AVAHO

When the first reports emerged of “cytokine storm” in patients with severe COVID-19, all eyes turned to cancer research. Oncologists have years of experience reigning in “cytokine release syndrome” (CRS) in patients treated with chimeric antigen receptor (CAR) therapies for advanced blood cancers.

There was hope that drugs used to quell CRS in patients with cancer would be effective in patients with severe COVID. But the promise of a quick fix with oncology medications has yet to be fully realized.

Part of the problem is that the two conditions, while analogous, are “not the same,” said Nirali Shah, MD, head of the hematologic malignancies section in the pediatric oncology branch at the National Cancer Institute.

“You have to understand the underlying pathophysiology, what triggers the inflammation,” Dr. Shah said.

CAR T–related CRS is caused by activated T cells in patients with cancer who often do not have an infection, she explained. In contrast, cytokine storm in COVID-19 is triggered by a viral pathogen that can drive “out of control” inflammation. These differences may explain why drugs work in the first instance, but not in the second, she added. Drugs that inhibit interleukin-6 (such as tocilizumab, sarilumab, and siltuximab) are used with great success to dampen down the CRS in patients receiving CAR therapy for blood cancers. And although trials of these agents in patients with COVID are still ongoing, initial results are disappointing.

The first global, phase 3 randomized controlled trial of tocilizumab in severe COVID-19 failed to meet its primary endpoint of improved clinical status, and it did not meet its secondary endpoint of improved mortality at week 4.

In its recent recommendations, the National Institutes of Health noted a lack of data to support the efficacy of IL-6 inhibitors in COVID-19, and recommended against their use, except as part of a clinical trial.
 

Trimming the tree vs. cutting it down

As researchers have begun to decode the immune process underlying severe COVID-19, they have turned to other cancer drugs to tame cytokine storm.

Louis Staudt, MD, PhD, and Wyndham Wilson, MD, PhD, both at the NCI, think that cytokine storm in COVID-19 is driven by macrophages, which trigger release of multiple cytokines.

For years, the pair have been studying lymphoid tumors. Dr. Staudt is chief of the lymphoid malignancies branch at the NCI, and Wilson is head of the lymphoma therapeutics section. In past work, Dr. Staudt discovered that inhibiting an enzyme called bruton tyrosine kinase (BTK) dampens macrophage function.

When the pandemic began, Dr. Staudt and Dr. Wilson realized that singling out just one cytokine like IL-6 may not be enough. They thought that a more effective approach may be to target macrophages with a BTK inhibitor called acalabrutinib (Calquence), which would inhibit multiple cytokines at the same time.

Dr. Staudt likens the immune response to a tree, with the macrophages composing the tree trunk and the limbs made up of individual cytokines.

“Targeting macrophages is getting at the trunk of the problem,” he said. “You’re only cutting off the limbs with tocilizumab.”

In just 3 days, Dr. Staudt and Dr. Wilson went from concept to approval to launching a prospective, observational study. The study took place at five centers in the US, and included 19 patients hospitalized with COVID-19; the results were published in Science Immunology. Over a treatment course of 14 days, the majority of patients treated off-label with acalabrutinib improved, some within 24 hours. Eight of 11 patients on supplemental oxygen were discharged on room air. Four of eight patients on ventilators were extubated, with two of these discharged on room air. Two patients on ventilators died. No discernible toxicity was noted.

Analyses also showed increased BTK activity and elevated IL-6 levels in monocytes – precursors of macrophages – in patients with severe COVID-19, compared with healthy volunteers.

“We showed that the target of acalabrutinib was active in the immune cells of patients with severe COVID-19,” Dr. Staudt said. “So we have the target. We have the drug to hit the target. And we have an apparent clinical benefit.”

Those three things were compelling enough to launch the CALAVI phase 2 trial, an open-label, randomized, controlled trial, sponsored by AstraZeneca and the NCI, that is being conducted in the United States and internationally. It is testing acalabrutinib with best supportive care versus BSC alone in people hospitalized with COVID-19. The trial is scheduled to be completed on Nov. 26.

Preliminary insights from this trial are expected soon. “These are not insights that we will likely publish, but they are important insights that will lead to the launch of a definitive double-blind, randomized, phase 3 trial, which we hope to launch in the next month or so,” Dr. Wilson said.
 

Targeting inflammation and infection simultaneously

Other scientists are investigating inhibitors of Janus kinase (JAK), a family of enzymes that play a key role in orchestrating immune responses, particularly cytokines. Interest in JAK inhibition to control hyperinflammation in cancer goes back at least 15 years, and drugs that act as JAK inhibitors are already approved for use in the treatment of myelofibrosis (ruxolitinib [Jakafi], fedratinib [Inrebic]) and also for rheumatoid arthritis (upadacitinib [Rinvoq], baricitinib [Olumiant]).

“It wasn’t a huge leap for those of us with a lot of understanding of JAK inhibitors to propose taking them into the clinic to treat patients with COVID-19,” commented John Mascarenhas, MD, the leader of clinical investigation in the myeloproliferative disorders program at the Icahn School of Medicine at Mount Sinai, New York.

Dr. Mascarenhas is also principal investigator of the PRE-VENT trial, which is comparing the investigational JAK2 inhibitor pacritinib plus standard of care to standard of care alone in patients hospitalized with severe COVID-19, with and without cancer. The trial is sponsored by CTI BioPharma (manufacturer of pacritinib), and is taking place at 10 sites in the United States.

In a move that may raise eyebrows, PRE-VENT skipped phase 1 and 2 and went straight to phase 3. Pacritinib has yet to receive FDA approval and has mostly been studied in myelofibrosis, an intensely inflammatory disease.

The decision was based on trials of pacritinib in hematologic malignancies and also on results from a phase 2 study in China that found possible clinical benefit for the JAK 1/2 inhibitor ruxolitinib in 43 patients hospitalized with severe COVID-19, although results were not statistically significant, Dr. Mascarenhas explained.

Recent results from Lilly’s ACTT-2 study have provided further support for the role of JAK inhibitors in treating cytokine storm. ACTT-2 is a phase 3, double-blind, placebo-controlled, randomized, controlled trial sponsored by the NIH and NIAID comparing the JAK 1/2 inhibitor baricitinib plus the antiviral remdesivir with remdesivir alone in patients hospitalized with COVID-19. In September, Lilly announced that the trial met its primary endpoint of decreased time to recovery in patients who received baricitinib in combination with remdesivir.

But pacritinib’s mechanism of action may take things a step further. The drug selectively inhibits JAK2 and spares JAK1, which is important for antiviral activity in the immune system. Also, in vitro data suggests pacritinib may simultaneously reduce inflammation and fight off the virus by selectively inhibiting two additional enzymes and two other receptors.

“The rationale to me is very strong for using pacritinib,” Dr. Mascarenhas said. “I think this approach was bold but appropriate.”

The main safety concern with pacritinib could be bleeding, especially among patients on anticoagulants, Dr. Mascarenhas said. Because some patients with severe COVID-19 tend to develop blood clots, anticoagulation has become the standard of care at many institutions.

Because the trial is just beginning – only a minority of the total planned population of 358 patients has been enrolled – no interim results are available.
 

Right drug, wrong time?

IL-6 inhibition could still have a role to play in COVID-19, but the trick could be in the timing. Most of the trials so far have studied tocilizumab in patients with severe COVID-19, many of whom were already on ventilators. At that point, it may be too late to reverse the damage that has already taken place.

One of the main reasons tocilizumab works so well in CRS after CAR T therapy is that oncologists have learned how to use it early, often within 24 hours of fever onset. Oncologists use the American Society for Transplantation and Cellular Therapy consensus grading system, which helps them identify CRS when it is easier to control.

But applying the ASTCT grading system to COVID-19 is problematic. “Almost by definition, patients hospitalized with COVID-19 have low oxygen levels, which throws off the scale,” said Joshua Hill, MD, an infectious disease specialist at Fred Hutchinson Cancer Research Center in Seattle, who has research expertise in infectious complications after CAR T therapy.

“The key is to intervene earlier to prevent damage to the lungs and other end organs. We don’t have anything magical that will reverse that damage,” Dr. Hill said.

Results from the phase 3 trial EMPACTA trial (sponsored by Genentech) seem to bear this out. EMPACTA is evaluating use of tocilizumab in hospitalized patients with less severe COVID-19 who do not yet require mechanical ventilation. The trial is notable for being the first global phase 3 trial to demonstrate efficacy for tocilizumab vs placebo in hospitalized patients with COVID-19 pneumonia, and for including a high percentage of racial/ethnic minorities (85% of 389 participants), who have been hard hit by the pandemic and have historically been underrepresented in drug trials.

Last month, Roche announced that EMPACTA met its primary endpoint. Results showed that patients hospitalized with COVID-19 pneumonia who received tocilizumab plus standard of care were 44% less likely to go on mechanical ventilation or die, compared with those who received placebo plus standard of care (P = .0348), although there were no statistically significant differences in death by day 28 between tocilizumab and placebo (10.4% vs. 8.6%, P = .5146).

However, earlier administration of tocilizumab raises another issue. IL-6 and its pathway are important for clearing viral infections. Using tocilizumab in the context of an ongoing infection could raise safety issues.

Also, tocilizumab sticks around in the body for a relatively long time. In the treatment of rheumatoid arthritis, it is dosed once a month, and it carries a black box warning for reactivation of tuberculosis.

Whereas results from EMPACTA showed similar rates of infection associated with tocilizumab and placebo (10% vs. 11%), at least one other study has found increased rates of superinfection in patients with severe COVID-19 who received tocilizumab. Overall, though, the drug was associated with decreased risk of death in the latter study.

A phase 2 trial called COVIDOSE is tackling the safety issue. COVIDOSE is evaluating whether low-dose tocilizumab is effective in noncritical COVID-19 patients, with the idea that lower doses could be safer. Early results published as a preprint before peer review indicated that low-dose tocilizumab (ranging from 40 mg to 200 mg) was associated with clinical improvement in 32 noncritical patients hospitalized with COVID-19.

Five patients (15.6%) developed bacterial superinfections, and five (15.6%) died by 28-day follow-up, although there wasn’t a perfect “overlap” between these groups of patients. Bacterial superinfection was not the cause of death in all five patients who died, and not all patients who died developed bacterial superinfections, according to senior author Pankti Reid, MD, MPH, an assistant professor of medicine at the University of Chicago.

Results from COVIDOSE also showed that treatment with tocilizumab did not seem to affect the ability of patients to develop antibodies against COVID-19. The results set the stage for a larger randomized, controlled trial (still ongoing) to determine the optimal dose of tocilizumab.

Still, Dr. Hill urges caution.

Many of these immunomodulators have been used only in the context of a clinical trial, or only for patients with terminal cancer and no other treatment options. In patients with cancer, these drugs have been studied and have shown an “acceptable safety profile,” according to Dr. Shah.

But this is a different situation, and when it comes to repurposing them to relatively healthy patients with COVID-19, Dr. Hill emphasized the need for careful research.

“We’re always very concerned about giving drugs that suppress the immune response if people have active infections,” Dr. Hill said. “Often times we think it makes things worse, and it typically does.”

Dr. Mascarenhas reported institutional research funding from CTI Biopharma. Dr. Hill, Dr. Staudt, Dr. Wilson, and Dr. Shah disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

When the first reports emerged of “cytokine storm” in patients with severe COVID-19, all eyes turned to cancer research. Oncologists have years of experience reigning in “cytokine release syndrome” (CRS) in patients treated with chimeric antigen receptor (CAR) therapies for advanced blood cancers.

There was hope that drugs used to quell CRS in patients with cancer would be effective in patients with severe COVID. But the promise of a quick fix with oncology medications has yet to be fully realized.

Part of the problem is that the two conditions, while analogous, are “not the same,” said Nirali Shah, MD, head of the hematologic malignancies section in the pediatric oncology branch at the National Cancer Institute.

“You have to understand the underlying pathophysiology, what triggers the inflammation,” Dr. Shah said.

CAR T–related CRS is caused by activated T cells in patients with cancer who often do not have an infection, she explained. In contrast, cytokine storm in COVID-19 is triggered by a viral pathogen that can drive “out of control” inflammation. These differences may explain why drugs work in the first instance, but not in the second, she added. Drugs that inhibit interleukin-6 (such as tocilizumab, sarilumab, and siltuximab) are used with great success to dampen down the CRS in patients receiving CAR therapy for blood cancers. And although trials of these agents in patients with COVID are still ongoing, initial results are disappointing.

The first global, phase 3 randomized controlled trial of tocilizumab in severe COVID-19 failed to meet its primary endpoint of improved clinical status, and it did not meet its secondary endpoint of improved mortality at week 4.

In its recent recommendations, the National Institutes of Health noted a lack of data to support the efficacy of IL-6 inhibitors in COVID-19, and recommended against their use, except as part of a clinical trial.
 

Trimming the tree vs. cutting it down

As researchers have begun to decode the immune process underlying severe COVID-19, they have turned to other cancer drugs to tame cytokine storm.

Louis Staudt, MD, PhD, and Wyndham Wilson, MD, PhD, both at the NCI, think that cytokine storm in COVID-19 is driven by macrophages, which trigger release of multiple cytokines.

For years, the pair have been studying lymphoid tumors. Dr. Staudt is chief of the lymphoid malignancies branch at the NCI, and Wilson is head of the lymphoma therapeutics section. In past work, Dr. Staudt discovered that inhibiting an enzyme called bruton tyrosine kinase (BTK) dampens macrophage function.

When the pandemic began, Dr. Staudt and Dr. Wilson realized that singling out just one cytokine like IL-6 may not be enough. They thought that a more effective approach may be to target macrophages with a BTK inhibitor called acalabrutinib (Calquence), which would inhibit multiple cytokines at the same time.

Dr. Staudt likens the immune response to a tree, with the macrophages composing the tree trunk and the limbs made up of individual cytokines.

“Targeting macrophages is getting at the trunk of the problem,” he said. “You’re only cutting off the limbs with tocilizumab.”

In just 3 days, Dr. Staudt and Dr. Wilson went from concept to approval to launching a prospective, observational study. The study took place at five centers in the US, and included 19 patients hospitalized with COVID-19; the results were published in Science Immunology. Over a treatment course of 14 days, the majority of patients treated off-label with acalabrutinib improved, some within 24 hours. Eight of 11 patients on supplemental oxygen were discharged on room air. Four of eight patients on ventilators were extubated, with two of these discharged on room air. Two patients on ventilators died. No discernible toxicity was noted.

Analyses also showed increased BTK activity and elevated IL-6 levels in monocytes – precursors of macrophages – in patients with severe COVID-19, compared with healthy volunteers.

“We showed that the target of acalabrutinib was active in the immune cells of patients with severe COVID-19,” Dr. Staudt said. “So we have the target. We have the drug to hit the target. And we have an apparent clinical benefit.”

Those three things were compelling enough to launch the CALAVI phase 2 trial, an open-label, randomized, controlled trial, sponsored by AstraZeneca and the NCI, that is being conducted in the United States and internationally. It is testing acalabrutinib with best supportive care versus BSC alone in people hospitalized with COVID-19. The trial is scheduled to be completed on Nov. 26.

Preliminary insights from this trial are expected soon. “These are not insights that we will likely publish, but they are important insights that will lead to the launch of a definitive double-blind, randomized, phase 3 trial, which we hope to launch in the next month or so,” Dr. Wilson said.
 

Targeting inflammation and infection simultaneously

Other scientists are investigating inhibitors of Janus kinase (JAK), a family of enzymes that play a key role in orchestrating immune responses, particularly cytokines. Interest in JAK inhibition to control hyperinflammation in cancer goes back at least 15 years, and drugs that act as JAK inhibitors are already approved for use in the treatment of myelofibrosis (ruxolitinib [Jakafi], fedratinib [Inrebic]) and also for rheumatoid arthritis (upadacitinib [Rinvoq], baricitinib [Olumiant]).

“It wasn’t a huge leap for those of us with a lot of understanding of JAK inhibitors to propose taking them into the clinic to treat patients with COVID-19,” commented John Mascarenhas, MD, the leader of clinical investigation in the myeloproliferative disorders program at the Icahn School of Medicine at Mount Sinai, New York.

Dr. Mascarenhas is also principal investigator of the PRE-VENT trial, which is comparing the investigational JAK2 inhibitor pacritinib plus standard of care to standard of care alone in patients hospitalized with severe COVID-19, with and without cancer. The trial is sponsored by CTI BioPharma (manufacturer of pacritinib), and is taking place at 10 sites in the United States.

In a move that may raise eyebrows, PRE-VENT skipped phase 1 and 2 and went straight to phase 3. Pacritinib has yet to receive FDA approval and has mostly been studied in myelofibrosis, an intensely inflammatory disease.

The decision was based on trials of pacritinib in hematologic malignancies and also on results from a phase 2 study in China that found possible clinical benefit for the JAK 1/2 inhibitor ruxolitinib in 43 patients hospitalized with severe COVID-19, although results were not statistically significant, Dr. Mascarenhas explained.

Recent results from Lilly’s ACTT-2 study have provided further support for the role of JAK inhibitors in treating cytokine storm. ACTT-2 is a phase 3, double-blind, placebo-controlled, randomized, controlled trial sponsored by the NIH and NIAID comparing the JAK 1/2 inhibitor baricitinib plus the antiviral remdesivir with remdesivir alone in patients hospitalized with COVID-19. In September, Lilly announced that the trial met its primary endpoint of decreased time to recovery in patients who received baricitinib in combination with remdesivir.

But pacritinib’s mechanism of action may take things a step further. The drug selectively inhibits JAK2 and spares JAK1, which is important for antiviral activity in the immune system. Also, in vitro data suggests pacritinib may simultaneously reduce inflammation and fight off the virus by selectively inhibiting two additional enzymes and two other receptors.

“The rationale to me is very strong for using pacritinib,” Dr. Mascarenhas said. “I think this approach was bold but appropriate.”

The main safety concern with pacritinib could be bleeding, especially among patients on anticoagulants, Dr. Mascarenhas said. Because some patients with severe COVID-19 tend to develop blood clots, anticoagulation has become the standard of care at many institutions.

Because the trial is just beginning – only a minority of the total planned population of 358 patients has been enrolled – no interim results are available.
 

Right drug, wrong time?

IL-6 inhibition could still have a role to play in COVID-19, but the trick could be in the timing. Most of the trials so far have studied tocilizumab in patients with severe COVID-19, many of whom were already on ventilators. At that point, it may be too late to reverse the damage that has already taken place.

One of the main reasons tocilizumab works so well in CRS after CAR T therapy is that oncologists have learned how to use it early, often within 24 hours of fever onset. Oncologists use the American Society for Transplantation and Cellular Therapy consensus grading system, which helps them identify CRS when it is easier to control.

But applying the ASTCT grading system to COVID-19 is problematic. “Almost by definition, patients hospitalized with COVID-19 have low oxygen levels, which throws off the scale,” said Joshua Hill, MD, an infectious disease specialist at Fred Hutchinson Cancer Research Center in Seattle, who has research expertise in infectious complications after CAR T therapy.

“The key is to intervene earlier to prevent damage to the lungs and other end organs. We don’t have anything magical that will reverse that damage,” Dr. Hill said.

Results from the phase 3 trial EMPACTA trial (sponsored by Genentech) seem to bear this out. EMPACTA is evaluating use of tocilizumab in hospitalized patients with less severe COVID-19 who do not yet require mechanical ventilation. The trial is notable for being the first global phase 3 trial to demonstrate efficacy for tocilizumab vs placebo in hospitalized patients with COVID-19 pneumonia, and for including a high percentage of racial/ethnic minorities (85% of 389 participants), who have been hard hit by the pandemic and have historically been underrepresented in drug trials.

Last month, Roche announced that EMPACTA met its primary endpoint. Results showed that patients hospitalized with COVID-19 pneumonia who received tocilizumab plus standard of care were 44% less likely to go on mechanical ventilation or die, compared with those who received placebo plus standard of care (P = .0348), although there were no statistically significant differences in death by day 28 between tocilizumab and placebo (10.4% vs. 8.6%, P = .5146).

However, earlier administration of tocilizumab raises another issue. IL-6 and its pathway are important for clearing viral infections. Using tocilizumab in the context of an ongoing infection could raise safety issues.

Also, tocilizumab sticks around in the body for a relatively long time. In the treatment of rheumatoid arthritis, it is dosed once a month, and it carries a black box warning for reactivation of tuberculosis.

Whereas results from EMPACTA showed similar rates of infection associated with tocilizumab and placebo (10% vs. 11%), at least one other study has found increased rates of superinfection in patients with severe COVID-19 who received tocilizumab. Overall, though, the drug was associated with decreased risk of death in the latter study.

A phase 2 trial called COVIDOSE is tackling the safety issue. COVIDOSE is evaluating whether low-dose tocilizumab is effective in noncritical COVID-19 patients, with the idea that lower doses could be safer. Early results published as a preprint before peer review indicated that low-dose tocilizumab (ranging from 40 mg to 200 mg) was associated with clinical improvement in 32 noncritical patients hospitalized with COVID-19.

Five patients (15.6%) developed bacterial superinfections, and five (15.6%) died by 28-day follow-up, although there wasn’t a perfect “overlap” between these groups of patients. Bacterial superinfection was not the cause of death in all five patients who died, and not all patients who died developed bacterial superinfections, according to senior author Pankti Reid, MD, MPH, an assistant professor of medicine at the University of Chicago.

Results from COVIDOSE also showed that treatment with tocilizumab did not seem to affect the ability of patients to develop antibodies against COVID-19. The results set the stage for a larger randomized, controlled trial (still ongoing) to determine the optimal dose of tocilizumab.

Still, Dr. Hill urges caution.

Many of these immunomodulators have been used only in the context of a clinical trial, or only for patients with terminal cancer and no other treatment options. In patients with cancer, these drugs have been studied and have shown an “acceptable safety profile,” according to Dr. Shah.

But this is a different situation, and when it comes to repurposing them to relatively healthy patients with COVID-19, Dr. Hill emphasized the need for careful research.

“We’re always very concerned about giving drugs that suppress the immune response if people have active infections,” Dr. Hill said. “Often times we think it makes things worse, and it typically does.”

Dr. Mascarenhas reported institutional research funding from CTI Biopharma. Dr. Hill, Dr. Staudt, Dr. Wilson, and Dr. Shah disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

When the first reports emerged of “cytokine storm” in patients with severe COVID-19, all eyes turned to cancer research. Oncologists have years of experience reigning in “cytokine release syndrome” (CRS) in patients treated with chimeric antigen receptor (CAR) therapies for advanced blood cancers.

There was hope that drugs used to quell CRS in patients with cancer would be effective in patients with severe COVID. But the promise of a quick fix with oncology medications has yet to be fully realized.

Part of the problem is that the two conditions, while analogous, are “not the same,” said Nirali Shah, MD, head of the hematologic malignancies section in the pediatric oncology branch at the National Cancer Institute.

“You have to understand the underlying pathophysiology, what triggers the inflammation,” Dr. Shah said.

CAR T–related CRS is caused by activated T cells in patients with cancer who often do not have an infection, she explained. In contrast, cytokine storm in COVID-19 is triggered by a viral pathogen that can drive “out of control” inflammation. These differences may explain why drugs work in the first instance, but not in the second, she added. Drugs that inhibit interleukin-6 (such as tocilizumab, sarilumab, and siltuximab) are used with great success to dampen down the CRS in patients receiving CAR therapy for blood cancers. And although trials of these agents in patients with COVID are still ongoing, initial results are disappointing.

The first global, phase 3 randomized controlled trial of tocilizumab in severe COVID-19 failed to meet its primary endpoint of improved clinical status, and it did not meet its secondary endpoint of improved mortality at week 4.

In its recent recommendations, the National Institutes of Health noted a lack of data to support the efficacy of IL-6 inhibitors in COVID-19, and recommended against their use, except as part of a clinical trial.
 

Trimming the tree vs. cutting it down

As researchers have begun to decode the immune process underlying severe COVID-19, they have turned to other cancer drugs to tame cytokine storm.

Louis Staudt, MD, PhD, and Wyndham Wilson, MD, PhD, both at the NCI, think that cytokine storm in COVID-19 is driven by macrophages, which trigger release of multiple cytokines.

For years, the pair have been studying lymphoid tumors. Dr. Staudt is chief of the lymphoid malignancies branch at the NCI, and Wilson is head of the lymphoma therapeutics section. In past work, Dr. Staudt discovered that inhibiting an enzyme called bruton tyrosine kinase (BTK) dampens macrophage function.

When the pandemic began, Dr. Staudt and Dr. Wilson realized that singling out just one cytokine like IL-6 may not be enough. They thought that a more effective approach may be to target macrophages with a BTK inhibitor called acalabrutinib (Calquence), which would inhibit multiple cytokines at the same time.

Dr. Staudt likens the immune response to a tree, with the macrophages composing the tree trunk and the limbs made up of individual cytokines.

“Targeting macrophages is getting at the trunk of the problem,” he said. “You’re only cutting off the limbs with tocilizumab.”

In just 3 days, Dr. Staudt and Dr. Wilson went from concept to approval to launching a prospective, observational study. The study took place at five centers in the US, and included 19 patients hospitalized with COVID-19; the results were published in Science Immunology. Over a treatment course of 14 days, the majority of patients treated off-label with acalabrutinib improved, some within 24 hours. Eight of 11 patients on supplemental oxygen were discharged on room air. Four of eight patients on ventilators were extubated, with two of these discharged on room air. Two patients on ventilators died. No discernible toxicity was noted.

Analyses also showed increased BTK activity and elevated IL-6 levels in monocytes – precursors of macrophages – in patients with severe COVID-19, compared with healthy volunteers.

“We showed that the target of acalabrutinib was active in the immune cells of patients with severe COVID-19,” Dr. Staudt said. “So we have the target. We have the drug to hit the target. And we have an apparent clinical benefit.”

Those three things were compelling enough to launch the CALAVI phase 2 trial, an open-label, randomized, controlled trial, sponsored by AstraZeneca and the NCI, that is being conducted in the United States and internationally. It is testing acalabrutinib with best supportive care versus BSC alone in people hospitalized with COVID-19. The trial is scheduled to be completed on Nov. 26.

Preliminary insights from this trial are expected soon. “These are not insights that we will likely publish, but they are important insights that will lead to the launch of a definitive double-blind, randomized, phase 3 trial, which we hope to launch in the next month or so,” Dr. Wilson said.
 

Targeting inflammation and infection simultaneously

Other scientists are investigating inhibitors of Janus kinase (JAK), a family of enzymes that play a key role in orchestrating immune responses, particularly cytokines. Interest in JAK inhibition to control hyperinflammation in cancer goes back at least 15 years, and drugs that act as JAK inhibitors are already approved for use in the treatment of myelofibrosis (ruxolitinib [Jakafi], fedratinib [Inrebic]) and also for rheumatoid arthritis (upadacitinib [Rinvoq], baricitinib [Olumiant]).

“It wasn’t a huge leap for those of us with a lot of understanding of JAK inhibitors to propose taking them into the clinic to treat patients with COVID-19,” commented John Mascarenhas, MD, the leader of clinical investigation in the myeloproliferative disorders program at the Icahn School of Medicine at Mount Sinai, New York.

Dr. Mascarenhas is also principal investigator of the PRE-VENT trial, which is comparing the investigational JAK2 inhibitor pacritinib plus standard of care to standard of care alone in patients hospitalized with severe COVID-19, with and without cancer. The trial is sponsored by CTI BioPharma (manufacturer of pacritinib), and is taking place at 10 sites in the United States.

In a move that may raise eyebrows, PRE-VENT skipped phase 1 and 2 and went straight to phase 3. Pacritinib has yet to receive FDA approval and has mostly been studied in myelofibrosis, an intensely inflammatory disease.

The decision was based on trials of pacritinib in hematologic malignancies and also on results from a phase 2 study in China that found possible clinical benefit for the JAK 1/2 inhibitor ruxolitinib in 43 patients hospitalized with severe COVID-19, although results were not statistically significant, Dr. Mascarenhas explained.

Recent results from Lilly’s ACTT-2 study have provided further support for the role of JAK inhibitors in treating cytokine storm. ACTT-2 is a phase 3, double-blind, placebo-controlled, randomized, controlled trial sponsored by the NIH and NIAID comparing the JAK 1/2 inhibitor baricitinib plus the antiviral remdesivir with remdesivir alone in patients hospitalized with COVID-19. In September, Lilly announced that the trial met its primary endpoint of decreased time to recovery in patients who received baricitinib in combination with remdesivir.

But pacritinib’s mechanism of action may take things a step further. The drug selectively inhibits JAK2 and spares JAK1, which is important for antiviral activity in the immune system. Also, in vitro data suggests pacritinib may simultaneously reduce inflammation and fight off the virus by selectively inhibiting two additional enzymes and two other receptors.

“The rationale to me is very strong for using pacritinib,” Dr. Mascarenhas said. “I think this approach was bold but appropriate.”

The main safety concern with pacritinib could be bleeding, especially among patients on anticoagulants, Dr. Mascarenhas said. Because some patients with severe COVID-19 tend to develop blood clots, anticoagulation has become the standard of care at many institutions.

Because the trial is just beginning – only a minority of the total planned population of 358 patients has been enrolled – no interim results are available.
 

Right drug, wrong time?

IL-6 inhibition could still have a role to play in COVID-19, but the trick could be in the timing. Most of the trials so far have studied tocilizumab in patients with severe COVID-19, many of whom were already on ventilators. At that point, it may be too late to reverse the damage that has already taken place.

One of the main reasons tocilizumab works so well in CRS after CAR T therapy is that oncologists have learned how to use it early, often within 24 hours of fever onset. Oncologists use the American Society for Transplantation and Cellular Therapy consensus grading system, which helps them identify CRS when it is easier to control.

But applying the ASTCT grading system to COVID-19 is problematic. “Almost by definition, patients hospitalized with COVID-19 have low oxygen levels, which throws off the scale,” said Joshua Hill, MD, an infectious disease specialist at Fred Hutchinson Cancer Research Center in Seattle, who has research expertise in infectious complications after CAR T therapy.

“The key is to intervene earlier to prevent damage to the lungs and other end organs. We don’t have anything magical that will reverse that damage,” Dr. Hill said.

Results from the phase 3 trial EMPACTA trial (sponsored by Genentech) seem to bear this out. EMPACTA is evaluating use of tocilizumab in hospitalized patients with less severe COVID-19 who do not yet require mechanical ventilation. The trial is notable for being the first global phase 3 trial to demonstrate efficacy for tocilizumab vs placebo in hospitalized patients with COVID-19 pneumonia, and for including a high percentage of racial/ethnic minorities (85% of 389 participants), who have been hard hit by the pandemic and have historically been underrepresented in drug trials.

Last month, Roche announced that EMPACTA met its primary endpoint. Results showed that patients hospitalized with COVID-19 pneumonia who received tocilizumab plus standard of care were 44% less likely to go on mechanical ventilation or die, compared with those who received placebo plus standard of care (P = .0348), although there were no statistically significant differences in death by day 28 between tocilizumab and placebo (10.4% vs. 8.6%, P = .5146).

However, earlier administration of tocilizumab raises another issue. IL-6 and its pathway are important for clearing viral infections. Using tocilizumab in the context of an ongoing infection could raise safety issues.

Also, tocilizumab sticks around in the body for a relatively long time. In the treatment of rheumatoid arthritis, it is dosed once a month, and it carries a black box warning for reactivation of tuberculosis.

Whereas results from EMPACTA showed similar rates of infection associated with tocilizumab and placebo (10% vs. 11%), at least one other study has found increased rates of superinfection in patients with severe COVID-19 who received tocilizumab. Overall, though, the drug was associated with decreased risk of death in the latter study.

A phase 2 trial called COVIDOSE is tackling the safety issue. COVIDOSE is evaluating whether low-dose tocilizumab is effective in noncritical COVID-19 patients, with the idea that lower doses could be safer. Early results published as a preprint before peer review indicated that low-dose tocilizumab (ranging from 40 mg to 200 mg) was associated with clinical improvement in 32 noncritical patients hospitalized with COVID-19.

Five patients (15.6%) developed bacterial superinfections, and five (15.6%) died by 28-day follow-up, although there wasn’t a perfect “overlap” between these groups of patients. Bacterial superinfection was not the cause of death in all five patients who died, and not all patients who died developed bacterial superinfections, according to senior author Pankti Reid, MD, MPH, an assistant professor of medicine at the University of Chicago.

Results from COVIDOSE also showed that treatment with tocilizumab did not seem to affect the ability of patients to develop antibodies against COVID-19. The results set the stage for a larger randomized, controlled trial (still ongoing) to determine the optimal dose of tocilizumab.

Still, Dr. Hill urges caution.

Many of these immunomodulators have been used only in the context of a clinical trial, or only for patients with terminal cancer and no other treatment options. In patients with cancer, these drugs have been studied and have shown an “acceptable safety profile,” according to Dr. Shah.

But this is a different situation, and when it comes to repurposing them to relatively healthy patients with COVID-19, Dr. Hill emphasized the need for careful research.

“We’re always very concerned about giving drugs that suppress the immune response if people have active infections,” Dr. Hill said. “Often times we think it makes things worse, and it typically does.”

Dr. Mascarenhas reported institutional research funding from CTI Biopharma. Dr. Hill, Dr. Staudt, Dr. Wilson, and Dr. Shah disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

National guidelines failed to classify many younger African American lung cancer patients as being eligible for lung cancer screening in a recent retrospective study, the lead author reported at the annual meeting of the American College of Chest Physicians.

The finding highlights a health disparity issue that may be addressed through an update of those guidelines that is in the works, said Carol Velez Martinez, MD, a third-year internal medicine resident at Louisiana State University Health Sciences Center in Shreveport, La.

About one-third of the lung cancer patients in the retrospective cohort study were diagnosed before the age of 55 years, which means they would not have been recommended for screening with low-dose computed tomography (LDCT) based on the 2013 lung cancer guidelines from the United States Preventive Services Task Force (USPSTF), said Dr. Velez Martinez.

By contrast, 12.5% of screening-ineligible patients would have been counted as LDCT eligible based on guidelines from the National Comprehensive Cancer Network (NCCN), Dr. Velez Martinez and coauthors found in their analysis.

In a draft recommendation statement posted July 7, the USPSTF said they would now recommend that screening at age 50 years, rather than 55, and that the pack-years of smoking history that would make an individual eligible for screening would be dropped from 30 pack-years to 20, changes that task force members said would be more inclusive of African Americans and women.

Dr. Velez Martinez said she is looking forward to a formal recommendation from USPSTF soon: “I’m hoping that’s where they’re heading,” she said in an interview. “When I’m in practice as a resident, I actually bring it up to my patients, and if I have to call the insurance I don’t have a problem – but I still have to call them because they’re still going by the prior guidelines.”

“I think there are going to be a lot of other health disparities,” Dr. Revelo said in an interview. “[Dr. Velez Martinez’s] study was limited by the fact that she cared mostly for Caucasians and also African Americans, but maybe no Latinos or Hispanics that I’m sure would also be affected if we were looking to that in a bigger or national study.”

The 2013 USPSTF guidelines were based on benefits observed in the National Lung Screening Trial (NLST), which indicated a 20% relative risk reduction in death from lung cancer; however, the generalizability of the study beyond White males has been questioned, said Dr. Velez Martinez in a presentation at the CHEST annual meeting.

About 90% of NSLT participants were White and 59% were male, according to results published in 2011.

Other studies have shown that African Americans are more likely to get lung cancer than Whites, despite comparable smoking rates between the races, and that African American men are more likely to die from lung cancer than White men, Dr. Velez Martinez said. Many African Americans live below the poverty line, which means they have limited resources for insurance and health providers, and they also participate less often in clinical trials, she added.

In their retrospective observational cohort study, Dr. Velez Martinez and coinvestigators reviewed 1,500 medical records of patients with newly diagnosed stage 1-4 lung cancers from the LSU Health Science Center Shreveport between 2011 and 2015.

They found that 33% of those lung cancer patients were diagnosed before the age of 55 years, meaning they did not meet the 2013 USPSTF screening guidelines, which recommend annual LDCT in adults aged 55-80 years with a 30 pack-year smoking history who currently smoke or have quit within the past 15 years.

Next, they sought to classify those screening-ineligible patients based on NCCN guidelines, which recommend LDCT in patients 50 years of age or older with at least a 20 pack-year smoking history and a 6-year risk of lung cancer of at least 1.3% based on the Tammemagi lung cancer risk calculator. The Tammemagi calculator considers factors such as age, education, body mass index, prior lung disease, familial cancer history, race and ethnicity, and smoking history.

After applying the risk stratification, the investigators found that 12.5% of these patients would have been categorized as high risk and therefore recommended for LDCT, and of that group, more than 65% were African American, Dr. Velez Martinez reported.

Dr. Revelo, who chaired the CHEST session where the findings were reported, said that shared decision-making will still be as important regardless of any changes to lung screening guidelines given the recognized potential harms of LDCT screening, such as false positives, radiation exposure, and psychological distress.

“I think we will continue to have a very personal conversation and make important decisions focused on what the patient wants,” he said.

Authors reported no disclosures.

National guidelines failed to classify many younger African American lung cancer patients as being eligible for lung cancer screening in a recent retrospective study, the lead author reported at the annual meeting of the American College of Chest Physicians.

The finding highlights a health disparity issue that may be addressed through an update of those guidelines that is in the works, said Carol Velez Martinez, MD, a third-year internal medicine resident at Louisiana State University Health Sciences Center in Shreveport, La.

About one-third of the lung cancer patients in the retrospective cohort study were diagnosed before the age of 55 years, which means they would not have been recommended for screening with low-dose computed tomography (LDCT) based on the 2013 lung cancer guidelines from the United States Preventive Services Task Force (USPSTF), said Dr. Velez Martinez.

By contrast, 12.5% of screening-ineligible patients would have been counted as LDCT eligible based on guidelines from the National Comprehensive Cancer Network (NCCN), Dr. Velez Martinez and coauthors found in their analysis.

In a draft recommendation statement posted July 7, the USPSTF said they would now recommend that screening at age 50 years, rather than 55, and that the pack-years of smoking history that would make an individual eligible for screening would be dropped from 30 pack-years to 20, changes that task force members said would be more inclusive of African Americans and women.

Dr. Velez Martinez said she is looking forward to a formal recommendation from USPSTF soon: “I’m hoping that’s where they’re heading,” she said in an interview. “When I’m in practice as a resident, I actually bring it up to my patients, and if I have to call the insurance I don’t have a problem – but I still have to call them because they’re still going by the prior guidelines.”

“I think there are going to be a lot of other health disparities,” Dr. Revelo said in an interview. “[Dr. Velez Martinez’s] study was limited by the fact that she cared mostly for Caucasians and also African Americans, but maybe no Latinos or Hispanics that I’m sure would also be affected if we were looking to that in a bigger or national study.”

The 2013 USPSTF guidelines were based on benefits observed in the National Lung Screening Trial (NLST), which indicated a 20% relative risk reduction in death from lung cancer; however, the generalizability of the study beyond White males has been questioned, said Dr. Velez Martinez in a presentation at the CHEST annual meeting.

About 90% of NSLT participants were White and 59% were male, according to results published in 2011.

Other studies have shown that African Americans are more likely to get lung cancer than Whites, despite comparable smoking rates between the races, and that African American men are more likely to die from lung cancer than White men, Dr. Velez Martinez said. Many African Americans live below the poverty line, which means they have limited resources for insurance and health providers, and they also participate less often in clinical trials, she added.

In their retrospective observational cohort study, Dr. Velez Martinez and coinvestigators reviewed 1,500 medical records of patients with newly diagnosed stage 1-4 lung cancers from the LSU Health Science Center Shreveport between 2011 and 2015.

They found that 33% of those lung cancer patients were diagnosed before the age of 55 years, meaning they did not meet the 2013 USPSTF screening guidelines, which recommend annual LDCT in adults aged 55-80 years with a 30 pack-year smoking history who currently smoke or have quit within the past 15 years.

Next, they sought to classify those screening-ineligible patients based on NCCN guidelines, which recommend LDCT in patients 50 years of age or older with at least a 20 pack-year smoking history and a 6-year risk of lung cancer of at least 1.3% based on the Tammemagi lung cancer risk calculator. The Tammemagi calculator considers factors such as age, education, body mass index, prior lung disease, familial cancer history, race and ethnicity, and smoking history.

After applying the risk stratification, the investigators found that 12.5% of these patients would have been categorized as high risk and therefore recommended for LDCT, and of that group, more than 65% were African American, Dr. Velez Martinez reported.

Dr. Revelo, who chaired the CHEST session where the findings were reported, said that shared decision-making will still be as important regardless of any changes to lung screening guidelines given the recognized potential harms of LDCT screening, such as false positives, radiation exposure, and psychological distress.

“I think we will continue to have a very personal conversation and make important decisions focused on what the patient wants,” he said.

Authors reported no disclosures.

National guidelines failed to classify many younger African American lung cancer patients as being eligible for lung cancer screening in a recent retrospective study, the lead author reported at the annual meeting of the American College of Chest Physicians.

The finding highlights a health disparity issue that may be addressed through an update of those guidelines that is in the works, said Carol Velez Martinez, MD, a third-year internal medicine resident at Louisiana State University Health Sciences Center in Shreveport, La.

About one-third of the lung cancer patients in the retrospective cohort study were diagnosed before the age of 55 years, which means they would not have been recommended for screening with low-dose computed tomography (LDCT) based on the 2013 lung cancer guidelines from the United States Preventive Services Task Force (USPSTF), said Dr. Velez Martinez.

By contrast, 12.5% of screening-ineligible patients would have been counted as LDCT eligible based on guidelines from the National Comprehensive Cancer Network (NCCN), Dr. Velez Martinez and coauthors found in their analysis.

In a draft recommendation statement posted July 7, the USPSTF said they would now recommend that screening at age 50 years, rather than 55, and that the pack-years of smoking history that would make an individual eligible for screening would be dropped from 30 pack-years to 20, changes that task force members said would be more inclusive of African Americans and women.

Dr. Velez Martinez said she is looking forward to a formal recommendation from USPSTF soon: “I’m hoping that’s where they’re heading,” she said in an interview. “When I’m in practice as a resident, I actually bring it up to my patients, and if I have to call the insurance I don’t have a problem – but I still have to call them because they’re still going by the prior guidelines.”

“I think there are going to be a lot of other health disparities,” Dr. Revelo said in an interview. “[Dr. Velez Martinez’s] study was limited by the fact that she cared mostly for Caucasians and also African Americans, but maybe no Latinos or Hispanics that I’m sure would also be affected if we were looking to that in a bigger or national study.”

The 2013 USPSTF guidelines were based on benefits observed in the National Lung Screening Trial (NLST), which indicated a 20% relative risk reduction in death from lung cancer; however, the generalizability of the study beyond White males has been questioned, said Dr. Velez Martinez in a presentation at the CHEST annual meeting.

About 90% of NSLT participants were White and 59% were male, according to results published in 2011.

Other studies have shown that African Americans are more likely to get lung cancer than Whites, despite comparable smoking rates between the races, and that African American men are more likely to die from lung cancer than White men, Dr. Velez Martinez said. Many African Americans live below the poverty line, which means they have limited resources for insurance and health providers, and they also participate less often in clinical trials, she added.

In their retrospective observational cohort study, Dr. Velez Martinez and coinvestigators reviewed 1,500 medical records of patients with newly diagnosed stage 1-4 lung cancers from the LSU Health Science Center Shreveport between 2011 and 2015.

They found that 33% of those lung cancer patients were diagnosed before the age of 55 years, meaning they did not meet the 2013 USPSTF screening guidelines, which recommend annual LDCT in adults aged 55-80 years with a 30 pack-year smoking history who currently smoke or have quit within the past 15 years.

Next, they sought to classify those screening-ineligible patients based on NCCN guidelines, which recommend LDCT in patients 50 years of age or older with at least a 20 pack-year smoking history and a 6-year risk of lung cancer of at least 1.3% based on the Tammemagi lung cancer risk calculator. The Tammemagi calculator considers factors such as age, education, body mass index, prior lung disease, familial cancer history, race and ethnicity, and smoking history.

After applying the risk stratification, the investigators found that 12.5% of these patients would have been categorized as high risk and therefore recommended for LDCT, and of that group, more than 65% were African American, Dr. Velez Martinez reported.

Dr. Revelo, who chaired the CHEST session where the findings were reported, said that shared decision-making will still be as important regardless of any changes to lung screening guidelines given the recognized potential harms of LDCT screening, such as false positives, radiation exposure, and psychological distress.

“I think we will continue to have a very personal conversation and make important decisions focused on what the patient wants,” he said.

Authors reported no disclosures.

Over half of surgeons who reported treating melanoma with Mohs micrographic surgery (MMS) are using the technique to treat invasive melanoma, according to a national cross-sectional survey of members of the American College of Mohs Surgery.

Of 513 survey participants, 40.9% reported using MMS to treat any subtype of melanoma. Most of these surgeons reported treating both lentigo maligna (97.5%) and other melanoma in situ (MIS) subtypes (91.4%). A slight majority – 58.6% – reported treating invasive T1 melanoma, and 20.5% reported treating invasive T2 and/or higher-stage melanoma with MMS.

The analysis, published in Dermatologic Surgery, was done by Spyros M. Siscos, MD, and a team of residents and faculty in the division of dermatology at the University of Kansas Medical Center, Kansas City.

It comes on the heels of an analysis of claims data for Mohs surgery, published last year in JAMA Dermatology, which showed a more than threefold increase in the use of Mohs surgery for melanoma from 2.6% of all surgical cases in 2001 to 7.9% in 2016.

With the increased use of MMS for treatment of melanoma, “Mohs surgeons who previously treated MIS with MMS may be increasingly doing so and/or expanding their scope of treatment to include invasive melanoma,” the University of Kansas investigators wrote.

That a slight majority now report treating invasive melanoma with MMS “may be due, in part, to upstaging during the MMS procedure and the increasing evidence demonstrating improved survival of early-invasive melanoma treated with MMS compared with [wide local excision],” as well as the advent of melanocytic immunohistochemical (IHC) stains, particularly melanoma antigen recognized by T-cells 1 (MART-1), they said. However, 29% of surveyed Mohs surgeons treating melanoma with MMS do not use IHC stains “despite growing evidence supporting” their use, the authors wrote.

The advent of IHC stains, particularly MART-1, has improved the accuracy of interpreting frozen sections of melanoma, they reported, noting that MMS without IHC has been associated with a recurrence rate as high as 33%. Of the 71% who reported using IHC stains, MART-1 was the primary IHC stain for virtually all of them (97.3%).

There was also variation in the number of surgeons who reported debulking MIS. Eighty-two percent take this approach, excising the clinically visible tumor before excising the initial Mohs stage – almost all with a scalpel. More than half of these surgeons – 58.5% – submit the entire debulked MIS specimen for permanent vertical sectioning (breadloafing) to evaluate for deeper tumor invasion.

The others reported submitting the entire debulked specimen for frozen vertical sectioning, or portions of the specimen for both permanent and frozen vertical sectioning. “It is unclear why a minority of surveyed Mohs surgeons reported not debulking MIS,” wrote Dr. Siscos and his colleagues.

The average margin size of the first Mohs stage for MIS was 4.96 ± 1.74 mm, which is at the lower end of the 0.5-1.0 cm range for wide local excision (WLE) recommended by the National Comprehensive Cancer Network (NCCN) and the American Academy of Dermatology (AAD), according to a clinical practice guideline. (The survey did not investigate initial margins for invasive melanoma treated with MMS.)

Jeremy R. Etzhorn, MD, of the department of dermatology at the University of Pennsylvania, Philadelphia, and an author of a 2019 claims data analysis of excisional surgery practices for melanoma, said that the new survey findings – like the prior analysis – highlight the variability in approaches to using MMS for melanoma.

“Mohs for melanoma [seems] like a one-liner ... but really, there are [a lot] of different techniques that fall under that umbrella, if you parse out all the variations,” he said in an interview.

Per the 2016 claims analysis, he noted, IHC was used in less than 40% of Mohs surgery cases for melanoma, and there were wide geographic variations. “The biggest critique of Mohs surgery for melanoma over the last two decades has been that it’s hard to see the tumor,” he said. “But with the advent of IHC, that challenge was overcome.”

Surgical excision practices are evolving without the development of best practice guidelines, said Dr. Etzkorn, who is director of clinical research for the University of Pennsylvania dermatologic oncology center. Multisociety guidelines published in 2012 on appropriate use criteria for Mohs surgery do not offer specific recommendations on the use of MMS for invasive melanoma. Nor do guidelines from the AAD and the NCCN, he said.

“What this [new] study highlights and what’s being discussed amongst Moh’s surgeons” is that Mohs for melanoma “has be to be standardized” to some extent and then clinical trials conducted comparing Mohs to conventional excision. The studies that have been published in recent years comparing MMS with WLE for MIS and invasive melanoma are “not gold standard studies,” he said.

Practice guidelines then can be informed by high-quality evidence on its safety and efficacy, he said.

The 513 participants in the newly published survey represent a 31.5% response rate. Invasive T2 and/or higher stage melanoma was more likely to be treated with MMS in academic hospitals, compared with other practice settings (30.2% v. 18.1%), Dr. Siscos and his coauthors reported.

Participants who reported treating melanoma with MMS were more likely to report fellowship exposure and more likely to have received fellowship training on melanocytic IHC stains. The study “highlights the importance of fellowship exposure to MMS and IHC staining for melanoma,” the authors wrote, adding that postfellowship training opportunities in MMS and IHC staining for melanoma may help broaden its use among Mohs surgeons who received inadequate fellowship exposure.

Dr. Siscos and his colleagues reported no significant interest with commercial supporters. Dr. Etzkorn had no disclosures.

SOURCE: Siscos S et al. Dermatol Surg. 2020 Oct;46(10):1267-71.
 

Over half of surgeons who reported treating melanoma with Mohs micrographic surgery (MMS) are using the technique to treat invasive melanoma, according to a national cross-sectional survey of members of the American College of Mohs Surgery.

Of 513 survey participants, 40.9% reported using MMS to treat any subtype of melanoma. Most of these surgeons reported treating both lentigo maligna (97.5%) and other melanoma in situ (MIS) subtypes (91.4%). A slight majority – 58.6% – reported treating invasive T1 melanoma, and 20.5% reported treating invasive T2 and/or higher-stage melanoma with MMS.

The analysis, published in Dermatologic Surgery, was done by Spyros M. Siscos, MD, and a team of residents and faculty in the division of dermatology at the University of Kansas Medical Center, Kansas City.

It comes on the heels of an analysis of claims data for Mohs surgery, published last year in JAMA Dermatology, which showed a more than threefold increase in the use of Mohs surgery for melanoma from 2.6% of all surgical cases in 2001 to 7.9% in 2016.

With the increased use of MMS for treatment of melanoma, “Mohs surgeons who previously treated MIS with MMS may be increasingly doing so and/or expanding their scope of treatment to include invasive melanoma,” the University of Kansas investigators wrote.

That a slight majority now report treating invasive melanoma with MMS “may be due, in part, to upstaging during the MMS procedure and the increasing evidence demonstrating improved survival of early-invasive melanoma treated with MMS compared with [wide local excision],” as well as the advent of melanocytic immunohistochemical (IHC) stains, particularly melanoma antigen recognized by T-cells 1 (MART-1), they said. However, 29% of surveyed Mohs surgeons treating melanoma with MMS do not use IHC stains “despite growing evidence supporting” their use, the authors wrote.

The advent of IHC stains, particularly MART-1, has improved the accuracy of interpreting frozen sections of melanoma, they reported, noting that MMS without IHC has been associated with a recurrence rate as high as 33%. Of the 71% who reported using IHC stains, MART-1 was the primary IHC stain for virtually all of them (97.3%).

There was also variation in the number of surgeons who reported debulking MIS. Eighty-two percent take this approach, excising the clinically visible tumor before excising the initial Mohs stage – almost all with a scalpel. More than half of these surgeons – 58.5% – submit the entire debulked MIS specimen for permanent vertical sectioning (breadloafing) to evaluate for deeper tumor invasion.

The others reported submitting the entire debulked specimen for frozen vertical sectioning, or portions of the specimen for both permanent and frozen vertical sectioning. “It is unclear why a minority of surveyed Mohs surgeons reported not debulking MIS,” wrote Dr. Siscos and his colleagues.

The average margin size of the first Mohs stage for MIS was 4.96 ± 1.74 mm, which is at the lower end of the 0.5-1.0 cm range for wide local excision (WLE) recommended by the National Comprehensive Cancer Network (NCCN) and the American Academy of Dermatology (AAD), according to a clinical practice guideline. (The survey did not investigate initial margins for invasive melanoma treated with MMS.)

Jeremy R. Etzhorn, MD, of the department of dermatology at the University of Pennsylvania, Philadelphia, and an author of a 2019 claims data analysis of excisional surgery practices for melanoma, said that the new survey findings – like the prior analysis – highlight the variability in approaches to using MMS for melanoma.

“Mohs for melanoma [seems] like a one-liner ... but really, there are [a lot] of different techniques that fall under that umbrella, if you parse out all the variations,” he said in an interview.

Per the 2016 claims analysis, he noted, IHC was used in less than 40% of Mohs surgery cases for melanoma, and there were wide geographic variations. “The biggest critique of Mohs surgery for melanoma over the last two decades has been that it’s hard to see the tumor,” he said. “But with the advent of IHC, that challenge was overcome.”

Surgical excision practices are evolving without the development of best practice guidelines, said Dr. Etzkorn, who is director of clinical research for the University of Pennsylvania dermatologic oncology center. Multisociety guidelines published in 2012 on appropriate use criteria for Mohs surgery do not offer specific recommendations on the use of MMS for invasive melanoma. Nor do guidelines from the AAD and the NCCN, he said.

“What this [new] study highlights and what’s being discussed amongst Moh’s surgeons” is that Mohs for melanoma “has be to be standardized” to some extent and then clinical trials conducted comparing Mohs to conventional excision. The studies that have been published in recent years comparing MMS with WLE for MIS and invasive melanoma are “not gold standard studies,” he said.

Practice guidelines then can be informed by high-quality evidence on its safety and efficacy, he said.

The 513 participants in the newly published survey represent a 31.5% response rate. Invasive T2 and/or higher stage melanoma was more likely to be treated with MMS in academic hospitals, compared with other practice settings (30.2% v. 18.1%), Dr. Siscos and his coauthors reported.

Participants who reported treating melanoma with MMS were more likely to report fellowship exposure and more likely to have received fellowship training on melanocytic IHC stains. The study “highlights the importance of fellowship exposure to MMS and IHC staining for melanoma,” the authors wrote, adding that postfellowship training opportunities in MMS and IHC staining for melanoma may help broaden its use among Mohs surgeons who received inadequate fellowship exposure.

Dr. Siscos and his colleagues reported no significant interest with commercial supporters. Dr. Etzkorn had no disclosures.

SOURCE: Siscos S et al. Dermatol Surg. 2020 Oct;46(10):1267-71.
 

Over half of surgeons who reported treating melanoma with Mohs micrographic surgery (MMS) are using the technique to treat invasive melanoma, according to a national cross-sectional survey of members of the American College of Mohs Surgery.

Of 513 survey participants, 40.9% reported using MMS to treat any subtype of melanoma. Most of these surgeons reported treating both lentigo maligna (97.5%) and other melanoma in situ (MIS) subtypes (91.4%). A slight majority – 58.6% – reported treating invasive T1 melanoma, and 20.5% reported treating invasive T2 and/or higher-stage melanoma with MMS.

The analysis, published in Dermatologic Surgery, was done by Spyros M. Siscos, MD, and a team of residents and faculty in the division of dermatology at the University of Kansas Medical Center, Kansas City.

It comes on the heels of an analysis of claims data for Mohs surgery, published last year in JAMA Dermatology, which showed a more than threefold increase in the use of Mohs surgery for melanoma from 2.6% of all surgical cases in 2001 to 7.9% in 2016.

With the increased use of MMS for treatment of melanoma, “Mohs surgeons who previously treated MIS with MMS may be increasingly doing so and/or expanding their scope of treatment to include invasive melanoma,” the University of Kansas investigators wrote.

That a slight majority now report treating invasive melanoma with MMS “may be due, in part, to upstaging during the MMS procedure and the increasing evidence demonstrating improved survival of early-invasive melanoma treated with MMS compared with [wide local excision],” as well as the advent of melanocytic immunohistochemical (IHC) stains, particularly melanoma antigen recognized by T-cells 1 (MART-1), they said. However, 29% of surveyed Mohs surgeons treating melanoma with MMS do not use IHC stains “despite growing evidence supporting” their use, the authors wrote.

The advent of IHC stains, particularly MART-1, has improved the accuracy of interpreting frozen sections of melanoma, they reported, noting that MMS without IHC has been associated with a recurrence rate as high as 33%. Of the 71% who reported using IHC stains, MART-1 was the primary IHC stain for virtually all of them (97.3%).

There was also variation in the number of surgeons who reported debulking MIS. Eighty-two percent take this approach, excising the clinically visible tumor before excising the initial Mohs stage – almost all with a scalpel. More than half of these surgeons – 58.5% – submit the entire debulked MIS specimen for permanent vertical sectioning (breadloafing) to evaluate for deeper tumor invasion.

The others reported submitting the entire debulked specimen for frozen vertical sectioning, or portions of the specimen for both permanent and frozen vertical sectioning. “It is unclear why a minority of surveyed Mohs surgeons reported not debulking MIS,” wrote Dr. Siscos and his colleagues.

The average margin size of the first Mohs stage for MIS was 4.96 ± 1.74 mm, which is at the lower end of the 0.5-1.0 cm range for wide local excision (WLE) recommended by the National Comprehensive Cancer Network (NCCN) and the American Academy of Dermatology (AAD), according to a clinical practice guideline. (The survey did not investigate initial margins for invasive melanoma treated with MMS.)

Jeremy R. Etzhorn, MD, of the department of dermatology at the University of Pennsylvania, Philadelphia, and an author of a 2019 claims data analysis of excisional surgery practices for melanoma, said that the new survey findings – like the prior analysis – highlight the variability in approaches to using MMS for melanoma.

“Mohs for melanoma [seems] like a one-liner ... but really, there are [a lot] of different techniques that fall under that umbrella, if you parse out all the variations,” he said in an interview.

Per the 2016 claims analysis, he noted, IHC was used in less than 40% of Mohs surgery cases for melanoma, and there were wide geographic variations. “The biggest critique of Mohs surgery for melanoma over the last two decades has been that it’s hard to see the tumor,” he said. “But with the advent of IHC, that challenge was overcome.”

Surgical excision practices are evolving without the development of best practice guidelines, said Dr. Etzkorn, who is director of clinical research for the University of Pennsylvania dermatologic oncology center. Multisociety guidelines published in 2012 on appropriate use criteria for Mohs surgery do not offer specific recommendations on the use of MMS for invasive melanoma. Nor do guidelines from the AAD and the NCCN, he said.

“What this [new] study highlights and what’s being discussed amongst Moh’s surgeons” is that Mohs for melanoma “has be to be standardized” to some extent and then clinical trials conducted comparing Mohs to conventional excision. The studies that have been published in recent years comparing MMS with WLE for MIS and invasive melanoma are “not gold standard studies,” he said.

Practice guidelines then can be informed by high-quality evidence on its safety and efficacy, he said.

The 513 participants in the newly published survey represent a 31.5% response rate. Invasive T2 and/or higher stage melanoma was more likely to be treated with MMS in academic hospitals, compared with other practice settings (30.2% v. 18.1%), Dr. Siscos and his coauthors reported.

Participants who reported treating melanoma with MMS were more likely to report fellowship exposure and more likely to have received fellowship training on melanocytic IHC stains. The study “highlights the importance of fellowship exposure to MMS and IHC staining for melanoma,” the authors wrote, adding that postfellowship training opportunities in MMS and IHC staining for melanoma may help broaden its use among Mohs surgeons who received inadequate fellowship exposure.

Dr. Siscos and his colleagues reported no significant interest with commercial supporters. Dr. Etzkorn had no disclosures.

SOURCE: Siscos S et al. Dermatol Surg. 2020 Oct;46(10):1267-71.
 

Delays in colorectal cancer screening due to the COVID-19 pandemic could lead to higher rates of advanced-stage cancer and death, according to a new study.

When compared with a delay of less than three months, the longer delay seen this year may result in an 11.9% increase in death rates.

“Across the globe, health care systems are facing serious difficulties while dealing with COVID-19, and it is imperative that support is given to the public and patients throughout the crisis, including for high-impact diseases such as colorectal cancer,” Luigi Ricciardiello, the lead study author and a professor at the University of Bologna in Italy, said in a statement.

Ricciardiello and colleagues presented their research on Monday at UEG Week Virtual 2020, an international conference for gastroenterologists. The study will be published in the UEG Journal .

The researchers created a model to forecast the effects of delayed cancer screening during 2020. A “moderate” delay of 7-12 months caused a 3% increase in advanced-stage colon cancer, and a long delay of more than 12 months caused a 7% increase in advanced cancer.

Based on a survival rate of 5 years for stage 3 or stage 4 colorectal cancer, the death rate would increase nearly 12% when screening is delayed for more than a year, as compared with less than three months of delay.

The research team found similar results when forecasting advanced-stage cancer and deaths earlier this year. In a paper published in Clinical Gastroenterology and Hepatology in early September, they projected that deaths could increase 12% if screening is delayed for more than a year.

Throughout the pandemic, screening programs have been delayed in many countries, particularly across Europe.

“Healthcare authorities need to act urgently on how they reorganise activities during COVID-19, without compromising the diagnosis of other high-impact diseases like this research shows,” Ricciardiello said.

United European Gastroenterology, a professional medical organization for digestive health specialists, has called for policymakers to implement colon cancer screening programs across the European Union. Annually, more than 375,000 new cases are diagnosed across the EU, and more than 170,000 people die from colorectal cancer, according to a UEG report.

“Early-stage diagnosis of colorectal cancer is crucial — it’s far easier to treat and enhances optimal patient outcomes,” Ricciardiello said. “It is therefore essential that vital diagnosis tools, like screening programmes, continue and help to prevent mortality rates from rising even further.”
 

This article first appeared on Medscape.com.

Delays in colorectal cancer screening due to the COVID-19 pandemic could lead to higher rates of advanced-stage cancer and death, according to a new study.

When compared with a delay of less than three months, the longer delay seen this year may result in an 11.9% increase in death rates.

“Across the globe, health care systems are facing serious difficulties while dealing with COVID-19, and it is imperative that support is given to the public and patients throughout the crisis, including for high-impact diseases such as colorectal cancer,” Luigi Ricciardiello, the lead study author and a professor at the University of Bologna in Italy, said in a statement.

Ricciardiello and colleagues presented their research on Monday at UEG Week Virtual 2020, an international conference for gastroenterologists. The study will be published in the UEG Journal .

The researchers created a model to forecast the effects of delayed cancer screening during 2020. A “moderate” delay of 7-12 months caused a 3% increase in advanced-stage colon cancer, and a long delay of more than 12 months caused a 7% increase in advanced cancer.

Based on a survival rate of 5 years for stage 3 or stage 4 colorectal cancer, the death rate would increase nearly 12% when screening is delayed for more than a year, as compared with less than three months of delay.

The research team found similar results when forecasting advanced-stage cancer and deaths earlier this year. In a paper published in Clinical Gastroenterology and Hepatology in early September, they projected that deaths could increase 12% if screening is delayed for more than a year.

Throughout the pandemic, screening programs have been delayed in many countries, particularly across Europe.

“Healthcare authorities need to act urgently on how they reorganise activities during COVID-19, without compromising the diagnosis of other high-impact diseases like this research shows,” Ricciardiello said.

United European Gastroenterology, a professional medical organization for digestive health specialists, has called for policymakers to implement colon cancer screening programs across the European Union. Annually, more than 375,000 new cases are diagnosed across the EU, and more than 170,000 people die from colorectal cancer, according to a UEG report.

“Early-stage diagnosis of colorectal cancer is crucial — it’s far easier to treat and enhances optimal patient outcomes,” Ricciardiello said. “It is therefore essential that vital diagnosis tools, like screening programmes, continue and help to prevent mortality rates from rising even further.”
 

This article first appeared on Medscape.com.

Delays in colorectal cancer screening due to the COVID-19 pandemic could lead to higher rates of advanced-stage cancer and death, according to a new study.

When compared with a delay of less than three months, the longer delay seen this year may result in an 11.9% increase in death rates.

“Across the globe, health care systems are facing serious difficulties while dealing with COVID-19, and it is imperative that support is given to the public and patients throughout the crisis, including for high-impact diseases such as colorectal cancer,” Luigi Ricciardiello, the lead study author and a professor at the University of Bologna in Italy, said in a statement.

Ricciardiello and colleagues presented their research on Monday at UEG Week Virtual 2020, an international conference for gastroenterologists. The study will be published in the UEG Journal .

The researchers created a model to forecast the effects of delayed cancer screening during 2020. A “moderate” delay of 7-12 months caused a 3% increase in advanced-stage colon cancer, and a long delay of more than 12 months caused a 7% increase in advanced cancer.

Based on a survival rate of 5 years for stage 3 or stage 4 colorectal cancer, the death rate would increase nearly 12% when screening is delayed for more than a year, as compared with less than three months of delay.

The research team found similar results when forecasting advanced-stage cancer and deaths earlier this year. In a paper published in Clinical Gastroenterology and Hepatology in early September, they projected that deaths could increase 12% if screening is delayed for more than a year.

Throughout the pandemic, screening programs have been delayed in many countries, particularly across Europe.

“Healthcare authorities need to act urgently on how they reorganise activities during COVID-19, without compromising the diagnosis of other high-impact diseases like this research shows,” Ricciardiello said.

United European Gastroenterology, a professional medical organization for digestive health specialists, has called for policymakers to implement colon cancer screening programs across the European Union. Annually, more than 375,000 new cases are diagnosed across the EU, and more than 170,000 people die from colorectal cancer, according to a UEG report.

“Early-stage diagnosis of colorectal cancer is crucial — it’s far easier to treat and enhances optimal patient outcomes,” Ricciardiello said. “It is therefore essential that vital diagnosis tools, like screening programmes, continue and help to prevent mortality rates from rising even further.”
 

This article first appeared on Medscape.com.

Intensive surveillance with carcinoembryonic antigen (CEA) testing and CT scans after colorectal cancer resection did not improve recurrence-free or overall survival when compared with standard abdominal ultrasound and chest x-ray monitoring in a phase 3 trial of almost 2,000 patients.

However, among patients with colon cancer recurrence, those randomized to intensive surveillance more often had a second surgery with curative intent. Even so, there was no overall survival benefit versus standard surveillance in this group.

In short, “none of the follow-up modalities resulted in a difference,” said investigator Come Lepage, MD, PhD, of Centre Hospitalier Universitaire de Dijon (France).

Dr. Lepage presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

Dr. Lepage said the study’s results suggest guidelines that include CT and CEA monitoring should be amended, and the standard surveillance methods should be ultrasound and chest x-ray. Dr. LePage called CEA surveillance “useless” and said CT scans should be performed only in cases of suspected recurrence.

However, study discussant Tim Price, MBBS, DHSc, of the University of Adelaide, noted that both the intensive and standard arms in this study had abdominal imaging every 3 months, be it ultrasound or CT, so even in the standard arms, surveillance “was still fairly aggressive.”

Because of that, the study does not “suggest we should decrease our intensity,” Dr. Price said.

He added that the study’s major finding was that more intensive surveillance led to higher rates of secondary surgery with curative intent, probably because recurrences were caught earlier than they would have been with standard surveillance, when curative surgery was still possible.

Patients in the study were treated during 2009-2015, and that might have also made a difference. “We need to remember that, in 2020, care is very different,” Dr. Price said. This includes increased surgical interventions and options for oligometastatic disease, plus systemic therapies such as pembrolizumab. With modern treatments, detecting recurrences earlier “may well have an impact on survival.”

Perhaps patients would live longer with “earlier diagnosis in today’s setting with more active agents and more aggressive surgery and radiotherapy [e.g., stereotactic ablative radiation therapy],” Dr. Price said in an interview.
 

Study details

The trial, dubbed PRODIGE 13, was done to bring clarity to the surveillance issue. Intensive follow-up after curative surgery for colorectal cancer, including CT and CEA monitoring, is recommended by various scientific societies, but it’s based mainly on expert opinion. Results of the few clinical trials on the issue have been controversial, Dr. Lepage explained.

PRODIGE 13 included 1,995 subjects with colorectal cancer. About half of patients had stage II disease, and the other half had stage III. Most patients were 75 years or younger at baseline, and there were more men in the study than women. All patients underwent resection with curative intent and had no evidence of residual disease 3 months after surgery. Some patients received adjuvant chemotherapy.

Patients were first randomized to no CEA monitoring or CEA monitoring every 3 months for the first 2 years, then every 6 months for an additional 3 years. Members in both groups were then randomized a second time to either intensive or standard radiologic surveillance.

Surveillance in the standard arm consisted of an abdominal ultrasound every 3 months for the first 3 years, then biannually for an additional 2 years, plus chest x-rays every 6 months for 5 years. Intensive surveillance consisted of CT imaging, including thoracic imaging, alternating with abdominal ultrasound, every 3 months, then biannually for another 2 years.

At baseline, the surveillance groups were well balanced with regard to demographics, primary tumor location, and other factors, but stage III disease was more prevalent among patients randomized to standard radiologic monitoring without CEA.
 

Results

The median follow up was 6.5 years. There were no significant differences between the surveillance groups with regard to 5-year overall survival (P = .340) or recurrence-free survival (P = .473).

There were no significant differences in recurrence-free or overall survival when patients were stratified by age, sex, stage, CEA at a cut point of 5 mcg/L, and primary tumor characteristics including location, perineural invasion, and occlusion/perforation.

There were 356 recurrences in patients initially treated for colon cancer. CEA surveillance with or without CT scan was associated with an increased incidence of secondary resection with curative intent. The rate of secondary resection was 66.3% in the standard imaging with CEA arm, 59.5% in the CT plus CEA arm, 50.7% with CT imaging but no CEA, and 40.9% with standard imaging and no CEA (P = .0035).

The rates were similar among the 83 patients with recurrence after initial treatment for rectal cancer, but the between-arm differences were not significant. The rate of secondary resection with curative intent was 57.9% in the standard imaging with CEA arm, 47.8% in the CT plus CEA arm, 55% with CT imaging but no CEA, and 42.9% with standard imaging and no CEA.

The research is ongoing, and the team expects to report on secondary outcomes and ancillary studies of circulating tumor DNA, among other things, in 2021.

The study is being funded by the Federation Francophone de Cancerologie Digestive. Dr. Lepage disclosed ties with Novartis, Amgen, Bayer, Servier, and AAA. Dr. Price disclosed institutional research funding from Amgen and being an uncompensated adviser to Pierre-Fabre and Merck.

[email protected]

SOURCE: Lepage C et al. ESMO 2020, Abstract 398O.

Intensive surveillance with carcinoembryonic antigen (CEA) testing and CT scans after colorectal cancer resection did not improve recurrence-free or overall survival when compared with standard abdominal ultrasound and chest x-ray monitoring in a phase 3 trial of almost 2,000 patients.

However, among patients with colon cancer recurrence, those randomized to intensive surveillance more often had a second surgery with curative intent. Even so, there was no overall survival benefit versus standard surveillance in this group.

In short, “none of the follow-up modalities resulted in a difference,” said investigator Come Lepage, MD, PhD, of Centre Hospitalier Universitaire de Dijon (France).

Dr. Lepage presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

Dr. Lepage said the study’s results suggest guidelines that include CT and CEA monitoring should be amended, and the standard surveillance methods should be ultrasound and chest x-ray. Dr. LePage called CEA surveillance “useless” and said CT scans should be performed only in cases of suspected recurrence.

However, study discussant Tim Price, MBBS, DHSc, of the University of Adelaide, noted that both the intensive and standard arms in this study had abdominal imaging every 3 months, be it ultrasound or CT, so even in the standard arms, surveillance “was still fairly aggressive.”

Because of that, the study does not “suggest we should decrease our intensity,” Dr. Price said.

He added that the study’s major finding was that more intensive surveillance led to higher rates of secondary surgery with curative intent, probably because recurrences were caught earlier than they would have been with standard surveillance, when curative surgery was still possible.

Patients in the study were treated during 2009-2015, and that might have also made a difference. “We need to remember that, in 2020, care is very different,” Dr. Price said. This includes increased surgical interventions and options for oligometastatic disease, plus systemic therapies such as pembrolizumab. With modern treatments, detecting recurrences earlier “may well have an impact on survival.”

Perhaps patients would live longer with “earlier diagnosis in today’s setting with more active agents and more aggressive surgery and radiotherapy [e.g., stereotactic ablative radiation therapy],” Dr. Price said in an interview.
 

Study details

The trial, dubbed PRODIGE 13, was done to bring clarity to the surveillance issue. Intensive follow-up after curative surgery for colorectal cancer, including CT and CEA monitoring, is recommended by various scientific societies, but it’s based mainly on expert opinion. Results of the few clinical trials on the issue have been controversial, Dr. Lepage explained.

PRODIGE 13 included 1,995 subjects with colorectal cancer. About half of patients had stage II disease, and the other half had stage III. Most patients were 75 years or younger at baseline, and there were more men in the study than women. All patients underwent resection with curative intent and had no evidence of residual disease 3 months after surgery. Some patients received adjuvant chemotherapy.

Patients were first randomized to no CEA monitoring or CEA monitoring every 3 months for the first 2 years, then every 6 months for an additional 3 years. Members in both groups were then randomized a second time to either intensive or standard radiologic surveillance.

Surveillance in the standard arm consisted of an abdominal ultrasound every 3 months for the first 3 years, then biannually for an additional 2 years, plus chest x-rays every 6 months for 5 years. Intensive surveillance consisted of CT imaging, including thoracic imaging, alternating with abdominal ultrasound, every 3 months, then biannually for another 2 years.

At baseline, the surveillance groups were well balanced with regard to demographics, primary tumor location, and other factors, but stage III disease was more prevalent among patients randomized to standard radiologic monitoring without CEA.
 

Results

The median follow up was 6.5 years. There were no significant differences between the surveillance groups with regard to 5-year overall survival (P = .340) or recurrence-free survival (P = .473).

There were no significant differences in recurrence-free or overall survival when patients were stratified by age, sex, stage, CEA at a cut point of 5 mcg/L, and primary tumor characteristics including location, perineural invasion, and occlusion/perforation.

There were 356 recurrences in patients initially treated for colon cancer. CEA surveillance with or without CT scan was associated with an increased incidence of secondary resection with curative intent. The rate of secondary resection was 66.3% in the standard imaging with CEA arm, 59.5% in the CT plus CEA arm, 50.7% with CT imaging but no CEA, and 40.9% with standard imaging and no CEA (P = .0035).

The rates were similar among the 83 patients with recurrence after initial treatment for rectal cancer, but the between-arm differences were not significant. The rate of secondary resection with curative intent was 57.9% in the standard imaging with CEA arm, 47.8% in the CT plus CEA arm, 55% with CT imaging but no CEA, and 42.9% with standard imaging and no CEA.

The research is ongoing, and the team expects to report on secondary outcomes and ancillary studies of circulating tumor DNA, among other things, in 2021.

The study is being funded by the Federation Francophone de Cancerologie Digestive. Dr. Lepage disclosed ties with Novartis, Amgen, Bayer, Servier, and AAA. Dr. Price disclosed institutional research funding from Amgen and being an uncompensated adviser to Pierre-Fabre and Merck.

[email protected]

SOURCE: Lepage C et al. ESMO 2020, Abstract 398O.

Intensive surveillance with carcinoembryonic antigen (CEA) testing and CT scans after colorectal cancer resection did not improve recurrence-free or overall survival when compared with standard abdominal ultrasound and chest x-ray monitoring in a phase 3 trial of almost 2,000 patients.

However, among patients with colon cancer recurrence, those randomized to intensive surveillance more often had a second surgery with curative intent. Even so, there was no overall survival benefit versus standard surveillance in this group.

In short, “none of the follow-up modalities resulted in a difference,” said investigator Come Lepage, MD, PhD, of Centre Hospitalier Universitaire de Dijon (France).

Dr. Lepage presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

Dr. Lepage said the study’s results suggest guidelines that include CT and CEA monitoring should be amended, and the standard surveillance methods should be ultrasound and chest x-ray. Dr. LePage called CEA surveillance “useless” and said CT scans should be performed only in cases of suspected recurrence.

However, study discussant Tim Price, MBBS, DHSc, of the University of Adelaide, noted that both the intensive and standard arms in this study had abdominal imaging every 3 months, be it ultrasound or CT, so even in the standard arms, surveillance “was still fairly aggressive.”

Because of that, the study does not “suggest we should decrease our intensity,” Dr. Price said.

He added that the study’s major finding was that more intensive surveillance led to higher rates of secondary surgery with curative intent, probably because recurrences were caught earlier than they would have been with standard surveillance, when curative surgery was still possible.

Patients in the study were treated during 2009-2015, and that might have also made a difference. “We need to remember that, in 2020, care is very different,” Dr. Price said. This includes increased surgical interventions and options for oligometastatic disease, plus systemic therapies such as pembrolizumab. With modern treatments, detecting recurrences earlier “may well have an impact on survival.”

Perhaps patients would live longer with “earlier diagnosis in today’s setting with more active agents and more aggressive surgery and radiotherapy [e.g., stereotactic ablative radiation therapy],” Dr. Price said in an interview.
 

Study details

The trial, dubbed PRODIGE 13, was done to bring clarity to the surveillance issue. Intensive follow-up after curative surgery for colorectal cancer, including CT and CEA monitoring, is recommended by various scientific societies, but it’s based mainly on expert opinion. Results of the few clinical trials on the issue have been controversial, Dr. Lepage explained.

PRODIGE 13 included 1,995 subjects with colorectal cancer. About half of patients had stage II disease, and the other half had stage III. Most patients were 75 years or younger at baseline, and there were more men in the study than women. All patients underwent resection with curative intent and had no evidence of residual disease 3 months after surgery. Some patients received adjuvant chemotherapy.

Patients were first randomized to no CEA monitoring or CEA monitoring every 3 months for the first 2 years, then every 6 months for an additional 3 years. Members in both groups were then randomized a second time to either intensive or standard radiologic surveillance.

Surveillance in the standard arm consisted of an abdominal ultrasound every 3 months for the first 3 years, then biannually for an additional 2 years, plus chest x-rays every 6 months for 5 years. Intensive surveillance consisted of CT imaging, including thoracic imaging, alternating with abdominal ultrasound, every 3 months, then biannually for another 2 years.

At baseline, the surveillance groups were well balanced with regard to demographics, primary tumor location, and other factors, but stage III disease was more prevalent among patients randomized to standard radiologic monitoring without CEA.
 

Results

The median follow up was 6.5 years. There were no significant differences between the surveillance groups with regard to 5-year overall survival (P = .340) or recurrence-free survival (P = .473).

There were no significant differences in recurrence-free or overall survival when patients were stratified by age, sex, stage, CEA at a cut point of 5 mcg/L, and primary tumor characteristics including location, perineural invasion, and occlusion/perforation.

There were 356 recurrences in patients initially treated for colon cancer. CEA surveillance with or without CT scan was associated with an increased incidence of secondary resection with curative intent. The rate of secondary resection was 66.3% in the standard imaging with CEA arm, 59.5% in the CT plus CEA arm, 50.7% with CT imaging but no CEA, and 40.9% with standard imaging and no CEA (P = .0035).

The rates were similar among the 83 patients with recurrence after initial treatment for rectal cancer, but the between-arm differences were not significant. The rate of secondary resection with curative intent was 57.9% in the standard imaging with CEA arm, 47.8% in the CT plus CEA arm, 55% with CT imaging but no CEA, and 42.9% with standard imaging and no CEA.

The research is ongoing, and the team expects to report on secondary outcomes and ancillary studies of circulating tumor DNA, among other things, in 2021.

The study is being funded by the Federation Francophone de Cancerologie Digestive. Dr. Lepage disclosed ties with Novartis, Amgen, Bayer, Servier, and AAA. Dr. Price disclosed institutional research funding from Amgen and being an uncompensated adviser to Pierre-Fabre and Merck.

[email protected]

SOURCE: Lepage C et al. ESMO 2020, Abstract 398O.

Most older women with estrogen receptor–positive (ER+) breast cancer can tolerate and should be offered surgery, and a new tool helps them decide between treatment options, the U.K. Age Gap study suggests. Findings from the study were reported at the 12th European Breast Cancer Conference.

“Primary endocrine therapy is usually reserved for older, less fit, and frail women. Rates of use vary widely,” noted investigator Lynda Wyld, MBChB, PhD, of the University of Sheffield (England).

“Although there is no set threshold for who is suitable, some women are undoubtedly over- and undertreated for their breast cancer,” she added.

Dr. Wyld and colleagues undertook the Age Gap study among women older than 70 years with breast cancer recruited from 56 U.K. breast units during 2013-2018.

The main goals were to determine which women can be safely offered primary endocrine therapy as nonstandard care and to develop and test a tool to help women in this age group make treatment decisions.

The first component of the study was a multicenter, prospective cohort study of women with ER+ disease who were eligible for surgery. Results showed that breast cancer–specific mortality was greater with primary endocrine therapy than with surgery in the entire cohort. However, breast cancer–specific mortality was lower with primary endocrine therapy than with surgery in a cohort matched with propensity scores to achieve similar age, fitness, and frailty.

The second component of the study was a cluster-randomized controlled trial of women with operable breast cancer, most of whom had ER+ disease. Results showed that a decision support tool increased awareness of treatment options and readiness to decide. The tool also altered treatment choices, prompting a larger share of patients with ER+ disease to choose primary endocrine therapy.
 

Prospective cohort study

The prospective observational study was conducted in 2,854 women with ER+ disease who were eligible for surgery and treated in usual practice. Most women (n = 2,354) were treated with surgery (followed by antiestrogen therapy), while the rest received primary endocrine therapy (n = 500).

In the entire cohort, patients undergoing surgery were younger, had a lower level of comorbidity, and were less often frail. But these characteristics were generally similar in a propensity-matched cohort of 672 patients.

At a median follow-up of 52 months, overall and breast cancer–specific survival were significantly poorer with primary endocrine therapy versus surgery in the entire cohort but not in the propensity-matched cohort.

In the entire cohort, the breast cancer–specific mortality was 9.5% with primary endocrine therapy and 4.9% with surgery. In the propensity-matched cohort, breast cancer–specific mortality was 3.1% and 6.6%, respectively.

The overall mortality was 41.8% with primary endocrine therapy and 14.6% with surgery in the entire cohort, but the gap narrowed to 34.5% and 25.6%, respectively, in the propensity-matched cohort.

In the latter, “although there is a slight divergence in overall survival and it’s likely that with longer-term follow-up this will become significant, at the moment, it isn’t,” Dr. Wyld commented.

Curves for breast cancer–specific survival basically overlapped until 5 years, when surgery started to show an advantage. The rate of locoregional recurrence or progression was low and not significantly different by treatment.

None of the women in the entire cohort died from surgery. “But it’s worth bearing in mind that these were all women selected for surgery, who were thought to be fit for it by their surgeons. The least fit women in this cohort will have obviously been offered primary endocrine therapy,” Dr. Wyld cautioned.

Although 19% of patients had a surgical complication, only 2.1% had a systemic surgical complication.
 

Cluster-randomized controlled trial

In the cluster-randomized controlled trial, researchers compared a decision support tool to usual care. The tool was developed using U.K. registry data from almost 30,000 older women and input from women in this age group on their preferred format and method of presentation, according to Dr. Wyld.

The tool consists of an algorithm available to clinicians online (for input of tumor stage and biology, comorbidities, and functional status) plus a booklet and outcome sheets for patients to take home after discussions that can be personalized to their particulars.

Intention-to-treat analyses were based on 1,339 patients with operable breast cancer, 1,161 of whom had ER+ disease. Per-protocol analyses were based on the subset of 449 patients who were offered a choice between surgery and primary endocrine therapy, presumably because they were less fit and frailer.

Results showed that, at 6 months, mean scores for global quality of life on the EORTC questionnaire did not differ between decision support and usual care in the intention-to-treat population (69.0 vs. 68.9; P = .900), but scores were more favorable with decision support in the per-protocol population (70.7 vs. 66.8; P = .044).

The tool also altered treatment choices, with a larger share of ER+ patients choosing primary endocrine therapy (21.0% vs. 15.4%; P = .029) but still having similar disease outcomes.

Although ER+ patients in the decision support group more often selected primary endocrine therapy, at a median follow-up of 36 months, the groups did not differ significantly on overall survival, cause-specific survival, or time to recurrence in either intention-to-treat or per-protocol analyses.

Larger shares of women in the decision support group reported that they had adequate knowledge about the treatment options available to them (94% vs. 74%), were aware of the advantages and disadvantages of each option (91% vs. 76%), knew which option they preferred (96% vs. 91%), and were ready to make a decision (99% vs. 90%).
 

Applying results to practice

“Most women over the age of 70 are relatively fit, and the aim should be to treat them with surgery,” Dr. Wyld said. “For the less fit, a point is reached where the oncology benefits of surgery disappear and surgery may just cause harm. This threshold appears to be for women in their mid-80s with moderate to poor health.”

“Use of the Age Gap online tool may enhance shared decision-making for these women while increasing knowledge. And whilst it does seem to increase the use of primary endocrine therapy, this does not seem to have an adverse impact on survival at 36 months of follow-up,” she added.

“The study by Dr. Wyld and colleagues adds to the available literature regarding the scenarios in which some treatments may be omitted without impacting overall survival in older women with breast cancer,” Lesly A. Dossett, MD, of Michigan Medicine in Ann Arbor, commented in an interview.

In her own practice, Dr. Dossett emphasizes the generally favorable prognosis for older women with hormone receptor–positive breast cancer, she said. However, tools that help communicate risk and clarify the value of various therapies are welcome.

“The decision support tool appears to be a promising tool in helping to avoid treatments that are unlikely to benefit older women with breast cancer,” Dr. Dossett said. “The results will be widely applicable, as there is growing recognition that this patient population is at risk for overtreatment.”

The study was funded by the U.K. National Institute for Health Research programme grant for applied research. Dr. Wyld and Dr. Dossett said they had no relevant conflicts of interest.

SOURCES: Wyld L et al. EBCC-12 Virtual Congress. Abstract 8A and Abstract 8B.

Most older women with estrogen receptor–positive (ER+) breast cancer can tolerate and should be offered surgery, and a new tool helps them decide between treatment options, the U.K. Age Gap study suggests. Findings from the study were reported at the 12th European Breast Cancer Conference.

“Primary endocrine therapy is usually reserved for older, less fit, and frail women. Rates of use vary widely,” noted investigator Lynda Wyld, MBChB, PhD, of the University of Sheffield (England).

“Although there is no set threshold for who is suitable, some women are undoubtedly over- and undertreated for their breast cancer,” she added.

Dr. Wyld and colleagues undertook the Age Gap study among women older than 70 years with breast cancer recruited from 56 U.K. breast units during 2013-2018.

The main goals were to determine which women can be safely offered primary endocrine therapy as nonstandard care and to develop and test a tool to help women in this age group make treatment decisions.

The first component of the study was a multicenter, prospective cohort study of women with ER+ disease who were eligible for surgery. Results showed that breast cancer–specific mortality was greater with primary endocrine therapy than with surgery in the entire cohort. However, breast cancer–specific mortality was lower with primary endocrine therapy than with surgery in a cohort matched with propensity scores to achieve similar age, fitness, and frailty.

The second component of the study was a cluster-randomized controlled trial of women with operable breast cancer, most of whom had ER+ disease. Results showed that a decision support tool increased awareness of treatment options and readiness to decide. The tool also altered treatment choices, prompting a larger share of patients with ER+ disease to choose primary endocrine therapy.
 

Prospective cohort study

The prospective observational study was conducted in 2,854 women with ER+ disease who were eligible for surgery and treated in usual practice. Most women (n = 2,354) were treated with surgery (followed by antiestrogen therapy), while the rest received primary endocrine therapy (n = 500).

In the entire cohort, patients undergoing surgery were younger, had a lower level of comorbidity, and were less often frail. But these characteristics were generally similar in a propensity-matched cohort of 672 patients.

At a median follow-up of 52 months, overall and breast cancer–specific survival were significantly poorer with primary endocrine therapy versus surgery in the entire cohort but not in the propensity-matched cohort.

In the entire cohort, the breast cancer–specific mortality was 9.5% with primary endocrine therapy and 4.9% with surgery. In the propensity-matched cohort, breast cancer–specific mortality was 3.1% and 6.6%, respectively.

The overall mortality was 41.8% with primary endocrine therapy and 14.6% with surgery in the entire cohort, but the gap narrowed to 34.5% and 25.6%, respectively, in the propensity-matched cohort.

In the latter, “although there is a slight divergence in overall survival and it’s likely that with longer-term follow-up this will become significant, at the moment, it isn’t,” Dr. Wyld commented.

Curves for breast cancer–specific survival basically overlapped until 5 years, when surgery started to show an advantage. The rate of locoregional recurrence or progression was low and not significantly different by treatment.

None of the women in the entire cohort died from surgery. “But it’s worth bearing in mind that these were all women selected for surgery, who were thought to be fit for it by their surgeons. The least fit women in this cohort will have obviously been offered primary endocrine therapy,” Dr. Wyld cautioned.

Although 19% of patients had a surgical complication, only 2.1% had a systemic surgical complication.
 

Cluster-randomized controlled trial

In the cluster-randomized controlled trial, researchers compared a decision support tool to usual care. The tool was developed using U.K. registry data from almost 30,000 older women and input from women in this age group on their preferred format and method of presentation, according to Dr. Wyld.

The tool consists of an algorithm available to clinicians online (for input of tumor stage and biology, comorbidities, and functional status) plus a booklet and outcome sheets for patients to take home after discussions that can be personalized to their particulars.

Intention-to-treat analyses were based on 1,339 patients with operable breast cancer, 1,161 of whom had ER+ disease. Per-protocol analyses were based on the subset of 449 patients who were offered a choice between surgery and primary endocrine therapy, presumably because they were less fit and frailer.

Results showed that, at 6 months, mean scores for global quality of life on the EORTC questionnaire did not differ between decision support and usual care in the intention-to-treat population (69.0 vs. 68.9; P = .900), but scores were more favorable with decision support in the per-protocol population (70.7 vs. 66.8; P = .044).

The tool also altered treatment choices, with a larger share of ER+ patients choosing primary endocrine therapy (21.0% vs. 15.4%; P = .029) but still having similar disease outcomes.

Although ER+ patients in the decision support group more often selected primary endocrine therapy, at a median follow-up of 36 months, the groups did not differ significantly on overall survival, cause-specific survival, or time to recurrence in either intention-to-treat or per-protocol analyses.

Larger shares of women in the decision support group reported that they had adequate knowledge about the treatment options available to them (94% vs. 74%), were aware of the advantages and disadvantages of each option (91% vs. 76%), knew which option they preferred (96% vs. 91%), and were ready to make a decision (99% vs. 90%).
 

Applying results to practice

“Most women over the age of 70 are relatively fit, and the aim should be to treat them with surgery,” Dr. Wyld said. “For the less fit, a point is reached where the oncology benefits of surgery disappear and surgery may just cause harm. This threshold appears to be for women in their mid-80s with moderate to poor health.”

“Use of the Age Gap online tool may enhance shared decision-making for these women while increasing knowledge. And whilst it does seem to increase the use of primary endocrine therapy, this does not seem to have an adverse impact on survival at 36 months of follow-up,” she added.

“The study by Dr. Wyld and colleagues adds to the available literature regarding the scenarios in which some treatments may be omitted without impacting overall survival in older women with breast cancer,” Lesly A. Dossett, MD, of Michigan Medicine in Ann Arbor, commented in an interview.

In her own practice, Dr. Dossett emphasizes the generally favorable prognosis for older women with hormone receptor–positive breast cancer, she said. However, tools that help communicate risk and clarify the value of various therapies are welcome.

“The decision support tool appears to be a promising tool in helping to avoid treatments that are unlikely to benefit older women with breast cancer,” Dr. Dossett said. “The results will be widely applicable, as there is growing recognition that this patient population is at risk for overtreatment.”

The study was funded by the U.K. National Institute for Health Research programme grant for applied research. Dr. Wyld and Dr. Dossett said they had no relevant conflicts of interest.

SOURCES: Wyld L et al. EBCC-12 Virtual Congress. Abstract 8A and Abstract 8B.

Most older women with estrogen receptor–positive (ER+) breast cancer can tolerate and should be offered surgery, and a new tool helps them decide between treatment options, the U.K. Age Gap study suggests. Findings from the study were reported at the 12th European Breast Cancer Conference.

“Primary endocrine therapy is usually reserved for older, less fit, and frail women. Rates of use vary widely,” noted investigator Lynda Wyld, MBChB, PhD, of the University of Sheffield (England).

“Although there is no set threshold for who is suitable, some women are undoubtedly over- and undertreated for their breast cancer,” she added.

Dr. Wyld and colleagues undertook the Age Gap study among women older than 70 years with breast cancer recruited from 56 U.K. breast units during 2013-2018.

The main goals were to determine which women can be safely offered primary endocrine therapy as nonstandard care and to develop and test a tool to help women in this age group make treatment decisions.

The first component of the study was a multicenter, prospective cohort study of women with ER+ disease who were eligible for surgery. Results showed that breast cancer–specific mortality was greater with primary endocrine therapy than with surgery in the entire cohort. However, breast cancer–specific mortality was lower with primary endocrine therapy than with surgery in a cohort matched with propensity scores to achieve similar age, fitness, and frailty.

The second component of the study was a cluster-randomized controlled trial of women with operable breast cancer, most of whom had ER+ disease. Results showed that a decision support tool increased awareness of treatment options and readiness to decide. The tool also altered treatment choices, prompting a larger share of patients with ER+ disease to choose primary endocrine therapy.
 

Prospective cohort study

The prospective observational study was conducted in 2,854 women with ER+ disease who were eligible for surgery and treated in usual practice. Most women (n = 2,354) were treated with surgery (followed by antiestrogen therapy), while the rest received primary endocrine therapy (n = 500).

In the entire cohort, patients undergoing surgery were younger, had a lower level of comorbidity, and were less often frail. But these characteristics were generally similar in a propensity-matched cohort of 672 patients.

At a median follow-up of 52 months, overall and breast cancer–specific survival were significantly poorer with primary endocrine therapy versus surgery in the entire cohort but not in the propensity-matched cohort.

In the entire cohort, the breast cancer–specific mortality was 9.5% with primary endocrine therapy and 4.9% with surgery. In the propensity-matched cohort, breast cancer–specific mortality was 3.1% and 6.6%, respectively.

The overall mortality was 41.8% with primary endocrine therapy and 14.6% with surgery in the entire cohort, but the gap narrowed to 34.5% and 25.6%, respectively, in the propensity-matched cohort.

In the latter, “although there is a slight divergence in overall survival and it’s likely that with longer-term follow-up this will become significant, at the moment, it isn’t,” Dr. Wyld commented.

Curves for breast cancer–specific survival basically overlapped until 5 years, when surgery started to show an advantage. The rate of locoregional recurrence or progression was low and not significantly different by treatment.

None of the women in the entire cohort died from surgery. “But it’s worth bearing in mind that these were all women selected for surgery, who were thought to be fit for it by their surgeons. The least fit women in this cohort will have obviously been offered primary endocrine therapy,” Dr. Wyld cautioned.

Although 19% of patients had a surgical complication, only 2.1% had a systemic surgical complication.
 

Cluster-randomized controlled trial

In the cluster-randomized controlled trial, researchers compared a decision support tool to usual care. The tool was developed using U.K. registry data from almost 30,000 older women and input from women in this age group on their preferred format and method of presentation, according to Dr. Wyld.

The tool consists of an algorithm available to clinicians online (for input of tumor stage and biology, comorbidities, and functional status) plus a booklet and outcome sheets for patients to take home after discussions that can be personalized to their particulars.

Intention-to-treat analyses were based on 1,339 patients with operable breast cancer, 1,161 of whom had ER+ disease. Per-protocol analyses were based on the subset of 449 patients who were offered a choice between surgery and primary endocrine therapy, presumably because they were less fit and frailer.

Results showed that, at 6 months, mean scores for global quality of life on the EORTC questionnaire did not differ between decision support and usual care in the intention-to-treat population (69.0 vs. 68.9; P = .900), but scores were more favorable with decision support in the per-protocol population (70.7 vs. 66.8; P = .044).

The tool also altered treatment choices, with a larger share of ER+ patients choosing primary endocrine therapy (21.0% vs. 15.4%; P = .029) but still having similar disease outcomes.

Although ER+ patients in the decision support group more often selected primary endocrine therapy, at a median follow-up of 36 months, the groups did not differ significantly on overall survival, cause-specific survival, or time to recurrence in either intention-to-treat or per-protocol analyses.

Larger shares of women in the decision support group reported that they had adequate knowledge about the treatment options available to them (94% vs. 74%), were aware of the advantages and disadvantages of each option (91% vs. 76%), knew which option they preferred (96% vs. 91%), and were ready to make a decision (99% vs. 90%).
 

Applying results to practice

“Most women over the age of 70 are relatively fit, and the aim should be to treat them with surgery,” Dr. Wyld said. “For the less fit, a point is reached where the oncology benefits of surgery disappear and surgery may just cause harm. This threshold appears to be for women in their mid-80s with moderate to poor health.”

“Use of the Age Gap online tool may enhance shared decision-making for these women while increasing knowledge. And whilst it does seem to increase the use of primary endocrine therapy, this does not seem to have an adverse impact on survival at 36 months of follow-up,” she added.

“The study by Dr. Wyld and colleagues adds to the available literature regarding the scenarios in which some treatments may be omitted without impacting overall survival in older women with breast cancer,” Lesly A. Dossett, MD, of Michigan Medicine in Ann Arbor, commented in an interview.

In her own practice, Dr. Dossett emphasizes the generally favorable prognosis for older women with hormone receptor–positive breast cancer, she said. However, tools that help communicate risk and clarify the value of various therapies are welcome.

“The decision support tool appears to be a promising tool in helping to avoid treatments that are unlikely to benefit older women with breast cancer,” Dr. Dossett said. “The results will be widely applicable, as there is growing recognition that this patient population is at risk for overtreatment.”

The study was funded by the U.K. National Institute for Health Research programme grant for applied research. Dr. Wyld and Dr. Dossett said they had no relevant conflicts of interest.

SOURCES: Wyld L et al. EBCC-12 Virtual Congress. Abstract 8A and Abstract 8B.

A higher dose of thoracic radiotherapy (TRT) may improve overall survival in limited-stage small-cell lung cancer (LS-SCLC), but it’s not clear if this dose should become the new standard of care.

In a phase 2 trial, the 2-year overall survival rate was 51.3% when twice-daily TRT was given at a dose of 45 Gy in 30 fractions and 75% when it was given at a dose of 60 Gy in 40 fractions in patients with LS-SCLC. The two treatment arms had similar safety and quality of life outcomes.

The higher dose “did not add toxicity,” a significant concern with higher radiation doses, said Bjorn Gronberg, MD, PhD, of the Norwegian University of Science and Technology in Trondheim, when presenting this study at the European Society for Medical Oncology Virtual Congress 2020.

However, the discussant for this study pointed out several limitations of the trial and concluded that the 45 Gy dose should remain the standard of care.

Dr. Gonberg explained that concurrent platinum/etoposide (PE) chemotherapy and TRT is the standard treatment for LS-SCLC, and the most recommended schedule for TRT is twice daily at 45 Gy in 30 fractions. He noted, however, that “there’s clearly a need for better treatment” because less than 30% of patients are cured.

“We hypothesized that increasing the dose of radiotherapy might improve survival,” he said.
 

Study details

Dr. Gonberg and colleagues conducted a phase 2 trial of patients with stage I-III SCLC confined to one hemithorax plus regional lymph nodes. The trial enrolled 176 patients and randomized 170 of them.

The patients received four courses of PE 3 weeks apart. For TRT, 81 patients were randomized to 45 Gy in 30 fractions, and 89 patients were randomized to 60 Gy in 40 fractions, with 10 fractions per week starting with the second PE course.

All patients who responded to chemoradiotherapy were offered prophylactic cranial irradiation at 25 Gy in 10 fractions or 30 Gy in 15 fractions.

Baseline characteristics were well balanced between the treatment arms. The median age was 65 years in both arms, and most patients were women (60.5% in the 45 Gy arm and 56% in the 60 Gy arm).

The mean number of chemotherapy courses was 3.8 in each arm, about 85% of patients received prophylactic cranial radiation, and roughly half received second-line chemotherapy. Overall, 73 patients completed TRT in the 45 Gy arm, and 81 completed TRT in the 60 Gy arm.
 

Efficacy

There was no significant difference in overall response rate between the treatment arms. It was 81.6% in the 45 Gy arm and 82.1% in the 60 Gy arm (P = .81).

Similarly, there was no significant difference in progression-free survival. The median progression-free survival was 11.1 months in the lower-dose arm and 18.7 months in the higher-dose arm (P = .22).

Still, there was a significant difference in overall survival between the arms. The 2-year overall survival rate was 51.3% in the lower-dose arm and 75% in the higher-dose arm (P = .002). The median overall survival was 24 months and 37.2 months, respectively (P = .034).

Discussant Corinne Faivre-Finn, MD, PhD, of the University of Manchester (England), cautioned that the lower-dose arm appeared to underperform, compared with prior research.

Additionally, “the survival curves separate at about 9 months, [with a] significant difference at 2 years, but the survival curves are coming back together at around 5 years, and that shows that there is a small difference in terms of long-term cure,” she said.
 

Safety

There were no significant differences in toxicity between the treatment arms.

Dr. Gronberg noted that esophagitis is considered the main dose-limiting toxicity with TRT, but there was no difference in incidence between the two arms (P = .916). Grade 3 esophagitis occurred in 18.4% of patients in the lower-dose arm and 19% of those in the higher-dose arm. There was no grade 4 esophagitis.

Rates of grade 3 and 4 neutropenic infections were higher in the lower-dose arm than in the higher-dose arm, but the difference was not statistically significant (P = .08).

There were also no significant differences in quality of life surveys that patients filled out periodically from baseline until week 52.

“Not so surprisingly,” Dr. Gronberg said, dysphagia was more common at the end of TRT. However, patients had recovered to baseline levels at week 22.

“There’s no difference in the maximum dysphagia reported between the treatment arms, but ... patients in the high-dose arm needed longer time to recover from dysphagia,” Dr. Gronberg said.

Scores for dyspnea, physical function, and global quality of life were similar between the treatment arms.

The similar toxicity between the arms “is quite puzzling,” Dr. Faivre-Finn said, given the 33% increase in radiation dose in the experimental arm. She said this “probably points out an imbalance in some of the factors” between the groups, including tumor volume and doses to organs at risk, which were not reported.

“There are some important missing data, in terms of interpretation of results,” she said.

Given the limitations, and the fact that the study population was relatively small, Dr. Faivre-Finn said “the results cannot be considered definitive and practice changing,” pending additional study.

“So my final conclusion is that twice-a-day radiotherapy at a dose of 45 Gy remains the standard of care, as recommended in the recently published ASTRO [American Society for Radiation Oncology] guidelines,” Dr. Faivre-Finn said.

The study was funded by the Norwegian Cancer Society, the Nordic Cancer Union, and the Norwegian University of Science and Technology. Dr. Gronberg disclosed relationships with Pfizer, Roche, Eli Lilly, and other companies. Dr. Faivre-Finn disclosed relationships with AstraZeneca, Merck, Pfizer, Elekta, and Boehringer Ingelheim.

[email protected]

SOURCE: Gronberg B et al. ESMO 2020, Abstract 1783O.

A higher dose of thoracic radiotherapy (TRT) may improve overall survival in limited-stage small-cell lung cancer (LS-SCLC), but it’s not clear if this dose should become the new standard of care.

In a phase 2 trial, the 2-year overall survival rate was 51.3% when twice-daily TRT was given at a dose of 45 Gy in 30 fractions and 75% when it was given at a dose of 60 Gy in 40 fractions in patients with LS-SCLC. The two treatment arms had similar safety and quality of life outcomes.

The higher dose “did not add toxicity,” a significant concern with higher radiation doses, said Bjorn Gronberg, MD, PhD, of the Norwegian University of Science and Technology in Trondheim, when presenting this study at the European Society for Medical Oncology Virtual Congress 2020.

However, the discussant for this study pointed out several limitations of the trial and concluded that the 45 Gy dose should remain the standard of care.

Dr. Gonberg explained that concurrent platinum/etoposide (PE) chemotherapy and TRT is the standard treatment for LS-SCLC, and the most recommended schedule for TRT is twice daily at 45 Gy in 30 fractions. He noted, however, that “there’s clearly a need for better treatment” because less than 30% of patients are cured.

“We hypothesized that increasing the dose of radiotherapy might improve survival,” he said.
 

Study details

Dr. Gonberg and colleagues conducted a phase 2 trial of patients with stage I-III SCLC confined to one hemithorax plus regional lymph nodes. The trial enrolled 176 patients and randomized 170 of them.

The patients received four courses of PE 3 weeks apart. For TRT, 81 patients were randomized to 45 Gy in 30 fractions, and 89 patients were randomized to 60 Gy in 40 fractions, with 10 fractions per week starting with the second PE course.

All patients who responded to chemoradiotherapy were offered prophylactic cranial irradiation at 25 Gy in 10 fractions or 30 Gy in 15 fractions.

Baseline characteristics were well balanced between the treatment arms. The median age was 65 years in both arms, and most patients were women (60.5% in the 45 Gy arm and 56% in the 60 Gy arm).

The mean number of chemotherapy courses was 3.8 in each arm, about 85% of patients received prophylactic cranial radiation, and roughly half received second-line chemotherapy. Overall, 73 patients completed TRT in the 45 Gy arm, and 81 completed TRT in the 60 Gy arm.
 

Efficacy

There was no significant difference in overall response rate between the treatment arms. It was 81.6% in the 45 Gy arm and 82.1% in the 60 Gy arm (P = .81).

Similarly, there was no significant difference in progression-free survival. The median progression-free survival was 11.1 months in the lower-dose arm and 18.7 months in the higher-dose arm (P = .22).

Still, there was a significant difference in overall survival between the arms. The 2-year overall survival rate was 51.3% in the lower-dose arm and 75% in the higher-dose arm (P = .002). The median overall survival was 24 months and 37.2 months, respectively (P = .034).

Discussant Corinne Faivre-Finn, MD, PhD, of the University of Manchester (England), cautioned that the lower-dose arm appeared to underperform, compared with prior research.

Additionally, “the survival curves separate at about 9 months, [with a] significant difference at 2 years, but the survival curves are coming back together at around 5 years, and that shows that there is a small difference in terms of long-term cure,” she said.
 

Safety

There were no significant differences in toxicity between the treatment arms.

Dr. Gronberg noted that esophagitis is considered the main dose-limiting toxicity with TRT, but there was no difference in incidence between the two arms (P = .916). Grade 3 esophagitis occurred in 18.4% of patients in the lower-dose arm and 19% of those in the higher-dose arm. There was no grade 4 esophagitis.

Rates of grade 3 and 4 neutropenic infections were higher in the lower-dose arm than in the higher-dose arm, but the difference was not statistically significant (P = .08).

There were also no significant differences in quality of life surveys that patients filled out periodically from baseline until week 52.

“Not so surprisingly,” Dr. Gronberg said, dysphagia was more common at the end of TRT. However, patients had recovered to baseline levels at week 22.

“There’s no difference in the maximum dysphagia reported between the treatment arms, but ... patients in the high-dose arm needed longer time to recover from dysphagia,” Dr. Gronberg said.

Scores for dyspnea, physical function, and global quality of life were similar between the treatment arms.

The similar toxicity between the arms “is quite puzzling,” Dr. Faivre-Finn said, given the 33% increase in radiation dose in the experimental arm. She said this “probably points out an imbalance in some of the factors” between the groups, including tumor volume and doses to organs at risk, which were not reported.

“There are some important missing data, in terms of interpretation of results,” she said.

Given the limitations, and the fact that the study population was relatively small, Dr. Faivre-Finn said “the results cannot be considered definitive and practice changing,” pending additional study.

“So my final conclusion is that twice-a-day radiotherapy at a dose of 45 Gy remains the standard of care, as recommended in the recently published ASTRO [American Society for Radiation Oncology] guidelines,” Dr. Faivre-Finn said.

The study was funded by the Norwegian Cancer Society, the Nordic Cancer Union, and the Norwegian University of Science and Technology. Dr. Gronberg disclosed relationships with Pfizer, Roche, Eli Lilly, and other companies. Dr. Faivre-Finn disclosed relationships with AstraZeneca, Merck, Pfizer, Elekta, and Boehringer Ingelheim.

[email protected]

SOURCE: Gronberg B et al. ESMO 2020, Abstract 1783O.

A higher dose of thoracic radiotherapy (TRT) may improve overall survival in limited-stage small-cell lung cancer (LS-SCLC), but it’s not clear if this dose should become the new standard of care.

In a phase 2 trial, the 2-year overall survival rate was 51.3% when twice-daily TRT was given at a dose of 45 Gy in 30 fractions and 75% when it was given at a dose of 60 Gy in 40 fractions in patients with LS-SCLC. The two treatment arms had similar safety and quality of life outcomes.

The higher dose “did not add toxicity,” a significant concern with higher radiation doses, said Bjorn Gronberg, MD, PhD, of the Norwegian University of Science and Technology in Trondheim, when presenting this study at the European Society for Medical Oncology Virtual Congress 2020.

However, the discussant for this study pointed out several limitations of the trial and concluded that the 45 Gy dose should remain the standard of care.

Dr. Gonberg explained that concurrent platinum/etoposide (PE) chemotherapy and TRT is the standard treatment for LS-SCLC, and the most recommended schedule for TRT is twice daily at 45 Gy in 30 fractions. He noted, however, that “there’s clearly a need for better treatment” because less than 30% of patients are cured.

“We hypothesized that increasing the dose of radiotherapy might improve survival,” he said.
 

Study details

Dr. Gonberg and colleagues conducted a phase 2 trial of patients with stage I-III SCLC confined to one hemithorax plus regional lymph nodes. The trial enrolled 176 patients and randomized 170 of them.

The patients received four courses of PE 3 weeks apart. For TRT, 81 patients were randomized to 45 Gy in 30 fractions, and 89 patients were randomized to 60 Gy in 40 fractions, with 10 fractions per week starting with the second PE course.

All patients who responded to chemoradiotherapy were offered prophylactic cranial irradiation at 25 Gy in 10 fractions or 30 Gy in 15 fractions.

Baseline characteristics were well balanced between the treatment arms. The median age was 65 years in both arms, and most patients were women (60.5% in the 45 Gy arm and 56% in the 60 Gy arm).

The mean number of chemotherapy courses was 3.8 in each arm, about 85% of patients received prophylactic cranial radiation, and roughly half received second-line chemotherapy. Overall, 73 patients completed TRT in the 45 Gy arm, and 81 completed TRT in the 60 Gy arm.
 

Efficacy

There was no significant difference in overall response rate between the treatment arms. It was 81.6% in the 45 Gy arm and 82.1% in the 60 Gy arm (P = .81).

Similarly, there was no significant difference in progression-free survival. The median progression-free survival was 11.1 months in the lower-dose arm and 18.7 months in the higher-dose arm (P = .22).

Still, there was a significant difference in overall survival between the arms. The 2-year overall survival rate was 51.3% in the lower-dose arm and 75% in the higher-dose arm (P = .002). The median overall survival was 24 months and 37.2 months, respectively (P = .034).

Discussant Corinne Faivre-Finn, MD, PhD, of the University of Manchester (England), cautioned that the lower-dose arm appeared to underperform, compared with prior research.

Additionally, “the survival curves separate at about 9 months, [with a] significant difference at 2 years, but the survival curves are coming back together at around 5 years, and that shows that there is a small difference in terms of long-term cure,” she said.
 

Safety

There were no significant differences in toxicity between the treatment arms.

Dr. Gronberg noted that esophagitis is considered the main dose-limiting toxicity with TRT, but there was no difference in incidence between the two arms (P = .916). Grade 3 esophagitis occurred in 18.4% of patients in the lower-dose arm and 19% of those in the higher-dose arm. There was no grade 4 esophagitis.

Rates of grade 3 and 4 neutropenic infections were higher in the lower-dose arm than in the higher-dose arm, but the difference was not statistically significant (P = .08).

There were also no significant differences in quality of life surveys that patients filled out periodically from baseline until week 52.

“Not so surprisingly,” Dr. Gronberg said, dysphagia was more common at the end of TRT. However, patients had recovered to baseline levels at week 22.

“There’s no difference in the maximum dysphagia reported between the treatment arms, but ... patients in the high-dose arm needed longer time to recover from dysphagia,” Dr. Gronberg said.

Scores for dyspnea, physical function, and global quality of life were similar between the treatment arms.

The similar toxicity between the arms “is quite puzzling,” Dr. Faivre-Finn said, given the 33% increase in radiation dose in the experimental arm. She said this “probably points out an imbalance in some of the factors” between the groups, including tumor volume and doses to organs at risk, which were not reported.

“There are some important missing data, in terms of interpretation of results,” she said.

Given the limitations, and the fact that the study population was relatively small, Dr. Faivre-Finn said “the results cannot be considered definitive and practice changing,” pending additional study.

“So my final conclusion is that twice-a-day radiotherapy at a dose of 45 Gy remains the standard of care, as recommended in the recently published ASTRO [American Society for Radiation Oncology] guidelines,” Dr. Faivre-Finn said.

The study was funded by the Norwegian Cancer Society, the Nordic Cancer Union, and the Norwegian University of Science and Technology. Dr. Gronberg disclosed relationships with Pfizer, Roche, Eli Lilly, and other companies. Dr. Faivre-Finn disclosed relationships with AstraZeneca, Merck, Pfizer, Elekta, and Boehringer Ingelheim.

[email protected]

SOURCE: Gronberg B et al. ESMO 2020, Abstract 1783O.

A new meta-analysis has largely confirmed what is already known about the lifestyle factors that increase and those that decrease the risk of developing colorectal cancer.

The use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a decreased risk for colorectal cancer, the new article concludes. But it also adds a number of other factors that are associated with a decreased risk for the disease, including taking magnesium and folate supplements and eating dairy products, fiber, soy, and fruits and vegetables.

On the other hand, consumption of meat and alcohol was associated with an increased risk for colorectal cancer in almost all of the analyses included in this article.

The study was published online September 28 in Gut.

However, the authors pointed out that it is important to keep in mind that in most cases, the level of evidence is low or very low, primarily because of the heterogeneity of the various published studies, as well as the type of study.

“Furthermore, in most cases, we were unable to identify an optimal dose and duration of exposure/intake for any of the products, even in the case of low-dose aspirin and other compounds that have been extensively assessed,” they wrote.

The findings of this new meta-analysis echo previous findings on this issue.

A number of studies, for example, have found varying associations between the consumption of red meat and cancer. The American Institute for Cancer Research and the World Cancer Research Fund have published several reports during the past 10 years on the effect of diet, nutrition, and/or physical activity on risk for several cancer types. Their most recent study, published in 2017, concluded that eating red meat and processed meat may increase the risk for colorectal cancer, as may drinking two or more alcoholic beverages per day.

Another large meta-analysis published earlier this year found that regular use of aspirin reduced the risk for cancers of the digestive tract by 22%-38%, compared with nonuse.
 

Umbrella review

In the latest article in Gut, researchers led by Marc Bardou, MD, PhD, Centre Hospitalier Universitaire de Dijon (France), conducted an umbrella review of systematic reviews and meta-analyses of interventions that assessed chemopreventive products for colorectal cancer in an average-risk population.

A total of 80 meta-analyses of interventional and observational studies were included. The studies investigated a wide range of chemopreventive agents in an average-risk population and the risk for colorectal cancer. Agents included medications (aspirin, NSAIDs, statins), vitamins or supplements (magnesium; calcium; folic acid; vitamin A, B, C, E, and D; beta-carotene; and selenium), and dietary items (coffee, tea, fish, dairy products, fiber, fruits, vegetables, meat, and alcohol).

The studies included randomized controlled trials and observational studies. Most of the meta-analyses found a protective effect for aspirin, which lowered the risk by between 14% and 29% even at doses as low as 75 mg/day, with a dose-response effect of up to 325 mg/day. The certainty of evidence was moderate.

NSAID use was also associated with a protective effect, with a significant 26%-43% decrease in the incidence in colorectal cancer. The optimal duration for the observed protective effect remains unclear. Two meta-analyses suggested that NSAIDs may need to be taken for at least 5 years, although one article suggested a protective effect after the first year. The certainty of evidence was low.

Use of magnesium was found to be protective, with a relative risk (RR) of 0.78-0.87. High intake of folic acid was associated with a significant decrease in risk (RR, 0.85-0.88). The certainty of evidence was low and very low, respectively.

Consumption of dairy products was associated with 13%-19% lower risk for the disease. However, the authors note that, because of the small number of available meta-analyses, the multiplicity of outcomes, and the variety of dairy products, it was not possible to reach any firm conclusions about the amount needed or the duration necessary for a protective effect.

Another dietary item, fiber, was associated with a 22%-43% lower risk. Consumption of fruits and vegetables was associated with up to a 52% lower risk, with an added benefit for every additional 100 g/day increase in intake. Soy intake was also associated with a small but significant decrease in risk (8%-15%).

For many of the other items reviewed, evidence was either weak or no beneficial effect was seen.
 

Increased risk

Consumption of both meat and alcohol was found to increase the risk for colorectal cancer.

Most of the meta-analyses of observational studies have reported a significant increase in risk (RR, 1.12-1.21) with meat consumption (particularly red and processed) and the incidence of colorectal cancer. Studies of the dose effect reported a 10%-30% increased risk for each increment of 100 g/day of total or red meat.

Alcohol consumption was also associated with a significantly increased risk. The higher the intake, the greater the risk. The risk was evident even at the lowest consumption doses that were investigated (1-2 drinks per day).
 

Balanced for the individual patient

Commenting on the article, Thomas J. George Jr, MD, professor of medicine and director, GI Oncology Program, the University of Florida Health Cancer Center, Gainesville, feels that the take-home message for clinicians and patients alike is that these data help to reinforce behaviors that have already been recommended.

“We know that excessive alcohol and red meat consumption is not healthy, so seeing that there may be a negative effect on colorectal cancer is just more evidence that we should be avoiding that and recommend avoiding that,” said Dr. George. “So yes, I recommend minimizing those, and likewise, a diet that is inclusive of fruits, vegetables, fiber, soy – perhaps as an alternative to meat consumption – is healthier than a diet devoid of these, so again, more reassuring data to support doing what we should already be doing.”

However, he pointed out that there are risks associated with medications such as NSAIDs and aspirin, including bleeding, gastric ulcer formation, and kidney damage. “The risks are low but very real,” Dr. George said. “So I think those recommendations need to be considered on a very individual level, balancing any other risk factors that the patient may have for both colorectal cancer, as well as risks from the medications.”

The study had no outside funding. The authors have disclosed no relevant financial relationships.

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

A new meta-analysis has largely confirmed what is already known about the lifestyle factors that increase and those that decrease the risk of developing colorectal cancer.

The use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a decreased risk for colorectal cancer, the new article concludes. But it also adds a number of other factors that are associated with a decreased risk for the disease, including taking magnesium and folate supplements and eating dairy products, fiber, soy, and fruits and vegetables.

On the other hand, consumption of meat and alcohol was associated with an increased risk for colorectal cancer in almost all of the analyses included in this article.

The study was published online September 28 in Gut.

However, the authors pointed out that it is important to keep in mind that in most cases, the level of evidence is low or very low, primarily because of the heterogeneity of the various published studies, as well as the type of study.

“Furthermore, in most cases, we were unable to identify an optimal dose and duration of exposure/intake for any of the products, even in the case of low-dose aspirin and other compounds that have been extensively assessed,” they wrote.

The findings of this new meta-analysis echo previous findings on this issue.

A number of studies, for example, have found varying associations between the consumption of red meat and cancer. The American Institute for Cancer Research and the World Cancer Research Fund have published several reports during the past 10 years on the effect of diet, nutrition, and/or physical activity on risk for several cancer types. Their most recent study, published in 2017, concluded that eating red meat and processed meat may increase the risk for colorectal cancer, as may drinking two or more alcoholic beverages per day.

Another large meta-analysis published earlier this year found that regular use of aspirin reduced the risk for cancers of the digestive tract by 22%-38%, compared with nonuse.
 

Umbrella review

In the latest article in Gut, researchers led by Marc Bardou, MD, PhD, Centre Hospitalier Universitaire de Dijon (France), conducted an umbrella review of systematic reviews and meta-analyses of interventions that assessed chemopreventive products for colorectal cancer in an average-risk population.

A total of 80 meta-analyses of interventional and observational studies were included. The studies investigated a wide range of chemopreventive agents in an average-risk population and the risk for colorectal cancer. Agents included medications (aspirin, NSAIDs, statins), vitamins or supplements (magnesium; calcium; folic acid; vitamin A, B, C, E, and D; beta-carotene; and selenium), and dietary items (coffee, tea, fish, dairy products, fiber, fruits, vegetables, meat, and alcohol).

The studies included randomized controlled trials and observational studies. Most of the meta-analyses found a protective effect for aspirin, which lowered the risk by between 14% and 29% even at doses as low as 75 mg/day, with a dose-response effect of up to 325 mg/day. The certainty of evidence was moderate.

NSAID use was also associated with a protective effect, with a significant 26%-43% decrease in the incidence in colorectal cancer. The optimal duration for the observed protective effect remains unclear. Two meta-analyses suggested that NSAIDs may need to be taken for at least 5 years, although one article suggested a protective effect after the first year. The certainty of evidence was low.

Use of magnesium was found to be protective, with a relative risk (RR) of 0.78-0.87. High intake of folic acid was associated with a significant decrease in risk (RR, 0.85-0.88). The certainty of evidence was low and very low, respectively.

Consumption of dairy products was associated with 13%-19% lower risk for the disease. However, the authors note that, because of the small number of available meta-analyses, the multiplicity of outcomes, and the variety of dairy products, it was not possible to reach any firm conclusions about the amount needed or the duration necessary for a protective effect.

Another dietary item, fiber, was associated with a 22%-43% lower risk. Consumption of fruits and vegetables was associated with up to a 52% lower risk, with an added benefit for every additional 100 g/day increase in intake. Soy intake was also associated with a small but significant decrease in risk (8%-15%).

For many of the other items reviewed, evidence was either weak or no beneficial effect was seen.
 

Increased risk

Consumption of both meat and alcohol was found to increase the risk for colorectal cancer.

Most of the meta-analyses of observational studies have reported a significant increase in risk (RR, 1.12-1.21) with meat consumption (particularly red and processed) and the incidence of colorectal cancer. Studies of the dose effect reported a 10%-30% increased risk for each increment of 100 g/day of total or red meat.

Alcohol consumption was also associated with a significantly increased risk. The higher the intake, the greater the risk. The risk was evident even at the lowest consumption doses that were investigated (1-2 drinks per day).
 

Balanced for the individual patient

Commenting on the article, Thomas J. George Jr, MD, professor of medicine and director, GI Oncology Program, the University of Florida Health Cancer Center, Gainesville, feels that the take-home message for clinicians and patients alike is that these data help to reinforce behaviors that have already been recommended.

“We know that excessive alcohol and red meat consumption is not healthy, so seeing that there may be a negative effect on colorectal cancer is just more evidence that we should be avoiding that and recommend avoiding that,” said Dr. George. “So yes, I recommend minimizing those, and likewise, a diet that is inclusive of fruits, vegetables, fiber, soy – perhaps as an alternative to meat consumption – is healthier than a diet devoid of these, so again, more reassuring data to support doing what we should already be doing.”

However, he pointed out that there are risks associated with medications such as NSAIDs and aspirin, including bleeding, gastric ulcer formation, and kidney damage. “The risks are low but very real,” Dr. George said. “So I think those recommendations need to be considered on a very individual level, balancing any other risk factors that the patient may have for both colorectal cancer, as well as risks from the medications.”

The study had no outside funding. The authors have disclosed no relevant financial relationships.

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

A new meta-analysis has largely confirmed what is already known about the lifestyle factors that increase and those that decrease the risk of developing colorectal cancer.

The use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a decreased risk for colorectal cancer, the new article concludes. But it also adds a number of other factors that are associated with a decreased risk for the disease, including taking magnesium and folate supplements and eating dairy products, fiber, soy, and fruits and vegetables.

On the other hand, consumption of meat and alcohol was associated with an increased risk for colorectal cancer in almost all of the analyses included in this article.

The study was published online September 28 in Gut.

However, the authors pointed out that it is important to keep in mind that in most cases, the level of evidence is low or very low, primarily because of the heterogeneity of the various published studies, as well as the type of study.

“Furthermore, in most cases, we were unable to identify an optimal dose and duration of exposure/intake for any of the products, even in the case of low-dose aspirin and other compounds that have been extensively assessed,” they wrote.

The findings of this new meta-analysis echo previous findings on this issue.

A number of studies, for example, have found varying associations between the consumption of red meat and cancer. The American Institute for Cancer Research and the World Cancer Research Fund have published several reports during the past 10 years on the effect of diet, nutrition, and/or physical activity on risk for several cancer types. Their most recent study, published in 2017, concluded that eating red meat and processed meat may increase the risk for colorectal cancer, as may drinking two or more alcoholic beverages per day.

Another large meta-analysis published earlier this year found that regular use of aspirin reduced the risk for cancers of the digestive tract by 22%-38%, compared with nonuse.
 

Umbrella review

In the latest article in Gut, researchers led by Marc Bardou, MD, PhD, Centre Hospitalier Universitaire de Dijon (France), conducted an umbrella review of systematic reviews and meta-analyses of interventions that assessed chemopreventive products for colorectal cancer in an average-risk population.

A total of 80 meta-analyses of interventional and observational studies were included. The studies investigated a wide range of chemopreventive agents in an average-risk population and the risk for colorectal cancer. Agents included medications (aspirin, NSAIDs, statins), vitamins or supplements (magnesium; calcium; folic acid; vitamin A, B, C, E, and D; beta-carotene; and selenium), and dietary items (coffee, tea, fish, dairy products, fiber, fruits, vegetables, meat, and alcohol).

The studies included randomized controlled trials and observational studies. Most of the meta-analyses found a protective effect for aspirin, which lowered the risk by between 14% and 29% even at doses as low as 75 mg/day, with a dose-response effect of up to 325 mg/day. The certainty of evidence was moderate.

NSAID use was also associated with a protective effect, with a significant 26%-43% decrease in the incidence in colorectal cancer. The optimal duration for the observed protective effect remains unclear. Two meta-analyses suggested that NSAIDs may need to be taken for at least 5 years, although one article suggested a protective effect after the first year. The certainty of evidence was low.

Use of magnesium was found to be protective, with a relative risk (RR) of 0.78-0.87. High intake of folic acid was associated with a significant decrease in risk (RR, 0.85-0.88). The certainty of evidence was low and very low, respectively.

Consumption of dairy products was associated with 13%-19% lower risk for the disease. However, the authors note that, because of the small number of available meta-analyses, the multiplicity of outcomes, and the variety of dairy products, it was not possible to reach any firm conclusions about the amount needed or the duration necessary for a protective effect.

Another dietary item, fiber, was associated with a 22%-43% lower risk. Consumption of fruits and vegetables was associated with up to a 52% lower risk, with an added benefit for every additional 100 g/day increase in intake. Soy intake was also associated with a small but significant decrease in risk (8%-15%).

For many of the other items reviewed, evidence was either weak or no beneficial effect was seen.
 

Increased risk

Consumption of both meat and alcohol was found to increase the risk for colorectal cancer.

Most of the meta-analyses of observational studies have reported a significant increase in risk (RR, 1.12-1.21) with meat consumption (particularly red and processed) and the incidence of colorectal cancer. Studies of the dose effect reported a 10%-30% increased risk for each increment of 100 g/day of total or red meat.

Alcohol consumption was also associated with a significantly increased risk. The higher the intake, the greater the risk. The risk was evident even at the lowest consumption doses that were investigated (1-2 drinks per day).
 

Balanced for the individual patient

Commenting on the article, Thomas J. George Jr, MD, professor of medicine and director, GI Oncology Program, the University of Florida Health Cancer Center, Gainesville, feels that the take-home message for clinicians and patients alike is that these data help to reinforce behaviors that have already been recommended.

“We know that excessive alcohol and red meat consumption is not healthy, so seeing that there may be a negative effect on colorectal cancer is just more evidence that we should be avoiding that and recommend avoiding that,” said Dr. George. “So yes, I recommend minimizing those, and likewise, a diet that is inclusive of fruits, vegetables, fiber, soy – perhaps as an alternative to meat consumption – is healthier than a diet devoid of these, so again, more reassuring data to support doing what we should already be doing.”

However, he pointed out that there are risks associated with medications such as NSAIDs and aspirin, including bleeding, gastric ulcer formation, and kidney damage. “The risks are low but very real,” Dr. George said. “So I think those recommendations need to be considered on a very individual level, balancing any other risk factors that the patient may have for both colorectal cancer, as well as risks from the medications.”

The study had no outside funding. The authors have disclosed no relevant financial relationships.

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

Because of physiological changes with aging and differences in cancer biology, caring for older adults (OAs) with cancer requires careful assessment and planning.

Clark Dumontier, MD, of Brigham and Women’s Hospital in Boston, and colleagues sought to define the meaning of the terms “undertreatment” and “overtreatment” for OAs with cancer in a scoping literature review published in the Journal of Clinical Oncology.

Though OAs are typically defined as adults aged 65 years and older, in this review, the authors defined OAs as patients aged 60 years and older.

The authors theorized that a scoping review of papers about this patient population could provide clues about limitations in the oncology literature and guidance about patient management and future research. Despite comprising the majority of cancer patients, OAs are underrepresented in clinical trials.
 

About scoping reviews

Scoping reviews are used to identify existing evidence in a field, clarify concepts or definitions in the literature, survey how research on a topic is conducted, and identify knowledge gaps. In addition, scoping reviews summarize available evidence without answering a discrete research question.

Industry standards for scoping reviews have been established by the Johanna Briggs Institute and Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for scoping reviews. According to these standards, scoping reviews should:

• Establish eligibility criteria with a rationale for each criterion clearly explained
• Search multiple databases in multiple languages
• Include “gray literature,” defined as studies that are unpublished or difficult to locate
• Have several independent reviewers screen titles and abstracts
• Ask multiple independent reviewers to review full text articles
• Present results with charts or diagrams that align with the review’s objective
• Graphically depict the decision process for including/excluding sources
• Identify implications for further research.

In their review, Dr. DuMontier and colleagues fulfilled many of the aforementioned criteria. The team searched three English-language databases for titles and abstracts that included the terms undertreatment and/or overtreatment, and were related to OAs with cancer, inclusive of all types of articles, cancer types, and treatments.

Definitions of undertreatment and overtreatment were extracted, and categories underlying these definitions were derived. Within a random subset of articles, two coauthors independently determined final categories of definitions and independently assigned those categories.
 

Findings and implications

To define OA, Dr. DuMontier and colleagues used a cutoff of 60 years or older. Articles mentioning undertreatment (n = 236), overtreatment (n = 71), or both (n = 51) met criteria for inclusion (n = 256), but only 14 articles (5.5%) explicitly provided formal definitions.

For most of the reviewed articles, the authors judged definitions from the surrounding context. In a random subset of 50 articles, there was a high level of agreement (87.1%; κ = 0.81) between two coauthors in independently assigning categories of definitions.

Undertreatment was applied to therapy that was less than recommended (148 articles; 62.7%) or less than recommended with worse outcomes (88 articles; 37.3%).

Overtreatment most commonly denoted intensive treatment of an OA in whom harms outweighed the benefits of treatment (38 articles; 53.5%) or intensive treatment of a cancer not expected to affect the OA during the patient’s remaining life (33 articles; 46.5%).

Overall, the authors found that undertreatment and overtreatment of OAs with cancer are imprecisely defined concepts. Formal geriatric assessment was recommended in just over half of articles, and only 26.2% recommended formal assessments of age-related vulnerabilities for management. The authors proposed definitions that accounted for both oncologic factors and geriatric domains.
 

Care of individual patients and clinical research

National Comprehensive Cancer Network (NCCN) guidelines for OAs with cancer recommend initial consideration of overall life expectancy. If a patient is a candidate for cancer treatment on that basis, the next recommended assessment is that of the patient’s capacity to understand the relevant information, appreciate the underlying values and overall medical situation, reason through decisions, and communicate a choice that is consistent with the patient’s articulated goals.

In the pretreatment evaluation of OAs in whom there are no concerns about tolerance to antineoplastic therapy, NCCN guidelines suggest geriatric screening with standardized tools and, if abnormal, comprehensive geriatric screening. The guidelines recommend considering alternative treatment options if nonmodifiable abnormalities are identified.

Referral to a geriatric clinical specialist, use of the Cancer and Aging Research Group’s Chemo Toxicity Calculator, and calculation of Chemotherapy Risk Assessment Scale for High-Age Patients score are specifically suggested if high-risk procedures (such as chemotherapy, radiation, or complex surgery, which most oncologists would consider to be “another day in the office”) are contemplated.

The American Society of Clinical Oncology (ASCO) guidelines for geriatric oncology are similarly detailed and endorse similar evaluations and management.

Employing disease-centric and geriatric domains

Dr. DuMontier and colleagues noted that, for OAs with comorbidity or psychosocial challenges, surrogate survival endpoints are unrelated to quality of life (QOL) outcomes. Nonetheless, QOL is valued by OAs at least as much as survival improvement.

Through no fault of their own, the authors’ conclusion that undertreatment and overtreatment are imperfectly defined concepts has a certain neutrality to it. However, the terms undertreatment and overtreatment are commonly used to signify that inappropriate treatment decisions were made. Therefore, the terms are inherently negative and pejorative.

As with most emotionally charged issues in oncology, it is ideal for professionals in our field to take charge when deficiencies exist. ASCO, NCCN, and the authors of this scoping review have provided a conceptual basis for doing so.

An integrated oncologist-geriatrician approach was shown to be effective in the randomized INTEGERATE trial, showing improved QOL, reduced hospital admissions, and reduced early treatment discontinuation from adverse events (ASCO 2020, Abstract 12011).

Therefore, those clinicians who have not formally, systematically, and routinely supplemented the traditional disease-centric endpoints with patient-centered criteria need to do so.

Similarly, a retrospective study published in JAMA Network Open demonstrated that geriatric and surgical comanagement of OAs with cancer was associated with significantly lower 90-day postoperative mortality and receipt of more supportive care services (physical therapy, occupational therapy, speech and swallow rehabilitation, and nutrition services), in comparison with management from the surgical service only.

These clinical and administrative changes will not only enhance patient management but also facilitate the clinical trials required to clarify optimal treatment intensity. As that occurs, we will be able to apply as much precision to the care of OAs with cancer as we do in other areas of cancer treatment.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Dumontier C et al. J Clin Oncol. 2020 Aug 1;38(22):2558-2569.

Because of physiological changes with aging and differences in cancer biology, caring for older adults (OAs) with cancer requires careful assessment and planning.

Clark Dumontier, MD, of Brigham and Women’s Hospital in Boston, and colleagues sought to define the meaning of the terms “undertreatment” and “overtreatment” for OAs with cancer in a scoping literature review published in the Journal of Clinical Oncology.

Though OAs are typically defined as adults aged 65 years and older, in this review, the authors defined OAs as patients aged 60 years and older.

The authors theorized that a scoping review of papers about this patient population could provide clues about limitations in the oncology literature and guidance about patient management and future research. Despite comprising the majority of cancer patients, OAs are underrepresented in clinical trials.
 

About scoping reviews

Scoping reviews are used to identify existing evidence in a field, clarify concepts or definitions in the literature, survey how research on a topic is conducted, and identify knowledge gaps. In addition, scoping reviews summarize available evidence without answering a discrete research question.

Industry standards for scoping reviews have been established by the Johanna Briggs Institute and Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for scoping reviews. According to these standards, scoping reviews should:

• Establish eligibility criteria with a rationale for each criterion clearly explained
• Search multiple databases in multiple languages
• Include “gray literature,” defined as studies that are unpublished or difficult to locate
• Have several independent reviewers screen titles and abstracts
• Ask multiple independent reviewers to review full text articles
• Present results with charts or diagrams that align with the review’s objective
• Graphically depict the decision process for including/excluding sources
• Identify implications for further research.

In their review, Dr. DuMontier and colleagues fulfilled many of the aforementioned criteria. The team searched three English-language databases for titles and abstracts that included the terms undertreatment and/or overtreatment, and were related to OAs with cancer, inclusive of all types of articles, cancer types, and treatments.

Definitions of undertreatment and overtreatment were extracted, and categories underlying these definitions were derived. Within a random subset of articles, two coauthors independently determined final categories of definitions and independently assigned those categories.
 

Findings and implications

To define OA, Dr. DuMontier and colleagues used a cutoff of 60 years or older. Articles mentioning undertreatment (n = 236), overtreatment (n = 71), or both (n = 51) met criteria for inclusion (n = 256), but only 14 articles (5.5%) explicitly provided formal definitions.

For most of the reviewed articles, the authors judged definitions from the surrounding context. In a random subset of 50 articles, there was a high level of agreement (87.1%; κ = 0.81) between two coauthors in independently assigning categories of definitions.

Undertreatment was applied to therapy that was less than recommended (148 articles; 62.7%) or less than recommended with worse outcomes (88 articles; 37.3%).

Overtreatment most commonly denoted intensive treatment of an OA in whom harms outweighed the benefits of treatment (38 articles; 53.5%) or intensive treatment of a cancer not expected to affect the OA during the patient’s remaining life (33 articles; 46.5%).

Overall, the authors found that undertreatment and overtreatment of OAs with cancer are imprecisely defined concepts. Formal geriatric assessment was recommended in just over half of articles, and only 26.2% recommended formal assessments of age-related vulnerabilities for management. The authors proposed definitions that accounted for both oncologic factors and geriatric domains.
 

Care of individual patients and clinical research

National Comprehensive Cancer Network (NCCN) guidelines for OAs with cancer recommend initial consideration of overall life expectancy. If a patient is a candidate for cancer treatment on that basis, the next recommended assessment is that of the patient’s capacity to understand the relevant information, appreciate the underlying values and overall medical situation, reason through decisions, and communicate a choice that is consistent with the patient’s articulated goals.

In the pretreatment evaluation of OAs in whom there are no concerns about tolerance to antineoplastic therapy, NCCN guidelines suggest geriatric screening with standardized tools and, if abnormal, comprehensive geriatric screening. The guidelines recommend considering alternative treatment options if nonmodifiable abnormalities are identified.

Referral to a geriatric clinical specialist, use of the Cancer and Aging Research Group’s Chemo Toxicity Calculator, and calculation of Chemotherapy Risk Assessment Scale for High-Age Patients score are specifically suggested if high-risk procedures (such as chemotherapy, radiation, or complex surgery, which most oncologists would consider to be “another day in the office”) are contemplated.

The American Society of Clinical Oncology (ASCO) guidelines for geriatric oncology are similarly detailed and endorse similar evaluations and management.

Employing disease-centric and geriatric domains

Dr. DuMontier and colleagues noted that, for OAs with comorbidity or psychosocial challenges, surrogate survival endpoints are unrelated to quality of life (QOL) outcomes. Nonetheless, QOL is valued by OAs at least as much as survival improvement.

Through no fault of their own, the authors’ conclusion that undertreatment and overtreatment are imperfectly defined concepts has a certain neutrality to it. However, the terms undertreatment and overtreatment are commonly used to signify that inappropriate treatment decisions were made. Therefore, the terms are inherently negative and pejorative.

As with most emotionally charged issues in oncology, it is ideal for professionals in our field to take charge when deficiencies exist. ASCO, NCCN, and the authors of this scoping review have provided a conceptual basis for doing so.

An integrated oncologist-geriatrician approach was shown to be effective in the randomized INTEGERATE trial, showing improved QOL, reduced hospital admissions, and reduced early treatment discontinuation from adverse events (ASCO 2020, Abstract 12011).

Therefore, those clinicians who have not formally, systematically, and routinely supplemented the traditional disease-centric endpoints with patient-centered criteria need to do so.

Similarly, a retrospective study published in JAMA Network Open demonstrated that geriatric and surgical comanagement of OAs with cancer was associated with significantly lower 90-day postoperative mortality and receipt of more supportive care services (physical therapy, occupational therapy, speech and swallow rehabilitation, and nutrition services), in comparison with management from the surgical service only.

These clinical and administrative changes will not only enhance patient management but also facilitate the clinical trials required to clarify optimal treatment intensity. As that occurs, we will be able to apply as much precision to the care of OAs with cancer as we do in other areas of cancer treatment.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Dumontier C et al. J Clin Oncol. 2020 Aug 1;38(22):2558-2569.

Because of physiological changes with aging and differences in cancer biology, caring for older adults (OAs) with cancer requires careful assessment and planning.

Clark Dumontier, MD, of Brigham and Women’s Hospital in Boston, and colleagues sought to define the meaning of the terms “undertreatment” and “overtreatment” for OAs with cancer in a scoping literature review published in the Journal of Clinical Oncology.

Though OAs are typically defined as adults aged 65 years and older, in this review, the authors defined OAs as patients aged 60 years and older.

The authors theorized that a scoping review of papers about this patient population could provide clues about limitations in the oncology literature and guidance about patient management and future research. Despite comprising the majority of cancer patients, OAs are underrepresented in clinical trials.
 

About scoping reviews

Scoping reviews are used to identify existing evidence in a field, clarify concepts or definitions in the literature, survey how research on a topic is conducted, and identify knowledge gaps. In addition, scoping reviews summarize available evidence without answering a discrete research question.

Industry standards for scoping reviews have been established by the Johanna Briggs Institute and Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for scoping reviews. According to these standards, scoping reviews should:

• Establish eligibility criteria with a rationale for each criterion clearly explained
• Search multiple databases in multiple languages
• Include “gray literature,” defined as studies that are unpublished or difficult to locate
• Have several independent reviewers screen titles and abstracts
• Ask multiple independent reviewers to review full text articles
• Present results with charts or diagrams that align with the review’s objective
• Graphically depict the decision process for including/excluding sources
• Identify implications for further research.

In their review, Dr. DuMontier and colleagues fulfilled many of the aforementioned criteria. The team searched three English-language databases for titles and abstracts that included the terms undertreatment and/or overtreatment, and were related to OAs with cancer, inclusive of all types of articles, cancer types, and treatments.

Definitions of undertreatment and overtreatment were extracted, and categories underlying these definitions were derived. Within a random subset of articles, two coauthors independently determined final categories of definitions and independently assigned those categories.
 

Findings and implications

To define OA, Dr. DuMontier and colleagues used a cutoff of 60 years or older. Articles mentioning undertreatment (n = 236), overtreatment (n = 71), or both (n = 51) met criteria for inclusion (n = 256), but only 14 articles (5.5%) explicitly provided formal definitions.

For most of the reviewed articles, the authors judged definitions from the surrounding context. In a random subset of 50 articles, there was a high level of agreement (87.1%; κ = 0.81) between two coauthors in independently assigning categories of definitions.

Undertreatment was applied to therapy that was less than recommended (148 articles; 62.7%) or less than recommended with worse outcomes (88 articles; 37.3%).

Overtreatment most commonly denoted intensive treatment of an OA in whom harms outweighed the benefits of treatment (38 articles; 53.5%) or intensive treatment of a cancer not expected to affect the OA during the patient’s remaining life (33 articles; 46.5%).

Overall, the authors found that undertreatment and overtreatment of OAs with cancer are imprecisely defined concepts. Formal geriatric assessment was recommended in just over half of articles, and only 26.2% recommended formal assessments of age-related vulnerabilities for management. The authors proposed definitions that accounted for both oncologic factors and geriatric domains.
 

Care of individual patients and clinical research

National Comprehensive Cancer Network (NCCN) guidelines for OAs with cancer recommend initial consideration of overall life expectancy. If a patient is a candidate for cancer treatment on that basis, the next recommended assessment is that of the patient’s capacity to understand the relevant information, appreciate the underlying values and overall medical situation, reason through decisions, and communicate a choice that is consistent with the patient’s articulated goals.

In the pretreatment evaluation of OAs in whom there are no concerns about tolerance to antineoplastic therapy, NCCN guidelines suggest geriatric screening with standardized tools and, if abnormal, comprehensive geriatric screening. The guidelines recommend considering alternative treatment options if nonmodifiable abnormalities are identified.

Referral to a geriatric clinical specialist, use of the Cancer and Aging Research Group’s Chemo Toxicity Calculator, and calculation of Chemotherapy Risk Assessment Scale for High-Age Patients score are specifically suggested if high-risk procedures (such as chemotherapy, radiation, or complex surgery, which most oncologists would consider to be “another day in the office”) are contemplated.

The American Society of Clinical Oncology (ASCO) guidelines for geriatric oncology are similarly detailed and endorse similar evaluations and management.

Employing disease-centric and geriatric domains

Dr. DuMontier and colleagues noted that, for OAs with comorbidity or psychosocial challenges, surrogate survival endpoints are unrelated to quality of life (QOL) outcomes. Nonetheless, QOL is valued by OAs at least as much as survival improvement.

Through no fault of their own, the authors’ conclusion that undertreatment and overtreatment are imperfectly defined concepts has a certain neutrality to it. However, the terms undertreatment and overtreatment are commonly used to signify that inappropriate treatment decisions were made. Therefore, the terms are inherently negative and pejorative.

As with most emotionally charged issues in oncology, it is ideal for professionals in our field to take charge when deficiencies exist. ASCO, NCCN, and the authors of this scoping review have provided a conceptual basis for doing so.

An integrated oncologist-geriatrician approach was shown to be effective in the randomized INTEGERATE trial, showing improved QOL, reduced hospital admissions, and reduced early treatment discontinuation from adverse events (ASCO 2020, Abstract 12011).

Therefore, those clinicians who have not formally, systematically, and routinely supplemented the traditional disease-centric endpoints with patient-centered criteria need to do so.

Similarly, a retrospective study published in JAMA Network Open demonstrated that geriatric and surgical comanagement of OAs with cancer was associated with significantly lower 90-day postoperative mortality and receipt of more supportive care services (physical therapy, occupational therapy, speech and swallow rehabilitation, and nutrition services), in comparison with management from the surgical service only.

These clinical and administrative changes will not only enhance patient management but also facilitate the clinical trials required to clarify optimal treatment intensity. As that occurs, we will be able to apply as much precision to the care of OAs with cancer as we do in other areas of cancer treatment.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

SOURCE: Dumontier C et al. J Clin Oncol. 2020 Aug 1;38(22):2558-2569.

A global analysis of premature deaths from noncommunicable diseases (NCDs) has shown mixed results for gastrointestinal (GI) cancers.

The data suggest fewer people are dying from stomach cancer, but in some countries, the risk of colorectal cancer death is increasing or declining much more slowly than other causes of premature death.

As for other cancers, in more than half of the countries analyzed, the risk of liver and prostate cancer death is on the rise in men, and the risk of lung cancer death is on the rise in women.

The global decrease in the risk of stomach cancer death may be explained by the fact that stomach cancer’s main cause is Helicobacter pylori infection, which correlates with general food hygiene, the study’s corresponding author Majid Ezzati, PhD, professor of global environmental health at Imperial College London, said in an interview.

“Factors such as more widespread electrification and refrigeration tend to drive the rates down,” he explained.

Dr. Ezzati and colleagues detailed their findings in the second edition of the NCD Countdown 2030 report, recently published in The Lancet.

The report revolves around the Sustainable Development Goal (SDG) target 3.4, which is to reduce premature deaths from NCDs by one-third between 2015 and 2030. The causes of death include cancer, cardiovascular disease, chronic respiratory disease, and diabetes, which are collectively known as NCD4. “Premature” deaths are defined as deaths in people aged 30-70 years.

SDG target 3.4 is still attainable, according to Dr. Ezzati and colleagues. However, their report showed that many countries are falling short of this goal.

The findings come from an analysis of 2016 World Health Organization global estimate data on age-, sex-, and cause-specific mortality for 176 countries and territories with at least 200,000 inhabitants. Mathematical modeling was used to assess the number of approaches countries used to accelerate declines in mortality.
 

Results of the analysis

“Trends in the risk of death from 2010 to 2016 varied considerably among NCD4 causes of death,” Dr. Ezzati and colleagues wrote.

Stomach cancer, ischemic and hemorrhagic stroke, ischemic heart disease, and chronic respiratory diseases had the fastest rates of decline among risks of premature death.

In fact, stomach cancer was the fastest declining cause of death in 45 countries (25.6%) among men and in 40 countries (22.7%) among women.

On the other hand, the risk of premature death from colorectal, liver, breast, prostate, and other cancers declined more slowly than the risk of premature death from other NCDs.

The risk of death from colorectal, liver, and prostate cancers in men and lung cancer in women rose in more than 50% of the countries surveyed.

“The median annual rate of change in the probability of dying prematurely from various causes ranged from +0.2% per year for lung cancer to –2.5% per year for hemorrhagic stroke in women, and from +0.5% per year for colorectal cancer to –1.8% per year for hemorrhagic stroke in men,” the investigators summarized.
 

Explaining the GI cancer results

“There are dramatic differences between the upper and lower GI tract, both in terms of anatomy/embryologic origin but also in terms of exposures,” observed Mark Lewis, MD, medical director of the gastrointestinal oncology program at Intermountain Healthcare in Salt Lake City, in an interview.

H. pylori infection, family history, and diet factor into stomach cancer risk, Dr. Lewis said.

While family history isn’t modifiable, “we are much better now at identifying and eradicating the potentially carcinogenic H. pylori bacterium. In terms of diet, the advent of modern refrigeration has made the prevalence of heavily salted/preserved foods decline,” he added.

A 14-day course of treatment (with a proton pump inhibitor and antibiotics) can eliminate H. pylori, Dr. Lewis continued. “The prophylactic effect against gastric cancer is massive, cutting risk by roughly half,” he said.

At least in the United States, colorectal cancer rates have declined in people 50 years and older, but rates have risen sharply in younger age groups, increasing by 2% annually in the last decade, according to statistics in CA: A Cancer Journal for Clinicians.

“One prevailing theory is prior antibiotic prescriptions [even in childhood] might perturb the microbiome of the lower GI tract and predispose to cancer,” Dr. Lewis said, pointing to a recent study in the British Journal of Cancer that identified an association between repeated antibiotic use and colorectal cancer.
 

Reducing NCD deaths

Dr. Ezzati and colleagues said six high-income countries – Denmark, Luxembourg, New Zealand, Norway, Singapore, and South Korea – are likely to meet SDG target 3.4 if they maintain or exceed average rates of decline seen during 2010-2016. Seventeen countries are on track to reach the target for women, and 15 countries are on track for men.

High-income countries in Asia-Pacific, western Europe, Australasia, and Canada have seen the lowest NCD4 mortality risk, whereas low- and middle-income countries in sub-Saharan Africa and men in central Asia and eastern Europe have seen the highest risk.

“To move forward, we must learn from those countries that are doing well and replicate their strategies to NCD prevention and healthcare,” Dr. Ezzati said in a statement. “Our analysis shows that every country still has options to achieve SDG target 3.4, but they need to address multiple diseases and have strong health systems.”

Increasing access to effective cancer screening and diagnosing and treating cancers earlier could help reduce long-term health consequences and premature deaths from cancer, according to Dr. Ezzati and colleagues. Screening would help even the playing field on cancer diagnosis and survival rates between higher-income countries and low- and middle-income countries.

“This approach will allow earlier diagnosis during precancerous or early stages of disease, followed by treatment of those cancers with effective treatment,” the authors stated.

Tobacco and alcohol interventions and increasing access to quality primary care would also help tamp down on NCD-related deaths.

The authors acknowledged that low-income countries, which may be struggling with other health crises such as COVID-19 and Ebola, may find it a challenge to stage such interventions.

“COVID-19 has exposed how a failure to invest in effective public health to prevent NCDs and provide health care for people living with NCDs can come back to bite us,” said Katie Dain, CEO of the NCD Alliance.

“The good news is that all countries can still meet the 2030 targets, with sound policies and smart investments. NCD prevention and treatment can no longer be seen a ‘nice to have.’ It must be considered as part of pandemic preparedness,” she added.

COVID-19 should serve as an impetus for governments to invest in healthier lifestyle and diet habits and curb alcohol and tobacco use, according to an editorial in The Lancet related to the analysis.

The current report updates 2018’s first NCD Countdown Report, which linked NCD4 conditions to approximately 32 million or 80% of NCD deaths. Unlike the recent report, 2018’s data didn’t focus on specific diseases.

The current report was funded by Research England. Dr. Ezzati received a charitable grant from the AstraZeneca Young Health Programme and personal fees from Prudential and Scor, outside of this report. None of the other authors reported competing interests. Dr. Lewis has no relevant disclosures except that he is a commentator for Medscape, which is owned by the same parent company as MDedge.
 

SOURCE: Bennett JE et al. Lancet. 2020 Sep 3. doi: 10.1016/S0140-6736(20)31761-X.

A global analysis of premature deaths from noncommunicable diseases (NCDs) has shown mixed results for gastrointestinal (GI) cancers.

The data suggest fewer people are dying from stomach cancer, but in some countries, the risk of colorectal cancer death is increasing or declining much more slowly than other causes of premature death.

As for other cancers, in more than half of the countries analyzed, the risk of liver and prostate cancer death is on the rise in men, and the risk of lung cancer death is on the rise in women.

The global decrease in the risk of stomach cancer death may be explained by the fact that stomach cancer’s main cause is Helicobacter pylori infection, which correlates with general food hygiene, the study’s corresponding author Majid Ezzati, PhD, professor of global environmental health at Imperial College London, said in an interview.

“Factors such as more widespread electrification and refrigeration tend to drive the rates down,” he explained.

Dr. Ezzati and colleagues detailed their findings in the second edition of the NCD Countdown 2030 report, recently published in The Lancet.

The report revolves around the Sustainable Development Goal (SDG) target 3.4, which is to reduce premature deaths from NCDs by one-third between 2015 and 2030. The causes of death include cancer, cardiovascular disease, chronic respiratory disease, and diabetes, which are collectively known as NCD4. “Premature” deaths are defined as deaths in people aged 30-70 years.

SDG target 3.4 is still attainable, according to Dr. Ezzati and colleagues. However, their report showed that many countries are falling short of this goal.

The findings come from an analysis of 2016 World Health Organization global estimate data on age-, sex-, and cause-specific mortality for 176 countries and territories with at least 200,000 inhabitants. Mathematical modeling was used to assess the number of approaches countries used to accelerate declines in mortality.
 

Results of the analysis

“Trends in the risk of death from 2010 to 2016 varied considerably among NCD4 causes of death,” Dr. Ezzati and colleagues wrote.

Stomach cancer, ischemic and hemorrhagic stroke, ischemic heart disease, and chronic respiratory diseases had the fastest rates of decline among risks of premature death.

In fact, stomach cancer was the fastest declining cause of death in 45 countries (25.6%) among men and in 40 countries (22.7%) among women.

On the other hand, the risk of premature death from colorectal, liver, breast, prostate, and other cancers declined more slowly than the risk of premature death from other NCDs.

The risk of death from colorectal, liver, and prostate cancers in men and lung cancer in women rose in more than 50% of the countries surveyed.

“The median annual rate of change in the probability of dying prematurely from various causes ranged from +0.2% per year for lung cancer to –2.5% per year for hemorrhagic stroke in women, and from +0.5% per year for colorectal cancer to –1.8% per year for hemorrhagic stroke in men,” the investigators summarized.
 

Explaining the GI cancer results

“There are dramatic differences between the upper and lower GI tract, both in terms of anatomy/embryologic origin but also in terms of exposures,” observed Mark Lewis, MD, medical director of the gastrointestinal oncology program at Intermountain Healthcare in Salt Lake City, in an interview.

H. pylori infection, family history, and diet factor into stomach cancer risk, Dr. Lewis said.

While family history isn’t modifiable, “we are much better now at identifying and eradicating the potentially carcinogenic H. pylori bacterium. In terms of diet, the advent of modern refrigeration has made the prevalence of heavily salted/preserved foods decline,” he added.

A 14-day course of treatment (with a proton pump inhibitor and antibiotics) can eliminate H. pylori, Dr. Lewis continued. “The prophylactic effect against gastric cancer is massive, cutting risk by roughly half,” he said.

At least in the United States, colorectal cancer rates have declined in people 50 years and older, but rates have risen sharply in younger age groups, increasing by 2% annually in the last decade, according to statistics in CA: A Cancer Journal for Clinicians.

“One prevailing theory is prior antibiotic prescriptions [even in childhood] might perturb the microbiome of the lower GI tract and predispose to cancer,” Dr. Lewis said, pointing to a recent study in the British Journal of Cancer that identified an association between repeated antibiotic use and colorectal cancer.
 

Reducing NCD deaths

Dr. Ezzati and colleagues said six high-income countries – Denmark, Luxembourg, New Zealand, Norway, Singapore, and South Korea – are likely to meet SDG target 3.4 if they maintain or exceed average rates of decline seen during 2010-2016. Seventeen countries are on track to reach the target for women, and 15 countries are on track for men.

High-income countries in Asia-Pacific, western Europe, Australasia, and Canada have seen the lowest NCD4 mortality risk, whereas low- and middle-income countries in sub-Saharan Africa and men in central Asia and eastern Europe have seen the highest risk.

“To move forward, we must learn from those countries that are doing well and replicate their strategies to NCD prevention and healthcare,” Dr. Ezzati said in a statement. “Our analysis shows that every country still has options to achieve SDG target 3.4, but they need to address multiple diseases and have strong health systems.”

Increasing access to effective cancer screening and diagnosing and treating cancers earlier could help reduce long-term health consequences and premature deaths from cancer, according to Dr. Ezzati and colleagues. Screening would help even the playing field on cancer diagnosis and survival rates between higher-income countries and low- and middle-income countries.

“This approach will allow earlier diagnosis during precancerous or early stages of disease, followed by treatment of those cancers with effective treatment,” the authors stated.

Tobacco and alcohol interventions and increasing access to quality primary care would also help tamp down on NCD-related deaths.

The authors acknowledged that low-income countries, which may be struggling with other health crises such as COVID-19 and Ebola, may find it a challenge to stage such interventions.

“COVID-19 has exposed how a failure to invest in effective public health to prevent NCDs and provide health care for people living with NCDs can come back to bite us,” said Katie Dain, CEO of the NCD Alliance.

“The good news is that all countries can still meet the 2030 targets, with sound policies and smart investments. NCD prevention and treatment can no longer be seen a ‘nice to have.’ It must be considered as part of pandemic preparedness,” she added.

COVID-19 should serve as an impetus for governments to invest in healthier lifestyle and diet habits and curb alcohol and tobacco use, according to an editorial in The Lancet related to the analysis.

The current report updates 2018’s first NCD Countdown Report, which linked NCD4 conditions to approximately 32 million or 80% of NCD deaths. Unlike the recent report, 2018’s data didn’t focus on specific diseases.

The current report was funded by Research England. Dr. Ezzati received a charitable grant from the AstraZeneca Young Health Programme and personal fees from Prudential and Scor, outside of this report. None of the other authors reported competing interests. Dr. Lewis has no relevant disclosures except that he is a commentator for Medscape, which is owned by the same parent company as MDedge.
 

SOURCE: Bennett JE et al. Lancet. 2020 Sep 3. doi: 10.1016/S0140-6736(20)31761-X.

A global analysis of premature deaths from noncommunicable diseases (NCDs) has shown mixed results for gastrointestinal (GI) cancers.

The data suggest fewer people are dying from stomach cancer, but in some countries, the risk of colorectal cancer death is increasing or declining much more slowly than other causes of premature death.

As for other cancers, in more than half of the countries analyzed, the risk of liver and prostate cancer death is on the rise in men, and the risk of lung cancer death is on the rise in women.

The global decrease in the risk of stomach cancer death may be explained by the fact that stomach cancer’s main cause is Helicobacter pylori infection, which correlates with general food hygiene, the study’s corresponding author Majid Ezzati, PhD, professor of global environmental health at Imperial College London, said in an interview.

“Factors such as more widespread electrification and refrigeration tend to drive the rates down,” he explained.

Dr. Ezzati and colleagues detailed their findings in the second edition of the NCD Countdown 2030 report, recently published in The Lancet.

The report revolves around the Sustainable Development Goal (SDG) target 3.4, which is to reduce premature deaths from NCDs by one-third between 2015 and 2030. The causes of death include cancer, cardiovascular disease, chronic respiratory disease, and diabetes, which are collectively known as NCD4. “Premature” deaths are defined as deaths in people aged 30-70 years.

SDG target 3.4 is still attainable, according to Dr. Ezzati and colleagues. However, their report showed that many countries are falling short of this goal.

The findings come from an analysis of 2016 World Health Organization global estimate data on age-, sex-, and cause-specific mortality for 176 countries and territories with at least 200,000 inhabitants. Mathematical modeling was used to assess the number of approaches countries used to accelerate declines in mortality.
 

Results of the analysis

“Trends in the risk of death from 2010 to 2016 varied considerably among NCD4 causes of death,” Dr. Ezzati and colleagues wrote.

Stomach cancer, ischemic and hemorrhagic stroke, ischemic heart disease, and chronic respiratory diseases had the fastest rates of decline among risks of premature death.

In fact, stomach cancer was the fastest declining cause of death in 45 countries (25.6%) among men and in 40 countries (22.7%) among women.

On the other hand, the risk of premature death from colorectal, liver, breast, prostate, and other cancers declined more slowly than the risk of premature death from other NCDs.

The risk of death from colorectal, liver, and prostate cancers in men and lung cancer in women rose in more than 50% of the countries surveyed.

“The median annual rate of change in the probability of dying prematurely from various causes ranged from +0.2% per year for lung cancer to –2.5% per year for hemorrhagic stroke in women, and from +0.5% per year for colorectal cancer to –1.8% per year for hemorrhagic stroke in men,” the investigators summarized.
 

Explaining the GI cancer results

“There are dramatic differences between the upper and lower GI tract, both in terms of anatomy/embryologic origin but also in terms of exposures,” observed Mark Lewis, MD, medical director of the gastrointestinal oncology program at Intermountain Healthcare in Salt Lake City, in an interview.

H. pylori infection, family history, and diet factor into stomach cancer risk, Dr. Lewis said.

While family history isn’t modifiable, “we are much better now at identifying and eradicating the potentially carcinogenic H. pylori bacterium. In terms of diet, the advent of modern refrigeration has made the prevalence of heavily salted/preserved foods decline,” he added.

A 14-day course of treatment (with a proton pump inhibitor and antibiotics) can eliminate H. pylori, Dr. Lewis continued. “The prophylactic effect against gastric cancer is massive, cutting risk by roughly half,” he said.

At least in the United States, colorectal cancer rates have declined in people 50 years and older, but rates have risen sharply in younger age groups, increasing by 2% annually in the last decade, according to statistics in CA: A Cancer Journal for Clinicians.

“One prevailing theory is prior antibiotic prescriptions [even in childhood] might perturb the microbiome of the lower GI tract and predispose to cancer,” Dr. Lewis said, pointing to a recent study in the British Journal of Cancer that identified an association between repeated antibiotic use and colorectal cancer.
 

Reducing NCD deaths

Dr. Ezzati and colleagues said six high-income countries – Denmark, Luxembourg, New Zealand, Norway, Singapore, and South Korea – are likely to meet SDG target 3.4 if they maintain or exceed average rates of decline seen during 2010-2016. Seventeen countries are on track to reach the target for women, and 15 countries are on track for men.

High-income countries in Asia-Pacific, western Europe, Australasia, and Canada have seen the lowest NCD4 mortality risk, whereas low- and middle-income countries in sub-Saharan Africa and men in central Asia and eastern Europe have seen the highest risk.

“To move forward, we must learn from those countries that are doing well and replicate their strategies to NCD prevention and healthcare,” Dr. Ezzati said in a statement. “Our analysis shows that every country still has options to achieve SDG target 3.4, but they need to address multiple diseases and have strong health systems.”

Increasing access to effective cancer screening and diagnosing and treating cancers earlier could help reduce long-term health consequences and premature deaths from cancer, according to Dr. Ezzati and colleagues. Screening would help even the playing field on cancer diagnosis and survival rates between higher-income countries and low- and middle-income countries.

“This approach will allow earlier diagnosis during precancerous or early stages of disease, followed by treatment of those cancers with effective treatment,” the authors stated.

Tobacco and alcohol interventions and increasing access to quality primary care would also help tamp down on NCD-related deaths.

The authors acknowledged that low-income countries, which may be struggling with other health crises such as COVID-19 and Ebola, may find it a challenge to stage such interventions.

“COVID-19 has exposed how a failure to invest in effective public health to prevent NCDs and provide health care for people living with NCDs can come back to bite us,” said Katie Dain, CEO of the NCD Alliance.

“The good news is that all countries can still meet the 2030 targets, with sound policies and smart investments. NCD prevention and treatment can no longer be seen a ‘nice to have.’ It must be considered as part of pandemic preparedness,” she added.

COVID-19 should serve as an impetus for governments to invest in healthier lifestyle and diet habits and curb alcohol and tobacco use, according to an editorial in The Lancet related to the analysis.

The current report updates 2018’s first NCD Countdown Report, which linked NCD4 conditions to approximately 32 million or 80% of NCD deaths. Unlike the recent report, 2018’s data didn’t focus on specific diseases.

The current report was funded by Research England. Dr. Ezzati received a charitable grant from the AstraZeneca Young Health Programme and personal fees from Prudential and Scor, outside of this report. None of the other authors reported competing interests. Dr. Lewis has no relevant disclosures except that he is a commentator for Medscape, which is owned by the same parent company as MDedge.
 

SOURCE: Bennett JE et al. Lancet. 2020 Sep 3. doi: 10.1016/S0140-6736(20)31761-X.