatitis C infection.
The cases of NAFLD reported in the study had been diagnosed by ultrasound or other imaging. Importantly, the prevalence of NAFLD was adjusted for alcohol use in the various national populations, explained Dr. Younossi.
In 2019, they reported that the overall global prevalence of liver disease reached 1.69 billion (liver cancer, 0.04%; chronic liver disease, 99.96%), with an incidence of 2.59 million (liver cancer, 20.7%; chronic liver disease, 79.3%), mortality of 1.95 million (liver cancer, 24.8%; chronic liver disease, 75.3%), and DALYs of 58.7 million (liver cancer, 21.3%; chronic liver disease, 78.7%).
Between 2009 and 2019, deaths from liver cancer rose by 27.2%, and deaths from chronic liver disease rose by 10.6%. DALYs from liver cancer rose by 21.9%, and DALYs from chronic liver disease were up by 5.1%.
In contrast to the increase in liver cancer deaths, deaths from chronic liver disease decreased (APC, –0.18%). The decrease was driven by a decrease in hepatitis B (APC, –1.83%). APCs for hepatitis C (+0.37%), alcoholic liver disease (+0.45%), and NAFLD (+1.33%) increased.
“The burden of hepatitis B–related mortality has decreased because we have been so good at vaccinating people,” Dr. Younossi remarked.
NAFLD ‘exploding’ in Middle East, North Africa, and East Asia
The increase in NAFLD has been seen in all regions of the world, but a breakdown by region shows that NAFLD is primarily “exploding” with highest prevalence and mortality in the Middle East (mostly Egypt, Iran, and Turkey), North Africa, and East Asia, said Dr. Younossi. In addition, there are large increases in the West and South America.
“We knew that the prevalence was high in the Middle East, but we now know that mortality is also high, so we are connecting these data,” said Dr. Younossi.
Awareness lacking
Dr. Younossi pressed the fact that awareness among the general population, primary care providers, and policy makers is very low. “From my perspective, raising awareness of NAFLD is the No. 1 priority, and that is the value of this study.”
He added that more people will become aware as testing becomes more manageable.
“There are some noninvasive tests being developed, so in the future, we won’t have to do liver biopsies to diagnose these patients,” he said. “Currently, there are some excellent treatments being developed.”
“The [World Health Organization] does not mention NAFLD as an important noncommunicable disease, and this too has to change,” Dr. Younossi added.
Dr. Younossi has received research funds and/or has consulted for Abbott, Allergan, Bristol-Myers Squibb, Echosens, Genfit, Gilead Sciences, Intercept, Madrigal, Merck, and Novo Nordisk. Dr. Karg disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ILC 2022
My picks for best of ASCO 2022
CHICAGO – The American Society of Clinical Oncology recently wrapped its annual meeting in Chicago. Here, I highlight some presentations that stood out to me.
A first-line treatment for metastatic colorectal cancer
The plenary session did not disappoint. In abstract LBA1, investigators presented first-line treatment for patients with metastatic colorectal cancer who were randomized to receive mFOLFOX6 with either bevacizumab or panitumumab in RAS wild-type positive patients. This was the phase 3 PARADIGM trial.
The primary outcome for this study was overall survival. It included 823 patients who were randomized 1:1 with a subset analysis of whether the primary tumor was on the left or right side of the colon. At 61 months follow-up, the median overall survival results for left-sided colon cancer was 38 months versus 34 months. It was statistically significant favoring the panitumumab arm. It improved the curable resection rate for patients with left-sided tumors from 11% in the bevacizumab arm to 18% in the panitumumab arm. Interestingly, patients randomized with right-sided tumors showed no difference in overall survival. The investigator, Takayuki Yoshino, MD, PhD, National Cancer Center Hospital East, Kashiwa, Japan, said the study findings support the use of mFOLFOX6 with panitumumab in left-sided RAS wild type as first-line therapy in metastatic colorectal patients.
A possible new standard of care in breast cancer
Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center, New York, received a standing ovation and deserved it. In the phase 3 clinical trial DESTINY-Breast04 (abstract LBA3), she demonstrated that trastuzumab deruxtecan (T-DXd) for patients with metastatic breast cancer who were HER2 low (IHC 1+ or 2+ ISH-), led to a statistically significant and clinically meaningful benefit in both progression free survival and overall survival. In this trial, patients were randomized 2:1 to receive trastuzumab deruxtecan or physician’s choice of chemotherapy. All patients had at least one to two lines of chemotherapy before entering the trial. Hormone-positive patients were allowed if they had already received and failed, or progressed on hormone therapy.
Previously, most patients were treated either with eribulin with some receiving capecitabine, gemcitabine or taxane, or hormone therapy if hormone positive.
The progression-free survival was 10.1 versus 5.4 months in hormone-positive patients, and in all patients (hormone receptor positive or negative), there was a likewise improvement of 9.9 versus 5.1 months progression free survival.
Overall survival was equally impressive. In the hormone receptor–positive patients, the hazard ratio was 0.64 with a 23.9 versus 17.5 month survival. If all patients were included, the HR was again 0.64 with 23.4 versus 16.8 month survival. Even the triple-negative breast cancer patients had a HR of 0.48 with 18.2 versus 8.3 months survival. Adverse events were quite tolerable with some nausea, some decreased white count, and only an interstitial lung disease of grade 2 or less in 12%.
Trastuzumab deruxtecan is a targeted treatment which, in addition to striking its target, also targets other tumor cells that are part of the cancer. The results of this study may lead to a new standard of care of this patient population.
The study by Dr. Modi and colleagues was simultaneously published in the New England Journal of Medicine.
Improving outcomes in multiple myeloma
In abstract LBA4, Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, Boston, asks if autologous stem cell transplant (ASCT) can improve outcomes after induction with an RVD regimen (lenalidomide, bortezomib, and dexamethasone) and lenalidomide (Revlimid) maintenance for newly diagnosed patients with multiple myeloma in the DETERMINATION study.
The take home here was quite interesting. In fact, there is no difference in overall survival if patients get this standard RVD/lenalidomide maintenance induction with or without ASCT. However, the progression free survival was better with ASCT: 46 versus 67 months (improvement of 21 months). However, there were some caveats. There was toxicity and change in quality of life for a while in those patients receiving ASCT as would be expected. Furthermore, the study only allowed 65 years old or younger and ASCT may not be wise for older patients. The discussant made a strong point that African Americans tend to have higher risk disease with different mutations and might also be better served by have ASCT later.
The conclusion was that, given all the new therapies in myeloma for second line and beyond, ASCT should be a discussion with each new patient and not an automatic decision.
This study was simultaneously published in the New England Journal of Medicine.
Adagrasib promising for pretreated patients with NSCLC with KRAS mutation
In patients with advanced or metastatic non–small cell lung cancer (NSCLC), adagrasib was found to be well tolerated and “demonstrates promising efficacy” for patients with the KRAS G12C mutation (KRYSTAL-1, abstract 9002). This was a phase 2 registration trial of 116 patients who were treated with 600 mg of adagrasib twice orally. Patients all had previous chemotherapy or immunotherapy or both. The overall response rate was a surprisingly good 43% (complete response and partial response). Disease control was an incredible 80% if stable disease was included. The duration of response was 8.5 months, progression-free survival was 6.5 months, and overall survival was 12.6 months. Furthermore, 33% of those with brain metastases had a complete response or partial response.
The take-home message is that, since 15% of NSCLC metastatic patients are KRAS mutant G12C, we should be watching for such patients in our biomarker analysis. While we have sotorasib – approved by the Food and Drug Administration for NSCLC – the results of this study suggests we may have another new molecule in the same class.
Neoadjuvant chemotherapy with immunotherapy for NSCLC
It may be time to consider neoadjuvant chemotherapy with immunotherapy, such as nivolumab, for patients with NSCLC in order to achieve the best response possible.
In NADIM II, investigators led by Mariano Provencio-Pulla, MD, of the Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, confirmed the superiority of chemotherapy with immunotherapy for patients with resectable stage IIIA NSCLC. NADIM included patients with resectable stage IIIA/B NSCLC who were randomized 2:1 to receive carboplatin taxol neoadjuvant therapy with or without nivolumab before and after surgery. The pathological complete response rates overall were 36% versus 7%, favoring the nivolumab arm, but even higher pCR rates occurred in patients with PD-L1 over 50%.
In closing, always check MMR, KRAS, BRAF, and HER2. For wild-type left-sided mCRC, consider FOLFOX or FOLFIRI with an anti-EGFR. For KRAS mutant or right-sided colon tumor, consider FOLFOX or FOLFIRI with bevacizumab, followed by maintenance 5FU or capecitabine, with or without bevacizumab.
CHICAGO – The American Society of Clinical Oncology recently wrapped its annual meeting in Chicago. Here, I highlight some presentations that stood out to me.
A first-line treatment for metastatic colorectal cancer
The plenary session did not disappoint. In abstract LBA1, investigators presented first-line treatment for patients with metastatic colorectal cancer who were randomized to receive mFOLFOX6 with either bevacizumab or panitumumab in RAS wild-type positive patients. This was the phase 3 PARADIGM trial.
The primary outcome for this study was overall survival. It included 823 patients who were randomized 1:1 with a subset analysis of whether the primary tumor was on the left or right side of the colon. At 61 months follow-up, the median overall survival results for left-sided colon cancer was 38 months versus 34 months. It was statistically significant favoring the panitumumab arm. It improved the curable resection rate for patients with left-sided tumors from 11% in the bevacizumab arm to 18% in the panitumumab arm. Interestingly, patients randomized with right-sided tumors showed no difference in overall survival. The investigator, Takayuki Yoshino, MD, PhD, National Cancer Center Hospital East, Kashiwa, Japan, said the study findings support the use of mFOLFOX6 with panitumumab in left-sided RAS wild type as first-line therapy in metastatic colorectal patients.
A possible new standard of care in breast cancer
Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center, New York, received a standing ovation and deserved it. In the phase 3 clinical trial DESTINY-Breast04 (abstract LBA3), she demonstrated that trastuzumab deruxtecan (T-DXd) for patients with metastatic breast cancer who were HER2 low (IHC 1+ or 2+ ISH-), led to a statistically significant and clinically meaningful benefit in both progression free survival and overall survival. In this trial, patients were randomized 2:1 to receive trastuzumab deruxtecan or physician’s choice of chemotherapy. All patients had at least one to two lines of chemotherapy before entering the trial. Hormone-positive patients were allowed if they had already received and failed, or progressed on hormone therapy.
Previously, most patients were treated either with eribulin with some receiving capecitabine, gemcitabine or taxane, or hormone therapy if hormone positive.
The progression-free survival was 10.1 versus 5.4 months in hormone-positive patients, and in all patients (hormone receptor positive or negative), there was a likewise improvement of 9.9 versus 5.1 months progression free survival.
Overall survival was equally impressive. In the hormone receptor–positive patients, the hazard ratio was 0.64 with a 23.9 versus 17.5 month survival. If all patients were included, the HR was again 0.64 with 23.4 versus 16.8 month survival. Even the triple-negative breast cancer patients had a HR of 0.48 with 18.2 versus 8.3 months survival. Adverse events were quite tolerable with some nausea, some decreased white count, and only an interstitial lung disease of grade 2 or less in 12%.
Trastuzumab deruxtecan is a targeted treatment which, in addition to striking its target, also targets other tumor cells that are part of the cancer. The results of this study may lead to a new standard of care of this patient population.
The study by Dr. Modi and colleagues was simultaneously published in the New England Journal of Medicine.
Improving outcomes in multiple myeloma
In abstract LBA4, Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, Boston, asks if autologous stem cell transplant (ASCT) can improve outcomes after induction with an RVD regimen (lenalidomide, bortezomib, and dexamethasone) and lenalidomide (Revlimid) maintenance for newly diagnosed patients with multiple myeloma in the DETERMINATION study.
The take home here was quite interesting. In fact, there is no difference in overall survival if patients get this standard RVD/lenalidomide maintenance induction with or without ASCT. However, the progression free survival was better with ASCT: 46 versus 67 months (improvement of 21 months). However, there were some caveats. There was toxicity and change in quality of life for a while in those patients receiving ASCT as would be expected. Furthermore, the study only allowed 65 years old or younger and ASCT may not be wise for older patients. The discussant made a strong point that African Americans tend to have higher risk disease with different mutations and might also be better served by have ASCT later.
The conclusion was that, given all the new therapies in myeloma for second line and beyond, ASCT should be a discussion with each new patient and not an automatic decision.
This study was simultaneously published in the New England Journal of Medicine.
Adagrasib promising for pretreated patients with NSCLC with KRAS mutation
In patients with advanced or metastatic non–small cell lung cancer (NSCLC), adagrasib was found to be well tolerated and “demonstrates promising efficacy” for patients with the KRAS G12C mutation (KRYSTAL-1, abstract 9002). This was a phase 2 registration trial of 116 patients who were treated with 600 mg of adagrasib twice orally. Patients all had previous chemotherapy or immunotherapy or both. The overall response rate was a surprisingly good 43% (complete response and partial response). Disease control was an incredible 80% if stable disease was included. The duration of response was 8.5 months, progression-free survival was 6.5 months, and overall survival was 12.6 months. Furthermore, 33% of those with brain metastases had a complete response or partial response.
The take-home message is that, since 15% of NSCLC metastatic patients are KRAS mutant G12C, we should be watching for such patients in our biomarker analysis. While we have sotorasib – approved by the Food and Drug Administration for NSCLC – the results of this study suggests we may have another new molecule in the same class.
Neoadjuvant chemotherapy with immunotherapy for NSCLC
It may be time to consider neoadjuvant chemotherapy with immunotherapy, such as nivolumab, for patients with NSCLC in order to achieve the best response possible.
In NADIM II, investigators led by Mariano Provencio-Pulla, MD, of the Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, confirmed the superiority of chemotherapy with immunotherapy for patients with resectable stage IIIA NSCLC. NADIM included patients with resectable stage IIIA/B NSCLC who were randomized 2:1 to receive carboplatin taxol neoadjuvant therapy with or without nivolumab before and after surgery. The pathological complete response rates overall were 36% versus 7%, favoring the nivolumab arm, but even higher pCR rates occurred in patients with PD-L1 over 50%.
In closing, always check MMR, KRAS, BRAF, and HER2. For wild-type left-sided mCRC, consider FOLFOX or FOLFIRI with an anti-EGFR. For KRAS mutant or right-sided colon tumor, consider FOLFOX or FOLFIRI with bevacizumab, followed by maintenance 5FU or capecitabine, with or without bevacizumab.
CHICAGO – The American Society of Clinical Oncology recently wrapped its annual meeting in Chicago. Here, I highlight some presentations that stood out to me.
A first-line treatment for metastatic colorectal cancer
The plenary session did not disappoint. In abstract LBA1, investigators presented first-line treatment for patients with metastatic colorectal cancer who were randomized to receive mFOLFOX6 with either bevacizumab or panitumumab in RAS wild-type positive patients. This was the phase 3 PARADIGM trial.
The primary outcome for this study was overall survival. It included 823 patients who were randomized 1:1 with a subset analysis of whether the primary tumor was on the left or right side of the colon. At 61 months follow-up, the median overall survival results for left-sided colon cancer was 38 months versus 34 months. It was statistically significant favoring the panitumumab arm. It improved the curable resection rate for patients with left-sided tumors from 11% in the bevacizumab arm to 18% in the panitumumab arm. Interestingly, patients randomized with right-sided tumors showed no difference in overall survival. The investigator, Takayuki Yoshino, MD, PhD, National Cancer Center Hospital East, Kashiwa, Japan, said the study findings support the use of mFOLFOX6 with panitumumab in left-sided RAS wild type as first-line therapy in metastatic colorectal patients.
A possible new standard of care in breast cancer
Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center, New York, received a standing ovation and deserved it. In the phase 3 clinical trial DESTINY-Breast04 (abstract LBA3), she demonstrated that trastuzumab deruxtecan (T-DXd) for patients with metastatic breast cancer who were HER2 low (IHC 1+ or 2+ ISH-), led to a statistically significant and clinically meaningful benefit in both progression free survival and overall survival. In this trial, patients were randomized 2:1 to receive trastuzumab deruxtecan or physician’s choice of chemotherapy. All patients had at least one to two lines of chemotherapy before entering the trial. Hormone-positive patients were allowed if they had already received and failed, or progressed on hormone therapy.
Previously, most patients were treated either with eribulin with some receiving capecitabine, gemcitabine or taxane, or hormone therapy if hormone positive.
The progression-free survival was 10.1 versus 5.4 months in hormone-positive patients, and in all patients (hormone receptor positive or negative), there was a likewise improvement of 9.9 versus 5.1 months progression free survival.
Overall survival was equally impressive. In the hormone receptor–positive patients, the hazard ratio was 0.64 with a 23.9 versus 17.5 month survival. If all patients were included, the HR was again 0.64 with 23.4 versus 16.8 month survival. Even the triple-negative breast cancer patients had a HR of 0.48 with 18.2 versus 8.3 months survival. Adverse events were quite tolerable with some nausea, some decreased white count, and only an interstitial lung disease of grade 2 or less in 12%.
Trastuzumab deruxtecan is a targeted treatment which, in addition to striking its target, also targets other tumor cells that are part of the cancer. The results of this study may lead to a new standard of care of this patient population.
The study by Dr. Modi and colleagues was simultaneously published in the New England Journal of Medicine.
Improving outcomes in multiple myeloma
In abstract LBA4, Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, Boston, asks if autologous stem cell transplant (ASCT) can improve outcomes after induction with an RVD regimen (lenalidomide, bortezomib, and dexamethasone) and lenalidomide (Revlimid) maintenance for newly diagnosed patients with multiple myeloma in the DETERMINATION study.
The take home here was quite interesting. In fact, there is no difference in overall survival if patients get this standard RVD/lenalidomide maintenance induction with or without ASCT. However, the progression free survival was better with ASCT: 46 versus 67 months (improvement of 21 months). However, there were some caveats. There was toxicity and change in quality of life for a while in those patients receiving ASCT as would be expected. Furthermore, the study only allowed 65 years old or younger and ASCT may not be wise for older patients. The discussant made a strong point that African Americans tend to have higher risk disease with different mutations and might also be better served by have ASCT later.
The conclusion was that, given all the new therapies in myeloma for second line and beyond, ASCT should be a discussion with each new patient and not an automatic decision.
This study was simultaneously published in the New England Journal of Medicine.
Adagrasib promising for pretreated patients with NSCLC with KRAS mutation
In patients with advanced or metastatic non–small cell lung cancer (NSCLC), adagrasib was found to be well tolerated and “demonstrates promising efficacy” for patients with the KRAS G12C mutation (KRYSTAL-1, abstract 9002). This was a phase 2 registration trial of 116 patients who were treated with 600 mg of adagrasib twice orally. Patients all had previous chemotherapy or immunotherapy or both. The overall response rate was a surprisingly good 43% (complete response and partial response). Disease control was an incredible 80% if stable disease was included. The duration of response was 8.5 months, progression-free survival was 6.5 months, and overall survival was 12.6 months. Furthermore, 33% of those with brain metastases had a complete response or partial response.
The take-home message is that, since 15% of NSCLC metastatic patients are KRAS mutant G12C, we should be watching for such patients in our biomarker analysis. While we have sotorasib – approved by the Food and Drug Administration for NSCLC – the results of this study suggests we may have another new molecule in the same class.
Neoadjuvant chemotherapy with immunotherapy for NSCLC
It may be time to consider neoadjuvant chemotherapy with immunotherapy, such as nivolumab, for patients with NSCLC in order to achieve the best response possible.
In NADIM II, investigators led by Mariano Provencio-Pulla, MD, of the Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, confirmed the superiority of chemotherapy with immunotherapy for patients with resectable stage IIIA NSCLC. NADIM included patients with resectable stage IIIA/B NSCLC who were randomized 2:1 to receive carboplatin taxol neoadjuvant therapy with or without nivolumab before and after surgery. The pathological complete response rates overall were 36% versus 7%, favoring the nivolumab arm, but even higher pCR rates occurred in patients with PD-L1 over 50%.
In closing, always check MMR, KRAS, BRAF, and HER2. For wild-type left-sided mCRC, consider FOLFOX or FOLFIRI with an anti-EGFR. For KRAS mutant or right-sided colon tumor, consider FOLFOX or FOLFIRI with bevacizumab, followed by maintenance 5FU or capecitabine, with or without bevacizumab.
AT ASCO 2022
Twin study offers new insight into genetics of migraine
DENVER – , even though testosterone is thought to be protective. The findings, presented at the annual meeting of the American Headache Society, also hint at a possible role played by the prenatal environment.
The study marks the first time a large-scale twin dataset has been used to assess sex differences in underlying genetic factors of migraine, lead author Morgan Fitzgerald, a senior research associate at the University of California at San Diego, said in a presentation at the conference. The findings were previously published in Frontiers in Pain Research.
More than genetics
The researchers analyzed data regarding 51,872 participants in the Swedish Twin Registry. According to Dr. Fitzgerald, the database is ideal because it is large and includes both genders.
Per the database, female twins were more likely to have migraines without aura than were male twins (17.6% vs. 5.5%, respectively), reflecting global numbers that suggest 18% of females and 6% of males have migraines each year.
To better understand heritability, the researchers compared identical twins with fraternal twins, and looked for gender-related correlations, Dr. Fitzgerald said.
One analysis suggests that migraine is equally heritable in men and women with a broad sense heritability of 0.45 (95% confidence interval [CI], 0.40-0.50). However, another analysis model provides evidence “that there are differences in the underlying genetic factors contributing to migraine across males and females,” she said.
Unexpectedly, the researchers also found that females with male twins were more likely to have migraines than were those with female twins (odds ratio, 1.51, 95% CI, 1.26-1.81) even though males are less affected by the headaches.
“These results suggest that the prominent sex difference in migraine prevalence is not entirely accounted for by genetic factors, while demonstrating that masculinization of the prenatal environment may increase migraine risk for females,” the authors wrote in the published study. “This effect points to a potential prenatal neuroendocrine factor in the development of migraine.”
Probing the migraine gender gap
Commenting on the research, University of Texas at Dallas neuroscientist and headache researcher Gregory Dussor, PhD, said the new study is “a very unique approach to address the question of nature versus nurture in migraine. It was well designed and used robust statistical modeling.”
As for the findings, “the conclusion that genetics do not explain sex differences in migraine risk by themselves is not surprising given how big of a role hormones in later life are likely to play in the disease and how many factors there are that can influence hormone levels,” he said.
“On the other hand, the surprising part of the findings was that the presence of a male co-twin increases risk of migraine in females. I would have expected to see the opposite, given the lower prevalence of migraine in males and the seemingly protective role that male hormones can play in migraine.”
Overall, the study adds to data implicating environment and hormones in the migraine gender gap, he said. “One thing I wonder from this study is what influence a female co-twin growing up with a male co-twin can have on migraine susceptibility. That female co-twin may end up with a very different set of childhood experiences than if she was with another female co-twin. Twins generally spend an enormous amount of time together and the same sex versus opposite sex experiences are likely to be quite different. This may have an influence on migraine later in life.”
As for the value of the study in terms of diagnosis, treatment, or prevention of migraine, Dr. Dussor said, “it’s possible it could help to identify risk factors for higher migraine susceptibility but it’s far too early to know how this could be used.”
The authors have no disclosures. Dr. Dussor disclosed an NIH-funded grant to study the role of the hormone prolactin in preclinical migraine models.
DENVER – , even though testosterone is thought to be protective. The findings, presented at the annual meeting of the American Headache Society, also hint at a possible role played by the prenatal environment.
The study marks the first time a large-scale twin dataset has been used to assess sex differences in underlying genetic factors of migraine, lead author Morgan Fitzgerald, a senior research associate at the University of California at San Diego, said in a presentation at the conference. The findings were previously published in Frontiers in Pain Research.
More than genetics
The researchers analyzed data regarding 51,872 participants in the Swedish Twin Registry. According to Dr. Fitzgerald, the database is ideal because it is large and includes both genders.
Per the database, female twins were more likely to have migraines without aura than were male twins (17.6% vs. 5.5%, respectively), reflecting global numbers that suggest 18% of females and 6% of males have migraines each year.
To better understand heritability, the researchers compared identical twins with fraternal twins, and looked for gender-related correlations, Dr. Fitzgerald said.
One analysis suggests that migraine is equally heritable in men and women with a broad sense heritability of 0.45 (95% confidence interval [CI], 0.40-0.50). However, another analysis model provides evidence “that there are differences in the underlying genetic factors contributing to migraine across males and females,” she said.
Unexpectedly, the researchers also found that females with male twins were more likely to have migraines than were those with female twins (odds ratio, 1.51, 95% CI, 1.26-1.81) even though males are less affected by the headaches.
“These results suggest that the prominent sex difference in migraine prevalence is not entirely accounted for by genetic factors, while demonstrating that masculinization of the prenatal environment may increase migraine risk for females,” the authors wrote in the published study. “This effect points to a potential prenatal neuroendocrine factor in the development of migraine.”
Probing the migraine gender gap
Commenting on the research, University of Texas at Dallas neuroscientist and headache researcher Gregory Dussor, PhD, said the new study is “a very unique approach to address the question of nature versus nurture in migraine. It was well designed and used robust statistical modeling.”
As for the findings, “the conclusion that genetics do not explain sex differences in migraine risk by themselves is not surprising given how big of a role hormones in later life are likely to play in the disease and how many factors there are that can influence hormone levels,” he said.
“On the other hand, the surprising part of the findings was that the presence of a male co-twin increases risk of migraine in females. I would have expected to see the opposite, given the lower prevalence of migraine in males and the seemingly protective role that male hormones can play in migraine.”
Overall, the study adds to data implicating environment and hormones in the migraine gender gap, he said. “One thing I wonder from this study is what influence a female co-twin growing up with a male co-twin can have on migraine susceptibility. That female co-twin may end up with a very different set of childhood experiences than if she was with another female co-twin. Twins generally spend an enormous amount of time together and the same sex versus opposite sex experiences are likely to be quite different. This may have an influence on migraine later in life.”
As for the value of the study in terms of diagnosis, treatment, or prevention of migraine, Dr. Dussor said, “it’s possible it could help to identify risk factors for higher migraine susceptibility but it’s far too early to know how this could be used.”
The authors have no disclosures. Dr. Dussor disclosed an NIH-funded grant to study the role of the hormone prolactin in preclinical migraine models.
DENVER – , even though testosterone is thought to be protective. The findings, presented at the annual meeting of the American Headache Society, also hint at a possible role played by the prenatal environment.
The study marks the first time a large-scale twin dataset has been used to assess sex differences in underlying genetic factors of migraine, lead author Morgan Fitzgerald, a senior research associate at the University of California at San Diego, said in a presentation at the conference. The findings were previously published in Frontiers in Pain Research.
More than genetics
The researchers analyzed data regarding 51,872 participants in the Swedish Twin Registry. According to Dr. Fitzgerald, the database is ideal because it is large and includes both genders.
Per the database, female twins were more likely to have migraines without aura than were male twins (17.6% vs. 5.5%, respectively), reflecting global numbers that suggest 18% of females and 6% of males have migraines each year.
To better understand heritability, the researchers compared identical twins with fraternal twins, and looked for gender-related correlations, Dr. Fitzgerald said.
One analysis suggests that migraine is equally heritable in men and women with a broad sense heritability of 0.45 (95% confidence interval [CI], 0.40-0.50). However, another analysis model provides evidence “that there are differences in the underlying genetic factors contributing to migraine across males and females,” she said.
Unexpectedly, the researchers also found that females with male twins were more likely to have migraines than were those with female twins (odds ratio, 1.51, 95% CI, 1.26-1.81) even though males are less affected by the headaches.
“These results suggest that the prominent sex difference in migraine prevalence is not entirely accounted for by genetic factors, while demonstrating that masculinization of the prenatal environment may increase migraine risk for females,” the authors wrote in the published study. “This effect points to a potential prenatal neuroendocrine factor in the development of migraine.”
Probing the migraine gender gap
Commenting on the research, University of Texas at Dallas neuroscientist and headache researcher Gregory Dussor, PhD, said the new study is “a very unique approach to address the question of nature versus nurture in migraine. It was well designed and used robust statistical modeling.”
As for the findings, “the conclusion that genetics do not explain sex differences in migraine risk by themselves is not surprising given how big of a role hormones in later life are likely to play in the disease and how many factors there are that can influence hormone levels,” he said.
“On the other hand, the surprising part of the findings was that the presence of a male co-twin increases risk of migraine in females. I would have expected to see the opposite, given the lower prevalence of migraine in males and the seemingly protective role that male hormones can play in migraine.”
Overall, the study adds to data implicating environment and hormones in the migraine gender gap, he said. “One thing I wonder from this study is what influence a female co-twin growing up with a male co-twin can have on migraine susceptibility. That female co-twin may end up with a very different set of childhood experiences than if she was with another female co-twin. Twins generally spend an enormous amount of time together and the same sex versus opposite sex experiences are likely to be quite different. This may have an influence on migraine later in life.”
As for the value of the study in terms of diagnosis, treatment, or prevention of migraine, Dr. Dussor said, “it’s possible it could help to identify risk factors for higher migraine susceptibility but it’s far too early to know how this could be used.”
The authors have no disclosures. Dr. Dussor disclosed an NIH-funded grant to study the role of the hormone prolactin in preclinical migraine models.
AT AHS 2022
Melanoma incidence is up, but death rates are down
CHICAGO – , according to a new analysis of the National Cancer Institute SEER database between 1975 and 2019.
“This is very encouraging data and represents the real-world effectiveness of these therapies. The cost of these therapies can be prohibitive for universal treatment access, so the ways to address the accessibility of these treatments and the health care costs need to be supported,” said lead author Navkirat Kaur Kahlon MD, a hematology/oncology fellow at the University of Toledo (Ohio). The study was presented at the annual meeting of the American Society of Clinical Oncology.
According to the American Cancer Society, the 5-year mortality for regional melanoma metastasis is 68%, and 30% for distant metastasis. However, these numbers may underestimate current survival. “People now being diagnosed with melanoma may have a better outlook than these numbers show. Treatments have improved over time, and these numbers are based on people who were diagnosed and treated at least 5 years earlier,” the American Cancer Society wrote.
Other studies have found similar trends. According to Cancer Research UK, 5-year melanoma skin cancer survival approximately doubled, from 46% to 90%, between 1971 and 2010. And, 1-year survival increased from 74% to 96%, but these improvements predated immune checkpoint inhibitors. An analysis of the Canadian Cancer Registry and Canadian Vital Statistics found an increasing incidence of melanoma, but a drop in mortality since 2013. A study of melanoma outcomes in Hungary also found increased incidence, while mortality declined by 16.55% between 2011 and 2019 (P =.013).
“These new drugs, which include immunotherapies and targeted therapies, are effective treatments in the clinical trial data, so the magnitude of drop seen in population mortality was not surprising but very exciting,” Dr. Kahlon said.
The findings are encouraging, but prevention remains the most important strategy. “The utility of sun-protective strategies and policies should be encouraged,” she added.
Cytotoxic chemotherapy has poor efficacy against metastatic melanoma, but novel therapies such as checkpoint inhibitors increased expected survival from months to years. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world population is deriving the same benefit,” Dr. Kahlon said.
The researchers found that the annual percentage change (APC) melanoma mortality rate (MMR) was +1.65% between 1975 and 1988 (P < .01). The APC was 0.01% between 1988 and 2013, which was not statistically significant (P = .85). Between 2013 and 2017, APC was –6.24% (P < .01), and it was –1.56% between 2017 and 2019 (P = .53).
The increase in melanoma mortality between 1975 and 1988 may be due to changes in the way that SEER data was collected. “It is possible that this increase was at least in part due to better capturing of the data. There may also be a contribution of increased mortality due to increased incidence of diagnoses related to increased UV exposure. From the 1920s, increased sun exposure and bronzed skin became fashionable. In the 1940s-1960s, tanning oils and lotions became more popular, and there may have been an increase in UV exposure during that time, which later led to an increase in diagnosis and, without effective therapies, mortality. Further, the use of indoor tanning beds from the 1970s onward may have contributed to increased UV exposure, incidence, and mortality,” she said.
On the other hand, the researchers noted a slowing of mortality reduction between 2017 and 2019. This was not a surprise, Dr. Kahlon said, since by that time most novel therapies were being introduced in the adjuvant setting. “The mortality benefit, if any, from adjuvant treatments is seen over a longer period and may not yet be captured in SEER data. Even the clinical trial data for most of these treatments have not shown an overall survival advantage and require more time for the data to mature. It will be interesting to see how these trends change in the near future,” Dr. Kahlon said.
The study was limited by its retrospective nature. Dr. Kahlon has no relevant financial disclosures.
CHICAGO – , according to a new analysis of the National Cancer Institute SEER database between 1975 and 2019.
“This is very encouraging data and represents the real-world effectiveness of these therapies. The cost of these therapies can be prohibitive for universal treatment access, so the ways to address the accessibility of these treatments and the health care costs need to be supported,” said lead author Navkirat Kaur Kahlon MD, a hematology/oncology fellow at the University of Toledo (Ohio). The study was presented at the annual meeting of the American Society of Clinical Oncology.
According to the American Cancer Society, the 5-year mortality for regional melanoma metastasis is 68%, and 30% for distant metastasis. However, these numbers may underestimate current survival. “People now being diagnosed with melanoma may have a better outlook than these numbers show. Treatments have improved over time, and these numbers are based on people who were diagnosed and treated at least 5 years earlier,” the American Cancer Society wrote.
Other studies have found similar trends. According to Cancer Research UK, 5-year melanoma skin cancer survival approximately doubled, from 46% to 90%, between 1971 and 2010. And, 1-year survival increased from 74% to 96%, but these improvements predated immune checkpoint inhibitors. An analysis of the Canadian Cancer Registry and Canadian Vital Statistics found an increasing incidence of melanoma, but a drop in mortality since 2013. A study of melanoma outcomes in Hungary also found increased incidence, while mortality declined by 16.55% between 2011 and 2019 (P =.013).
“These new drugs, which include immunotherapies and targeted therapies, are effective treatments in the clinical trial data, so the magnitude of drop seen in population mortality was not surprising but very exciting,” Dr. Kahlon said.
The findings are encouraging, but prevention remains the most important strategy. “The utility of sun-protective strategies and policies should be encouraged,” she added.
Cytotoxic chemotherapy has poor efficacy against metastatic melanoma, but novel therapies such as checkpoint inhibitors increased expected survival from months to years. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world population is deriving the same benefit,” Dr. Kahlon said.
The researchers found that the annual percentage change (APC) melanoma mortality rate (MMR) was +1.65% between 1975 and 1988 (P < .01). The APC was 0.01% between 1988 and 2013, which was not statistically significant (P = .85). Between 2013 and 2017, APC was –6.24% (P < .01), and it was –1.56% between 2017 and 2019 (P = .53).
The increase in melanoma mortality between 1975 and 1988 may be due to changes in the way that SEER data was collected. “It is possible that this increase was at least in part due to better capturing of the data. There may also be a contribution of increased mortality due to increased incidence of diagnoses related to increased UV exposure. From the 1920s, increased sun exposure and bronzed skin became fashionable. In the 1940s-1960s, tanning oils and lotions became more popular, and there may have been an increase in UV exposure during that time, which later led to an increase in diagnosis and, without effective therapies, mortality. Further, the use of indoor tanning beds from the 1970s onward may have contributed to increased UV exposure, incidence, and mortality,” she said.
On the other hand, the researchers noted a slowing of mortality reduction between 2017 and 2019. This was not a surprise, Dr. Kahlon said, since by that time most novel therapies were being introduced in the adjuvant setting. “The mortality benefit, if any, from adjuvant treatments is seen over a longer period and may not yet be captured in SEER data. Even the clinical trial data for most of these treatments have not shown an overall survival advantage and require more time for the data to mature. It will be interesting to see how these trends change in the near future,” Dr. Kahlon said.
The study was limited by its retrospective nature. Dr. Kahlon has no relevant financial disclosures.
CHICAGO – , according to a new analysis of the National Cancer Institute SEER database between 1975 and 2019.
“This is very encouraging data and represents the real-world effectiveness of these therapies. The cost of these therapies can be prohibitive for universal treatment access, so the ways to address the accessibility of these treatments and the health care costs need to be supported,” said lead author Navkirat Kaur Kahlon MD, a hematology/oncology fellow at the University of Toledo (Ohio). The study was presented at the annual meeting of the American Society of Clinical Oncology.
According to the American Cancer Society, the 5-year mortality for regional melanoma metastasis is 68%, and 30% for distant metastasis. However, these numbers may underestimate current survival. “People now being diagnosed with melanoma may have a better outlook than these numbers show. Treatments have improved over time, and these numbers are based on people who were diagnosed and treated at least 5 years earlier,” the American Cancer Society wrote.
Other studies have found similar trends. According to Cancer Research UK, 5-year melanoma skin cancer survival approximately doubled, from 46% to 90%, between 1971 and 2010. And, 1-year survival increased from 74% to 96%, but these improvements predated immune checkpoint inhibitors. An analysis of the Canadian Cancer Registry and Canadian Vital Statistics found an increasing incidence of melanoma, but a drop in mortality since 2013. A study of melanoma outcomes in Hungary also found increased incidence, while mortality declined by 16.55% between 2011 and 2019 (P =.013).
“These new drugs, which include immunotherapies and targeted therapies, are effective treatments in the clinical trial data, so the magnitude of drop seen in population mortality was not surprising but very exciting,” Dr. Kahlon said.
The findings are encouraging, but prevention remains the most important strategy. “The utility of sun-protective strategies and policies should be encouraged,” she added.
Cytotoxic chemotherapy has poor efficacy against metastatic melanoma, but novel therapies such as checkpoint inhibitors increased expected survival from months to years. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world population is deriving the same benefit,” Dr. Kahlon said.
The researchers found that the annual percentage change (APC) melanoma mortality rate (MMR) was +1.65% between 1975 and 1988 (P < .01). The APC was 0.01% between 1988 and 2013, which was not statistically significant (P = .85). Between 2013 and 2017, APC was –6.24% (P < .01), and it was –1.56% between 2017 and 2019 (P = .53).
The increase in melanoma mortality between 1975 and 1988 may be due to changes in the way that SEER data was collected. “It is possible that this increase was at least in part due to better capturing of the data. There may also be a contribution of increased mortality due to increased incidence of diagnoses related to increased UV exposure. From the 1920s, increased sun exposure and bronzed skin became fashionable. In the 1940s-1960s, tanning oils and lotions became more popular, and there may have been an increase in UV exposure during that time, which later led to an increase in diagnosis and, without effective therapies, mortality. Further, the use of indoor tanning beds from the 1970s onward may have contributed to increased UV exposure, incidence, and mortality,” she said.
On the other hand, the researchers noted a slowing of mortality reduction between 2017 and 2019. This was not a surprise, Dr. Kahlon said, since by that time most novel therapies were being introduced in the adjuvant setting. “The mortality benefit, if any, from adjuvant treatments is seen over a longer period and may not yet be captured in SEER data. Even the clinical trial data for most of these treatments have not shown an overall survival advantage and require more time for the data to mature. It will be interesting to see how these trends change in the near future,” Dr. Kahlon said.
The study was limited by its retrospective nature. Dr. Kahlon has no relevant financial disclosures.
AT ASCO 2022
Novel liver-targeting drug offers hope for AAT deficiency
LONDON – The novel liver-targeting agent fazirsiran has fared well in a small, but significant, study looking at its ability to improve liver histology in adults with alpha-1 antitrypsin (AAT) deficiency.
Not only were serum and liver levels of the aberrant Z-AAT protein decreased, but also reductions in key liver enzymes were observed.
AAT is “a greatly understudied disease,” said study investigator Pavel Strnad, MD, who presented the results of the phase 2 AROAAT-2002 study at a meeting sponsored by the European Association for the Study of the Liver. The results were published simultaneously in the New England Journal of Medicine.
“We have a great candidate drug, but we will only be able to bring this drug into the clinic when we understand the disease much better, and for this I would like to ask all of you for your support,” he said to delegates at the meeting.
There is currently no pharmacological treatment for AAT, observed Emmanuel Tsochatzis, MD, who chaired the late-breaker session during which the study findings were presented.
“It is a rare disease, but it really does affect the patients who have it. So it would be great to have a therapeutic solution for these patients,” said Dr. Tsochatzis in an interview.
Dr. Tsochatzis, who is professor of hepatology and Consultant Hepatologist at the UCL Institute for Liver and Digestive Health, Royal Free Hospital in London, noted that AAT was associated with liver impairment, fibrosis and cirrhosis, and ultimately end-stage liver disease in which the only option for some patients would be a liver transplant.
“It depends on the stage; many patients are not at the stage that they require a liver transplant,” he said. “For those with significant liver disease, not yet at the cirrhosis stage, you might be able to intervene early and prevent them from progressing to needing a liver transplant.”
Dr. Tsochatzis speculated: “If this becomes an approved treatment, it is a breakthrough for patients.”
New hope for AAT deficiency
There is still a long way to go before fazirsiran is anywhere near ready for clinical use, but the early data presented by Dr. Strnad offer a glimpse that a treatment could be on the horizon.
Naturally occurring AAT is produced in the liver and is thought to play a role in protecting against lung damage via its antiprotease activity. However, mutations in the SERPINA1 gene coding for the AAT protein leads to loss-of-function pulmonary disease and gain-of-function liver disease.
“The PI ZZ [proteinase inhibitor ZZ] genotype occurs in about one in 2,500 to 3,500 Caucasians, so actually is pretty common, and a third of them may actually have a clinically significant liver fibrosis,” said Dr. Strnad.
As levels of Z-AAT accumulate in the liver this “presumably causes the liver toxicity,” he observed. So, the thinking is that stopping the production of this mutant protein might help to reduce liver damage and allow the liver to regenerate and repair itself.
Study details
To test out this theory, a phase 2, open-label study was performed in 16 patients with confirmed AAT deficiency, all of whom had the PI ZZ genotype.
Eight patients were treated with fazirsiran, also known as ARO-AAT, for 24 weeks (cohorts 1 and 1b), while the other eight were treated for 48 weeks (cohort 2); cohort 1 (n = 4) and cohort 2 (n = 8) received 200 mg, while cohort 1b (n = 4), which was added during the trial to evaluate dose response, received 100 mg. In all cases, fazirsiran was given as a subcutaneous injection on day 1, day 4, and then every 12 weeks. All patients had biopsies at baseline, then at either 24 weeks (cohorts 1/1b) or 48 weeks (cohort 2).
“We saw a dramatic reduction in Z-AAT both in serum and in liver biopsies,” Dr. Strnad reported. Indeed, reductions in Z-AAT were around 80%-88%, he said, with a median reduction of 83% at week 24 or 48 according to the published paper.
To illustrate the clear results, Dr. Strand showed a sample biopsy slide where globules of Z-AAT present at the initial assessment were “virtually gone after 48 weeks of treatment.”
“The change in the serum and hepatic Z-AAT levels translated into improvement in liver function tests,” said Dr. Strnad.
Alanine aminotransferase levels were normalized in all patients and there was “marked improvement” in gamma glutamyl transferase (GGT) with the 200-mg dose of fazirsiran. Substantial changes in liver stiffness were recorded with the higher dose, –18% at 24 weeks and –15% at 48 weeks. There were also reductions in serum Pro-C3 of –36% and –17% at 52 weeks.
“Histological changes showed an improvement in liver inflammation and hepatocyte cell death in most of the patients,” Dr. Strnad said. He also noted that there were multiple cases where there was no change and a few where there was a deterioration.
Liver fibrosis was improved in seven of 12 patients given the highest dose of fazirsiran; however, there was no change in three patients and a worsening of 1 point or more in two patients. None of the three patients with evaluable biopsies who received 100 mg showed regression of fibrosis.
Stopping or rolling back fibrosis will be the final goal of proving clinical benefit in liver disease associated with AAT, Dr. Strnad and coinvestigators observe in their published paper, and while the changes seen so far with fazirsiran may not be uniform, they appear to be in the right direction.
Safety findings
”We didn’t see any drug discontinuation, dose interruption, or premature study withdrawals,” said Dr. Strnad.
“We had four different SAE [serious adverse events] which were kind of all over the place and did not seem to be related to treatment.” Those SAEs included viral myocarditis associated with Epstein-Barr virus infection, diverticulitis, dyspnea in a subject with a history of lung disease, and vestibular neuronitis after COVID-19 vaccination.
No significant safety signals were seen regarding lung function. Time will of course tell, he said in response to a question, but “our hope, our hypothesis, is that this will not change lung function dramatically.
“I would not expect any major things over a few years. Of course, whether this can lead to something over 20 years it is difficult to say.”
The current experience with fazirsiran looks good so far, but placebo-controlled, larger and longer studies are needed.
The study was funded by Arrowhead Pharmaceuticals. Dr. Strnad was an investigator in the study and acknowledged receipt of research funding via his institution from the company. Dr. Strnad also acknowledged paid and unpaid relationships with Alnylam Pharmaceuticals, Alpha1 Deutschland, Alpha1 Global, CSL Behring, Grifols Biologicals, Ono Pharmaceuticals, and Takeda California. Dr. Tsochatzis, chaired the late-breaker session at ILC 2022 during which the study findings were presented, was not connected to the study, and reported no relevant conflicts of interest.
LONDON – The novel liver-targeting agent fazirsiran has fared well in a small, but significant, study looking at its ability to improve liver histology in adults with alpha-1 antitrypsin (AAT) deficiency.
Not only were serum and liver levels of the aberrant Z-AAT protein decreased, but also reductions in key liver enzymes were observed.
AAT is “a greatly understudied disease,” said study investigator Pavel Strnad, MD, who presented the results of the phase 2 AROAAT-2002 study at a meeting sponsored by the European Association for the Study of the Liver. The results were published simultaneously in the New England Journal of Medicine.
“We have a great candidate drug, but we will only be able to bring this drug into the clinic when we understand the disease much better, and for this I would like to ask all of you for your support,” he said to delegates at the meeting.
There is currently no pharmacological treatment for AAT, observed Emmanuel Tsochatzis, MD, who chaired the late-breaker session during which the study findings were presented.
“It is a rare disease, but it really does affect the patients who have it. So it would be great to have a therapeutic solution for these patients,” said Dr. Tsochatzis in an interview.
Dr. Tsochatzis, who is professor of hepatology and Consultant Hepatologist at the UCL Institute for Liver and Digestive Health, Royal Free Hospital in London, noted that AAT was associated with liver impairment, fibrosis and cirrhosis, and ultimately end-stage liver disease in which the only option for some patients would be a liver transplant.
“It depends on the stage; many patients are not at the stage that they require a liver transplant,” he said. “For those with significant liver disease, not yet at the cirrhosis stage, you might be able to intervene early and prevent them from progressing to needing a liver transplant.”
Dr. Tsochatzis speculated: “If this becomes an approved treatment, it is a breakthrough for patients.”
New hope for AAT deficiency
There is still a long way to go before fazirsiran is anywhere near ready for clinical use, but the early data presented by Dr. Strnad offer a glimpse that a treatment could be on the horizon.
Naturally occurring AAT is produced in the liver and is thought to play a role in protecting against lung damage via its antiprotease activity. However, mutations in the SERPINA1 gene coding for the AAT protein leads to loss-of-function pulmonary disease and gain-of-function liver disease.
“The PI ZZ [proteinase inhibitor ZZ] genotype occurs in about one in 2,500 to 3,500 Caucasians, so actually is pretty common, and a third of them may actually have a clinically significant liver fibrosis,” said Dr. Strnad.
As levels of Z-AAT accumulate in the liver this “presumably causes the liver toxicity,” he observed. So, the thinking is that stopping the production of this mutant protein might help to reduce liver damage and allow the liver to regenerate and repair itself.
Study details
To test out this theory, a phase 2, open-label study was performed in 16 patients with confirmed AAT deficiency, all of whom had the PI ZZ genotype.
Eight patients were treated with fazirsiran, also known as ARO-AAT, for 24 weeks (cohorts 1 and 1b), while the other eight were treated for 48 weeks (cohort 2); cohort 1 (n = 4) and cohort 2 (n = 8) received 200 mg, while cohort 1b (n = 4), which was added during the trial to evaluate dose response, received 100 mg. In all cases, fazirsiran was given as a subcutaneous injection on day 1, day 4, and then every 12 weeks. All patients had biopsies at baseline, then at either 24 weeks (cohorts 1/1b) or 48 weeks (cohort 2).
“We saw a dramatic reduction in Z-AAT both in serum and in liver biopsies,” Dr. Strnad reported. Indeed, reductions in Z-AAT were around 80%-88%, he said, with a median reduction of 83% at week 24 or 48 according to the published paper.
To illustrate the clear results, Dr. Strand showed a sample biopsy slide where globules of Z-AAT present at the initial assessment were “virtually gone after 48 weeks of treatment.”
“The change in the serum and hepatic Z-AAT levels translated into improvement in liver function tests,” said Dr. Strnad.
Alanine aminotransferase levels were normalized in all patients and there was “marked improvement” in gamma glutamyl transferase (GGT) with the 200-mg dose of fazirsiran. Substantial changes in liver stiffness were recorded with the higher dose, –18% at 24 weeks and –15% at 48 weeks. There were also reductions in serum Pro-C3 of –36% and –17% at 52 weeks.
“Histological changes showed an improvement in liver inflammation and hepatocyte cell death in most of the patients,” Dr. Strnad said. He also noted that there were multiple cases where there was no change and a few where there was a deterioration.
Liver fibrosis was improved in seven of 12 patients given the highest dose of fazirsiran; however, there was no change in three patients and a worsening of 1 point or more in two patients. None of the three patients with evaluable biopsies who received 100 mg showed regression of fibrosis.
Stopping or rolling back fibrosis will be the final goal of proving clinical benefit in liver disease associated with AAT, Dr. Strnad and coinvestigators observe in their published paper, and while the changes seen so far with fazirsiran may not be uniform, they appear to be in the right direction.
Safety findings
”We didn’t see any drug discontinuation, dose interruption, or premature study withdrawals,” said Dr. Strnad.
“We had four different SAE [serious adverse events] which were kind of all over the place and did not seem to be related to treatment.” Those SAEs included viral myocarditis associated with Epstein-Barr virus infection, diverticulitis, dyspnea in a subject with a history of lung disease, and vestibular neuronitis after COVID-19 vaccination.
No significant safety signals were seen regarding lung function. Time will of course tell, he said in response to a question, but “our hope, our hypothesis, is that this will not change lung function dramatically.
“I would not expect any major things over a few years. Of course, whether this can lead to something over 20 years it is difficult to say.”
The current experience with fazirsiran looks good so far, but placebo-controlled, larger and longer studies are needed.
The study was funded by Arrowhead Pharmaceuticals. Dr. Strnad was an investigator in the study and acknowledged receipt of research funding via his institution from the company. Dr. Strnad also acknowledged paid and unpaid relationships with Alnylam Pharmaceuticals, Alpha1 Deutschland, Alpha1 Global, CSL Behring, Grifols Biologicals, Ono Pharmaceuticals, and Takeda California. Dr. Tsochatzis, chaired the late-breaker session at ILC 2022 during which the study findings were presented, was not connected to the study, and reported no relevant conflicts of interest.
LONDON – The novel liver-targeting agent fazirsiran has fared well in a small, but significant, study looking at its ability to improve liver histology in adults with alpha-1 antitrypsin (AAT) deficiency.
Not only were serum and liver levels of the aberrant Z-AAT protein decreased, but also reductions in key liver enzymes were observed.
AAT is “a greatly understudied disease,” said study investigator Pavel Strnad, MD, who presented the results of the phase 2 AROAAT-2002 study at a meeting sponsored by the European Association for the Study of the Liver. The results were published simultaneously in the New England Journal of Medicine.
“We have a great candidate drug, but we will only be able to bring this drug into the clinic when we understand the disease much better, and for this I would like to ask all of you for your support,” he said to delegates at the meeting.
There is currently no pharmacological treatment for AAT, observed Emmanuel Tsochatzis, MD, who chaired the late-breaker session during which the study findings were presented.
“It is a rare disease, but it really does affect the patients who have it. So it would be great to have a therapeutic solution for these patients,” said Dr. Tsochatzis in an interview.
Dr. Tsochatzis, who is professor of hepatology and Consultant Hepatologist at the UCL Institute for Liver and Digestive Health, Royal Free Hospital in London, noted that AAT was associated with liver impairment, fibrosis and cirrhosis, and ultimately end-stage liver disease in which the only option for some patients would be a liver transplant.
“It depends on the stage; many patients are not at the stage that they require a liver transplant,” he said. “For those with significant liver disease, not yet at the cirrhosis stage, you might be able to intervene early and prevent them from progressing to needing a liver transplant.”
Dr. Tsochatzis speculated: “If this becomes an approved treatment, it is a breakthrough for patients.”
New hope for AAT deficiency
There is still a long way to go before fazirsiran is anywhere near ready for clinical use, but the early data presented by Dr. Strnad offer a glimpse that a treatment could be on the horizon.
Naturally occurring AAT is produced in the liver and is thought to play a role in protecting against lung damage via its antiprotease activity. However, mutations in the SERPINA1 gene coding for the AAT protein leads to loss-of-function pulmonary disease and gain-of-function liver disease.
“The PI ZZ [proteinase inhibitor ZZ] genotype occurs in about one in 2,500 to 3,500 Caucasians, so actually is pretty common, and a third of them may actually have a clinically significant liver fibrosis,” said Dr. Strnad.
As levels of Z-AAT accumulate in the liver this “presumably causes the liver toxicity,” he observed. So, the thinking is that stopping the production of this mutant protein might help to reduce liver damage and allow the liver to regenerate and repair itself.
Study details
To test out this theory, a phase 2, open-label study was performed in 16 patients with confirmed AAT deficiency, all of whom had the PI ZZ genotype.
Eight patients were treated with fazirsiran, also known as ARO-AAT, for 24 weeks (cohorts 1 and 1b), while the other eight were treated for 48 weeks (cohort 2); cohort 1 (n = 4) and cohort 2 (n = 8) received 200 mg, while cohort 1b (n = 4), which was added during the trial to evaluate dose response, received 100 mg. In all cases, fazirsiran was given as a subcutaneous injection on day 1, day 4, and then every 12 weeks. All patients had biopsies at baseline, then at either 24 weeks (cohorts 1/1b) or 48 weeks (cohort 2).
“We saw a dramatic reduction in Z-AAT both in serum and in liver biopsies,” Dr. Strnad reported. Indeed, reductions in Z-AAT were around 80%-88%, he said, with a median reduction of 83% at week 24 or 48 according to the published paper.
To illustrate the clear results, Dr. Strand showed a sample biopsy slide where globules of Z-AAT present at the initial assessment were “virtually gone after 48 weeks of treatment.”
“The change in the serum and hepatic Z-AAT levels translated into improvement in liver function tests,” said Dr. Strnad.
Alanine aminotransferase levels were normalized in all patients and there was “marked improvement” in gamma glutamyl transferase (GGT) with the 200-mg dose of fazirsiran. Substantial changes in liver stiffness were recorded with the higher dose, –18% at 24 weeks and –15% at 48 weeks. There were also reductions in serum Pro-C3 of –36% and –17% at 52 weeks.
“Histological changes showed an improvement in liver inflammation and hepatocyte cell death in most of the patients,” Dr. Strnad said. He also noted that there were multiple cases where there was no change and a few where there was a deterioration.
Liver fibrosis was improved in seven of 12 patients given the highest dose of fazirsiran; however, there was no change in three patients and a worsening of 1 point or more in two patients. None of the three patients with evaluable biopsies who received 100 mg showed regression of fibrosis.
Stopping or rolling back fibrosis will be the final goal of proving clinical benefit in liver disease associated with AAT, Dr. Strnad and coinvestigators observe in their published paper, and while the changes seen so far with fazirsiran may not be uniform, they appear to be in the right direction.
Safety findings
”We didn’t see any drug discontinuation, dose interruption, or premature study withdrawals,” said Dr. Strnad.
“We had four different SAE [serious adverse events] which were kind of all over the place and did not seem to be related to treatment.” Those SAEs included viral myocarditis associated with Epstein-Barr virus infection, diverticulitis, dyspnea in a subject with a history of lung disease, and vestibular neuronitis after COVID-19 vaccination.
No significant safety signals were seen regarding lung function. Time will of course tell, he said in response to a question, but “our hope, our hypothesis, is that this will not change lung function dramatically.
“I would not expect any major things over a few years. Of course, whether this can lead to something over 20 years it is difficult to say.”
The current experience with fazirsiran looks good so far, but placebo-controlled, larger and longer studies are needed.
The study was funded by Arrowhead Pharmaceuticals. Dr. Strnad was an investigator in the study and acknowledged receipt of research funding via his institution from the company. Dr. Strnad also acknowledged paid and unpaid relationships with Alnylam Pharmaceuticals, Alpha1 Deutschland, Alpha1 Global, CSL Behring, Grifols Biologicals, Ono Pharmaceuticals, and Takeda California. Dr. Tsochatzis, chaired the late-breaker session at ILC 2022 during which the study findings were presented, was not connected to the study, and reported no relevant conflicts of interest.
AT ILC 2022
Adjuvant vs. neoadjuvant? What has ASCO 2022 taught us regarding resectable NSCLC?
for non–small cell lung cancer (NSCLC). While there has been some notable progress in this area, we need phase 3 trials that compare the two therapeutic approaches.
Investigators reporting at the 2022 annual meeting of American Society of Clinical Oncology focused primarily on neoadjuvant treatment, which I’ll address here.
In the randomized, phase 2 NADIM II clinical trial reported at the meeting, researchers expanded on the results of NADIM published in 2020 in the Lancet Oncology and in May 2022 in the Journal of Clinical Oncology along with CheckMate 816 results published in the New England Journal of Medicine.
In each of these three studies, researchers compared nivolumab plus chemotherapy versus chemotherapy alone (abstract 8501) as a neoadjuvant treatment for resectable stage IIIA NSCLC. In the study reported at ASCO 2022, patients with resectable clinical stage IIIA-B (per American Joint Committee on Cancer 8th edition) NSCLC and no known EGFR/ALK alterations, were randomized to receive preoperative nivolumab plus chemotherapy (paclitaxel and carboplatin; n = 57) or chemotherapy (n = 29) alone followed by surgery.
The primary endpoint was pathological complete response (pCR); secondary endpoints included major pathological response, safety and tolerability, impact on surgical issues such as delayed or canceled surgeries or length of hospital stay, overall survival and progression free survival. The pCR rate was 36.8% in the neoadjuvant nivolumab plus chemotherapy arm and 6.9% in the chemotherapy alone arm. (P = .0068). 25% of patients on the nivolumab plus chemo arm had grade 3-4 adverse events, compared with 10.3% in the control arm. 93% of patients on the nivolumab plus chemo arm underwent definitive surgery whereas 69.0% of the patients on the chemo alone arm had definitive surgery. (P = .008)
What else did we learn about neoadjuvant treatment at the meeting?
Investigators looking at the optimal number of neoadjuvant cycles (abstract 8500) found that three cycles of sintilimab (an investigational PD-1 inhibitor) produced a numerically higher major pathological response rate, compared with two cycles (when given in concert with platinum-doublet chemotherapy). And, neoadjuvant chemoradiotherapy does not result in significant survival benefits when compared with neoadjuvant chemotherapy alone (abstract 8503).
Of course, when it comes to resectable NSCLC, the goal of treatment is to increase the cure rate and improve survival. No randomized studies have reported yet on overall survival, probably because they are too immature. Instead, disease-free survival (DFS) or event-free survival (EFS) are often used as surrogate endpoints. Since none of the studies reported at ASCO reported on DFS or EFS, we need to look elsewhere. CheckMate 816 was a phase 3 study which randomized patients with stages IB-IIIA NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy or neoadjuvant platinum-based chemotherapy alone, followed by resection. The median EFS was 31.6 months with nivolumab plus chemotherapy and 20.8 months with chemotherapy alone (P = .005). The percentage of patients with a pCR was 24.0% and 2.2%, respectively (P < .001).
We all know one has to be careful when doing cross-trial comparisons as these studies differ by the percentage of patients with various stages of disease, the type of immunotherapy and chemotherapy used, etc. However, I think we can agree that neoadjuvant chemoimmunotherapy results in better outcomes than chemotherapy alone.
Of course, resectable NSCLC is, by definition, resectable. And traditionally, resection is followed by adjuvant chemotherapy to eradicate micrometastases. Unfortunately, the current standard of care for completely resected early-stage NSCLC (stage I [tumor ≥ 4 cm] to IIIA) involves adjuvant platinum-based combination chemotherapy which results in only a modest 4%-5% improvement in survival versus observation.
Given these modest results, as in the neoadjuvant space, investigators have looked at the benefit of adding immunotherapy to adjuvant chemotherapy. One such study has been reported. IMpower 010 randomly assigned patients with completely resected stage IB (tumors ≥ 4 cm) to IIIA NSCLC, whose tumor cells expressed at least 1% PD-L1, to receive adjuvant atezolizumab or best supportive care after adjuvant platinum-based chemotherapy. In the stage II-IIIA population whose tumors expressed PD-L1 on 1% or more of tumor cells, 3-year DFS rates were 60% and 48% in the atezolizumab and best supportive care arms, respectively (hazard ratio, 0·66 P =·.0039). In all patients in the stage II-IIIA population, the 3-year DFS rates were 56% in the atezolizumab group and 49% in the best supportive care group, (HR, 0.79; P = .020).
KEYNOTE-091, reported at the 2021 annual meeting of the European Society for Medical Oncology, randomized early-stage NSCLC patients following complete resection and adjuvant chemotherapy to pembrolizumab or placebo. Median DFS for the overall population was 53.6 months for patients in the pembro arm versus 42 months in the placebo arm (HR, 0.76; P = .0014). Interestingly, the benefit was not seen in patients with PD-L1 with at least 50%, where the 18-month DFS rate was 71.7% in the pembro arm and 70.2% in the placebo arm (HR, 0.82; P = .14). Although the contradictory results of PD-L1 as a biomarker is puzzling, I think we can agree that the addition of immunotherapy following adjuvant chemotherapy improves outcomes compared to adjuvant chemotherapy alone.
What to do when a patient presents with resectable disease?
Cross-trial comparisons are fraught with danger. Until we have a phase 3 study comparing concurrent neoadjuvant chemo/immunotherapy with concurrent adjuvant chemo/immunotherapy, I do not think we can answer the question “which is better?” However, there are some caveats to keep in mind when deciding on which approach to recommend to our patients: First, neoadjuvant treatment requires biomarker testing to ensure the patient does not have EGFR or ALK mutations. This will necessitate a delay in the operation. Will patients be willing to wait? Will the surgeon? Or, would patients prefer to proceed with surgery while the results are pending? Yes, neoadjuvant therapy gives you information regarding the pCR rate, but does that help you in subsequent management of the patient? We do not know.
Secondly, the two adjuvant studies used adjuvant chemotherapy followed by adjuvant immunotherapy, as contrasted to the neoadjuvant study which used concurrent chemo/immunotherapy. Given the longer duration of treatment in postoperative sequential adjuvant studies, there tends to be more drop off because of patients being unwilling or unfit postoperatively to receive long courses of therapy. In IMpower 010, 1,269 patients completed adjuvant chemotherapy; 1,005 were randomized, and of the 507 assigned to the atezolizumab/chemo group, only 323 completed treatment.
Finally, we must beware of using neoadjuvant chemo/immunotherapy to “down-stage” a patient. KEYNOTE-091 included patients with IIIA disease and no benefit to adjuvant chemotherapy followed by immunotherapy was found in this subgroup of patients, which leads me to wonder if these patients were appropriately selected as surgical candidates. In the NADIM II trials, 9 of 29 patients on the neoadjuvant chemotherapy were not resected.
So, many questions remain. In addition to the ones we’ve raised, there is a clear and immediate need for predictive and prognostic biomarkers. In the NADIM II trial, PD-L1 expression was a predictive biomarker of response. The pCR rate for patients with a PD-L1 tumor expression of less than 1%, 1%-49%, and 50% or higher was 15%, 41.7%, and 61.1%, respectively. However, in KEYNOTE-091, the benefit was not seen in patients with PD-L1 of at least than 50%, where the 18-month DFS rate was 71.7% in the pembro arm and 70.2% in the placebo arm.
Another possible biomarker: circulating tumor DNA. In the first NADIM study, three low pretreatment levels of ctDNA were significantly associated with improved progression-free survival and overall survival (HR, 0.20 and HR, 0.07, respectively). Although clinical response did not predict survival outcomes, undetectable ctDNA levels after neoadjuvant treatment were significantly associated with progression-free survival and overall survival (HR, 0.26 and HR0.04, respectively). Similarly, in CheckMate 816, clearance of ctDNA was associated with longer EFS in patients with ctDNA clearance than in those without ctDNA clearance in both the nivolumab/chemotherapy group (HR, 0.60) and the chemotherapy-alone group (HR, 0.63).
Hopefully, ASCO 2023 will provide more answers.
Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.
for non–small cell lung cancer (NSCLC). While there has been some notable progress in this area, we need phase 3 trials that compare the two therapeutic approaches.
Investigators reporting at the 2022 annual meeting of American Society of Clinical Oncology focused primarily on neoadjuvant treatment, which I’ll address here.
In the randomized, phase 2 NADIM II clinical trial reported at the meeting, researchers expanded on the results of NADIM published in 2020 in the Lancet Oncology and in May 2022 in the Journal of Clinical Oncology along with CheckMate 816 results published in the New England Journal of Medicine.
In each of these three studies, researchers compared nivolumab plus chemotherapy versus chemotherapy alone (abstract 8501) as a neoadjuvant treatment for resectable stage IIIA NSCLC. In the study reported at ASCO 2022, patients with resectable clinical stage IIIA-B (per American Joint Committee on Cancer 8th edition) NSCLC and no known EGFR/ALK alterations, were randomized to receive preoperative nivolumab plus chemotherapy (paclitaxel and carboplatin; n = 57) or chemotherapy (n = 29) alone followed by surgery.
The primary endpoint was pathological complete response (pCR); secondary endpoints included major pathological response, safety and tolerability, impact on surgical issues such as delayed or canceled surgeries or length of hospital stay, overall survival and progression free survival. The pCR rate was 36.8% in the neoadjuvant nivolumab plus chemotherapy arm and 6.9% in the chemotherapy alone arm. (P = .0068). 25% of patients on the nivolumab plus chemo arm had grade 3-4 adverse events, compared with 10.3% in the control arm. 93% of patients on the nivolumab plus chemo arm underwent definitive surgery whereas 69.0% of the patients on the chemo alone arm had definitive surgery. (P = .008)
What else did we learn about neoadjuvant treatment at the meeting?
Investigators looking at the optimal number of neoadjuvant cycles (abstract 8500) found that three cycles of sintilimab (an investigational PD-1 inhibitor) produced a numerically higher major pathological response rate, compared with two cycles (when given in concert with platinum-doublet chemotherapy). And, neoadjuvant chemoradiotherapy does not result in significant survival benefits when compared with neoadjuvant chemotherapy alone (abstract 8503).
Of course, when it comes to resectable NSCLC, the goal of treatment is to increase the cure rate and improve survival. No randomized studies have reported yet on overall survival, probably because they are too immature. Instead, disease-free survival (DFS) or event-free survival (EFS) are often used as surrogate endpoints. Since none of the studies reported at ASCO reported on DFS or EFS, we need to look elsewhere. CheckMate 816 was a phase 3 study which randomized patients with stages IB-IIIA NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy or neoadjuvant platinum-based chemotherapy alone, followed by resection. The median EFS was 31.6 months with nivolumab plus chemotherapy and 20.8 months with chemotherapy alone (P = .005). The percentage of patients with a pCR was 24.0% and 2.2%, respectively (P < .001).
We all know one has to be careful when doing cross-trial comparisons as these studies differ by the percentage of patients with various stages of disease, the type of immunotherapy and chemotherapy used, etc. However, I think we can agree that neoadjuvant chemoimmunotherapy results in better outcomes than chemotherapy alone.
Of course, resectable NSCLC is, by definition, resectable. And traditionally, resection is followed by adjuvant chemotherapy to eradicate micrometastases. Unfortunately, the current standard of care for completely resected early-stage NSCLC (stage I [tumor ≥ 4 cm] to IIIA) involves adjuvant platinum-based combination chemotherapy which results in only a modest 4%-5% improvement in survival versus observation.
Given these modest results, as in the neoadjuvant space, investigators have looked at the benefit of adding immunotherapy to adjuvant chemotherapy. One such study has been reported. IMpower 010 randomly assigned patients with completely resected stage IB (tumors ≥ 4 cm) to IIIA NSCLC, whose tumor cells expressed at least 1% PD-L1, to receive adjuvant atezolizumab or best supportive care after adjuvant platinum-based chemotherapy. In the stage II-IIIA population whose tumors expressed PD-L1 on 1% or more of tumor cells, 3-year DFS rates were 60% and 48% in the atezolizumab and best supportive care arms, respectively (hazard ratio, 0·66 P =·.0039). In all patients in the stage II-IIIA population, the 3-year DFS rates were 56% in the atezolizumab group and 49% in the best supportive care group, (HR, 0.79; P = .020).
KEYNOTE-091, reported at the 2021 annual meeting of the European Society for Medical Oncology, randomized early-stage NSCLC patients following complete resection and adjuvant chemotherapy to pembrolizumab or placebo. Median DFS for the overall population was 53.6 months for patients in the pembro arm versus 42 months in the placebo arm (HR, 0.76; P = .0014). Interestingly, the benefit was not seen in patients with PD-L1 with at least 50%, where the 18-month DFS rate was 71.7% in the pembro arm and 70.2% in the placebo arm (HR, 0.82; P = .14). Although the contradictory results of PD-L1 as a biomarker is puzzling, I think we can agree that the addition of immunotherapy following adjuvant chemotherapy improves outcomes compared to adjuvant chemotherapy alone.
What to do when a patient presents with resectable disease?
Cross-trial comparisons are fraught with danger. Until we have a phase 3 study comparing concurrent neoadjuvant chemo/immunotherapy with concurrent adjuvant chemo/immunotherapy, I do not think we can answer the question “which is better?” However, there are some caveats to keep in mind when deciding on which approach to recommend to our patients: First, neoadjuvant treatment requires biomarker testing to ensure the patient does not have EGFR or ALK mutations. This will necessitate a delay in the operation. Will patients be willing to wait? Will the surgeon? Or, would patients prefer to proceed with surgery while the results are pending? Yes, neoadjuvant therapy gives you information regarding the pCR rate, but does that help you in subsequent management of the patient? We do not know.
Secondly, the two adjuvant studies used adjuvant chemotherapy followed by adjuvant immunotherapy, as contrasted to the neoadjuvant study which used concurrent chemo/immunotherapy. Given the longer duration of treatment in postoperative sequential adjuvant studies, there tends to be more drop off because of patients being unwilling or unfit postoperatively to receive long courses of therapy. In IMpower 010, 1,269 patients completed adjuvant chemotherapy; 1,005 were randomized, and of the 507 assigned to the atezolizumab/chemo group, only 323 completed treatment.
Finally, we must beware of using neoadjuvant chemo/immunotherapy to “down-stage” a patient. KEYNOTE-091 included patients with IIIA disease and no benefit to adjuvant chemotherapy followed by immunotherapy was found in this subgroup of patients, which leads me to wonder if these patients were appropriately selected as surgical candidates. In the NADIM II trials, 9 of 29 patients on the neoadjuvant chemotherapy were not resected.
So, many questions remain. In addition to the ones we’ve raised, there is a clear and immediate need for predictive and prognostic biomarkers. In the NADIM II trial, PD-L1 expression was a predictive biomarker of response. The pCR rate for patients with a PD-L1 tumor expression of less than 1%, 1%-49%, and 50% or higher was 15%, 41.7%, and 61.1%, respectively. However, in KEYNOTE-091, the benefit was not seen in patients with PD-L1 of at least than 50%, where the 18-month DFS rate was 71.7% in the pembro arm and 70.2% in the placebo arm.
Another possible biomarker: circulating tumor DNA. In the first NADIM study, three low pretreatment levels of ctDNA were significantly associated with improved progression-free survival and overall survival (HR, 0.20 and HR, 0.07, respectively). Although clinical response did not predict survival outcomes, undetectable ctDNA levels after neoadjuvant treatment were significantly associated with progression-free survival and overall survival (HR, 0.26 and HR0.04, respectively). Similarly, in CheckMate 816, clearance of ctDNA was associated with longer EFS in patients with ctDNA clearance than in those without ctDNA clearance in both the nivolumab/chemotherapy group (HR, 0.60) and the chemotherapy-alone group (HR, 0.63).
Hopefully, ASCO 2023 will provide more answers.
Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.
for non–small cell lung cancer (NSCLC). While there has been some notable progress in this area, we need phase 3 trials that compare the two therapeutic approaches.
Investigators reporting at the 2022 annual meeting of American Society of Clinical Oncology focused primarily on neoadjuvant treatment, which I’ll address here.
In the randomized, phase 2 NADIM II clinical trial reported at the meeting, researchers expanded on the results of NADIM published in 2020 in the Lancet Oncology and in May 2022 in the Journal of Clinical Oncology along with CheckMate 816 results published in the New England Journal of Medicine.
In each of these three studies, researchers compared nivolumab plus chemotherapy versus chemotherapy alone (abstract 8501) as a neoadjuvant treatment for resectable stage IIIA NSCLC. In the study reported at ASCO 2022, patients with resectable clinical stage IIIA-B (per American Joint Committee on Cancer 8th edition) NSCLC and no known EGFR/ALK alterations, were randomized to receive preoperative nivolumab plus chemotherapy (paclitaxel and carboplatin; n = 57) or chemotherapy (n = 29) alone followed by surgery.
The primary endpoint was pathological complete response (pCR); secondary endpoints included major pathological response, safety and tolerability, impact on surgical issues such as delayed or canceled surgeries or length of hospital stay, overall survival and progression free survival. The pCR rate was 36.8% in the neoadjuvant nivolumab plus chemotherapy arm and 6.9% in the chemotherapy alone arm. (P = .0068). 25% of patients on the nivolumab plus chemo arm had grade 3-4 adverse events, compared with 10.3% in the control arm. 93% of patients on the nivolumab plus chemo arm underwent definitive surgery whereas 69.0% of the patients on the chemo alone arm had definitive surgery. (P = .008)
What else did we learn about neoadjuvant treatment at the meeting?
Investigators looking at the optimal number of neoadjuvant cycles (abstract 8500) found that three cycles of sintilimab (an investigational PD-1 inhibitor) produced a numerically higher major pathological response rate, compared with two cycles (when given in concert with platinum-doublet chemotherapy). And, neoadjuvant chemoradiotherapy does not result in significant survival benefits when compared with neoadjuvant chemotherapy alone (abstract 8503).
Of course, when it comes to resectable NSCLC, the goal of treatment is to increase the cure rate and improve survival. No randomized studies have reported yet on overall survival, probably because they are too immature. Instead, disease-free survival (DFS) or event-free survival (EFS) are often used as surrogate endpoints. Since none of the studies reported at ASCO reported on DFS or EFS, we need to look elsewhere. CheckMate 816 was a phase 3 study which randomized patients with stages IB-IIIA NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy or neoadjuvant platinum-based chemotherapy alone, followed by resection. The median EFS was 31.6 months with nivolumab plus chemotherapy and 20.8 months with chemotherapy alone (P = .005). The percentage of patients with a pCR was 24.0% and 2.2%, respectively (P < .001).
We all know one has to be careful when doing cross-trial comparisons as these studies differ by the percentage of patients with various stages of disease, the type of immunotherapy and chemotherapy used, etc. However, I think we can agree that neoadjuvant chemoimmunotherapy results in better outcomes than chemotherapy alone.
Of course, resectable NSCLC is, by definition, resectable. And traditionally, resection is followed by adjuvant chemotherapy to eradicate micrometastases. Unfortunately, the current standard of care for completely resected early-stage NSCLC (stage I [tumor ≥ 4 cm] to IIIA) involves adjuvant platinum-based combination chemotherapy which results in only a modest 4%-5% improvement in survival versus observation.
Given these modest results, as in the neoadjuvant space, investigators have looked at the benefit of adding immunotherapy to adjuvant chemotherapy. One such study has been reported. IMpower 010 randomly assigned patients with completely resected stage IB (tumors ≥ 4 cm) to IIIA NSCLC, whose tumor cells expressed at least 1% PD-L1, to receive adjuvant atezolizumab or best supportive care after adjuvant platinum-based chemotherapy. In the stage II-IIIA population whose tumors expressed PD-L1 on 1% or more of tumor cells, 3-year DFS rates were 60% and 48% in the atezolizumab and best supportive care arms, respectively (hazard ratio, 0·66 P =·.0039). In all patients in the stage II-IIIA population, the 3-year DFS rates were 56% in the atezolizumab group and 49% in the best supportive care group, (HR, 0.79; P = .020).
KEYNOTE-091, reported at the 2021 annual meeting of the European Society for Medical Oncology, randomized early-stage NSCLC patients following complete resection and adjuvant chemotherapy to pembrolizumab or placebo. Median DFS for the overall population was 53.6 months for patients in the pembro arm versus 42 months in the placebo arm (HR, 0.76; P = .0014). Interestingly, the benefit was not seen in patients with PD-L1 with at least 50%, where the 18-month DFS rate was 71.7% in the pembro arm and 70.2% in the placebo arm (HR, 0.82; P = .14). Although the contradictory results of PD-L1 as a biomarker is puzzling, I think we can agree that the addition of immunotherapy following adjuvant chemotherapy improves outcomes compared to adjuvant chemotherapy alone.
What to do when a patient presents with resectable disease?
Cross-trial comparisons are fraught with danger. Until we have a phase 3 study comparing concurrent neoadjuvant chemo/immunotherapy with concurrent adjuvant chemo/immunotherapy, I do not think we can answer the question “which is better?” However, there are some caveats to keep in mind when deciding on which approach to recommend to our patients: First, neoadjuvant treatment requires biomarker testing to ensure the patient does not have EGFR or ALK mutations. This will necessitate a delay in the operation. Will patients be willing to wait? Will the surgeon? Or, would patients prefer to proceed with surgery while the results are pending? Yes, neoadjuvant therapy gives you information regarding the pCR rate, but does that help you in subsequent management of the patient? We do not know.
Secondly, the two adjuvant studies used adjuvant chemotherapy followed by adjuvant immunotherapy, as contrasted to the neoadjuvant study which used concurrent chemo/immunotherapy. Given the longer duration of treatment in postoperative sequential adjuvant studies, there tends to be more drop off because of patients being unwilling or unfit postoperatively to receive long courses of therapy. In IMpower 010, 1,269 patients completed adjuvant chemotherapy; 1,005 were randomized, and of the 507 assigned to the atezolizumab/chemo group, only 323 completed treatment.
Finally, we must beware of using neoadjuvant chemo/immunotherapy to “down-stage” a patient. KEYNOTE-091 included patients with IIIA disease and no benefit to adjuvant chemotherapy followed by immunotherapy was found in this subgroup of patients, which leads me to wonder if these patients were appropriately selected as surgical candidates. In the NADIM II trials, 9 of 29 patients on the neoadjuvant chemotherapy were not resected.
So, many questions remain. In addition to the ones we’ve raised, there is a clear and immediate need for predictive and prognostic biomarkers. In the NADIM II trial, PD-L1 expression was a predictive biomarker of response. The pCR rate for patients with a PD-L1 tumor expression of less than 1%, 1%-49%, and 50% or higher was 15%, 41.7%, and 61.1%, respectively. However, in KEYNOTE-091, the benefit was not seen in patients with PD-L1 of at least than 50%, where the 18-month DFS rate was 71.7% in the pembro arm and 70.2% in the placebo arm.
Another possible biomarker: circulating tumor DNA. In the first NADIM study, three low pretreatment levels of ctDNA were significantly associated with improved progression-free survival and overall survival (HR, 0.20 and HR, 0.07, respectively). Although clinical response did not predict survival outcomes, undetectable ctDNA levels after neoadjuvant treatment were significantly associated with progression-free survival and overall survival (HR, 0.26 and HR0.04, respectively). Similarly, in CheckMate 816, clearance of ctDNA was associated with longer EFS in patients with ctDNA clearance than in those without ctDNA clearance in both the nivolumab/chemotherapy group (HR, 0.60) and the chemotherapy-alone group (HR, 0.63).
Hopefully, ASCO 2023 will provide more answers.
Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.
Treat-to-target strategy with tapering proves effective in PsA and axSpA
Aiming for a disease activity target while reducing biologic therapy could be a winning approach for patients with psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), according to the results of a new study presented at the annual European Congress of Rheumatology.
The findings show that a treat-to-target (T2T) strategy with tapering using a tumor necrosis factor (TNF) inhibitor produces results that are noninferior to a T2T strategy that doesn’t include tapering in these patients.
“Our study has for the first time shown that a treat-to-target tapering strategy is just as good as full-dose continuation, while reducing medication use substantially,” first author Celia Michielsens, MD, a PhD student and researcher at Sint Maartenskliniek in Nijmegen, the Netherlands, said in an interview before her presentation of the study during an oral abstract session at the congress. “Stepwise tapering is also better than fixed-dose reduction or discontinuation, since it is much more individualized.”
The study is now published in Annals of the Rheumatic Diseases.
In the randomized, controlled, open-label, noninferiority study, researchers enrolled patients with PsA or axSpA who were using a TNF inhibitor such as etanercept, adalimumab, or infliximab, and had stable low disease activity for at least 6 months. Patients needed to have a Psoriatic Arthritis Disease Activity Score (PASDAS) of 3.2 or less, or an Ankylosing Spondylitis Disease Activity Score (ASDAS) of at 2.1 or less. In cases of flare, patients were treated with NSAIDs and/or glucorticoids, and if they still had not reached low disease activity after a month, their previous TNF inhibitor dose was reinstated to the last effective interval or dosage, which was maintained throughout the study period. When the patient was already using a full TNF-inhibitor dose or if dose adjustment did not suffice, patients were switched to another biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD).
Participants were randomized, from January 2019 to June 2021, to a tapering or a nontapering T2T strategy in a 2:1 fashion. Then researchers then followed them for 12 months and aimed to determine if the tapering strategy proved noninferior to not tapering within a predefined 20% margin for noninferiority, which Dr. Michielsens said was derived from other studies and what her group determined to be “an acceptable risk.”
Results show strategy is ‘feasible in daily clinical care’
A total of 81 patients – 42 with PsA and 39 with axSpA – were in the group with tapering, and 41 were in the group without tapering: 22 with PsA and 19 with axSpA.
At 12 months, researchers found that 69% of the patients in the group with tapering had low disease activity, measured via the PASDAS and ASDAS, compared with 73% in patients who did not taper. And those in the tapering group saw their medication use dramatically reduced. At the 12-month mark, they were taking just 53% of the defined daily dose for maintenance, compared with 91% of the defined daily dose for the group that didn’t taper.
The researchers were able to successfully taper 72% of the patients in the tapering group, with 28% of them discontinuing their TNF-inhibitor medication entirely. The incidence of flares was 85% in the tapering group and 78% in the nontapering group, a nonsignificant difference (P = .32).
The start of a new medication or an increase in use of an existing medication was more frequent in the tapering group, and significantly so for NSAIDs. An increase in NSAID use was seen in 54% of the tapering group and in just 24% of the nontapering group (P = .002).
Conventional synthetic DMARD use went up in the tapering group, compared with the nontapering group, but this was only among the PsA patients and the change in use was not statistically significant. There were also more frequent increases in glucocorticoid use in the tapering group, compared with the nontapering group, but this was not significant.
Dr. Michielsens said the findings show the value of an individualized approach in treating patients with PsA or axSpA.
“Our study – and those [studies] in rheumatoid arthritis earlier – deliver the highest quality of evidence that disease activity–guided dose personalization can, and in fact should, be used in clinical practice,” she said. “Our pragmatic treat-to-target tapering strategy is feasible in daily clinical care, although treat-to-target using PASDAS and ASDAS needs some implementation. In shared decision-making with patients, a 50% reduction in TNFi use is obtainable, while maintaining low disease activity.”
The increase in the use of NSAIDs is something to be aware of, but it is “not concerning,” Dr. Michielsens added. She pointed out that the NSAID use was typically temporary, used when flares arose, and that the drugs are effective, safe, and inexpensive. She also noted that the use of TNF blockers decreased more than the use of NSAIDs increased.
“This seems a perfectly acceptable trade-off that can be discussed with your patient,” she said.
The 12-month duration of the study is likely long enough to show that the tapering strategy works, Dr. Michielsens said. In rheumatoid arthritis studies, for example, differences in strategies didn’t change after 1 year.
“That said, we are doing an observational extension study to provide more insights in the long-term effects of this treat-to-target strategy,” she said. “At the end of this summer, all patients will have completed their extended follow-up period – a 12-month observational period – so hopefully we can present the results next year at EULAR.”
This study received funding from ReumaNederland. Dr. Michielsens did not have any financial interests to disclose. Two coauthors reported financial relationships with numerous pharmaceutical companies.
Aiming for a disease activity target while reducing biologic therapy could be a winning approach for patients with psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), according to the results of a new study presented at the annual European Congress of Rheumatology.
The findings show that a treat-to-target (T2T) strategy with tapering using a tumor necrosis factor (TNF) inhibitor produces results that are noninferior to a T2T strategy that doesn’t include tapering in these patients.
“Our study has for the first time shown that a treat-to-target tapering strategy is just as good as full-dose continuation, while reducing medication use substantially,” first author Celia Michielsens, MD, a PhD student and researcher at Sint Maartenskliniek in Nijmegen, the Netherlands, said in an interview before her presentation of the study during an oral abstract session at the congress. “Stepwise tapering is also better than fixed-dose reduction or discontinuation, since it is much more individualized.”
The study is now published in Annals of the Rheumatic Diseases.
In the randomized, controlled, open-label, noninferiority study, researchers enrolled patients with PsA or axSpA who were using a TNF inhibitor such as etanercept, adalimumab, or infliximab, and had stable low disease activity for at least 6 months. Patients needed to have a Psoriatic Arthritis Disease Activity Score (PASDAS) of 3.2 or less, or an Ankylosing Spondylitis Disease Activity Score (ASDAS) of at 2.1 or less. In cases of flare, patients were treated with NSAIDs and/or glucorticoids, and if they still had not reached low disease activity after a month, their previous TNF inhibitor dose was reinstated to the last effective interval or dosage, which was maintained throughout the study period. When the patient was already using a full TNF-inhibitor dose or if dose adjustment did not suffice, patients were switched to another biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD).
Participants were randomized, from January 2019 to June 2021, to a tapering or a nontapering T2T strategy in a 2:1 fashion. Then researchers then followed them for 12 months and aimed to determine if the tapering strategy proved noninferior to not tapering within a predefined 20% margin for noninferiority, which Dr. Michielsens said was derived from other studies and what her group determined to be “an acceptable risk.”
Results show strategy is ‘feasible in daily clinical care’
A total of 81 patients – 42 with PsA and 39 with axSpA – were in the group with tapering, and 41 were in the group without tapering: 22 with PsA and 19 with axSpA.
At 12 months, researchers found that 69% of the patients in the group with tapering had low disease activity, measured via the PASDAS and ASDAS, compared with 73% in patients who did not taper. And those in the tapering group saw their medication use dramatically reduced. At the 12-month mark, they were taking just 53% of the defined daily dose for maintenance, compared with 91% of the defined daily dose for the group that didn’t taper.
The researchers were able to successfully taper 72% of the patients in the tapering group, with 28% of them discontinuing their TNF-inhibitor medication entirely. The incidence of flares was 85% in the tapering group and 78% in the nontapering group, a nonsignificant difference (P = .32).
The start of a new medication or an increase in use of an existing medication was more frequent in the tapering group, and significantly so for NSAIDs. An increase in NSAID use was seen in 54% of the tapering group and in just 24% of the nontapering group (P = .002).
Conventional synthetic DMARD use went up in the tapering group, compared with the nontapering group, but this was only among the PsA patients and the change in use was not statistically significant. There were also more frequent increases in glucocorticoid use in the tapering group, compared with the nontapering group, but this was not significant.
Dr. Michielsens said the findings show the value of an individualized approach in treating patients with PsA or axSpA.
“Our study – and those [studies] in rheumatoid arthritis earlier – deliver the highest quality of evidence that disease activity–guided dose personalization can, and in fact should, be used in clinical practice,” she said. “Our pragmatic treat-to-target tapering strategy is feasible in daily clinical care, although treat-to-target using PASDAS and ASDAS needs some implementation. In shared decision-making with patients, a 50% reduction in TNFi use is obtainable, while maintaining low disease activity.”
The increase in the use of NSAIDs is something to be aware of, but it is “not concerning,” Dr. Michielsens added. She pointed out that the NSAID use was typically temporary, used when flares arose, and that the drugs are effective, safe, and inexpensive. She also noted that the use of TNF blockers decreased more than the use of NSAIDs increased.
“This seems a perfectly acceptable trade-off that can be discussed with your patient,” she said.
The 12-month duration of the study is likely long enough to show that the tapering strategy works, Dr. Michielsens said. In rheumatoid arthritis studies, for example, differences in strategies didn’t change after 1 year.
“That said, we are doing an observational extension study to provide more insights in the long-term effects of this treat-to-target strategy,” she said. “At the end of this summer, all patients will have completed their extended follow-up period – a 12-month observational period – so hopefully we can present the results next year at EULAR.”
This study received funding from ReumaNederland. Dr. Michielsens did not have any financial interests to disclose. Two coauthors reported financial relationships with numerous pharmaceutical companies.
Aiming for a disease activity target while reducing biologic therapy could be a winning approach for patients with psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), according to the results of a new study presented at the annual European Congress of Rheumatology.
The findings show that a treat-to-target (T2T) strategy with tapering using a tumor necrosis factor (TNF) inhibitor produces results that are noninferior to a T2T strategy that doesn’t include tapering in these patients.
“Our study has for the first time shown that a treat-to-target tapering strategy is just as good as full-dose continuation, while reducing medication use substantially,” first author Celia Michielsens, MD, a PhD student and researcher at Sint Maartenskliniek in Nijmegen, the Netherlands, said in an interview before her presentation of the study during an oral abstract session at the congress. “Stepwise tapering is also better than fixed-dose reduction or discontinuation, since it is much more individualized.”
The study is now published in Annals of the Rheumatic Diseases.
In the randomized, controlled, open-label, noninferiority study, researchers enrolled patients with PsA or axSpA who were using a TNF inhibitor such as etanercept, adalimumab, or infliximab, and had stable low disease activity for at least 6 months. Patients needed to have a Psoriatic Arthritis Disease Activity Score (PASDAS) of 3.2 or less, or an Ankylosing Spondylitis Disease Activity Score (ASDAS) of at 2.1 or less. In cases of flare, patients were treated with NSAIDs and/or glucorticoids, and if they still had not reached low disease activity after a month, their previous TNF inhibitor dose was reinstated to the last effective interval or dosage, which was maintained throughout the study period. When the patient was already using a full TNF-inhibitor dose or if dose adjustment did not suffice, patients were switched to another biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD).
Participants were randomized, from January 2019 to June 2021, to a tapering or a nontapering T2T strategy in a 2:1 fashion. Then researchers then followed them for 12 months and aimed to determine if the tapering strategy proved noninferior to not tapering within a predefined 20% margin for noninferiority, which Dr. Michielsens said was derived from other studies and what her group determined to be “an acceptable risk.”
Results show strategy is ‘feasible in daily clinical care’
A total of 81 patients – 42 with PsA and 39 with axSpA – were in the group with tapering, and 41 were in the group without tapering: 22 with PsA and 19 with axSpA.
At 12 months, researchers found that 69% of the patients in the group with tapering had low disease activity, measured via the PASDAS and ASDAS, compared with 73% in patients who did not taper. And those in the tapering group saw their medication use dramatically reduced. At the 12-month mark, they were taking just 53% of the defined daily dose for maintenance, compared with 91% of the defined daily dose for the group that didn’t taper.
The researchers were able to successfully taper 72% of the patients in the tapering group, with 28% of them discontinuing their TNF-inhibitor medication entirely. The incidence of flares was 85% in the tapering group and 78% in the nontapering group, a nonsignificant difference (P = .32).
The start of a new medication or an increase in use of an existing medication was more frequent in the tapering group, and significantly so for NSAIDs. An increase in NSAID use was seen in 54% of the tapering group and in just 24% of the nontapering group (P = .002).
Conventional synthetic DMARD use went up in the tapering group, compared with the nontapering group, but this was only among the PsA patients and the change in use was not statistically significant. There were also more frequent increases in glucocorticoid use in the tapering group, compared with the nontapering group, but this was not significant.
Dr. Michielsens said the findings show the value of an individualized approach in treating patients with PsA or axSpA.
“Our study – and those [studies] in rheumatoid arthritis earlier – deliver the highest quality of evidence that disease activity–guided dose personalization can, and in fact should, be used in clinical practice,” she said. “Our pragmatic treat-to-target tapering strategy is feasible in daily clinical care, although treat-to-target using PASDAS and ASDAS needs some implementation. In shared decision-making with patients, a 50% reduction in TNFi use is obtainable, while maintaining low disease activity.”
The increase in the use of NSAIDs is something to be aware of, but it is “not concerning,” Dr. Michielsens added. She pointed out that the NSAID use was typically temporary, used when flares arose, and that the drugs are effective, safe, and inexpensive. She also noted that the use of TNF blockers decreased more than the use of NSAIDs increased.
“This seems a perfectly acceptable trade-off that can be discussed with your patient,” she said.
The 12-month duration of the study is likely long enough to show that the tapering strategy works, Dr. Michielsens said. In rheumatoid arthritis studies, for example, differences in strategies didn’t change after 1 year.
“That said, we are doing an observational extension study to provide more insights in the long-term effects of this treat-to-target strategy,” she said. “At the end of this summer, all patients will have completed their extended follow-up period – a 12-month observational period – so hopefully we can present the results next year at EULAR.”
This study received funding from ReumaNederland. Dr. Michielsens did not have any financial interests to disclose. Two coauthors reported financial relationships with numerous pharmaceutical companies.
FROM THE EULAR 2022 CONGRESS
Artificial intelligence colonoscopy system shows promise
A new artificial intelligence (AI) system can help expert endoscopists improve their colonoscopies, a new study indicates.
Endoscopists using the computer program SKOUT (Iterative Scopes) achieved a 27% better detection rate of adenomas per colonoscopy, compared with endoscopists working without computer assistance, said lead author Aasma Shaukat, MD, MPH, director of outcomes research in the division of gastroenterology and hepatology at New York University.
The study showed that AI colonoscopy systems can work in a routine population of U.S. patients, Dr. Shaukat said in an interview.
“As gastroenterologists, we are very excited,” she said.
The study was published online in Gastroenterology and was presented at the annual Digestive Disease® Week.
Previous research has shown that experienced endoscopists miss many polyps. To improve their detection rate, multiple companies have used machine learning to develop algorithms to identify suspicious areas.
“Once the computer sees the polyp, it puts a bounding box around it,” said Dr. Shaukat. “It draws the attention of the endoscopist to it. It assists the endoscopist but doesn’t replace the endoscopist.”
The Food and Drug Administration has approved two such systems: EndoScreener (Wision AI) and GI Genius (Cosmo Pharmaceuticals).
The SKOUT algorithm was trained on 3,616 full-length colonoscopy procedure videos from multiple centers. In bench testing, it achieved a 93.5% polyp-level true positive rate and a 2.3% false positive rate.
Randomized trial pits AI against standard procedure
To see how well the system works in the clinic, Dr. Shaukat and colleagues recruited 22 U.S. board-certified gastroenterologists from five academic and community centers. The gastroenterologists all had a minimum adenoma detection rate of 25%, defined as the number of colonoscopies in which at least one adenoma is found, divided by the number of colonoscopies performed. All the gastroenterologists had performed a minimum of 1,000 colonoscopy procedures.
The researchers randomly assigned 682 patients to undergo colonoscopy with the SKOUT and 677 to undergo colonoscopy using the standard procedure. The patients were aged 40 years or older and were scheduled for either screening or surveillance.
The endoscopists who received computer assistance detected 1.05 adenomas per colonoscopy versus 0.83 for those who did not have computer assistance, a statistically significant difference.
The proportion of resections with clinically significant histology was 71.7% with standard colonoscopies versus 67.4% with computer-assisted colonoscopies. This fell within the 14% margin that the researchers had set to show noninferiority for the computer system.
“The important thing is not just detecting all polyps but the polyps we care about, which are adenomas, and doing so without increasing the false positive rate,” said Dr. Shaukat.
The adenoma detection rate was 43.9% for the standard procedure and 47.8% for the computer-assisted procedure. This difference was not statistically significant, but Dr. Shaukat argued that the adenoma detection rate is not the best measure of success, because endoscopists sometimes stop looking for polyps once they find one.
The overall sessile serrated lesion detection rate for the standard colonoscopies was 16.0% versus 12.6% for the computer-assisted colonoscopies, which also was not statistically significant.
Next steps
This study is important because it was a large, multicenter trial in the United States, said Omer Ahmad, BSc, MBBS, MRCP, a gastroenterologist and clinical researcher at University College London, who was not involved in the study. Most of the trials of AI have been in China or Europe. “It was very important just to see this replicated in the U.S. population.”
The average procedure time was 15.41 minutes for the standard colonoscopies versus 15.82 minutes for the computer-assisted colonoscopies, which was not statistically different.
“It is important to note that the studies so far suggest that false positives do not have a significant impact on workflow,” said Dr. Ahmad.
The next crucial step in evaluating AI colonoscopy will be to track the effects over the long term, said Dr. Shaukat.
“As these technologies get approved and we see them in practice, we need to see that it’s leading to some outcome, like reduced colon cancer,” she said.
That also may be necessary before payers in the United States are willing to pay the additional cost for this technology, she added.
In the meantime, Dr. Ahmad said computer assistance is improving his own colonoscopies.
“I have found the systems have spotted some polyps that I may have otherwise missed,” he said. “There is a false positive rate, but for me, it doesn’t distract from my workflow.”
He believes the systems will be particularly helpful in improving the performance of less-skilled endoscopists.
He is also looking forward to systems that can help complete the reports needed at the end of each colonoscopy. “Most of us dislike having to write a laborious report and having to code everything at the end of the procedure,” he said.
The study was funded by Iterative Scopes. Dr. Shaukat reported having received research funding to her institution for the current study from Iterative Scopes and consulting fees from Freenome and Medtronic. Dr. Ahmad reports receiving speaker fees from the Canadian Association of Gastroenterology/Medtronic.
A version of this article first appeared on Medscape.com.
A new artificial intelligence (AI) system can help expert endoscopists improve their colonoscopies, a new study indicates.
Endoscopists using the computer program SKOUT (Iterative Scopes) achieved a 27% better detection rate of adenomas per colonoscopy, compared with endoscopists working without computer assistance, said lead author Aasma Shaukat, MD, MPH, director of outcomes research in the division of gastroenterology and hepatology at New York University.
The study showed that AI colonoscopy systems can work in a routine population of U.S. patients, Dr. Shaukat said in an interview.
“As gastroenterologists, we are very excited,” she said.
The study was published online in Gastroenterology and was presented at the annual Digestive Disease® Week.
Previous research has shown that experienced endoscopists miss many polyps. To improve their detection rate, multiple companies have used machine learning to develop algorithms to identify suspicious areas.
“Once the computer sees the polyp, it puts a bounding box around it,” said Dr. Shaukat. “It draws the attention of the endoscopist to it. It assists the endoscopist but doesn’t replace the endoscopist.”
The Food and Drug Administration has approved two such systems: EndoScreener (Wision AI) and GI Genius (Cosmo Pharmaceuticals).
The SKOUT algorithm was trained on 3,616 full-length colonoscopy procedure videos from multiple centers. In bench testing, it achieved a 93.5% polyp-level true positive rate and a 2.3% false positive rate.
Randomized trial pits AI against standard procedure
To see how well the system works in the clinic, Dr. Shaukat and colleagues recruited 22 U.S. board-certified gastroenterologists from five academic and community centers. The gastroenterologists all had a minimum adenoma detection rate of 25%, defined as the number of colonoscopies in which at least one adenoma is found, divided by the number of colonoscopies performed. All the gastroenterologists had performed a minimum of 1,000 colonoscopy procedures.
The researchers randomly assigned 682 patients to undergo colonoscopy with the SKOUT and 677 to undergo colonoscopy using the standard procedure. The patients were aged 40 years or older and were scheduled for either screening or surveillance.
The endoscopists who received computer assistance detected 1.05 adenomas per colonoscopy versus 0.83 for those who did not have computer assistance, a statistically significant difference.
The proportion of resections with clinically significant histology was 71.7% with standard colonoscopies versus 67.4% with computer-assisted colonoscopies. This fell within the 14% margin that the researchers had set to show noninferiority for the computer system.
“The important thing is not just detecting all polyps but the polyps we care about, which are adenomas, and doing so without increasing the false positive rate,” said Dr. Shaukat.
The adenoma detection rate was 43.9% for the standard procedure and 47.8% for the computer-assisted procedure. This difference was not statistically significant, but Dr. Shaukat argued that the adenoma detection rate is not the best measure of success, because endoscopists sometimes stop looking for polyps once they find one.
The overall sessile serrated lesion detection rate for the standard colonoscopies was 16.0% versus 12.6% for the computer-assisted colonoscopies, which also was not statistically significant.
Next steps
This study is important because it was a large, multicenter trial in the United States, said Omer Ahmad, BSc, MBBS, MRCP, a gastroenterologist and clinical researcher at University College London, who was not involved in the study. Most of the trials of AI have been in China or Europe. “It was very important just to see this replicated in the U.S. population.”
The average procedure time was 15.41 minutes for the standard colonoscopies versus 15.82 minutes for the computer-assisted colonoscopies, which was not statistically different.
“It is important to note that the studies so far suggest that false positives do not have a significant impact on workflow,” said Dr. Ahmad.
The next crucial step in evaluating AI colonoscopy will be to track the effects over the long term, said Dr. Shaukat.
“As these technologies get approved and we see them in practice, we need to see that it’s leading to some outcome, like reduced colon cancer,” she said.
That also may be necessary before payers in the United States are willing to pay the additional cost for this technology, she added.
In the meantime, Dr. Ahmad said computer assistance is improving his own colonoscopies.
“I have found the systems have spotted some polyps that I may have otherwise missed,” he said. “There is a false positive rate, but for me, it doesn’t distract from my workflow.”
He believes the systems will be particularly helpful in improving the performance of less-skilled endoscopists.
He is also looking forward to systems that can help complete the reports needed at the end of each colonoscopy. “Most of us dislike having to write a laborious report and having to code everything at the end of the procedure,” he said.
The study was funded by Iterative Scopes. Dr. Shaukat reported having received research funding to her institution for the current study from Iterative Scopes and consulting fees from Freenome and Medtronic. Dr. Ahmad reports receiving speaker fees from the Canadian Association of Gastroenterology/Medtronic.
A version of this article first appeared on Medscape.com.
A new artificial intelligence (AI) system can help expert endoscopists improve their colonoscopies, a new study indicates.
Endoscopists using the computer program SKOUT (Iterative Scopes) achieved a 27% better detection rate of adenomas per colonoscopy, compared with endoscopists working without computer assistance, said lead author Aasma Shaukat, MD, MPH, director of outcomes research in the division of gastroenterology and hepatology at New York University.
The study showed that AI colonoscopy systems can work in a routine population of U.S. patients, Dr. Shaukat said in an interview.
“As gastroenterologists, we are very excited,” she said.
The study was published online in Gastroenterology and was presented at the annual Digestive Disease® Week.
Previous research has shown that experienced endoscopists miss many polyps. To improve their detection rate, multiple companies have used machine learning to develop algorithms to identify suspicious areas.
“Once the computer sees the polyp, it puts a bounding box around it,” said Dr. Shaukat. “It draws the attention of the endoscopist to it. It assists the endoscopist but doesn’t replace the endoscopist.”
The Food and Drug Administration has approved two such systems: EndoScreener (Wision AI) and GI Genius (Cosmo Pharmaceuticals).
The SKOUT algorithm was trained on 3,616 full-length colonoscopy procedure videos from multiple centers. In bench testing, it achieved a 93.5% polyp-level true positive rate and a 2.3% false positive rate.
Randomized trial pits AI against standard procedure
To see how well the system works in the clinic, Dr. Shaukat and colleagues recruited 22 U.S. board-certified gastroenterologists from five academic and community centers. The gastroenterologists all had a minimum adenoma detection rate of 25%, defined as the number of colonoscopies in which at least one adenoma is found, divided by the number of colonoscopies performed. All the gastroenterologists had performed a minimum of 1,000 colonoscopy procedures.
The researchers randomly assigned 682 patients to undergo colonoscopy with the SKOUT and 677 to undergo colonoscopy using the standard procedure. The patients were aged 40 years or older and were scheduled for either screening or surveillance.
The endoscopists who received computer assistance detected 1.05 adenomas per colonoscopy versus 0.83 for those who did not have computer assistance, a statistically significant difference.
The proportion of resections with clinically significant histology was 71.7% with standard colonoscopies versus 67.4% with computer-assisted colonoscopies. This fell within the 14% margin that the researchers had set to show noninferiority for the computer system.
“The important thing is not just detecting all polyps but the polyps we care about, which are adenomas, and doing so without increasing the false positive rate,” said Dr. Shaukat.
The adenoma detection rate was 43.9% for the standard procedure and 47.8% for the computer-assisted procedure. This difference was not statistically significant, but Dr. Shaukat argued that the adenoma detection rate is not the best measure of success, because endoscopists sometimes stop looking for polyps once they find one.
The overall sessile serrated lesion detection rate for the standard colonoscopies was 16.0% versus 12.6% for the computer-assisted colonoscopies, which also was not statistically significant.
Next steps
This study is important because it was a large, multicenter trial in the United States, said Omer Ahmad, BSc, MBBS, MRCP, a gastroenterologist and clinical researcher at University College London, who was not involved in the study. Most of the trials of AI have been in China or Europe. “It was very important just to see this replicated in the U.S. population.”
The average procedure time was 15.41 minutes for the standard colonoscopies versus 15.82 minutes for the computer-assisted colonoscopies, which was not statistically different.
“It is important to note that the studies so far suggest that false positives do not have a significant impact on workflow,” said Dr. Ahmad.
The next crucial step in evaluating AI colonoscopy will be to track the effects over the long term, said Dr. Shaukat.
“As these technologies get approved and we see them in practice, we need to see that it’s leading to some outcome, like reduced colon cancer,” she said.
That also may be necessary before payers in the United States are willing to pay the additional cost for this technology, she added.
In the meantime, Dr. Ahmad said computer assistance is improving his own colonoscopies.
“I have found the systems have spotted some polyps that I may have otherwise missed,” he said. “There is a false positive rate, but for me, it doesn’t distract from my workflow.”
He believes the systems will be particularly helpful in improving the performance of less-skilled endoscopists.
He is also looking forward to systems that can help complete the reports needed at the end of each colonoscopy. “Most of us dislike having to write a laborious report and having to code everything at the end of the procedure,” he said.
The study was funded by Iterative Scopes. Dr. Shaukat reported having received research funding to her institution for the current study from Iterative Scopes and consulting fees from Freenome and Medtronic. Dr. Ahmad reports receiving speaker fees from the Canadian Association of Gastroenterology/Medtronic.
A version of this article first appeared on Medscape.com.