AVAHO

Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.

Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.

A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.

Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.

However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.

Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.

“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
 

‘Herculean Effort’

“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.

“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.

The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.

The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.

The researchers found that the incidence of CP-AKI was 5.2% in the derivation cohort and 3.3% in the validation cohort. Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.

Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.

Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.

The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.

Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
 

‘Definitive Work’

Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”

“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”

In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”

An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.

By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.

All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”

“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
 

‘Certainly Useful’

Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.

As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.

“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”

Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.

Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.

Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.

Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”

If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.

Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.

A version of this article appeared on Medscape.com.

Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.

Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.

A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.

Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.

However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.

Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.

“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
 

‘Herculean Effort’

“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.

“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.

The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.

The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.

The researchers found that the incidence of CP-AKI was 5.2% in the derivation cohort and 3.3% in the validation cohort. Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.

Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.

Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.

The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.

Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
 

‘Definitive Work’

Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”

“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”

In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”

An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.

By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.

All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”

“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
 

‘Certainly Useful’

Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.

As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.

“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”

Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.

Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.

Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.

Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”

If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.

Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.

A version of this article appeared on Medscape.com.

Cisplatin is a preferred treatment for a wide range of cancers, including breast, head and neck, lung, ovary, and more. However, its side effects — particularly nephrotoxicity — can be severe. Kidney injury on cisplatin is associated with higher mortality and can jeopardize a patient’s eligibility for other therapies.

Now, in a large study using data from six US cancer centers, researchers have developed a risk algorithm to predict acute kidney injury (AKI) after cisplatin administration.

A risk prediction calculator based on the algorithm is available online for patients and providers to determine an individual patient›s risk for kidney injury from cisplatin using readily available clinical data.

Other risk scores and risk prediction models have been developed to help clinicians assess in advance whether a patient might develop AKI after receiving cisplatin, so that more careful monitoring, dose adjustments, or an alternative treatment, if available, might be considered.

However, previous models were limited by factors such as small sample sizes, lack of external validation, older data, and liberal definitions of AKI, said Shruti Gupta, MD, MPH, director of onco-nephrology at Brigham and Women’s Hospital (BWH) and Dana-Farber Cancer Institute, and David E. Leaf, MD, MMSc, director of clinical and translational research in AKI, Division of Renal Medicine, BWH, Boston.

Dr. Gupta and Dr. Leaf believe their risk score for predicting severe AKI after intravenous (IV) cisplatin, published online in The BMJ, is “more accurate and generalizable than prior models for several reasons,” they told this news organization in a joint email.

“First, we externally validated our findings across cancer centers other than the one where it was developed,” they said. “Second, we focused on moderate to severe kidney injury, the most clinically relevant form of kidney damage, whereas prior models examined more mild forms of kidney injury. Third, we collected data on nearly 25,000 patients receiving their first dose of IV cisplatin, which is larger than all previous studies combined.”
 

‘Herculean Effort’

“We conceived of this study back in 2018, contacted collaborators at each participating cancer center, and had numerous meetings to try to gather granular data on patients treated with their first dose of intravenous (IV) cisplatin,” Dr. Gupta and Dr. Leaf explained. They also incorporated patient feedback from focus groups and surveys.

“This was truly a Herculean effort that involved physicians, programmers, research coordinators, and patients,” they said.

The multicenter study included 24,717 patients — 11,766 in the derivation cohort and 12,951 in the validation cohort. Overall, the median age was about 60 years, about 58% were men, and about 78% were White.

The primary outcome was cisplatin-induced AKI (CP-AKI), defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of IV cisplatin.

The researchers found that the incidence of CP-AKI was 5.2% in the derivation cohort and 3.3% in the validation cohort. Their simple risk score consisting of nine covariates — age, hypertension, type 2 diabetes, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose — predicted a higher risk for CP-AKI in both cohorts.

Notably, adding serum creatinine to the model did not change the area under the curve, and therefore, serum creatinine, though also an independent risk factor for CP-AKI, was not included in the score.

Patients in the highest risk category had 24-fold higher odds of CP-AKI in the derivation cohort and close to 18-fold higher odds in the validation cohort than those in the lowest risk category.

The primary model had a C statistic of 0.75 (95% CI, 0.73-0.76) and showed better discrimination for CP-AKI than previously published models, for which the C statistics ranged from 0.60 to 0.68. The first author of a paper on an earlier model, Shveta Motwani, MD, MMSc, of BWH and Dana-Farber Cancer Institute in Boston, is also a coauthor of the new study.

Greater severity of CP-AKI was associated with shorter 90-day survival (adjusted hazard ratio, 4.63; 95% CI, 3.56-6.02) for stage III CP-AKI vs no CP-AKI.
 

‘Definitive Work’

Joel M. Topf, MD, a nephrologist with expertise in chronic kidney disease in Detroit, who wasn’t involved in the development of the risk score, called the study “a definitive work on an important concept in oncology and nephrology.”

“While this is not the first attempt to devise a risk score, it is by far the biggest,” he told this news organization. Furthermore, the authors “used a diverse population, recruiting patients with a variety of cancers (previous attempts had often used a homogenous diagnosis, putting into question how generalizable the results were) from six different cancer centers.”

In addition, he said, “The authors did not restrict patients with chronic kidney disease or other significant comorbidities and used the geographic diversity to produce a cohort that has an age, gender, racial, and ethnic distribution, which is more representative of the US than previous, single-center attempts to risk score patients.”

An earlier model used the Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI of an increase in serum creatinine of 0.3 mg/dL, he noted. “While a sensitive definition of AKI, it captures mild, hemodynamic increases in creatinine of questionable significance,” he said.

By contrast, the new score uses KDIGO stage II and above to define AKI. “This is a better choice, as we do not want to dissuade patients and doctors from choosing chemotherapy due to a fear of insignificant kidney damage,” he said.

All that said, Dr. Topf noted that neither the current score nor the earlier model included serum creatinine. “This is curious to me and may represent the small number of patients with representative elevated creatinine in the derivation cohort (only 1.3% with an estimated glomerular filtration rate [eGFR] < 45).”

“Since the cohort is made up of people who received cis-platinum, the low prevalence of eGFRs < 45 may be due to physicians steering away from cis-platinum in this group,” he suggested. “It would be unfortunate if this risk score gave an unintentional ‘green light’ to these patients, exposing them to predictable harm.”
 

‘Certainly Useful’

Anushree Shirali, MD, an associate professor in the Section of Nephrology and consulting physician, Yale Onco-Nephrology, Yale School of Medicine, in New Haven, Connecticut, said that having a prediction score for which patients are more likely to develop AKI after a single dose of cisplatin would be helpful for oncologists, as well as nephrologists.

As a nephrologist, Dr. Shirali mostly sees patients who already have AKI, she told this news organization. But there are circumstances in which the tool could still be helpful.

“Let’s say someone has abnormal kidney function at baseline — ie, creatinine is higher than the normal range — and they were on dialysis 5 years ago for something else, and now, they have cancer and may be given cisplatin. They worry about their chances of getting AKI and needing dialysis again,” she said. “That’s just one scenario in which I might be asked to answer that question and the tool would certainly be useful.”

Other scenarios could include someone who has just one kidney because they donated a kidney for transplant years ago, and now, they have a malignancy and wonder what their actual risk is of getting kidney issues on cisplatin.

Oncologists could use the tool to determine whether a patient should be treated with cisplatin, or if they’re at high risk, whether an alternative that’s not nephrotoxic might be used. By contrast, “if somebody’s low risk and an oncologist thinks cisplatin is the best agent they have, then they might want to go ahead and use it,” Dr. Shirali said.

Future research could take into consideration that CP-AKI is dose dependent, she suggested, because a prediction score that included the number of cisplatin doses could be even more helpful to determine risk. And, even though the derivation and validation cohorts for the new tool are representative of the US population, additional research should also include more racial/ethnic diversity, she said.

Dr. Gupta and Dr. Leaf hope their tool “will be utilized immediately by patients and providers to help predict an individual’s risk of cisplatin-associated kidney damage. It is easy to use, available for free online, and incorporates readily available clinical variables.”

If a patient is at high risk, the clinical team can consider preventive measures such as administering more IV fluids before receiving cisplatin or monitoring kidney function more closely afterward, they suggested.

Dr. Gupta reported research support from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. She also reported research funding from BTG International, GE HealthCare, and AstraZeneca outside the submitted work. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder and president emeritus of the American Society of Onconephrology (unpaid). Dr. Leaf is supported by NIH grants, reported research support from BioPorto, BTG International, and Metro International Biotech, and has served as a consultant. Dr. Topf reported an ownership stake in a few DaVita-run dialysis clinics. He also runs a vascular access center and has participated in advisory boards with Cara Therapeutics, Vifor, Astra Zeneca, Bayer, Renibus Therapeutics, Travere Therapeutics, and GlaxoSmithKline. He is president of NephJC, a nonprofit educational organization with no industry support. Dr. Shirali declared no competing interests.

A version of this article appeared on Medscape.com.

TOPLINE:

The recommended 10-year interval between screening colonoscopies may be safely extended to 15 years in adults with no family history of colorectal cancer (CRC) whose first colonoscopy is negative for CRC, a population-based study suggests.

METHODOLOGY:

• Using Swedish nationwide registry data, researchers compared 110,074 individuals who had a first colonoscopy with negative findings for CRC at age 45-69 years (exposed group) with more than 1.9 million matched controls who either did not have a colonoscopy during the study period or underwent colonoscopy that led to a CRC diagnosis.
• They calculated 10-year standardized incidence ratio (SIR) and standardized mortality ratio (SMR) to compare risks for CRC and CRC-specific death in the exposed and control groups based on different follow-up screening intervals.

TAKEAWAY:

• During up to 29 years of follow-up, 484 incident CRCs and 112 CRC deaths occurred in the group with a negative initial colonoscopy.
• Up to 15 years after negative colonoscopy, the 10-year cumulative risk for CRC and CRC mortality was lower than in the control group, with an SIR of 0.72 and SMR of 0.55, respectively.
• Extending the screening interval from 10 to 15 years would miss early detection of only two CRC cases and prevention of only one CRC death per 1000 individuals, while potentially avoiding 1000 colonoscopies.

IN PRACTICE:

“This study provides evidence for recommending a longer colonoscopy screening interval than what is currently recommended in most guidelines for populations with no familial risk of CRC,” the authors wrote. “A longer interval between colonoscopy screenings could be beneficial in avoiding unnecessary invasive examinations.”

SOURCE:

The study, with first author Qunfeng Liang, MSc, with the German Cancer Research Center, Heidelberg, Germany, was published online on May 2 in JAMA Oncology.

LIMITATIONS:

The study population primarily included White individuals, particularly ethnic Swedish individuals, so external validation would be necessary to generalize the recommendation to other populations. The researchers lacked data on non-endoscopic tests, such as fecal occult blood tests, which could have been performed as a substitution for colonoscopy during the interval between colonoscopy screenings.

DISCLOSURES:

The study had no specific funding. The authors had no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

The recommended 10-year interval between screening colonoscopies may be safely extended to 15 years in adults with no family history of colorectal cancer (CRC) whose first colonoscopy is negative for CRC, a population-based study suggests.

METHODOLOGY:

• Using Swedish nationwide registry data, researchers compared 110,074 individuals who had a first colonoscopy with negative findings for CRC at age 45-69 years (exposed group) with more than 1.9 million matched controls who either did not have a colonoscopy during the study period or underwent colonoscopy that led to a CRC diagnosis.
• They calculated 10-year standardized incidence ratio (SIR) and standardized mortality ratio (SMR) to compare risks for CRC and CRC-specific death in the exposed and control groups based on different follow-up screening intervals.

TAKEAWAY:

• During up to 29 years of follow-up, 484 incident CRCs and 112 CRC deaths occurred in the group with a negative initial colonoscopy.
• Up to 15 years after negative colonoscopy, the 10-year cumulative risk for CRC and CRC mortality was lower than in the control group, with an SIR of 0.72 and SMR of 0.55, respectively.
• Extending the screening interval from 10 to 15 years would miss early detection of only two CRC cases and prevention of only one CRC death per 1000 individuals, while potentially avoiding 1000 colonoscopies.

IN PRACTICE:

“This study provides evidence for recommending a longer colonoscopy screening interval than what is currently recommended in most guidelines for populations with no familial risk of CRC,” the authors wrote. “A longer interval between colonoscopy screenings could be beneficial in avoiding unnecessary invasive examinations.”

SOURCE:

The study, with first author Qunfeng Liang, MSc, with the German Cancer Research Center, Heidelberg, Germany, was published online on May 2 in JAMA Oncology.

LIMITATIONS:

The study population primarily included White individuals, particularly ethnic Swedish individuals, so external validation would be necessary to generalize the recommendation to other populations. The researchers lacked data on non-endoscopic tests, such as fecal occult blood tests, which could have been performed as a substitution for colonoscopy during the interval between colonoscopy screenings.

DISCLOSURES:

The study had no specific funding. The authors had no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

The recommended 10-year interval between screening colonoscopies may be safely extended to 15 years in adults with no family history of colorectal cancer (CRC) whose first colonoscopy is negative for CRC, a population-based study suggests.

METHODOLOGY:

• Using Swedish nationwide registry data, researchers compared 110,074 individuals who had a first colonoscopy with negative findings for CRC at age 45-69 years (exposed group) with more than 1.9 million matched controls who either did not have a colonoscopy during the study period or underwent colonoscopy that led to a CRC diagnosis.
• They calculated 10-year standardized incidence ratio (SIR) and standardized mortality ratio (SMR) to compare risks for CRC and CRC-specific death in the exposed and control groups based on different follow-up screening intervals.

TAKEAWAY:

• During up to 29 years of follow-up, 484 incident CRCs and 112 CRC deaths occurred in the group with a negative initial colonoscopy.
• Up to 15 years after negative colonoscopy, the 10-year cumulative risk for CRC and CRC mortality was lower than in the control group, with an SIR of 0.72 and SMR of 0.55, respectively.
• Extending the screening interval from 10 to 15 years would miss early detection of only two CRC cases and prevention of only one CRC death per 1000 individuals, while potentially avoiding 1000 colonoscopies.

IN PRACTICE:

“This study provides evidence for recommending a longer colonoscopy screening interval than what is currently recommended in most guidelines for populations with no familial risk of CRC,” the authors wrote. “A longer interval between colonoscopy screenings could be beneficial in avoiding unnecessary invasive examinations.”

SOURCE:

The study, with first author Qunfeng Liang, MSc, with the German Cancer Research Center, Heidelberg, Germany, was published online on May 2 in JAMA Oncology.

LIMITATIONS:

The study population primarily included White individuals, particularly ethnic Swedish individuals, so external validation would be necessary to generalize the recommendation to other populations. The researchers lacked data on non-endoscopic tests, such as fecal occult blood tests, which could have been performed as a substitution for colonoscopy during the interval between colonoscopy screenings.

DISCLOSURES:

The study had no specific funding. The authors had no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Overall, patients with solid tumors who receive an investigational cancer drug experience small progression-free survival (PFS) and overall survival benefits but much higher toxicity than those who receive a control intervention.

METHODOLOGY:

• The view that patients with cancer benefit from access to investigational drugs in the clinical trial setting is widely held but does necessarily align with trial findings, which often show limited evidence of a clinical benefit. First, most investigational treatments assessed in clinical trials fail to gain regulatory approval, and the minority that are approved tend to offer minimal clinical benefit, experts explained.
• To estimate the survival benefit and toxicities associated with receiving experimental treatments, researchers conducted a meta-analysis of 128 trials comprising 141 comparisons of an investigational drug and a control treatment, which included immunotherapies and targeted therapies.
• The analysis included 42 trials in non–small cell lung cancer (NSCLC), 37 in breast cancer, 15 in hepatobiliary cancer, 13 in pancreatic cancer, 12 in colorectal cancer, and 10 in prostate cancer, involving a total of 47,050 patients.
• The primary outcome was PFS and secondary outcomes were overall survival and grades 3-5 serious adverse events.

TAKEAWAY:

• Overall, the experimental treatment was associated with a 20% improvement in PFS (pooled hazard ratio [HR], 0.80), corresponding to a median 1.25-month PFS advantage. The PFS benefit was seen across all cancer types, except pancreatic cancer.
• Overall survival improved by 8% with experimental agents (HR, 0.92), corresponding to 1.18 additional months. A significant overall survival benefit was seen across NSCLC, breast cancer, and hepatobiliary cancer trials but not pancreatic, prostate, colorectal cancer trials.
• Patients in the experimental intervention group, however, experienced much higher risk for grade 3-5 serious adverse events (risk ratio [RR], 1.27), corresponding to 7.40% increase in absolute risk. The greater risk for serious adverse events was significant for all indications except prostate cancer (RR, 1.13; 95% CI, 0.91-1.40).

IN PRACTICE:

“We believe our findings are best interpreted as suggesting that access to experimental interventions that have not yet received full FDA approval is associated with a marginal but nonzero clinical benefit,” the authors wrote. 

“Although our findings seem to reflect poorly on trials as a vehicle for extending survival for participants, they have reassuring implications for clinical investigators, policymakers, and institutional review boards,” the researchers said, explaining that this “scenario allows clinical trials to continue to pursue promising new treatments — supporting incremental advances that sum to large gains over extended periods of research — without disadvantaging patients in comparator groups.”

SOURCE: 

Renata Iskander, MSc, of McGill University, Montreal, Quebec, Canada, led this work, which was published online on April 29, 2024, in Annals of Internal Medicine.

LIMITATIONS:

There was high heterogeneity across studies due to variations in drugs tested, comparators used, and populations involved. The use of comparators below standard care could have inflated survival benefits. Additionally, data collected from ClinicalTrials.gov might be biased due to some trials not being reported. 

DISCLOSURES:

Canadian Institutes of Health Research supported this work. The authors received grants for this work from McGill University, Rossy Cancer Network, and National Science Foundation. One author received consulting fees outside this work. The other authors declared no competing interests.

A version of this article appeared on Medscape.com.

TOPLINE:

Overall, patients with solid tumors who receive an investigational cancer drug experience small progression-free survival (PFS) and overall survival benefits but much higher toxicity than those who receive a control intervention.

METHODOLOGY:

• The view that patients with cancer benefit from access to investigational drugs in the clinical trial setting is widely held but does necessarily align with trial findings, which often show limited evidence of a clinical benefit. First, most investigational treatments assessed in clinical trials fail to gain regulatory approval, and the minority that are approved tend to offer minimal clinical benefit, experts explained.
• To estimate the survival benefit and toxicities associated with receiving experimental treatments, researchers conducted a meta-analysis of 128 trials comprising 141 comparisons of an investigational drug and a control treatment, which included immunotherapies and targeted therapies.
• The analysis included 42 trials in non–small cell lung cancer (NSCLC), 37 in breast cancer, 15 in hepatobiliary cancer, 13 in pancreatic cancer, 12 in colorectal cancer, and 10 in prostate cancer, involving a total of 47,050 patients.
• The primary outcome was PFS and secondary outcomes were overall survival and grades 3-5 serious adverse events.

TAKEAWAY:

• Overall, the experimental treatment was associated with a 20% improvement in PFS (pooled hazard ratio [HR], 0.80), corresponding to a median 1.25-month PFS advantage. The PFS benefit was seen across all cancer types, except pancreatic cancer.
• Overall survival improved by 8% with experimental agents (HR, 0.92), corresponding to 1.18 additional months. A significant overall survival benefit was seen across NSCLC, breast cancer, and hepatobiliary cancer trials but not pancreatic, prostate, colorectal cancer trials.
• Patients in the experimental intervention group, however, experienced much higher risk for grade 3-5 serious adverse events (risk ratio [RR], 1.27), corresponding to 7.40% increase in absolute risk. The greater risk for serious adverse events was significant for all indications except prostate cancer (RR, 1.13; 95% CI, 0.91-1.40).

IN PRACTICE:

“We believe our findings are best interpreted as suggesting that access to experimental interventions that have not yet received full FDA approval is associated with a marginal but nonzero clinical benefit,” the authors wrote. 

“Although our findings seem to reflect poorly on trials as a vehicle for extending survival for participants, they have reassuring implications for clinical investigators, policymakers, and institutional review boards,” the researchers said, explaining that this “scenario allows clinical trials to continue to pursue promising new treatments — supporting incremental advances that sum to large gains over extended periods of research — without disadvantaging patients in comparator groups.”

SOURCE: 

Renata Iskander, MSc, of McGill University, Montreal, Quebec, Canada, led this work, which was published online on April 29, 2024, in Annals of Internal Medicine.

LIMITATIONS:

There was high heterogeneity across studies due to variations in drugs tested, comparators used, and populations involved. The use of comparators below standard care could have inflated survival benefits. Additionally, data collected from ClinicalTrials.gov might be biased due to some trials not being reported. 

DISCLOSURES:

Canadian Institutes of Health Research supported this work. The authors received grants for this work from McGill University, Rossy Cancer Network, and National Science Foundation. One author received consulting fees outside this work. The other authors declared no competing interests.

A version of this article appeared on Medscape.com.

TOPLINE:

Overall, patients with solid tumors who receive an investigational cancer drug experience small progression-free survival (PFS) and overall survival benefits but much higher toxicity than those who receive a control intervention.

METHODOLOGY:

• The view that patients with cancer benefit from access to investigational drugs in the clinical trial setting is widely held but does necessarily align with trial findings, which often show limited evidence of a clinical benefit. First, most investigational treatments assessed in clinical trials fail to gain regulatory approval, and the minority that are approved tend to offer minimal clinical benefit, experts explained.
• To estimate the survival benefit and toxicities associated with receiving experimental treatments, researchers conducted a meta-analysis of 128 trials comprising 141 comparisons of an investigational drug and a control treatment, which included immunotherapies and targeted therapies.
• The analysis included 42 trials in non–small cell lung cancer (NSCLC), 37 in breast cancer, 15 in hepatobiliary cancer, 13 in pancreatic cancer, 12 in colorectal cancer, and 10 in prostate cancer, involving a total of 47,050 patients.
• The primary outcome was PFS and secondary outcomes were overall survival and grades 3-5 serious adverse events.

TAKEAWAY:

• Overall, the experimental treatment was associated with a 20% improvement in PFS (pooled hazard ratio [HR], 0.80), corresponding to a median 1.25-month PFS advantage. The PFS benefit was seen across all cancer types, except pancreatic cancer.
• Overall survival improved by 8% with experimental agents (HR, 0.92), corresponding to 1.18 additional months. A significant overall survival benefit was seen across NSCLC, breast cancer, and hepatobiliary cancer trials but not pancreatic, prostate, colorectal cancer trials.
• Patients in the experimental intervention group, however, experienced much higher risk for grade 3-5 serious adverse events (risk ratio [RR], 1.27), corresponding to 7.40% increase in absolute risk. The greater risk for serious adverse events was significant for all indications except prostate cancer (RR, 1.13; 95% CI, 0.91-1.40).

IN PRACTICE:

“We believe our findings are best interpreted as suggesting that access to experimental interventions that have not yet received full FDA approval is associated with a marginal but nonzero clinical benefit,” the authors wrote. 

“Although our findings seem to reflect poorly on trials as a vehicle for extending survival for participants, they have reassuring implications for clinical investigators, policymakers, and institutional review boards,” the researchers said, explaining that this “scenario allows clinical trials to continue to pursue promising new treatments — supporting incremental advances that sum to large gains over extended periods of research — without disadvantaging patients in comparator groups.”

SOURCE: 

Renata Iskander, MSc, of McGill University, Montreal, Quebec, Canada, led this work, which was published online on April 29, 2024, in Annals of Internal Medicine.

LIMITATIONS:

There was high heterogeneity across studies due to variations in drugs tested, comparators used, and populations involved. The use of comparators below standard care could have inflated survival benefits. Additionally, data collected from ClinicalTrials.gov might be biased due to some trials not being reported. 

DISCLOSURES:

Canadian Institutes of Health Research supported this work. The authors received grants for this work from McGill University, Rossy Cancer Network, and National Science Foundation. One author received consulting fees outside this work. The other authors declared no competing interests.

A version of this article appeared on Medscape.com.

TOPLINE:

Researchers have identified specific circulating microRNAs (miRNAs) in blood samples that can identify individuals at high risk of developing pancreatic cancer within 5 years, potentially improving early detection and outcomes.

METHODOLOGY:

• Early detection of pancreatic cancer could improve patient prognosis, but clinically viable biomarkers are lacking. In a two-stage study, researchers screened and validated circulating miRNAs as biomarkers for early detection using prediagnostic plasma samples from 462 case-control pairs across multiple cohorts.
• The discovery stage included 185 pairs from the PLCO Cancer Screening Trial, and the replication stage included 277 pairs from Shanghai Women’s/Men’s Health Study, Southern Community Cohort Study, and Multiethnic Cohort Study.
• Overall, 798 plasma microRNAs were measured using the NanoString nCounter Analysis System, and odds ratios (ORs) for pancreatic cancer risk were calculated on the basis of miRNA concentrations.
• Statistical analysis involved conditional logistic regression, stratified by age and time from sample collection to diagnosis.

TAKEAWAY:

• In the discovery stage, the researchers identified 120 miRNAs significantly associated with pancreatic cancer risk.
• Three of these miRNAs showed consistent significant associations in the replication stage. Specifically, hsa-miR-199a-3p/hsa-miR-199b-3p and hsa-miR-191-5p were associated with a 10%-11% lower risk for pancreatic cancer (OR, 0.89 and 0.90, respectively), and hsa-miR-767-5p was associated with an 8% higher risk for pancreatic cancer (OR, 1.08) within 5 years of the blood draw.
• In age-stratified analyses, hsa-miR-767-5p (OR, 1.23) along with four other miRNAs — hsa-miR-640 (OR, 1.33), hsa-miR-874-5p (OR, 1.25), hsa-miR-1299 (OR, 1.28), and hsa-miR-449b-5p (OR, 1.22) — were associated with an increased risk for pancreatic cancer among patients diagnosed at age 65 or older.
• One miRNA, hsa-miR-22-3p (OR, 0.76), was associated with a lower risk for pancreatic cancer in this older age group.

IN PRACTICE:

The findings provide evidence that miRNAs “have a potential utilization in clinical practice” to help “identify high-risk individuals who could subsequently undergo a more definitive but invasive diagnostic procedure,” the authors said. “Such a multistep strategy for pancreatic cancer screening and early detection, likely cost-efficient and low-risk, could be critical to improve survival.”

SOURCE:

The study, with first author Cong Wang, Vanderbilt University Medical Center, Nashville, Tennessee, was published online in the International Journal of Cancer.

LIMITATIONS:

The researchers lacked miRNA profiles of patients with pancreatic cancer at diagnosis and were not able to track the miRNA changes among pancreatic cancer cases at the time of clinical diagnosis. Sample collection protocols differed across study cohorts, and the researchers changed assay panels during the study.

DISCLOSURES:

The research was funded by grants from the National Cancer Institute. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Researchers have identified specific circulating microRNAs (miRNAs) in blood samples that can identify individuals at high risk of developing pancreatic cancer within 5 years, potentially improving early detection and outcomes.

METHODOLOGY:

• Early detection of pancreatic cancer could improve patient prognosis, but clinically viable biomarkers are lacking. In a two-stage study, researchers screened and validated circulating miRNAs as biomarkers for early detection using prediagnostic plasma samples from 462 case-control pairs across multiple cohorts.
• The discovery stage included 185 pairs from the PLCO Cancer Screening Trial, and the replication stage included 277 pairs from Shanghai Women’s/Men’s Health Study, Southern Community Cohort Study, and Multiethnic Cohort Study.
• Overall, 798 plasma microRNAs were measured using the NanoString nCounter Analysis System, and odds ratios (ORs) for pancreatic cancer risk were calculated on the basis of miRNA concentrations.
• Statistical analysis involved conditional logistic regression, stratified by age and time from sample collection to diagnosis.

TAKEAWAY:

• In the discovery stage, the researchers identified 120 miRNAs significantly associated with pancreatic cancer risk.
• Three of these miRNAs showed consistent significant associations in the replication stage. Specifically, hsa-miR-199a-3p/hsa-miR-199b-3p and hsa-miR-191-5p were associated with a 10%-11% lower risk for pancreatic cancer (OR, 0.89 and 0.90, respectively), and hsa-miR-767-5p was associated with an 8% higher risk for pancreatic cancer (OR, 1.08) within 5 years of the blood draw.
• In age-stratified analyses, hsa-miR-767-5p (OR, 1.23) along with four other miRNAs — hsa-miR-640 (OR, 1.33), hsa-miR-874-5p (OR, 1.25), hsa-miR-1299 (OR, 1.28), and hsa-miR-449b-5p (OR, 1.22) — were associated with an increased risk for pancreatic cancer among patients diagnosed at age 65 or older.
• One miRNA, hsa-miR-22-3p (OR, 0.76), was associated with a lower risk for pancreatic cancer in this older age group.

IN PRACTICE:

The findings provide evidence that miRNAs “have a potential utilization in clinical practice” to help “identify high-risk individuals who could subsequently undergo a more definitive but invasive diagnostic procedure,” the authors said. “Such a multistep strategy for pancreatic cancer screening and early detection, likely cost-efficient and low-risk, could be critical to improve survival.”

SOURCE:

The study, with first author Cong Wang, Vanderbilt University Medical Center, Nashville, Tennessee, was published online in the International Journal of Cancer.

LIMITATIONS:

The researchers lacked miRNA profiles of patients with pancreatic cancer at diagnosis and were not able to track the miRNA changes among pancreatic cancer cases at the time of clinical diagnosis. Sample collection protocols differed across study cohorts, and the researchers changed assay panels during the study.

DISCLOSURES:

The research was funded by grants from the National Cancer Institute. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Researchers have identified specific circulating microRNAs (miRNAs) in blood samples that can identify individuals at high risk of developing pancreatic cancer within 5 years, potentially improving early detection and outcomes.

METHODOLOGY:

• Early detection of pancreatic cancer could improve patient prognosis, but clinically viable biomarkers are lacking. In a two-stage study, researchers screened and validated circulating miRNAs as biomarkers for early detection using prediagnostic plasma samples from 462 case-control pairs across multiple cohorts.
• The discovery stage included 185 pairs from the PLCO Cancer Screening Trial, and the replication stage included 277 pairs from Shanghai Women’s/Men’s Health Study, Southern Community Cohort Study, and Multiethnic Cohort Study.
• Overall, 798 plasma microRNAs were measured using the NanoString nCounter Analysis System, and odds ratios (ORs) for pancreatic cancer risk were calculated on the basis of miRNA concentrations.
• Statistical analysis involved conditional logistic regression, stratified by age and time from sample collection to diagnosis.

TAKEAWAY:

• In the discovery stage, the researchers identified 120 miRNAs significantly associated with pancreatic cancer risk.
• Three of these miRNAs showed consistent significant associations in the replication stage. Specifically, hsa-miR-199a-3p/hsa-miR-199b-3p and hsa-miR-191-5p were associated with a 10%-11% lower risk for pancreatic cancer (OR, 0.89 and 0.90, respectively), and hsa-miR-767-5p was associated with an 8% higher risk for pancreatic cancer (OR, 1.08) within 5 years of the blood draw.
• In age-stratified analyses, hsa-miR-767-5p (OR, 1.23) along with four other miRNAs — hsa-miR-640 (OR, 1.33), hsa-miR-874-5p (OR, 1.25), hsa-miR-1299 (OR, 1.28), and hsa-miR-449b-5p (OR, 1.22) — were associated with an increased risk for pancreatic cancer among patients diagnosed at age 65 or older.
• One miRNA, hsa-miR-22-3p (OR, 0.76), was associated with a lower risk for pancreatic cancer in this older age group.

IN PRACTICE:

The findings provide evidence that miRNAs “have a potential utilization in clinical practice” to help “identify high-risk individuals who could subsequently undergo a more definitive but invasive diagnostic procedure,” the authors said. “Such a multistep strategy for pancreatic cancer screening and early detection, likely cost-efficient and low-risk, could be critical to improve survival.”

SOURCE:

The study, with first author Cong Wang, Vanderbilt University Medical Center, Nashville, Tennessee, was published online in the International Journal of Cancer.

LIMITATIONS:

The researchers lacked miRNA profiles of patients with pancreatic cancer at diagnosis and were not able to track the miRNA changes among pancreatic cancer cases at the time of clinical diagnosis. Sample collection protocols differed across study cohorts, and the researchers changed assay panels during the study.

DISCLOSURES:

The research was funded by grants from the National Cancer Institute. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

In the US Department of Veterans Affairs (VA) health care system, head and neck cancer is one of the most complex oncologic conditions to treat because so many medical professionals are involved in its care. Specialists in speech therapy, nutrition, lymphedema, and dentistry are all part of the picture.

“It takes a complete team to treat cancer in a comprehensive manner, and specialists work hand-in-hand,” said Cindy Bowman, MSN, RN, OCN, president of the Association of VA Hematology/Oncology (AVAHO).

AVAHO held a regional meeting in Seattle on May 4, 2024, that was entirely devoted to head and neck cancer. “The goal was to help the VA oncology professionals gain a global view of how various team members can seamlessly work together,” said Bowman, an oncology nurse navigator and coordinator of the Cancer Care Navigation Program at Bay Pines VA Healthcare System in the Tampa-St. Petersburg, FL area.

According to a 2017 report, 2031 cases of head and neck cancer were diagnosed in 2010 among VA patients, accounting for 4.4% of all cancers. “Veterans are especially vulnerable to this type of cancer for several reasons, such as high rates of smoking and alcohol use,” Bowman said. In addition, she said veterans who served in parts of Southeast Asia, North Africa, and the Middle East are at higher risk of nasopharyngeal carcinoma, which has been linked to Epstein-Barr virus infections in those regions.

Radiation treatment were a significant topic at the regional meeting, and 1 session was focused on the importance of prompt care. “Head and neck cancers are very aggressive,” Bowman said. “The sooner we identify them, the sooner we get treatment started.”

Attendees also heard from a speech therapist and a dietician, who discussed a collaborative approach to improving treatment outcomes. “These are two very important pieces of the puzzle.” Bowman said.

On the nutrition front, a lot of newly diagnosed patients already have malnutrition because they have been having difficulty swallowing. So right up front, a registered dietician works with them and individualizes their nutrition treatment plans all the way into recovery. Some of these folks will end up with their relationship with their dietitian for many years.

“Speech therapists work with patients to design swallowing and tongue exercises that target their individual cancer.” Bowman said. The goal is to prevent the need for a feeding tube.

Another session at the regional conference focused on lymphedema—swelling that can develop due to radiation treatment. “All patients with head and neck cancer should be sent to a lymphedema specialist prior to starting treatment since the specialists can prevent this from happening by giving the patients tools, such as compression garments,” Bowman said. “This way, we don’t end up with somebody 15 or 20 years from now coming back and saying they’re not able to move their neck or unable to swallow the right way.”

Another session highlighted the important role of dental care for patients with head and neck cancer. “We send patients to the dentist prior to ever starting anything. We know that radiation therapy can cause osteoradionecrosis, in which people’s teeth begin to crumble. Fortunately, the VA is now covering dentures for these patients, and they automatically get dental care coverage.” Bowman said.

“In the big picture,” she said, “Attendees should come out of the regional meeting with new insight into the importance of teamwork in head and neck cancer care. We need to make sure that all the pieces to the puzzle are there, and everybody is working together to expedite care for the veterans so that they have the best outcomes possible.”

In the US Department of Veterans Affairs (VA) health care system, head and neck cancer is one of the most complex oncologic conditions to treat because so many medical professionals are involved in its care. Specialists in speech therapy, nutrition, lymphedema, and dentistry are all part of the picture.

“It takes a complete team to treat cancer in a comprehensive manner, and specialists work hand-in-hand,” said Cindy Bowman, MSN, RN, OCN, president of the Association of VA Hematology/Oncology (AVAHO).

AVAHO held a regional meeting in Seattle on May 4, 2024, that was entirely devoted to head and neck cancer. “The goal was to help the VA oncology professionals gain a global view of how various team members can seamlessly work together,” said Bowman, an oncology nurse navigator and coordinator of the Cancer Care Navigation Program at Bay Pines VA Healthcare System in the Tampa-St. Petersburg, FL area.

According to a 2017 report, 2031 cases of head and neck cancer were diagnosed in 2010 among VA patients, accounting for 4.4% of all cancers. “Veterans are especially vulnerable to this type of cancer for several reasons, such as high rates of smoking and alcohol use,” Bowman said. In addition, she said veterans who served in parts of Southeast Asia, North Africa, and the Middle East are at higher risk of nasopharyngeal carcinoma, which has been linked to Epstein-Barr virus infections in those regions.

Radiation treatment were a significant topic at the regional meeting, and 1 session was focused on the importance of prompt care. “Head and neck cancers are very aggressive,” Bowman said. “The sooner we identify them, the sooner we get treatment started.”

Attendees also heard from a speech therapist and a dietician, who discussed a collaborative approach to improving treatment outcomes. “These are two very important pieces of the puzzle.” Bowman said.

On the nutrition front, a lot of newly diagnosed patients already have malnutrition because they have been having difficulty swallowing. So right up front, a registered dietician works with them and individualizes their nutrition treatment plans all the way into recovery. Some of these folks will end up with their relationship with their dietitian for many years.

“Speech therapists work with patients to design swallowing and tongue exercises that target their individual cancer.” Bowman said. The goal is to prevent the need for a feeding tube.

Another session at the regional conference focused on lymphedema—swelling that can develop due to radiation treatment. “All patients with head and neck cancer should be sent to a lymphedema specialist prior to starting treatment since the specialists can prevent this from happening by giving the patients tools, such as compression garments,” Bowman said. “This way, we don’t end up with somebody 15 or 20 years from now coming back and saying they’re not able to move their neck or unable to swallow the right way.”

Another session highlighted the important role of dental care for patients with head and neck cancer. “We send patients to the dentist prior to ever starting anything. We know that radiation therapy can cause osteoradionecrosis, in which people’s teeth begin to crumble. Fortunately, the VA is now covering dentures for these patients, and they automatically get dental care coverage.” Bowman said.

“In the big picture,” she said, “Attendees should come out of the regional meeting with new insight into the importance of teamwork in head and neck cancer care. We need to make sure that all the pieces to the puzzle are there, and everybody is working together to expedite care for the veterans so that they have the best outcomes possible.”

In the US Department of Veterans Affairs (VA) health care system, head and neck cancer is one of the most complex oncologic conditions to treat because so many medical professionals are involved in its care. Specialists in speech therapy, nutrition, lymphedema, and dentistry are all part of the picture.

“It takes a complete team to treat cancer in a comprehensive manner, and specialists work hand-in-hand,” said Cindy Bowman, MSN, RN, OCN, president of the Association of VA Hematology/Oncology (AVAHO).

AVAHO held a regional meeting in Seattle on May 4, 2024, that was entirely devoted to head and neck cancer. “The goal was to help the VA oncology professionals gain a global view of how various team members can seamlessly work together,” said Bowman, an oncology nurse navigator and coordinator of the Cancer Care Navigation Program at Bay Pines VA Healthcare System in the Tampa-St. Petersburg, FL area.

According to a 2017 report, 2031 cases of head and neck cancer were diagnosed in 2010 among VA patients, accounting for 4.4% of all cancers. “Veterans are especially vulnerable to this type of cancer for several reasons, such as high rates of smoking and alcohol use,” Bowman said. In addition, she said veterans who served in parts of Southeast Asia, North Africa, and the Middle East are at higher risk of nasopharyngeal carcinoma, which has been linked to Epstein-Barr virus infections in those regions.

Radiation treatment were a significant topic at the regional meeting, and 1 session was focused on the importance of prompt care. “Head and neck cancers are very aggressive,” Bowman said. “The sooner we identify them, the sooner we get treatment started.”

Attendees also heard from a speech therapist and a dietician, who discussed a collaborative approach to improving treatment outcomes. “These are two very important pieces of the puzzle.” Bowman said.

On the nutrition front, a lot of newly diagnosed patients already have malnutrition because they have been having difficulty swallowing. So right up front, a registered dietician works with them and individualizes their nutrition treatment plans all the way into recovery. Some of these folks will end up with their relationship with their dietitian for many years.

“Speech therapists work with patients to design swallowing and tongue exercises that target their individual cancer.” Bowman said. The goal is to prevent the need for a feeding tube.

Another session at the regional conference focused on lymphedema—swelling that can develop due to radiation treatment. “All patients with head and neck cancer should be sent to a lymphedema specialist prior to starting treatment since the specialists can prevent this from happening by giving the patients tools, such as compression garments,” Bowman said. “This way, we don’t end up with somebody 15 or 20 years from now coming back and saying they’re not able to move their neck or unable to swallow the right way.”

Another session highlighted the important role of dental care for patients with head and neck cancer. “We send patients to the dentist prior to ever starting anything. We know that radiation therapy can cause osteoradionecrosis, in which people’s teeth begin to crumble. Fortunately, the VA is now covering dentures for these patients, and they automatically get dental care coverage.” Bowman said.

“In the big picture,” she said, “Attendees should come out of the regional meeting with new insight into the importance of teamwork in head and neck cancer care. We need to make sure that all the pieces to the puzzle are there, and everybody is working together to expedite care for the veterans so that they have the best outcomes possible.”

A contentious scientific debate is clouding prospects for a deeper understanding of the microbiome’s role in cancer, a relatively young field of research that some believe could lead to breakthroughs in the diagnosis and treatment of the second-leading cause of death in the United States. 

Last year, the controversy heightened when experts questioned a high-profile study — a 2020 analysis claiming that the tumors of 33 different cancers had their own unique microbiomes — on whether the “signature” of these bacterial compositions could help diagnose cancer.

The incident renewed the spotlight on “tumor microbiomes” because of the bold claims of the original paper and the strongly worded refutations of those claims. The broader field has focused primarily on ways the body’s microbiome interacts with cancers and cancer treatment.

This controversy has highlighted the challenges of making headway in a field where researchers may not even have the tools yet to puzzle-out the wide-ranging implications the microbiome holds for cancer diagnosis and treatment.

But it is also part of a provocative question within that larger field: whether tumors in the body, far from the natural microbiome in the gut, have their own thriving communities of bacteria, viruses, and fungi. And, if they do, how do those tumor microbiomes affect the development and progression of the cancer and the effectiveness of cancer therapies? 
 

Cancer Controversy

The evidence is undeniable that some microbes can directly cause certain cancers and that the human gut microbiome can influence the effectiveness of certain therapies. Beyond that established science, however, the research has raised as many questions as answers about what we do and don’t know about microbiota and cancer.

The only confirmed microbiomes are on the skin and in the gut, mouth, and vagina, which are all areas with an easy direct route for bacteria to enter and grow in or on the body. A series of papers in recent years have suggested that other internal organs, and tumors within them, may have their own microbiomes. 

“Whether microbes exist in tumors of internal organs beyond body surfaces exposed to the environment is a different matter,” said Ivan Vujkovic-Cvijin, PhD, an assistant professor of biomedical sciences and gastroenterology at Cedars-Sinai Medical Center in Los Angeles, whose lab studies how human gut microbes affect inflammatory diseases. “We’ve only recently had the tools to study that question on a molecular level, and the reported results have been conflicting.” 

For example, research allegedly identified microbiota in the human placenta nearly one decade ago. But subsequent research contradicted those claims and showed that the source of the “placental microbiome” was actually contamination. Subsequent similar studies for other parts of the body faced the same scrutiny and, often, eventual debunking.

“Most likely, our immune system has undergone selective pressure to eliminate everything that crosses the gut barrier because there’s not much benefit to the body to have bacteria run amok in our internal organs,” Dr. Vujkovic-Cvijin said. “That can only disrupt the functioning of our tissues, to have an external organism living inside them.” 

The controversy that erupted last summer, surrounding research from the lab of Rob Knight, PhD, at the University of California, San Diego, centered on a slightly different but related question: Could tumors harbor their own microbiomes?

This news organization spoke with two of the authors who published a paper contesting Dr. Knight’s findings: Steven Salzberg, PhD, a professor of biomedical engineering at John Hopkins Medicine, Baltimore, Maryland, and Abraham Gihawi, PhD, a research fellow at Norwich Medical School at the University of East Anglia in the United Kingdom. 

Dr. Salzberg described two major problems with Dr. Knight’s study. 

“What they found were false positives because of contamination in the database and flaws in their methods,” Dr. Salzberg said. “I can’t prove there’s no cancer microbiome, but I can say the cancer microbiomes that they reported don’t exist because the species they were finding aren’t there.”

Dr. Knight disagrees with Dr. Salzberg’s findings, noting that Dr. Salzberg and his co-authors did not examine the publicly available databases used in his study. In a written response, he said that his team’s examination of the database revealed that less than 1% of the microbial genomes overlapped with human ones and that removing them did not change their findings.

Dr. Knight also noted that his team could still “distinguish cancer types by their microbiome” even after running their analysis without the technique that Dr. Salzberg found fault with.

Dr. Salzberg said that the database linked above is not the one Dr. Knight’s study used, however. “The primary database in their study was never made public (it’s too large, they said), and it has/had about 69,000 genomes,” Dr. Salzberg said by email. “But even if we did, this is irrelevant. He’s trying to distract from the primary errors in their study,” which Dr. Salzberg said Dr. Knight’s team has not addressed. 

The critiques Dr. Salzberg raised have been leveled at other studies investigating microbiomes specifically within tumors and independent of the body’s microbiome.

For example, a 2019 study in Nature described a fungal microbiome in pancreatic cancer that a Nature paper 4 years later directly contradicted, citing flaws that invalidated the original findings. A different 2019 study in Cell examined pancreatic tumor microbiota and patient outcomes, but it’s unclear whether the microorganisms moved from the gut to the pancreas or “constitute a durably colonized community that lives inside the tumor,” which remains a matter of debate, Dr. Vujkovic-Cvijin said.

A 2020 study in Science suggested diverse microbial communities in seven tumor types, but those findings were similarly called into question. That study stated that “bacteria were first detected in human tumors more than 100 years ago” and that “bacteria are well-known residents in human tumors,” but Dr. Salzberg considers those statements misleading. 

It’s true that bacteria and viruses have been detected in tumors because “there’s very good evidence that an acute infection caused by a very small number of viruses and bacteria can cause a tumor,” Dr. Salzberg said. Human papillomavirus, for example, can cause six different types of cancer. Inflammation and ulcers caused by Helicobacter pylori may progress to stomach cancer, and Fusobacterium nucleatum and Enterococcus faecalis have been shown to contribute to colorectal cancer. Those examples differ from a microbiome; this “a community of bacteria and possibly other microscopic bugs, like fungi, that are happily living in the tumor” the same way microbes reside in our guts, he said.

Dr. Knight said that many bacteria his team identified “have been confirmed independently in subsequent work.” He acknowledged, however, that more research is needed. 

Several of the contested studies above were among a lengthy list that Dr. Knight provided, noting that most of the disagreements “have two sides to them, and critiques from one particular group does not immediately invalidate a reported finding.” 

Yet, many of the papers Dr. Knight listed are precisely the types that skeptics like Dr. Salzberg believe are too flawed to draw reliable conclusions. 

“I think many agree that microbes may exist within tumors that are exposed to the environment, like tumors of the skin, gut, and mouth,” Dr. Vujkovic-Cvijin said. It’s less clear, however, whether tumors further from the body’s microbiome harbor any microbes or where they came from if they do. Microbial signals in organs elsewhere in the body become faint quickly, he said.
 

Underdeveloped Technology 

Though Dr. Salzberg said that the concept of a tumor microbiome is “implausible” because there’s no easy route for bacteria to reach internal organs, it’s unclear whether scientists have the technology yet to adequately answer this question. 

For one thing, samples in these types of studies are typically “ultra-low biomass samples, where the signal — the amount of microbes in the sample — is so low that it’s comparable to how much would be expected to be found in reagents and environmental contamination through processing,” Dr. Vujkovic-Cvijin explained. Many polymerases used to amplify a DNA signal, for example, are made in bacteria and may retain trace amounts identified in these studies. 

Dr. Knight agreed that low biomass is a challenge in this field but is not an unsurmountable one. 

Another challenge is that study samples, as with Dr. Knight’s work, were collected during routine surgeries without the intent to find a microbial signal. Simply using a scalpel to cut through the skin means cutting through a layer of bacteria, and surgery rooms are not designed to eliminate all bacteria. Some work has even shown there is a “hospital microbiome,” so “you can easily have that creep into your signal and mistake it for tumor-resident bacteria,” Dr. Vujkovic-Cvijin said. 

Dr. Knight asserted that the samples are taken under sterile conditions, but other researchers do not think the level of sterility necessary for completely clean samples is possible. 

“Just because it’s in your sample doesn’t mean it was in your tumor,” Dr. Gihawi said.

Even if scientists can retrieve a reliable sample without contamination, analyzing it requires comparing the genetic material to existing databases of microbial genomes. Yet, contamination and misclassification of genetic sequences can be problems in those reference genomes too, Dr. Gihawi explained.

Machine learning algorithms have a role in interpreting data, but “we need to be careful of what we use them for,” he added.

“These techniques are in their infancy, and we’re starting to chase them down, which is why we need to move microbiome research in a way that can be used clinically,” Dr. Gihawi said. 
 

Influence on Cancer Treatment Outcomes

Again, however, the question of whether microbiomes exist within tumors is only one slice of the much larger field looking at microbiomes and cancer, including its influence on cancer treatment outcomes. Although much remains to be learned, less controversy exists over the thousands of studies in the past two decades that have gradually revealed how the body’s microbiome can affect both the course of a cancer and the effectiveness of different treatments.

The growing research showing the importance of the gut microbiome in cancer treatments is not surprising given its role in immunity more broadly. Because the human immune system must recognize and defend against microbes, the microbiome helps train it, Dr. Vujkovic-Cvijin said. 

Some bacteria can escape the gut — a phenomenon called bacterial translocation — and may aid in fighting tumors. To grow large enough to be seen on imaging, tumors need to evolve several abilities, such as growing enough vascularization to receive blood flow and shutting down local immune responses.

“Any added boost, like immunotherapy, has a chance of breaking through that immune forcefield and killing the tumor cells,” Dr. Vujkovic-Cvijin said. Escaped gut bacteria may provide that boost. 

“There’s a lot of evidence that depletion of the gut microbiome impairs immunotherapy and chemotherapy. The thinking behind some of those studies is that gut microbes can cross the gut barrier and when they do, they activate the immune system,” he said. 

In mice engineered to have sterile guts, for example, the lack of bacteria results in less effective immune systems, Dr. Vujkovic-Cvijin pointed out. A host of research has shown that antibiotic exposure during and even 6 months before immunotherapy dramatically reduces survival rates. “That’s pretty convincing to me that gut microbes are important,” he said. 

Dr. Vujkovic-Cvijin cautioned that there continues to be controversy on understanding which bacteria are important for response to immunotherapy. “The field is still in its infancy in terms of understanding which bacteria are most important for these effects,” he said.

Dr. Knight suggested that escaped bacteria may be the genesis of the ones that he and other researchers believe exist in tumors. “Because tumor microbes must come from somewhere, it is to be expected that some of those microbes will be co-opted from body-site specific commensals.”

It’s also possible that metabolites released from gut bacteria escape the gut and could theoretically affect distant tumor growth, Dr. Gihawi said. The most promising avenue of research in this area is metabolites being used as biomarkers, added Dr. Gihawi, whose lab published research on a link between bacteria detected in men’s urine and a more aggressive subset of prostate cancers. But that research is not far enough along to develop lab tests for clinical use, he noted. 
 

No Consensus Yet

Even before the controversy erupted around Dr. Knight’s research, he co-founded the company Micronoma to develop cancer tests based on his microbe findings. The company has raised $17.5 million from private investors as of August 2023 and received the US Food and Drug Administration’s Breakthrough Device designation, allowing the firm to fast-track clinical trials testing the technology. The recent critiques have not changed the company’s plans. 

It’s safe to say that scientists will continue to research and debate the possibility of tumor microbiomes until a consensus emerges. 

“The field is evolving and studies testing the reproducibility of tumor-resident microbial signals are essential for developing our understanding in this area,” Dr. Vujkovic-Cvijin said.

Even if that path ultimately leads nowhere, as Dr. Salzberg expects, research into microbiomes and cancer has plenty of other directions to go.

“I’m actually quite an optimist,” Dr. Gihawi said. “I think there’s a lot of scope for some really good research here, especially in the sites where we know there is a strong microbiome, such as the gastrointestinal tract.”

A version of this article appeared on Medscape.com.

A contentious scientific debate is clouding prospects for a deeper understanding of the microbiome’s role in cancer, a relatively young field of research that some believe could lead to breakthroughs in the diagnosis and treatment of the second-leading cause of death in the United States. 

Last year, the controversy heightened when experts questioned a high-profile study — a 2020 analysis claiming that the tumors of 33 different cancers had their own unique microbiomes — on whether the “signature” of these bacterial compositions could help diagnose cancer.

The incident renewed the spotlight on “tumor microbiomes” because of the bold claims of the original paper and the strongly worded refutations of those claims. The broader field has focused primarily on ways the body’s microbiome interacts with cancers and cancer treatment.

This controversy has highlighted the challenges of making headway in a field where researchers may not even have the tools yet to puzzle-out the wide-ranging implications the microbiome holds for cancer diagnosis and treatment.

But it is also part of a provocative question within that larger field: whether tumors in the body, far from the natural microbiome in the gut, have their own thriving communities of bacteria, viruses, and fungi. And, if they do, how do those tumor microbiomes affect the development and progression of the cancer and the effectiveness of cancer therapies? 
 

Cancer Controversy

The evidence is undeniable that some microbes can directly cause certain cancers and that the human gut microbiome can influence the effectiveness of certain therapies. Beyond that established science, however, the research has raised as many questions as answers about what we do and don’t know about microbiota and cancer.

The only confirmed microbiomes are on the skin and in the gut, mouth, and vagina, which are all areas with an easy direct route for bacteria to enter and grow in or on the body. A series of papers in recent years have suggested that other internal organs, and tumors within them, may have their own microbiomes. 

“Whether microbes exist in tumors of internal organs beyond body surfaces exposed to the environment is a different matter,” said Ivan Vujkovic-Cvijin, PhD, an assistant professor of biomedical sciences and gastroenterology at Cedars-Sinai Medical Center in Los Angeles, whose lab studies how human gut microbes affect inflammatory diseases. “We’ve only recently had the tools to study that question on a molecular level, and the reported results have been conflicting.” 

For example, research allegedly identified microbiota in the human placenta nearly one decade ago. But subsequent research contradicted those claims and showed that the source of the “placental microbiome” was actually contamination. Subsequent similar studies for other parts of the body faced the same scrutiny and, often, eventual debunking.

“Most likely, our immune system has undergone selective pressure to eliminate everything that crosses the gut barrier because there’s not much benefit to the body to have bacteria run amok in our internal organs,” Dr. Vujkovic-Cvijin said. “That can only disrupt the functioning of our tissues, to have an external organism living inside them.” 

The controversy that erupted last summer, surrounding research from the lab of Rob Knight, PhD, at the University of California, San Diego, centered on a slightly different but related question: Could tumors harbor their own microbiomes?

This news organization spoke with two of the authors who published a paper contesting Dr. Knight’s findings: Steven Salzberg, PhD, a professor of biomedical engineering at John Hopkins Medicine, Baltimore, Maryland, and Abraham Gihawi, PhD, a research fellow at Norwich Medical School at the University of East Anglia in the United Kingdom. 

Dr. Salzberg described two major problems with Dr. Knight’s study. 

“What they found were false positives because of contamination in the database and flaws in their methods,” Dr. Salzberg said. “I can’t prove there’s no cancer microbiome, but I can say the cancer microbiomes that they reported don’t exist because the species they were finding aren’t there.”

Dr. Knight disagrees with Dr. Salzberg’s findings, noting that Dr. Salzberg and his co-authors did not examine the publicly available databases used in his study. In a written response, he said that his team’s examination of the database revealed that less than 1% of the microbial genomes overlapped with human ones and that removing them did not change their findings.

Dr. Knight also noted that his team could still “distinguish cancer types by their microbiome” even after running their analysis without the technique that Dr. Salzberg found fault with.

Dr. Salzberg said that the database linked above is not the one Dr. Knight’s study used, however. “The primary database in their study was never made public (it’s too large, they said), and it has/had about 69,000 genomes,” Dr. Salzberg said by email. “But even if we did, this is irrelevant. He’s trying to distract from the primary errors in their study,” which Dr. Salzberg said Dr. Knight’s team has not addressed. 

The critiques Dr. Salzberg raised have been leveled at other studies investigating microbiomes specifically within tumors and independent of the body’s microbiome.

For example, a 2019 study in Nature described a fungal microbiome in pancreatic cancer that a Nature paper 4 years later directly contradicted, citing flaws that invalidated the original findings. A different 2019 study in Cell examined pancreatic tumor microbiota and patient outcomes, but it’s unclear whether the microorganisms moved from the gut to the pancreas or “constitute a durably colonized community that lives inside the tumor,” which remains a matter of debate, Dr. Vujkovic-Cvijin said.

A 2020 study in Science suggested diverse microbial communities in seven tumor types, but those findings were similarly called into question. That study stated that “bacteria were first detected in human tumors more than 100 years ago” and that “bacteria are well-known residents in human tumors,” but Dr. Salzberg considers those statements misleading. 

It’s true that bacteria and viruses have been detected in tumors because “there’s very good evidence that an acute infection caused by a very small number of viruses and bacteria can cause a tumor,” Dr. Salzberg said. Human papillomavirus, for example, can cause six different types of cancer. Inflammation and ulcers caused by Helicobacter pylori may progress to stomach cancer, and Fusobacterium nucleatum and Enterococcus faecalis have been shown to contribute to colorectal cancer. Those examples differ from a microbiome; this “a community of bacteria and possibly other microscopic bugs, like fungi, that are happily living in the tumor” the same way microbes reside in our guts, he said.

Dr. Knight said that many bacteria his team identified “have been confirmed independently in subsequent work.” He acknowledged, however, that more research is needed. 

Several of the contested studies above were among a lengthy list that Dr. Knight provided, noting that most of the disagreements “have two sides to them, and critiques from one particular group does not immediately invalidate a reported finding.” 

Yet, many of the papers Dr. Knight listed are precisely the types that skeptics like Dr. Salzberg believe are too flawed to draw reliable conclusions. 

“I think many agree that microbes may exist within tumors that are exposed to the environment, like tumors of the skin, gut, and mouth,” Dr. Vujkovic-Cvijin said. It’s less clear, however, whether tumors further from the body’s microbiome harbor any microbes or where they came from if they do. Microbial signals in organs elsewhere in the body become faint quickly, he said.
 

Underdeveloped Technology 

Though Dr. Salzberg said that the concept of a tumor microbiome is “implausible” because there’s no easy route for bacteria to reach internal organs, it’s unclear whether scientists have the technology yet to adequately answer this question. 

For one thing, samples in these types of studies are typically “ultra-low biomass samples, where the signal — the amount of microbes in the sample — is so low that it’s comparable to how much would be expected to be found in reagents and environmental contamination through processing,” Dr. Vujkovic-Cvijin explained. Many polymerases used to amplify a DNA signal, for example, are made in bacteria and may retain trace amounts identified in these studies. 

Dr. Knight agreed that low biomass is a challenge in this field but is not an unsurmountable one. 

Another challenge is that study samples, as with Dr. Knight’s work, were collected during routine surgeries without the intent to find a microbial signal. Simply using a scalpel to cut through the skin means cutting through a layer of bacteria, and surgery rooms are not designed to eliminate all bacteria. Some work has even shown there is a “hospital microbiome,” so “you can easily have that creep into your signal and mistake it for tumor-resident bacteria,” Dr. Vujkovic-Cvijin said. 

Dr. Knight asserted that the samples are taken under sterile conditions, but other researchers do not think the level of sterility necessary for completely clean samples is possible. 

“Just because it’s in your sample doesn’t mean it was in your tumor,” Dr. Gihawi said.

Even if scientists can retrieve a reliable sample without contamination, analyzing it requires comparing the genetic material to existing databases of microbial genomes. Yet, contamination and misclassification of genetic sequences can be problems in those reference genomes too, Dr. Gihawi explained.

Machine learning algorithms have a role in interpreting data, but “we need to be careful of what we use them for,” he added.

“These techniques are in their infancy, and we’re starting to chase them down, which is why we need to move microbiome research in a way that can be used clinically,” Dr. Gihawi said. 
 

Influence on Cancer Treatment Outcomes

Again, however, the question of whether microbiomes exist within tumors is only one slice of the much larger field looking at microbiomes and cancer, including its influence on cancer treatment outcomes. Although much remains to be learned, less controversy exists over the thousands of studies in the past two decades that have gradually revealed how the body’s microbiome can affect both the course of a cancer and the effectiveness of different treatments.

The growing research showing the importance of the gut microbiome in cancer treatments is not surprising given its role in immunity more broadly. Because the human immune system must recognize and defend against microbes, the microbiome helps train it, Dr. Vujkovic-Cvijin said. 

Some bacteria can escape the gut — a phenomenon called bacterial translocation — and may aid in fighting tumors. To grow large enough to be seen on imaging, tumors need to evolve several abilities, such as growing enough vascularization to receive blood flow and shutting down local immune responses.

“Any added boost, like immunotherapy, has a chance of breaking through that immune forcefield and killing the tumor cells,” Dr. Vujkovic-Cvijin said. Escaped gut bacteria may provide that boost. 

“There’s a lot of evidence that depletion of the gut microbiome impairs immunotherapy and chemotherapy. The thinking behind some of those studies is that gut microbes can cross the gut barrier and when they do, they activate the immune system,” he said. 

In mice engineered to have sterile guts, for example, the lack of bacteria results in less effective immune systems, Dr. Vujkovic-Cvijin pointed out. A host of research has shown that antibiotic exposure during and even 6 months before immunotherapy dramatically reduces survival rates. “That’s pretty convincing to me that gut microbes are important,” he said. 

Dr. Vujkovic-Cvijin cautioned that there continues to be controversy on understanding which bacteria are important for response to immunotherapy. “The field is still in its infancy in terms of understanding which bacteria are most important for these effects,” he said.

Dr. Knight suggested that escaped bacteria may be the genesis of the ones that he and other researchers believe exist in tumors. “Because tumor microbes must come from somewhere, it is to be expected that some of those microbes will be co-opted from body-site specific commensals.”

It’s also possible that metabolites released from gut bacteria escape the gut and could theoretically affect distant tumor growth, Dr. Gihawi said. The most promising avenue of research in this area is metabolites being used as biomarkers, added Dr. Gihawi, whose lab published research on a link between bacteria detected in men’s urine and a more aggressive subset of prostate cancers. But that research is not far enough along to develop lab tests for clinical use, he noted. 
 

No Consensus Yet

Even before the controversy erupted around Dr. Knight’s research, he co-founded the company Micronoma to develop cancer tests based on his microbe findings. The company has raised $17.5 million from private investors as of August 2023 and received the US Food and Drug Administration’s Breakthrough Device designation, allowing the firm to fast-track clinical trials testing the technology. The recent critiques have not changed the company’s plans. 

It’s safe to say that scientists will continue to research and debate the possibility of tumor microbiomes until a consensus emerges. 

“The field is evolving and studies testing the reproducibility of tumor-resident microbial signals are essential for developing our understanding in this area,” Dr. Vujkovic-Cvijin said.

Even if that path ultimately leads nowhere, as Dr. Salzberg expects, research into microbiomes and cancer has plenty of other directions to go.

“I’m actually quite an optimist,” Dr. Gihawi said. “I think there’s a lot of scope for some really good research here, especially in the sites where we know there is a strong microbiome, such as the gastrointestinal tract.”

A version of this article appeared on Medscape.com.

A contentious scientific debate is clouding prospects for a deeper understanding of the microbiome’s role in cancer, a relatively young field of research that some believe could lead to breakthroughs in the diagnosis and treatment of the second-leading cause of death in the United States. 

Last year, the controversy heightened when experts questioned a high-profile study — a 2020 analysis claiming that the tumors of 33 different cancers had their own unique microbiomes — on whether the “signature” of these bacterial compositions could help diagnose cancer.

The incident renewed the spotlight on “tumor microbiomes” because of the bold claims of the original paper and the strongly worded refutations of those claims. The broader field has focused primarily on ways the body’s microbiome interacts with cancers and cancer treatment.

This controversy has highlighted the challenges of making headway in a field where researchers may not even have the tools yet to puzzle-out the wide-ranging implications the microbiome holds for cancer diagnosis and treatment.

But it is also part of a provocative question within that larger field: whether tumors in the body, far from the natural microbiome in the gut, have their own thriving communities of bacteria, viruses, and fungi. And, if they do, how do those tumor microbiomes affect the development and progression of the cancer and the effectiveness of cancer therapies? 
 

Cancer Controversy

The evidence is undeniable that some microbes can directly cause certain cancers and that the human gut microbiome can influence the effectiveness of certain therapies. Beyond that established science, however, the research has raised as many questions as answers about what we do and don’t know about microbiota and cancer.

The only confirmed microbiomes are on the skin and in the gut, mouth, and vagina, which are all areas with an easy direct route for bacteria to enter and grow in or on the body. A series of papers in recent years have suggested that other internal organs, and tumors within them, may have their own microbiomes. 

“Whether microbes exist in tumors of internal organs beyond body surfaces exposed to the environment is a different matter,” said Ivan Vujkovic-Cvijin, PhD, an assistant professor of biomedical sciences and gastroenterology at Cedars-Sinai Medical Center in Los Angeles, whose lab studies how human gut microbes affect inflammatory diseases. “We’ve only recently had the tools to study that question on a molecular level, and the reported results have been conflicting.” 

For example, research allegedly identified microbiota in the human placenta nearly one decade ago. But subsequent research contradicted those claims and showed that the source of the “placental microbiome” was actually contamination. Subsequent similar studies for other parts of the body faced the same scrutiny and, often, eventual debunking.

“Most likely, our immune system has undergone selective pressure to eliminate everything that crosses the gut barrier because there’s not much benefit to the body to have bacteria run amok in our internal organs,” Dr. Vujkovic-Cvijin said. “That can only disrupt the functioning of our tissues, to have an external organism living inside them.” 

The controversy that erupted last summer, surrounding research from the lab of Rob Knight, PhD, at the University of California, San Diego, centered on a slightly different but related question: Could tumors harbor their own microbiomes?

This news organization spoke with two of the authors who published a paper contesting Dr. Knight’s findings: Steven Salzberg, PhD, a professor of biomedical engineering at John Hopkins Medicine, Baltimore, Maryland, and Abraham Gihawi, PhD, a research fellow at Norwich Medical School at the University of East Anglia in the United Kingdom. 

Dr. Salzberg described two major problems with Dr. Knight’s study. 

“What they found were false positives because of contamination in the database and flaws in their methods,” Dr. Salzberg said. “I can’t prove there’s no cancer microbiome, but I can say the cancer microbiomes that they reported don’t exist because the species they were finding aren’t there.”

Dr. Knight disagrees with Dr. Salzberg’s findings, noting that Dr. Salzberg and his co-authors did not examine the publicly available databases used in his study. In a written response, he said that his team’s examination of the database revealed that less than 1% of the microbial genomes overlapped with human ones and that removing them did not change their findings.

Dr. Knight also noted that his team could still “distinguish cancer types by their microbiome” even after running their analysis without the technique that Dr. Salzberg found fault with.

Dr. Salzberg said that the database linked above is not the one Dr. Knight’s study used, however. “The primary database in their study was never made public (it’s too large, they said), and it has/had about 69,000 genomes,” Dr. Salzberg said by email. “But even if we did, this is irrelevant. He’s trying to distract from the primary errors in their study,” which Dr. Salzberg said Dr. Knight’s team has not addressed. 

The critiques Dr. Salzberg raised have been leveled at other studies investigating microbiomes specifically within tumors and independent of the body’s microbiome.

For example, a 2019 study in Nature described a fungal microbiome in pancreatic cancer that a Nature paper 4 years later directly contradicted, citing flaws that invalidated the original findings. A different 2019 study in Cell examined pancreatic tumor microbiota and patient outcomes, but it’s unclear whether the microorganisms moved from the gut to the pancreas or “constitute a durably colonized community that lives inside the tumor,” which remains a matter of debate, Dr. Vujkovic-Cvijin said.

A 2020 study in Science suggested diverse microbial communities in seven tumor types, but those findings were similarly called into question. That study stated that “bacteria were first detected in human tumors more than 100 years ago” and that “bacteria are well-known residents in human tumors,” but Dr. Salzberg considers those statements misleading. 

It’s true that bacteria and viruses have been detected in tumors because “there’s very good evidence that an acute infection caused by a very small number of viruses and bacteria can cause a tumor,” Dr. Salzberg said. Human papillomavirus, for example, can cause six different types of cancer. Inflammation and ulcers caused by Helicobacter pylori may progress to stomach cancer, and Fusobacterium nucleatum and Enterococcus faecalis have been shown to contribute to colorectal cancer. Those examples differ from a microbiome; this “a community of bacteria and possibly other microscopic bugs, like fungi, that are happily living in the tumor” the same way microbes reside in our guts, he said.

Dr. Knight said that many bacteria his team identified “have been confirmed independently in subsequent work.” He acknowledged, however, that more research is needed. 

Several of the contested studies above were among a lengthy list that Dr. Knight provided, noting that most of the disagreements “have two sides to them, and critiques from one particular group does not immediately invalidate a reported finding.” 

Yet, many of the papers Dr. Knight listed are precisely the types that skeptics like Dr. Salzberg believe are too flawed to draw reliable conclusions. 

“I think many agree that microbes may exist within tumors that are exposed to the environment, like tumors of the skin, gut, and mouth,” Dr. Vujkovic-Cvijin said. It’s less clear, however, whether tumors further from the body’s microbiome harbor any microbes or where they came from if they do. Microbial signals in organs elsewhere in the body become faint quickly, he said.
 

Underdeveloped Technology 

Though Dr. Salzberg said that the concept of a tumor microbiome is “implausible” because there’s no easy route for bacteria to reach internal organs, it’s unclear whether scientists have the technology yet to adequately answer this question. 

For one thing, samples in these types of studies are typically “ultra-low biomass samples, where the signal — the amount of microbes in the sample — is so low that it’s comparable to how much would be expected to be found in reagents and environmental contamination through processing,” Dr. Vujkovic-Cvijin explained. Many polymerases used to amplify a DNA signal, for example, are made in bacteria and may retain trace amounts identified in these studies. 

Dr. Knight agreed that low biomass is a challenge in this field but is not an unsurmountable one. 

Another challenge is that study samples, as with Dr. Knight’s work, were collected during routine surgeries without the intent to find a microbial signal. Simply using a scalpel to cut through the skin means cutting through a layer of bacteria, and surgery rooms are not designed to eliminate all bacteria. Some work has even shown there is a “hospital microbiome,” so “you can easily have that creep into your signal and mistake it for tumor-resident bacteria,” Dr. Vujkovic-Cvijin said. 

Dr. Knight asserted that the samples are taken under sterile conditions, but other researchers do not think the level of sterility necessary for completely clean samples is possible. 

“Just because it’s in your sample doesn’t mean it was in your tumor,” Dr. Gihawi said.

Even if scientists can retrieve a reliable sample without contamination, analyzing it requires comparing the genetic material to existing databases of microbial genomes. Yet, contamination and misclassification of genetic sequences can be problems in those reference genomes too, Dr. Gihawi explained.

Machine learning algorithms have a role in interpreting data, but “we need to be careful of what we use them for,” he added.

“These techniques are in their infancy, and we’re starting to chase them down, which is why we need to move microbiome research in a way that can be used clinically,” Dr. Gihawi said. 
 

Influence on Cancer Treatment Outcomes

Again, however, the question of whether microbiomes exist within tumors is only one slice of the much larger field looking at microbiomes and cancer, including its influence on cancer treatment outcomes. Although much remains to be learned, less controversy exists over the thousands of studies in the past two decades that have gradually revealed how the body’s microbiome can affect both the course of a cancer and the effectiveness of different treatments.

The growing research showing the importance of the gut microbiome in cancer treatments is not surprising given its role in immunity more broadly. Because the human immune system must recognize and defend against microbes, the microbiome helps train it, Dr. Vujkovic-Cvijin said. 

Some bacteria can escape the gut — a phenomenon called bacterial translocation — and may aid in fighting tumors. To grow large enough to be seen on imaging, tumors need to evolve several abilities, such as growing enough vascularization to receive blood flow and shutting down local immune responses.

“Any added boost, like immunotherapy, has a chance of breaking through that immune forcefield and killing the tumor cells,” Dr. Vujkovic-Cvijin said. Escaped gut bacteria may provide that boost. 

“There’s a lot of evidence that depletion of the gut microbiome impairs immunotherapy and chemotherapy. The thinking behind some of those studies is that gut microbes can cross the gut barrier and when they do, they activate the immune system,” he said. 

In mice engineered to have sterile guts, for example, the lack of bacteria results in less effective immune systems, Dr. Vujkovic-Cvijin pointed out. A host of research has shown that antibiotic exposure during and even 6 months before immunotherapy dramatically reduces survival rates. “That’s pretty convincing to me that gut microbes are important,” he said. 

Dr. Vujkovic-Cvijin cautioned that there continues to be controversy on understanding which bacteria are important for response to immunotherapy. “The field is still in its infancy in terms of understanding which bacteria are most important for these effects,” he said.

Dr. Knight suggested that escaped bacteria may be the genesis of the ones that he and other researchers believe exist in tumors. “Because tumor microbes must come from somewhere, it is to be expected that some of those microbes will be co-opted from body-site specific commensals.”

It’s also possible that metabolites released from gut bacteria escape the gut and could theoretically affect distant tumor growth, Dr. Gihawi said. The most promising avenue of research in this area is metabolites being used as biomarkers, added Dr. Gihawi, whose lab published research on a link between bacteria detected in men’s urine and a more aggressive subset of prostate cancers. But that research is not far enough along to develop lab tests for clinical use, he noted. 
 

No Consensus Yet

Even before the controversy erupted around Dr. Knight’s research, he co-founded the company Micronoma to develop cancer tests based on his microbe findings. The company has raised $17.5 million from private investors as of August 2023 and received the US Food and Drug Administration’s Breakthrough Device designation, allowing the firm to fast-track clinical trials testing the technology. The recent critiques have not changed the company’s plans. 

It’s safe to say that scientists will continue to research and debate the possibility of tumor microbiomes until a consensus emerges. 

“The field is evolving and studies testing the reproducibility of tumor-resident microbial signals are essential for developing our understanding in this area,” Dr. Vujkovic-Cvijin said.

Even if that path ultimately leads nowhere, as Dr. Salzberg expects, research into microbiomes and cancer has plenty of other directions to go.

“I’m actually quite an optimist,” Dr. Gihawi said. “I think there’s a lot of scope for some really good research here, especially in the sites where we know there is a strong microbiome, such as the gastrointestinal tract.”

A version of this article appeared on Medscape.com.

Smoldering multiple myeloma (SMM), a potential precursor to multiple myeloma (MM), has become a controversial topic. Some people diagnosed with SMM will live their whole lives without ever developing MM, while others will develop it quickly.

My approach to treating SMM takes into account what its history can teach us about 1) how advancements in imaging and diagnostic reclassifications can revise the entire natural history of a disease, and 2) how evidence generated by even the best of studies may have an expiration date.

Huntsman Cancer Institute

Much of what we know about SMM today dates to a pivotal study by Robert A. Kyle, MD, and colleagues, published in 2007. That inspirational team of investigators followed people diagnosed with SMM from 1970 to 1995 and established the first natural history of the condition. Their monumental effort and the data and conclusions it generated (eg,10% risk annually of SMM becoming MM for the first 5 years) are still cited today in references, papers, and slide sets.

Despite the seminal importance of this work, from today’s perspective the 2007 study might just as well have been describing a different disease. Back then people were diagnosed with SMM if their blood work detected a monoclonal protein and a follow-up bone marrow biopsy found at least 10% plasma cells (or a monoclonal protein exceeding 3g/dL). If there were no signs of end-organ damage (ie, no anemia or kidney problems) and an x-ray showed no fractures or lesions in the bones, the diagnosis was determined to be SMM.

What’s different in 2024? First and foremost: advanced, highly sensitive imaging techniques. MRIs can pick up small lytic lesions (and even the precursor to lytic lesions) that would not appear on an x-ray. In fact, relying solely on x-rays risks missing half of the lytic lesions.

Therefore, using the same criteria, many people who in the past were diagnosed with SMM would today be diagnosed with MM. Furthermore, in 2014 a diagnostic change reclassified people’s diagnosis from the highest risk category of SMM to the category of active MM.

Due to these scientific advances and classification changes, I believe that the natural history of SMM is unknown. Risk stratification models for SMM derived from data sets of people who had not undergone rigorous advanced imaging likely are skewed by data from people who had MM. In addition, current risk stratification models have very poor concordance with each other. I routinely see people whose 2-year risk according to different models varies by more than 30%-40%.

All this information tells us that SMM today is more indolent than the SMM of the past. Paradoxically, however, our therapies keep getting more and more aggressive, exposing this vulnerable group of people to intense treatment regimens that they may not require. Therapies tested on people diagnosed with SMM include an aggressive three-drug regimen, autologous stem cell transplant, and 2 years of additional therapy, as well as, more recently CAR T-cell therapy which so far has at least a 4%-5% treatment-related mortality risk in people with myeloma and a strong signal for secondary cancer risk. Other trials are testing bispecific therapies such as talquetamab, a drug which in my experience causes horrendous skin toxicity, profound weight loss, and one’s nails to fall off.

Doctors routinely keep showing slides from Kyle’s pivotal work to describe the natural history of SMM and to justify the need for treatment, and trials continue to use outdated progression prediction models. In my opinion, as people with MM keep living longer and treatments for MM keep getting better, the threshold for intervening with asymptomatic, healthy people with SMM should be getting higher, not lower.

I strongly believe that the current landscape of SMM treatment exemplifies good intentions leading to bad outcomes. A routine blood test in a completely healthy person that finds elevated total protein in the blood could culminate in well-intentioned but aggressive therapies that can lead to many serious side effects. (I repeat: Secondary cancers and deaths from infections have all occurred in SMM trials.)

With no control arm, we simply don’t know how well these people might have fared without any therapy. For all we know, treatment may have shortened their lives due to complications up to and including death — all because of a blood test often conducted for reasons that have no evidentiary basis.

For example, plasma cell diseases are not linked to low bone density or auto-immune diseases, yet these labs are sent routinely as part of a workup for those conditions, leading to increasing anxiety and costs.

So, what is my approach? When treating people with SMM, I hold nuanced discussions of this data to help prioritize and reach informed decisions. After our honest conversation about the limitations of SMM models, older data, and the limitations of prospective data studying pharmacological treatment, almost no one signs up for treatment.

I want these people to stay safe, and I’m proud to be a part of a trial (SPOTLIGHT, NCT06212323) that aims to show prospectively that these people can be watched off treatment with monitoring via advanced imaging modalities.

In conclusion: SMM teaches us how, even in the absence of pharmacological interventions, the natural history of a disease can change over time, simply via better imaging techniques and changes in diagnostic classifications. Unfortunately, SMM also illustrates how good intentions can lead to harm.
 

Dr. Mohyuddin is assistant professor in the multiple myeloma program at the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

Smoldering multiple myeloma (SMM), a potential precursor to multiple myeloma (MM), has become a controversial topic. Some people diagnosed with SMM will live their whole lives without ever developing MM, while others will develop it quickly.

My approach to treating SMM takes into account what its history can teach us about 1) how advancements in imaging and diagnostic reclassifications can revise the entire natural history of a disease, and 2) how evidence generated by even the best of studies may have an expiration date.

Huntsman Cancer Institute

Much of what we know about SMM today dates to a pivotal study by Robert A. Kyle, MD, and colleagues, published in 2007. That inspirational team of investigators followed people diagnosed with SMM from 1970 to 1995 and established the first natural history of the condition. Their monumental effort and the data and conclusions it generated (eg,10% risk annually of SMM becoming MM for the first 5 years) are still cited today in references, papers, and slide sets.

Despite the seminal importance of this work, from today’s perspective the 2007 study might just as well have been describing a different disease. Back then people were diagnosed with SMM if their blood work detected a monoclonal protein and a follow-up bone marrow biopsy found at least 10% plasma cells (or a monoclonal protein exceeding 3g/dL). If there were no signs of end-organ damage (ie, no anemia or kidney problems) and an x-ray showed no fractures or lesions in the bones, the diagnosis was determined to be SMM.

What’s different in 2024? First and foremost: advanced, highly sensitive imaging techniques. MRIs can pick up small lytic lesions (and even the precursor to lytic lesions) that would not appear on an x-ray. In fact, relying solely on x-rays risks missing half of the lytic lesions.

Therefore, using the same criteria, many people who in the past were diagnosed with SMM would today be diagnosed with MM. Furthermore, in 2014 a diagnostic change reclassified people’s diagnosis from the highest risk category of SMM to the category of active MM.

Due to these scientific advances and classification changes, I believe that the natural history of SMM is unknown. Risk stratification models for SMM derived from data sets of people who had not undergone rigorous advanced imaging likely are skewed by data from people who had MM. In addition, current risk stratification models have very poor concordance with each other. I routinely see people whose 2-year risk according to different models varies by more than 30%-40%.

All this information tells us that SMM today is more indolent than the SMM of the past. Paradoxically, however, our therapies keep getting more and more aggressive, exposing this vulnerable group of people to intense treatment regimens that they may not require. Therapies tested on people diagnosed with SMM include an aggressive three-drug regimen, autologous stem cell transplant, and 2 years of additional therapy, as well as, more recently CAR T-cell therapy which so far has at least a 4%-5% treatment-related mortality risk in people with myeloma and a strong signal for secondary cancer risk. Other trials are testing bispecific therapies such as talquetamab, a drug which in my experience causes horrendous skin toxicity, profound weight loss, and one’s nails to fall off.

Doctors routinely keep showing slides from Kyle’s pivotal work to describe the natural history of SMM and to justify the need for treatment, and trials continue to use outdated progression prediction models. In my opinion, as people with MM keep living longer and treatments for MM keep getting better, the threshold for intervening with asymptomatic, healthy people with SMM should be getting higher, not lower.

I strongly believe that the current landscape of SMM treatment exemplifies good intentions leading to bad outcomes. A routine blood test in a completely healthy person that finds elevated total protein in the blood could culminate in well-intentioned but aggressive therapies that can lead to many serious side effects. (I repeat: Secondary cancers and deaths from infections have all occurred in SMM trials.)

With no control arm, we simply don’t know how well these people might have fared without any therapy. For all we know, treatment may have shortened their lives due to complications up to and including death — all because of a blood test often conducted for reasons that have no evidentiary basis.

For example, plasma cell diseases are not linked to low bone density or auto-immune diseases, yet these labs are sent routinely as part of a workup for those conditions, leading to increasing anxiety and costs.

So, what is my approach? When treating people with SMM, I hold nuanced discussions of this data to help prioritize and reach informed decisions. After our honest conversation about the limitations of SMM models, older data, and the limitations of prospective data studying pharmacological treatment, almost no one signs up for treatment.

I want these people to stay safe, and I’m proud to be a part of a trial (SPOTLIGHT, NCT06212323) that aims to show prospectively that these people can be watched off treatment with monitoring via advanced imaging modalities.

In conclusion: SMM teaches us how, even in the absence of pharmacological interventions, the natural history of a disease can change over time, simply via better imaging techniques and changes in diagnostic classifications. Unfortunately, SMM also illustrates how good intentions can lead to harm.
 

Dr. Mohyuddin is assistant professor in the multiple myeloma program at the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

Smoldering multiple myeloma (SMM), a potential precursor to multiple myeloma (MM), has become a controversial topic. Some people diagnosed with SMM will live their whole lives without ever developing MM, while others will develop it quickly.

My approach to treating SMM takes into account what its history can teach us about 1) how advancements in imaging and diagnostic reclassifications can revise the entire natural history of a disease, and 2) how evidence generated by even the best of studies may have an expiration date.

Huntsman Cancer Institute

Much of what we know about SMM today dates to a pivotal study by Robert A. Kyle, MD, and colleagues, published in 2007. That inspirational team of investigators followed people diagnosed with SMM from 1970 to 1995 and established the first natural history of the condition. Their monumental effort and the data and conclusions it generated (eg,10% risk annually of SMM becoming MM for the first 5 years) are still cited today in references, papers, and slide sets.

Despite the seminal importance of this work, from today’s perspective the 2007 study might just as well have been describing a different disease. Back then people were diagnosed with SMM if their blood work detected a monoclonal protein and a follow-up bone marrow biopsy found at least 10% plasma cells (or a monoclonal protein exceeding 3g/dL). If there were no signs of end-organ damage (ie, no anemia or kidney problems) and an x-ray showed no fractures or lesions in the bones, the diagnosis was determined to be SMM.

What’s different in 2024? First and foremost: advanced, highly sensitive imaging techniques. MRIs can pick up small lytic lesions (and even the precursor to lytic lesions) that would not appear on an x-ray. In fact, relying solely on x-rays risks missing half of the lytic lesions.

Therefore, using the same criteria, many people who in the past were diagnosed with SMM would today be diagnosed with MM. Furthermore, in 2014 a diagnostic change reclassified people’s diagnosis from the highest risk category of SMM to the category of active MM.

Due to these scientific advances and classification changes, I believe that the natural history of SMM is unknown. Risk stratification models for SMM derived from data sets of people who had not undergone rigorous advanced imaging likely are skewed by data from people who had MM. In addition, current risk stratification models have very poor concordance with each other. I routinely see people whose 2-year risk according to different models varies by more than 30%-40%.

All this information tells us that SMM today is more indolent than the SMM of the past. Paradoxically, however, our therapies keep getting more and more aggressive, exposing this vulnerable group of people to intense treatment regimens that they may not require. Therapies tested on people diagnosed with SMM include an aggressive three-drug regimen, autologous stem cell transplant, and 2 years of additional therapy, as well as, more recently CAR T-cell therapy which so far has at least a 4%-5% treatment-related mortality risk in people with myeloma and a strong signal for secondary cancer risk. Other trials are testing bispecific therapies such as talquetamab, a drug which in my experience causes horrendous skin toxicity, profound weight loss, and one’s nails to fall off.

Doctors routinely keep showing slides from Kyle’s pivotal work to describe the natural history of SMM and to justify the need for treatment, and trials continue to use outdated progression prediction models. In my opinion, as people with MM keep living longer and treatments for MM keep getting better, the threshold for intervening with asymptomatic, healthy people with SMM should be getting higher, not lower.

I strongly believe that the current landscape of SMM treatment exemplifies good intentions leading to bad outcomes. A routine blood test in a completely healthy person that finds elevated total protein in the blood could culminate in well-intentioned but aggressive therapies that can lead to many serious side effects. (I repeat: Secondary cancers and deaths from infections have all occurred in SMM trials.)

With no control arm, we simply don’t know how well these people might have fared without any therapy. For all we know, treatment may have shortened their lives due to complications up to and including death — all because of a blood test often conducted for reasons that have no evidentiary basis.

For example, plasma cell diseases are not linked to low bone density or auto-immune diseases, yet these labs are sent routinely as part of a workup for those conditions, leading to increasing anxiety and costs.

So, what is my approach? When treating people with SMM, I hold nuanced discussions of this data to help prioritize and reach informed decisions. After our honest conversation about the limitations of SMM models, older data, and the limitations of prospective data studying pharmacological treatment, almost no one signs up for treatment.

I want these people to stay safe, and I’m proud to be a part of a trial (SPOTLIGHT, NCT06212323) that aims to show prospectively that these people can be watched off treatment with monitoring via advanced imaging modalities.

In conclusion: SMM teaches us how, even in the absence of pharmacological interventions, the natural history of a disease can change over time, simply via better imaging techniques and changes in diagnostic classifications. Unfortunately, SMM also illustrates how good intentions can lead to harm.
 

Dr. Mohyuddin is assistant professor in the multiple myeloma program at the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

Adjuvant therapy with aspirin offers no protection against recurrence or survival benefit in patients with high-risk nonmetastatic breast cancer, the results of a new phase 3 randomized controlled trial suggest.

These data are more robust than the efficacy signals from previous studies, meaning healthcare providers should not recommend aspirin as adjuvant therapy for breast cancer, reported lead author Wendy Y. Chen, MD, of Dana Farber Cancer Institute, Boston, and colleagues.

What Data Support Aspirin for Treating Breast Cancer?

“Multiple observational studies have reported a decreased risk of death among survivors of breast cancer who were regular aspirin users,” the investigators wrote in JAMA. “Even more compelling were data from randomized trials of aspirin for cardiovascular disease.”

This possible benefit was reported with mechanistic support, as aspirin’s anti-inflammatory and anti-platelet properties could theoretically control tumor growth, they added. Furthermore, aspirin impacts several cancer pathways currently targeted by agents approved by the US Food and Drug Administration (FDA).

Brigham &amp; Women&#039;s Hospital

What Were The Key Findings From The A011502 Trial?

The A011502 trial enrolled 3,020 patients aged 18-70 years with ERBB2-negative breast cancer who had received standard therapy via routine clinical care. Eligibility required that chemotherapy and local therapy were complete, but ongoing endocrine therapy was allowed.

Participants were randomized in a 1:1 ratio to receive aspirin 300 mg per day or matching placebo for 5 years. The primary outcome was invasive disease-free survival, and the key secondary outcome was overall survival.

After a median follow-up of almost 3 years, at the first interim analysis, the study was suspended early due to statistical futility. By that timepoint, 253 invasive disease-free survival events occurred, of which 141 occurred in the aspirin group, compared with 112 in the placebo group, providing a hazard ratio of 1.27 (95% CI, 0.99-1.63) that was not statistically significant  (P = .06). No statistically significant difference in overall survival was observed (hazard ratio, 1.19; 95% CI, 0.82-1.72). Safety profiles were similar across groups.

How Will This Study Change Practice?

In an accompanying editorial, Jeanne S. Mandelblatt, MD, of Georgetown Lombardi Institute for Cancer and Aging Research, Washington, and colleagues, praised the trial for its comprehensive approach, but they predicted that the negative result could spell friction for health care providers.

“[C]linicians may find it challenging to communicate with their patients about the negative result in the Alliance trial, because prior lay press articles, observational studies, and meta-analyses of cardiovascular trials suggested that aspirin may decrease breast cancer recurrence,” they wrote.

Georgetown University

How Might the Findings From the A011502 Trial Impact Future Research?

Finally, and “most critically,” the editorialists raised concerns about health equity, noting the limited diversity in trial participants and the potential exclusion of subgroups that might benefit from aspirin use, particularly those more likely to experience accelerated biological aging and disparities in cancer risk and outcomes due to systemic racism or adverse social determinants of health.

They concluded by emphasizing the need to consider the intersectionality of aging, cancer, and disparities in designing future trials to advance health equity.

This study was funded by the Department of Defense Breast Cancer Research Program and the National Cancer Institute of the National Institutes of Health. The research was also supported in part by Bayer, which provided the study drug. The investigators disclosed relationships with Novartis, Seagen, Orum Clinical, and others. The editorialists disclosed relationships with Cantex Pharmaceuticals, and Pfizer.

Adjuvant therapy with aspirin offers no protection against recurrence or survival benefit in patients with high-risk nonmetastatic breast cancer, the results of a new phase 3 randomized controlled trial suggest.

These data are more robust than the efficacy signals from previous studies, meaning healthcare providers should not recommend aspirin as adjuvant therapy for breast cancer, reported lead author Wendy Y. Chen, MD, of Dana Farber Cancer Institute, Boston, and colleagues.

What Data Support Aspirin for Treating Breast Cancer?

“Multiple observational studies have reported a decreased risk of death among survivors of breast cancer who were regular aspirin users,” the investigators wrote in JAMA. “Even more compelling were data from randomized trials of aspirin for cardiovascular disease.”

This possible benefit was reported with mechanistic support, as aspirin’s anti-inflammatory and anti-platelet properties could theoretically control tumor growth, they added. Furthermore, aspirin impacts several cancer pathways currently targeted by agents approved by the US Food and Drug Administration (FDA).

Brigham &amp; Women&#039;s Hospital

What Were The Key Findings From The A011502 Trial?

The A011502 trial enrolled 3,020 patients aged 18-70 years with ERBB2-negative breast cancer who had received standard therapy via routine clinical care. Eligibility required that chemotherapy and local therapy were complete, but ongoing endocrine therapy was allowed.

Participants were randomized in a 1:1 ratio to receive aspirin 300 mg per day or matching placebo for 5 years. The primary outcome was invasive disease-free survival, and the key secondary outcome was overall survival.

After a median follow-up of almost 3 years, at the first interim analysis, the study was suspended early due to statistical futility. By that timepoint, 253 invasive disease-free survival events occurred, of which 141 occurred in the aspirin group, compared with 112 in the placebo group, providing a hazard ratio of 1.27 (95% CI, 0.99-1.63) that was not statistically significant  (P = .06). No statistically significant difference in overall survival was observed (hazard ratio, 1.19; 95% CI, 0.82-1.72). Safety profiles were similar across groups.

How Will This Study Change Practice?

In an accompanying editorial, Jeanne S. Mandelblatt, MD, of Georgetown Lombardi Institute for Cancer and Aging Research, Washington, and colleagues, praised the trial for its comprehensive approach, but they predicted that the negative result could spell friction for health care providers.

“[C]linicians may find it challenging to communicate with their patients about the negative result in the Alliance trial, because prior lay press articles, observational studies, and meta-analyses of cardiovascular trials suggested that aspirin may decrease breast cancer recurrence,” they wrote.

Georgetown University

How Might the Findings From the A011502 Trial Impact Future Research?

Finally, and “most critically,” the editorialists raised concerns about health equity, noting the limited diversity in trial participants and the potential exclusion of subgroups that might benefit from aspirin use, particularly those more likely to experience accelerated biological aging and disparities in cancer risk and outcomes due to systemic racism or adverse social determinants of health.

They concluded by emphasizing the need to consider the intersectionality of aging, cancer, and disparities in designing future trials to advance health equity.

This study was funded by the Department of Defense Breast Cancer Research Program and the National Cancer Institute of the National Institutes of Health. The research was also supported in part by Bayer, which provided the study drug. The investigators disclosed relationships with Novartis, Seagen, Orum Clinical, and others. The editorialists disclosed relationships with Cantex Pharmaceuticals, and Pfizer.

Adjuvant therapy with aspirin offers no protection against recurrence or survival benefit in patients with high-risk nonmetastatic breast cancer, the results of a new phase 3 randomized controlled trial suggest.

These data are more robust than the efficacy signals from previous studies, meaning healthcare providers should not recommend aspirin as adjuvant therapy for breast cancer, reported lead author Wendy Y. Chen, MD, of Dana Farber Cancer Institute, Boston, and colleagues.

What Data Support Aspirin for Treating Breast Cancer?

“Multiple observational studies have reported a decreased risk of death among survivors of breast cancer who were regular aspirin users,” the investigators wrote in JAMA. “Even more compelling were data from randomized trials of aspirin for cardiovascular disease.”

This possible benefit was reported with mechanistic support, as aspirin’s anti-inflammatory and anti-platelet properties could theoretically control tumor growth, they added. Furthermore, aspirin impacts several cancer pathways currently targeted by agents approved by the US Food and Drug Administration (FDA).

Brigham &amp; Women&#039;s Hospital

What Were The Key Findings From The A011502 Trial?

The A011502 trial enrolled 3,020 patients aged 18-70 years with ERBB2-negative breast cancer who had received standard therapy via routine clinical care. Eligibility required that chemotherapy and local therapy were complete, but ongoing endocrine therapy was allowed.

Participants were randomized in a 1:1 ratio to receive aspirin 300 mg per day or matching placebo for 5 years. The primary outcome was invasive disease-free survival, and the key secondary outcome was overall survival.

After a median follow-up of almost 3 years, at the first interim analysis, the study was suspended early due to statistical futility. By that timepoint, 253 invasive disease-free survival events occurred, of which 141 occurred in the aspirin group, compared with 112 in the placebo group, providing a hazard ratio of 1.27 (95% CI, 0.99-1.63) that was not statistically significant  (P = .06). No statistically significant difference in overall survival was observed (hazard ratio, 1.19; 95% CI, 0.82-1.72). Safety profiles were similar across groups.

How Will This Study Change Practice?

In an accompanying editorial, Jeanne S. Mandelblatt, MD, of Georgetown Lombardi Institute for Cancer and Aging Research, Washington, and colleagues, praised the trial for its comprehensive approach, but they predicted that the negative result could spell friction for health care providers.

“[C]linicians may find it challenging to communicate with their patients about the negative result in the Alliance trial, because prior lay press articles, observational studies, and meta-analyses of cardiovascular trials suggested that aspirin may decrease breast cancer recurrence,” they wrote.

Georgetown University

How Might the Findings From the A011502 Trial Impact Future Research?

Finally, and “most critically,” the editorialists raised concerns about health equity, noting the limited diversity in trial participants and the potential exclusion of subgroups that might benefit from aspirin use, particularly those more likely to experience accelerated biological aging and disparities in cancer risk and outcomes due to systemic racism or adverse social determinants of health.

They concluded by emphasizing the need to consider the intersectionality of aging, cancer, and disparities in designing future trials to advance health equity.

This study was funded by the Department of Defense Breast Cancer Research Program and the National Cancer Institute of the National Institutes of Health. The research was also supported in part by Bayer, which provided the study drug. The investigators disclosed relationships with Novartis, Seagen, Orum Clinical, and others. The editorialists disclosed relationships with Cantex Pharmaceuticals, and Pfizer.

In the setting of conflicting national screening guidelines, the incidence of distant- and regional-stage colorectal adenocarcinoma (CRC) has been increasing in individuals aged 46-49 years, a cross-sectional study of stage-stratified CRC found.

It is well known that CRC is becoming more prevalent generally in the under 50-year population, but stage-related analyses have not been done.

Staging analysis in this age group is important, however, as an increasing burden of advance-staged disease would provide further evidence for earlier screening initiation, wrote Eric M. Montminy, MD, a gastroenterologist at John H. Stroger Hospital of County Cook, Chicago, Illinois, and colleagues in JAMA Network Open.

• Distant adenocarcinoma IRs increased faster than other stages: annual percentage change (APC), 2.2 (95% CI, 1.8-2.6).
• Regional IRs also significantly increased: APC, 1.3 (95% CI, 0.8-1.7).
• Absolute regional IRs of CRC in the age bracket of 46-49 years are similar to total pancreatic cancer IRs in all ages and all stages combined (13.2 of 100,000) over similar years. When distant IRs for CRC are included with regional IRs, those for IRs for CRC are double those for pancreatic cancer of all stages combined.
• The only decrease was seen in localized IRs: APC, -0.6 (95% CI, -1 to -0.2).

“My best advice for clinicians is to provide the facts from the data to patients so they can make an informed health decision,” Dr. Montminy said. “This includes taking an appropriate personal and family history and having the patient factor this aspect into their decision on when and how they want to perform colon cancer screening.”

His institution adheres to the USPSTF recommendation of initiation of CRC screening at age 45 years.
 

Findings From 2000 to 2020

During 2000-2020 period, 26,887 CRCs were diagnosed in adults aged 46-49 years (54.5% in men).

As of 2020, the localized adenocarcinoma IR decreased to 7.7 of 100,000, but regional adenocarcinoma IR increased to 13.4 of 100,000 and distant adenocarcinoma IR increased to 9.0 of 100,000.

Regional adenocarcinoma IR remained the highest of all stages in 2000-2020. From 2014 to 2020, distant IRs became similar to localized IRs, except in 2017 when distant IRs were significantly higher than localized.
 

Why the CRC Uptick?

“It remains an enigma at this time as to why we’re seeing this shift,” Dr. Montminy said, noting that etiologies from the colonic microbiome to cellphones have been postulated. “To date, no theory has substantially provided causality. But whatever the source is, it is affecting Western countries in unison with data demonstrating a birth cohort effect as well,” he added. “We additionally know, based on the current epidemiologic data, that current screening practices are failing, and a unified discussion must occur in order to prevent young patients from developing advanced colon cancer.”

Offering his perspective on the findings, Joshua Meyer, MD, vice chair of translational research in the Department of Radiation Oncology at Fox Chase Cancer Center in Philadelphia, said the findings reinforce the practice of offering screening to average-risk individuals starting at age 45 years, the threshold at his institution. “There are previously published data demonstrating an increase in advanced stage at the time of screening initiation, and these data support that,” said Dr. Meyer, who was not involved in the present analysis.

More research needs to be done, he continued, not just on optimal age but also on the effect of multiple other factors impacting risk. “These may include family history and genetic risk as well as the role of blood- and stool-based screening assays in an integrated strategy to screen for colorectal cancer.”

There are multiple screening tests, and while colonoscopy, the gold standard, is very safe, it is not completely without risks, Dr. Meyer added. “And the question of the appropriate allocation of limited societal resources continues to be discussed on a broader level and largely explains the difference between the two guidelines.”

This study received no specific funding. Co-author Jordan J. Karlitz, MD, reported personal fees from GRAIL (senior medical director) and an equity position from Gastro Girl/GI On Demand outside f the submitted work. Dr. Meyer disclosed no conflicts of interest relevant to his comments.

In the setting of conflicting national screening guidelines, the incidence of distant- and regional-stage colorectal adenocarcinoma (CRC) has been increasing in individuals aged 46-49 years, a cross-sectional study of stage-stratified CRC found.

It is well known that CRC is becoming more prevalent generally in the under 50-year population, but stage-related analyses have not been done.

Staging analysis in this age group is important, however, as an increasing burden of advance-staged disease would provide further evidence for earlier screening initiation, wrote Eric M. Montminy, MD, a gastroenterologist at John H. Stroger Hospital of County Cook, Chicago, Illinois, and colleagues in JAMA Network Open.

• Distant adenocarcinoma IRs increased faster than other stages: annual percentage change (APC), 2.2 (95% CI, 1.8-2.6).
• Regional IRs also significantly increased: APC, 1.3 (95% CI, 0.8-1.7).
• Absolute regional IRs of CRC in the age bracket of 46-49 years are similar to total pancreatic cancer IRs in all ages and all stages combined (13.2 of 100,000) over similar years. When distant IRs for CRC are included with regional IRs, those for IRs for CRC are double those for pancreatic cancer of all stages combined.
• The only decrease was seen in localized IRs: APC, -0.6 (95% CI, -1 to -0.2).

“My best advice for clinicians is to provide the facts from the data to patients so they can make an informed health decision,” Dr. Montminy said. “This includes taking an appropriate personal and family history and having the patient factor this aspect into their decision on when and how they want to perform colon cancer screening.”

His institution adheres to the USPSTF recommendation of initiation of CRC screening at age 45 years.
 

Findings From 2000 to 2020

During 2000-2020 period, 26,887 CRCs were diagnosed in adults aged 46-49 years (54.5% in men).

As of 2020, the localized adenocarcinoma IR decreased to 7.7 of 100,000, but regional adenocarcinoma IR increased to 13.4 of 100,000 and distant adenocarcinoma IR increased to 9.0 of 100,000.

Regional adenocarcinoma IR remained the highest of all stages in 2000-2020. From 2014 to 2020, distant IRs became similar to localized IRs, except in 2017 when distant IRs were significantly higher than localized.
 

Why the CRC Uptick?

“It remains an enigma at this time as to why we’re seeing this shift,” Dr. Montminy said, noting that etiologies from the colonic microbiome to cellphones have been postulated. “To date, no theory has substantially provided causality. But whatever the source is, it is affecting Western countries in unison with data demonstrating a birth cohort effect as well,” he added. “We additionally know, based on the current epidemiologic data, that current screening practices are failing, and a unified discussion must occur in order to prevent young patients from developing advanced colon cancer.”

Offering his perspective on the findings, Joshua Meyer, MD, vice chair of translational research in the Department of Radiation Oncology at Fox Chase Cancer Center in Philadelphia, said the findings reinforce the practice of offering screening to average-risk individuals starting at age 45 years, the threshold at his institution. “There are previously published data demonstrating an increase in advanced stage at the time of screening initiation, and these data support that,” said Dr. Meyer, who was not involved in the present analysis.

More research needs to be done, he continued, not just on optimal age but also on the effect of multiple other factors impacting risk. “These may include family history and genetic risk as well as the role of blood- and stool-based screening assays in an integrated strategy to screen for colorectal cancer.”

There are multiple screening tests, and while colonoscopy, the gold standard, is very safe, it is not completely without risks, Dr. Meyer added. “And the question of the appropriate allocation of limited societal resources continues to be discussed on a broader level and largely explains the difference between the two guidelines.”

This study received no specific funding. Co-author Jordan J. Karlitz, MD, reported personal fees from GRAIL (senior medical director) and an equity position from Gastro Girl/GI On Demand outside f the submitted work. Dr. Meyer disclosed no conflicts of interest relevant to his comments.

In the setting of conflicting national screening guidelines, the incidence of distant- and regional-stage colorectal adenocarcinoma (CRC) has been increasing in individuals aged 46-49 years, a cross-sectional study of stage-stratified CRC found.

It is well known that CRC is becoming more prevalent generally in the under 50-year population, but stage-related analyses have not been done.

Staging analysis in this age group is important, however, as an increasing burden of advance-staged disease would provide further evidence for earlier screening initiation, wrote Eric M. Montminy, MD, a gastroenterologist at John H. Stroger Hospital of County Cook, Chicago, Illinois, and colleagues in JAMA Network Open.

• Distant adenocarcinoma IRs increased faster than other stages: annual percentage change (APC), 2.2 (95% CI, 1.8-2.6).
• Regional IRs also significantly increased: APC, 1.3 (95% CI, 0.8-1.7).
• Absolute regional IRs of CRC in the age bracket of 46-49 years are similar to total pancreatic cancer IRs in all ages and all stages combined (13.2 of 100,000) over similar years. When distant IRs for CRC are included with regional IRs, those for IRs for CRC are double those for pancreatic cancer of all stages combined.
• The only decrease was seen in localized IRs: APC, -0.6 (95% CI, -1 to -0.2).

“My best advice for clinicians is to provide the facts from the data to patients so they can make an informed health decision,” Dr. Montminy said. “This includes taking an appropriate personal and family history and having the patient factor this aspect into their decision on when and how they want to perform colon cancer screening.”

His institution adheres to the USPSTF recommendation of initiation of CRC screening at age 45 years.
 

Findings From 2000 to 2020

During 2000-2020 period, 26,887 CRCs were diagnosed in adults aged 46-49 years (54.5% in men).

As of 2020, the localized adenocarcinoma IR decreased to 7.7 of 100,000, but regional adenocarcinoma IR increased to 13.4 of 100,000 and distant adenocarcinoma IR increased to 9.0 of 100,000.

Regional adenocarcinoma IR remained the highest of all stages in 2000-2020. From 2014 to 2020, distant IRs became similar to localized IRs, except in 2017 when distant IRs were significantly higher than localized.
 

Why the CRC Uptick?

“It remains an enigma at this time as to why we’re seeing this shift,” Dr. Montminy said, noting that etiologies from the colonic microbiome to cellphones have been postulated. “To date, no theory has substantially provided causality. But whatever the source is, it is affecting Western countries in unison with data demonstrating a birth cohort effect as well,” he added. “We additionally know, based on the current epidemiologic data, that current screening practices are failing, and a unified discussion must occur in order to prevent young patients from developing advanced colon cancer.”

Offering his perspective on the findings, Joshua Meyer, MD, vice chair of translational research in the Department of Radiation Oncology at Fox Chase Cancer Center in Philadelphia, said the findings reinforce the practice of offering screening to average-risk individuals starting at age 45 years, the threshold at his institution. “There are previously published data demonstrating an increase in advanced stage at the time of screening initiation, and these data support that,” said Dr. Meyer, who was not involved in the present analysis.

More research needs to be done, he continued, not just on optimal age but also on the effect of multiple other factors impacting risk. “These may include family history and genetic risk as well as the role of blood- and stool-based screening assays in an integrated strategy to screen for colorectal cancer.”

There are multiple screening tests, and while colonoscopy, the gold standard, is very safe, it is not completely without risks, Dr. Meyer added. “And the question of the appropriate allocation of limited societal resources continues to be discussed on a broader level and largely explains the difference between the two guidelines.”

This study received no specific funding. Co-author Jordan J. Karlitz, MD, reported personal fees from GRAIL (senior medical director) and an equity position from Gastro Girl/GI On Demand outside f the submitted work. Dr. Meyer disclosed no conflicts of interest relevant to his comments.