AVAHO

In Western diets, dairy and beef are ubiquitous: Milk goes with coffee, melted cheese with pizza, and chili with rice. But what if dairy products and beef contained a new kind of pathogen that could infect you as a child and trigger cancer or multiple sclerosis (MS) 40-70 years later?

Researchers from the German Cancer Research Center (DKFZ) suspect that such zoonoses are possibly widespread and are therefore recommending that infants not be given dairy products until they are at least age 1 year. However, in two joint statements, the German Federal Institute for Risk Assessment (BfR) and the Max Rubner Institute (MRI) have rejected such theories.

In 2008, Harald zur Hausen, MD, DSc, received the Nobel Prize in Medicine for his discovery that human papillomaviruses cause cervical cancer. His starting point was the observation that sexually abstinent women, such as nuns, rarely develop this cancer. So it was possible to draw the conclusion that pathogens are transmitted during sexual intercourse, explain Dr. zur Hausen and his wife Ethel-Michele de Villiers, PhD, both of DKFZ Heidelberg.

Papillomaviruses, as well as human herpes and Epstein-Barr viruses (EBV), polyomaviruses, and retroviruses, cause cancer in a direct way: by inserting their genes into the DNA of human cells. With a latency of a few years to a few decades, the proteins formed through expression stimulate malignant growth by altering the regulating host gene.
 

Acid radicals

However, viruses – just like bacteria and parasites – can also indirectly trigger cancer. One mechanism for this triggering is the disruption of immune defenses, as shown by the sometimes drastically increased tumor incidence with AIDS or with immunosuppressants after transplants. Chronic inflammation is a second mechanism that generates acid radicals and thereby causes random mutations in replicating cells. Examples include stomach cancer caused by Helicobacter pylori and liver cancer caused by Schistosoma, liver fluke, and hepatitis B and C viruses.

According to Dr. de Villiers and Dr. zur Hausen, there are good reasons to believe that other pathogens could cause chronic inflammation and thereby lead to cancer. Epidemiologic data suggest that dairy and meat products from European cows (Bos taurus) are a potential source. This is because colon cancer and breast cancer commonly occur in places where these foods are heavily consumed (that is, in North America, Argentina, Europe, and Australia). In contrast, the rate is low in India, where cows are revered as holy animals. Also noteworthy is that women with a lactose intolerance rarely develop breast cancer.
 

Viral progeny

In fact, the researchers found single-stranded DNA rings that originated in viruses, which they named bovine meat and milk factors (BMMF), in the intestines of patients with colon cancer. They reported, “This new class of pathogen deserves, in our opinion at least, to become the focus of cancer development and further chronic diseases.” They also detected elevated levels of acid radicals in these areas (that is, oxidative stress), which is typical for chronic inflammation.

The researchers assume that infants, whose immune system is not yet fully matured, ingest the BMMF as soon as they have dairy. Therefore, there is no need for adults to avoid dairy or beef because everyone is infected anyway, said Dr. zur Hausen.
 

‘Breast milk is healthy’

Dr. De Villiers and Dr. zur Hausen outlined more evidence of cancer-triggering pathogens. Mothers who have breastfed are less likely, especially after multiple pregnancies, to develop tumors in various organs or to have MS and type 2 diabetes. The authors attribute the protective effect to oligosaccharides in breast milk, which begin to be formed midway through the pregnancy. They bind to lectin receptors and, in so doing, mask the terminal molecule onto which the viruses need to dock. As a result, their port of entry into the cells is blocked.

The oligosaccharides also protect the baby against life-threatening infections by blocking access by rotaviruses and noroviruses. In this way, especially if breastfeeding lasts a long time – around 1 year – the period of incomplete immunocompetence is bridged.
 

Colon cancer

To date, it has been assumed that around 20% of all cancerous diseases globally are caused by infections, said the researchers. But if the suspected BMMF cases are included, this figure rises to 50%, even to around 80%, for colon cancer. If the suspicion is confirmed, the consequences for prevention and therapy would be significant.

The voice of a Nobel prize winner undoubtedly carries weight, but at the time, Dr. zur Hausen still had to convince a host of skeptics with his discovery that a viral infection is a major cause of cervical cancer. Nonetheless, some indicators suggest that he and his wife have found a dead end this time.
 

Institutional skepticism

When his working group made the results public in February 2019, the DKFZ felt the need to give an all-clear signal in response to alarmed press reports. There is no reason to see dairy and meat consumption as something negative. Similarly, in their first joint statement, the BfR and the MRI judged the data to be insufficient and called for further studies. Multiple research teams began to focus on BMMF as a result. In what foods can they be found? Are they more common in patients with cancer than in healthy people? Are they infectious? Do they cause inflammation and cancer?

The findings presented in a second statement by the BfR and MRI at the end of November 2022 contradicted the claims made by the DKFZ scientists across the board. In no way do BMMF represent new pathogens. They are variants of already known DNA sequences. In addition, they are present in numerous animal-based and plant-based foods, including pork, fish, fruit, vegetables, and nuts.

BMMF do not possess the ability to infect human cells, the institutes said. The proof that they are damaging to one’s health was also absent. It is true that the incidence of intestinal tumors correlates positively with the consumption of red and processed meat – which in no way signifies causality – but dairy products are linked to a reduced risk. On the other hand, breast cancer cannot be associated with the consumption of beef or dairy.

Therefore, both institutes recommend continuing to use these products as supplementary diet for infants because of their micronutrients. They further stated that the products are safe for people of all ages.
 

Association with MS?

Unperturbed, Dr. de Villiers and Dr. zur Hausen went one step further in their current article. They posited that MS is also associated with the consumption of dairy products and beef. Here too geographic distribution prompted the idea to look for BMMF in the brain lesions of patients with MS. The researchers isolated ring-shaped DNA molecules that proved to be closely related to BMMF from dairy and cattle blood. “The result was electrifying for us.”

However, there are several other factors to consider, such as vitamin D3 deficiency. This is because the incidence of MS decreases the further you travel from the poles toward the equator (that is, as solar radiation increases). Also, EBV clearly plays a role because patients with MS display increased titers of EBV antibodies. One study also showed that people in Antarctica excreted reactivated EBV in their saliva during winter and that vitamin D3 stopped the viral secretion.

Under these conditions, the researchers hypothesized that MS is caused by a double infection of brain cells by EBV and BMMF. EBV is reactivated by a lack of vitamin D3, and the BMMF multiply and are eventually converted into proteins. A focal immunoreaction causes the Schwann cells and oligodendrocytes to malfunction, which leads to the destruction of the myelin sheaths around the nerve fibers.

This article was translated from the Medscape German Edition. A version appeared on Medscape.com.

In Western diets, dairy and beef are ubiquitous: Milk goes with coffee, melted cheese with pizza, and chili with rice. But what if dairy products and beef contained a new kind of pathogen that could infect you as a child and trigger cancer or multiple sclerosis (MS) 40-70 years later?

Researchers from the German Cancer Research Center (DKFZ) suspect that such zoonoses are possibly widespread and are therefore recommending that infants not be given dairy products until they are at least age 1 year. However, in two joint statements, the German Federal Institute for Risk Assessment (BfR) and the Max Rubner Institute (MRI) have rejected such theories.

In 2008, Harald zur Hausen, MD, DSc, received the Nobel Prize in Medicine for his discovery that human papillomaviruses cause cervical cancer. His starting point was the observation that sexually abstinent women, such as nuns, rarely develop this cancer. So it was possible to draw the conclusion that pathogens are transmitted during sexual intercourse, explain Dr. zur Hausen and his wife Ethel-Michele de Villiers, PhD, both of DKFZ Heidelberg.

Papillomaviruses, as well as human herpes and Epstein-Barr viruses (EBV), polyomaviruses, and retroviruses, cause cancer in a direct way: by inserting their genes into the DNA of human cells. With a latency of a few years to a few decades, the proteins formed through expression stimulate malignant growth by altering the regulating host gene.
 

Acid radicals

However, viruses – just like bacteria and parasites – can also indirectly trigger cancer. One mechanism for this triggering is the disruption of immune defenses, as shown by the sometimes drastically increased tumor incidence with AIDS or with immunosuppressants after transplants. Chronic inflammation is a second mechanism that generates acid radicals and thereby causes random mutations in replicating cells. Examples include stomach cancer caused by Helicobacter pylori and liver cancer caused by Schistosoma, liver fluke, and hepatitis B and C viruses.

According to Dr. de Villiers and Dr. zur Hausen, there are good reasons to believe that other pathogens could cause chronic inflammation and thereby lead to cancer. Epidemiologic data suggest that dairy and meat products from European cows (Bos taurus) are a potential source. This is because colon cancer and breast cancer commonly occur in places where these foods are heavily consumed (that is, in North America, Argentina, Europe, and Australia). In contrast, the rate is low in India, where cows are revered as holy animals. Also noteworthy is that women with a lactose intolerance rarely develop breast cancer.
 

Viral progeny

In fact, the researchers found single-stranded DNA rings that originated in viruses, which they named bovine meat and milk factors (BMMF), in the intestines of patients with colon cancer. They reported, “This new class of pathogen deserves, in our opinion at least, to become the focus of cancer development and further chronic diseases.” They also detected elevated levels of acid radicals in these areas (that is, oxidative stress), which is typical for chronic inflammation.

The researchers assume that infants, whose immune system is not yet fully matured, ingest the BMMF as soon as they have dairy. Therefore, there is no need for adults to avoid dairy or beef because everyone is infected anyway, said Dr. zur Hausen.
 

‘Breast milk is healthy’

Dr. De Villiers and Dr. zur Hausen outlined more evidence of cancer-triggering pathogens. Mothers who have breastfed are less likely, especially after multiple pregnancies, to develop tumors in various organs or to have MS and type 2 diabetes. The authors attribute the protective effect to oligosaccharides in breast milk, which begin to be formed midway through the pregnancy. They bind to lectin receptors and, in so doing, mask the terminal molecule onto which the viruses need to dock. As a result, their port of entry into the cells is blocked.

The oligosaccharides also protect the baby against life-threatening infections by blocking access by rotaviruses and noroviruses. In this way, especially if breastfeeding lasts a long time – around 1 year – the period of incomplete immunocompetence is bridged.
 

Colon cancer

To date, it has been assumed that around 20% of all cancerous diseases globally are caused by infections, said the researchers. But if the suspected BMMF cases are included, this figure rises to 50%, even to around 80%, for colon cancer. If the suspicion is confirmed, the consequences for prevention and therapy would be significant.

The voice of a Nobel prize winner undoubtedly carries weight, but at the time, Dr. zur Hausen still had to convince a host of skeptics with his discovery that a viral infection is a major cause of cervical cancer. Nonetheless, some indicators suggest that he and his wife have found a dead end this time.
 

Institutional skepticism

When his working group made the results public in February 2019, the DKFZ felt the need to give an all-clear signal in response to alarmed press reports. There is no reason to see dairy and meat consumption as something negative. Similarly, in their first joint statement, the BfR and the MRI judged the data to be insufficient and called for further studies. Multiple research teams began to focus on BMMF as a result. In what foods can they be found? Are they more common in patients with cancer than in healthy people? Are they infectious? Do they cause inflammation and cancer?

The findings presented in a second statement by the BfR and MRI at the end of November 2022 contradicted the claims made by the DKFZ scientists across the board. In no way do BMMF represent new pathogens. They are variants of already known DNA sequences. In addition, they are present in numerous animal-based and plant-based foods, including pork, fish, fruit, vegetables, and nuts.

BMMF do not possess the ability to infect human cells, the institutes said. The proof that they are damaging to one’s health was also absent. It is true that the incidence of intestinal tumors correlates positively with the consumption of red and processed meat – which in no way signifies causality – but dairy products are linked to a reduced risk. On the other hand, breast cancer cannot be associated with the consumption of beef or dairy.

Therefore, both institutes recommend continuing to use these products as supplementary diet for infants because of their micronutrients. They further stated that the products are safe for people of all ages.
 

Association with MS?

Unperturbed, Dr. de Villiers and Dr. zur Hausen went one step further in their current article. They posited that MS is also associated with the consumption of dairy products and beef. Here too geographic distribution prompted the idea to look for BMMF in the brain lesions of patients with MS. The researchers isolated ring-shaped DNA molecules that proved to be closely related to BMMF from dairy and cattle blood. “The result was electrifying for us.”

However, there are several other factors to consider, such as vitamin D3 deficiency. This is because the incidence of MS decreases the further you travel from the poles toward the equator (that is, as solar radiation increases). Also, EBV clearly plays a role because patients with MS display increased titers of EBV antibodies. One study also showed that people in Antarctica excreted reactivated EBV in their saliva during winter and that vitamin D3 stopped the viral secretion.

Under these conditions, the researchers hypothesized that MS is caused by a double infection of brain cells by EBV and BMMF. EBV is reactivated by a lack of vitamin D3, and the BMMF multiply and are eventually converted into proteins. A focal immunoreaction causes the Schwann cells and oligodendrocytes to malfunction, which leads to the destruction of the myelin sheaths around the nerve fibers.

This article was translated from the Medscape German Edition. A version appeared on Medscape.com.

In Western diets, dairy and beef are ubiquitous: Milk goes with coffee, melted cheese with pizza, and chili with rice. But what if dairy products and beef contained a new kind of pathogen that could infect you as a child and trigger cancer or multiple sclerosis (MS) 40-70 years later?

Researchers from the German Cancer Research Center (DKFZ) suspect that such zoonoses are possibly widespread and are therefore recommending that infants not be given dairy products until they are at least age 1 year. However, in two joint statements, the German Federal Institute for Risk Assessment (BfR) and the Max Rubner Institute (MRI) have rejected such theories.

In 2008, Harald zur Hausen, MD, DSc, received the Nobel Prize in Medicine for his discovery that human papillomaviruses cause cervical cancer. His starting point was the observation that sexually abstinent women, such as nuns, rarely develop this cancer. So it was possible to draw the conclusion that pathogens are transmitted during sexual intercourse, explain Dr. zur Hausen and his wife Ethel-Michele de Villiers, PhD, both of DKFZ Heidelberg.

Papillomaviruses, as well as human herpes and Epstein-Barr viruses (EBV), polyomaviruses, and retroviruses, cause cancer in a direct way: by inserting their genes into the DNA of human cells. With a latency of a few years to a few decades, the proteins formed through expression stimulate malignant growth by altering the regulating host gene.
 

Acid radicals

However, viruses – just like bacteria and parasites – can also indirectly trigger cancer. One mechanism for this triggering is the disruption of immune defenses, as shown by the sometimes drastically increased tumor incidence with AIDS or with immunosuppressants after transplants. Chronic inflammation is a second mechanism that generates acid radicals and thereby causes random mutations in replicating cells. Examples include stomach cancer caused by Helicobacter pylori and liver cancer caused by Schistosoma, liver fluke, and hepatitis B and C viruses.

According to Dr. de Villiers and Dr. zur Hausen, there are good reasons to believe that other pathogens could cause chronic inflammation and thereby lead to cancer. Epidemiologic data suggest that dairy and meat products from European cows (Bos taurus) are a potential source. This is because colon cancer and breast cancer commonly occur in places where these foods are heavily consumed (that is, in North America, Argentina, Europe, and Australia). In contrast, the rate is low in India, where cows are revered as holy animals. Also noteworthy is that women with a lactose intolerance rarely develop breast cancer.
 

Viral progeny

In fact, the researchers found single-stranded DNA rings that originated in viruses, which they named bovine meat and milk factors (BMMF), in the intestines of patients with colon cancer. They reported, “This new class of pathogen deserves, in our opinion at least, to become the focus of cancer development and further chronic diseases.” They also detected elevated levels of acid radicals in these areas (that is, oxidative stress), which is typical for chronic inflammation.

The researchers assume that infants, whose immune system is not yet fully matured, ingest the BMMF as soon as they have dairy. Therefore, there is no need for adults to avoid dairy or beef because everyone is infected anyway, said Dr. zur Hausen.
 

‘Breast milk is healthy’

Dr. De Villiers and Dr. zur Hausen outlined more evidence of cancer-triggering pathogens. Mothers who have breastfed are less likely, especially after multiple pregnancies, to develop tumors in various organs or to have MS and type 2 diabetes. The authors attribute the protective effect to oligosaccharides in breast milk, which begin to be formed midway through the pregnancy. They bind to lectin receptors and, in so doing, mask the terminal molecule onto which the viruses need to dock. As a result, their port of entry into the cells is blocked.

The oligosaccharides also protect the baby against life-threatening infections by blocking access by rotaviruses and noroviruses. In this way, especially if breastfeeding lasts a long time – around 1 year – the period of incomplete immunocompetence is bridged.
 

Colon cancer

To date, it has been assumed that around 20% of all cancerous diseases globally are caused by infections, said the researchers. But if the suspected BMMF cases are included, this figure rises to 50%, even to around 80%, for colon cancer. If the suspicion is confirmed, the consequences for prevention and therapy would be significant.

The voice of a Nobel prize winner undoubtedly carries weight, but at the time, Dr. zur Hausen still had to convince a host of skeptics with his discovery that a viral infection is a major cause of cervical cancer. Nonetheless, some indicators suggest that he and his wife have found a dead end this time.
 

Institutional skepticism

When his working group made the results public in February 2019, the DKFZ felt the need to give an all-clear signal in response to alarmed press reports. There is no reason to see dairy and meat consumption as something negative. Similarly, in their first joint statement, the BfR and the MRI judged the data to be insufficient and called for further studies. Multiple research teams began to focus on BMMF as a result. In what foods can they be found? Are they more common in patients with cancer than in healthy people? Are they infectious? Do they cause inflammation and cancer?

The findings presented in a second statement by the BfR and MRI at the end of November 2022 contradicted the claims made by the DKFZ scientists across the board. In no way do BMMF represent new pathogens. They are variants of already known DNA sequences. In addition, they are present in numerous animal-based and plant-based foods, including pork, fish, fruit, vegetables, and nuts.

BMMF do not possess the ability to infect human cells, the institutes said. The proof that they are damaging to one’s health was also absent. It is true that the incidence of intestinal tumors correlates positively with the consumption of red and processed meat – which in no way signifies causality – but dairy products are linked to a reduced risk. On the other hand, breast cancer cannot be associated with the consumption of beef or dairy.

Therefore, both institutes recommend continuing to use these products as supplementary diet for infants because of their micronutrients. They further stated that the products are safe for people of all ages.
 

Association with MS?

Unperturbed, Dr. de Villiers and Dr. zur Hausen went one step further in their current article. They posited that MS is also associated with the consumption of dairy products and beef. Here too geographic distribution prompted the idea to look for BMMF in the brain lesions of patients with MS. The researchers isolated ring-shaped DNA molecules that proved to be closely related to BMMF from dairy and cattle blood. “The result was electrifying for us.”

However, there are several other factors to consider, such as vitamin D3 deficiency. This is because the incidence of MS decreases the further you travel from the poles toward the equator (that is, as solar radiation increases). Also, EBV clearly plays a role because patients with MS display increased titers of EBV antibodies. One study also showed that people in Antarctica excreted reactivated EBV in their saliva during winter and that vitamin D3 stopped the viral secretion.

Under these conditions, the researchers hypothesized that MS is caused by a double infection of brain cells by EBV and BMMF. EBV is reactivated by a lack of vitamin D3, and the BMMF multiply and are eventually converted into proteins. A focal immunoreaction causes the Schwann cells and oligodendrocytes to malfunction, which leads to the destruction of the myelin sheaths around the nerve fibers.

This article was translated from the Medscape German Edition. A version appeared on Medscape.com.

Digital rectal examination (DRE) is neither helpful nor useful as a solitary prostate cancer screening tool in middle-aged men, say investigators reporting the PROBASE study.

The study compared risk-adapted screening measures in men who had prostate-specific antigen (PSA) measured at age 45 with those who had PSA measurements plus DRE at age 50.

The results show that as a solitary screening tool, 99% of DREs did not raise suspicion for prostate cancer, and among the 57 cases where DRE did raise suspicion, only three men were found to have cancer, all of which were low-grade, reported Agne Krilaviciute, PhD, from the German Cancer Research Center in Heidelberg, and colleagues.

“We also see that the cancer detection rate by PSA is four times higher compared to the DRE detection. Around 18% of the tumors are located in the part of the prostate where DRE cannot detect them,” she said in an oral presentation at the European Association of Urology Congress.

The investigators found that the majority of prostate cancers that occurred in this relatively young population were International Society of Urological Pathology grade 1 (Gleason score 3 + 3 = 6) or grade 2 (Gleason 3 + 4 = 7). DRE yields positive results in only about 12% of cases of ISUP grade 1 or 2, they noted.

“We conclude that DRE as a solitary screening test does not lead to a significant PCa [prostate cancer] detection rate in young men,” Dr. Krilaviciute said.
 

Falling by the wayside

The study adds to the growing body of evidence that DRE may not be especially helpful as either a screening tool or when used in active surveillance of men with prostate cancer.

An international consensus panel found that DRE could be safely skipped for active surveillance when MRI and other more accurate and objective measures, such as biomarkers, are available.

A prostate cancer expert who was not involved in the PROBASE study told this news organization that when he was in medical school, it would have been considered a serious lapse of practice not to perform a DRE, but that things have changed considerably over the past several years.

“We have PSA now, we have technology with MRI, and the yield of digital rectal examination is very low,” commented Julio Pow-Sang, MD, chief of the genitourinary oncology program at Moffitt Cancer Center in Tampa, Fla.

“Empirically, it’s very rare to find positive cancer through rectal exam in this day and age of PSA,” he said, adding that the examination itself is highly subjective, with varying results depending on the skills of the particular examiner.

“I think that in time, with good studies like this, digital rectal exam specifically for prostate cancer is going to slowly fade away,” Dr. Pow-Sang said.
 

PROBASE results

PROBASE was a randomized screening study enrolling men at age 45 to test a risk-adapted screening strategy using a baseline PSA value with the additional offer of DRE in a large subcohort of participants.

The study was conducted in Germany, and the authors note that the “German statutory early detection program recommends DRE as a stand-alone screening test starting annually at age 45.”

The PROBASE investigators enrolled 46,495 men from February 2014 through December 2019.

Among the first 23,194 men enrolled, 6,537 underwent DRE at enrollment without a study PSA test.

In this group, 6,480 DREs (99%) were not suspicious for cancer, and 57 (1%) were. Of those with suspected prostate cancer, 37 underwent biopsy and 20 did not. Of those biopsied, only two were found to have prostate cancer. This translated into a cancer detection rate of 0.03% for DRE.

After a median of 6.6 years of follow-up, only one additional case of ISUP grade 2 prostate cancer was detected among the 6,357 men who had DREs at enrollment, translating into a prostate cancer detection rate of .05%.

The investigators also looked at men who suspicious DRE findings at baseline. They assumed that a DRE-detectable tumor at age 45 would still be manifest 5 years later and should be detectable with PSA at age 50. Of the 57 men with initially suspicious findings, 11 returned for PSA screening but refused biopsy, and of this group only one had an elevated PSA level. He then underwent biopsy, but the findings were negative.

Of those who underwent biopsy on the basis of DRE, 16 had prostatitis, 14 had benign prostatic hyperplasia, 1 had high-grade prostatic intraepithelial neoplasia, 1 had atypical small acinar proliferation, and 3 had equivocal findings.

In total, the investigators found 24 tumors among men screened with DRE. Of these, 3 occurred in men with results deemed suspicious and 21 were in men with unsuspicious digital exams. All of the tumors were ISUP grade 1, 2, or 3 tumors.

Among 245 men who had biopsies for a PSA level equal to or higher than 3 ng/mL, primarily Prostate Imaging Reporting and Data System (PI-RADS) 3-5 tumors, DRE findings at the time of biopsy were unsuspicious in about 82% of cases, Dr. Krilaviciute said.

“We also used MRI data to determine what proportion of tumors would be potentially detectable by DRE. We estimated that around 18% of tumors are located in the upper part of the prostate, which is not detectable by DRE,” she said. “Even excluding those tumors, still the DRE detection rate is low in palpable tumors.”

Although DRE performed better in higher-grade tumors, 80% of the tumors in the PROBASE participants were ISUP grade 1 or 2 and were likely to be undetected by DRE, she added.

“In Germany, the recommendations for the screening still include 45-year-olds to go with annual DRE. The PROBASE trial allowed us to evaluate for the first time what was the diagnostic performance for DRE at such a young age, and we see that 99% of men undergoing DRE have no suspicious findings, and among the 1% of suspicious findings having cancers extremely unlikely,” she said.

The study was supported by Deutsche Krebshilfe (German Cancer Aid). Dr. Krilaviciute and Dr. Pow-Sang reported having no relevant conflicts of interest.

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

Digital rectal examination (DRE) is neither helpful nor useful as a solitary prostate cancer screening tool in middle-aged men, say investigators reporting the PROBASE study.

The study compared risk-adapted screening measures in men who had prostate-specific antigen (PSA) measured at age 45 with those who had PSA measurements plus DRE at age 50.

The results show that as a solitary screening tool, 99% of DREs did not raise suspicion for prostate cancer, and among the 57 cases where DRE did raise suspicion, only three men were found to have cancer, all of which were low-grade, reported Agne Krilaviciute, PhD, from the German Cancer Research Center in Heidelberg, and colleagues.

“We also see that the cancer detection rate by PSA is four times higher compared to the DRE detection. Around 18% of the tumors are located in the part of the prostate where DRE cannot detect them,” she said in an oral presentation at the European Association of Urology Congress.

The investigators found that the majority of prostate cancers that occurred in this relatively young population were International Society of Urological Pathology grade 1 (Gleason score 3 + 3 = 6) or grade 2 (Gleason 3 + 4 = 7). DRE yields positive results in only about 12% of cases of ISUP grade 1 or 2, they noted.

“We conclude that DRE as a solitary screening test does not lead to a significant PCa [prostate cancer] detection rate in young men,” Dr. Krilaviciute said.
 

Falling by the wayside

The study adds to the growing body of evidence that DRE may not be especially helpful as either a screening tool or when used in active surveillance of men with prostate cancer.

An international consensus panel found that DRE could be safely skipped for active surveillance when MRI and other more accurate and objective measures, such as biomarkers, are available.

A prostate cancer expert who was not involved in the PROBASE study told this news organization that when he was in medical school, it would have been considered a serious lapse of practice not to perform a DRE, but that things have changed considerably over the past several years.

“We have PSA now, we have technology with MRI, and the yield of digital rectal examination is very low,” commented Julio Pow-Sang, MD, chief of the genitourinary oncology program at Moffitt Cancer Center in Tampa, Fla.

“Empirically, it’s very rare to find positive cancer through rectal exam in this day and age of PSA,” he said, adding that the examination itself is highly subjective, with varying results depending on the skills of the particular examiner.

“I think that in time, with good studies like this, digital rectal exam specifically for prostate cancer is going to slowly fade away,” Dr. Pow-Sang said.
 

PROBASE results

PROBASE was a randomized screening study enrolling men at age 45 to test a risk-adapted screening strategy using a baseline PSA value with the additional offer of DRE in a large subcohort of participants.

The study was conducted in Germany, and the authors note that the “German statutory early detection program recommends DRE as a stand-alone screening test starting annually at age 45.”

The PROBASE investigators enrolled 46,495 men from February 2014 through December 2019.

Among the first 23,194 men enrolled, 6,537 underwent DRE at enrollment without a study PSA test.

In this group, 6,480 DREs (99%) were not suspicious for cancer, and 57 (1%) were. Of those with suspected prostate cancer, 37 underwent biopsy and 20 did not. Of those biopsied, only two were found to have prostate cancer. This translated into a cancer detection rate of 0.03% for DRE.

After a median of 6.6 years of follow-up, only one additional case of ISUP grade 2 prostate cancer was detected among the 6,357 men who had DREs at enrollment, translating into a prostate cancer detection rate of .05%.

The investigators also looked at men who suspicious DRE findings at baseline. They assumed that a DRE-detectable tumor at age 45 would still be manifest 5 years later and should be detectable with PSA at age 50. Of the 57 men with initially suspicious findings, 11 returned for PSA screening but refused biopsy, and of this group only one had an elevated PSA level. He then underwent biopsy, but the findings were negative.

Of those who underwent biopsy on the basis of DRE, 16 had prostatitis, 14 had benign prostatic hyperplasia, 1 had high-grade prostatic intraepithelial neoplasia, 1 had atypical small acinar proliferation, and 3 had equivocal findings.

In total, the investigators found 24 tumors among men screened with DRE. Of these, 3 occurred in men with results deemed suspicious and 21 were in men with unsuspicious digital exams. All of the tumors were ISUP grade 1, 2, or 3 tumors.

Among 245 men who had biopsies for a PSA level equal to or higher than 3 ng/mL, primarily Prostate Imaging Reporting and Data System (PI-RADS) 3-5 tumors, DRE findings at the time of biopsy were unsuspicious in about 82% of cases, Dr. Krilaviciute said.

“We also used MRI data to determine what proportion of tumors would be potentially detectable by DRE. We estimated that around 18% of tumors are located in the upper part of the prostate, which is not detectable by DRE,” she said. “Even excluding those tumors, still the DRE detection rate is low in palpable tumors.”

Although DRE performed better in higher-grade tumors, 80% of the tumors in the PROBASE participants were ISUP grade 1 or 2 and were likely to be undetected by DRE, she added.

“In Germany, the recommendations for the screening still include 45-year-olds to go with annual DRE. The PROBASE trial allowed us to evaluate for the first time what was the diagnostic performance for DRE at such a young age, and we see that 99% of men undergoing DRE have no suspicious findings, and among the 1% of suspicious findings having cancers extremely unlikely,” she said.

The study was supported by Deutsche Krebshilfe (German Cancer Aid). Dr. Krilaviciute and Dr. Pow-Sang reported having no relevant conflicts of interest.

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

Digital rectal examination (DRE) is neither helpful nor useful as a solitary prostate cancer screening tool in middle-aged men, say investigators reporting the PROBASE study.

The study compared risk-adapted screening measures in men who had prostate-specific antigen (PSA) measured at age 45 with those who had PSA measurements plus DRE at age 50.

The results show that as a solitary screening tool, 99% of DREs did not raise suspicion for prostate cancer, and among the 57 cases where DRE did raise suspicion, only three men were found to have cancer, all of which were low-grade, reported Agne Krilaviciute, PhD, from the German Cancer Research Center in Heidelberg, and colleagues.

“We also see that the cancer detection rate by PSA is four times higher compared to the DRE detection. Around 18% of the tumors are located in the part of the prostate where DRE cannot detect them,” she said in an oral presentation at the European Association of Urology Congress.

The investigators found that the majority of prostate cancers that occurred in this relatively young population were International Society of Urological Pathology grade 1 (Gleason score 3 + 3 = 6) or grade 2 (Gleason 3 + 4 = 7). DRE yields positive results in only about 12% of cases of ISUP grade 1 or 2, they noted.

“We conclude that DRE as a solitary screening test does not lead to a significant PCa [prostate cancer] detection rate in young men,” Dr. Krilaviciute said.
 

Falling by the wayside

The study adds to the growing body of evidence that DRE may not be especially helpful as either a screening tool or when used in active surveillance of men with prostate cancer.

An international consensus panel found that DRE could be safely skipped for active surveillance when MRI and other more accurate and objective measures, such as biomarkers, are available.

A prostate cancer expert who was not involved in the PROBASE study told this news organization that when he was in medical school, it would have been considered a serious lapse of practice not to perform a DRE, but that things have changed considerably over the past several years.

“We have PSA now, we have technology with MRI, and the yield of digital rectal examination is very low,” commented Julio Pow-Sang, MD, chief of the genitourinary oncology program at Moffitt Cancer Center in Tampa, Fla.

“Empirically, it’s very rare to find positive cancer through rectal exam in this day and age of PSA,” he said, adding that the examination itself is highly subjective, with varying results depending on the skills of the particular examiner.

“I think that in time, with good studies like this, digital rectal exam specifically for prostate cancer is going to slowly fade away,” Dr. Pow-Sang said.
 

PROBASE results

PROBASE was a randomized screening study enrolling men at age 45 to test a risk-adapted screening strategy using a baseline PSA value with the additional offer of DRE in a large subcohort of participants.

The study was conducted in Germany, and the authors note that the “German statutory early detection program recommends DRE as a stand-alone screening test starting annually at age 45.”

The PROBASE investigators enrolled 46,495 men from February 2014 through December 2019.

Among the first 23,194 men enrolled, 6,537 underwent DRE at enrollment without a study PSA test.

In this group, 6,480 DREs (99%) were not suspicious for cancer, and 57 (1%) were. Of those with suspected prostate cancer, 37 underwent biopsy and 20 did not. Of those biopsied, only two were found to have prostate cancer. This translated into a cancer detection rate of 0.03% for DRE.

After a median of 6.6 years of follow-up, only one additional case of ISUP grade 2 prostate cancer was detected among the 6,357 men who had DREs at enrollment, translating into a prostate cancer detection rate of .05%.

The investigators also looked at men who suspicious DRE findings at baseline. They assumed that a DRE-detectable tumor at age 45 would still be manifest 5 years later and should be detectable with PSA at age 50. Of the 57 men with initially suspicious findings, 11 returned for PSA screening but refused biopsy, and of this group only one had an elevated PSA level. He then underwent biopsy, but the findings were negative.

Of those who underwent biopsy on the basis of DRE, 16 had prostatitis, 14 had benign prostatic hyperplasia, 1 had high-grade prostatic intraepithelial neoplasia, 1 had atypical small acinar proliferation, and 3 had equivocal findings.

In total, the investigators found 24 tumors among men screened with DRE. Of these, 3 occurred in men with results deemed suspicious and 21 were in men with unsuspicious digital exams. All of the tumors were ISUP grade 1, 2, or 3 tumors.

Among 245 men who had biopsies for a PSA level equal to or higher than 3 ng/mL, primarily Prostate Imaging Reporting and Data System (PI-RADS) 3-5 tumors, DRE findings at the time of biopsy were unsuspicious in about 82% of cases, Dr. Krilaviciute said.

“We also used MRI data to determine what proportion of tumors would be potentially detectable by DRE. We estimated that around 18% of tumors are located in the upper part of the prostate, which is not detectable by DRE,” she said. “Even excluding those tumors, still the DRE detection rate is low in palpable tumors.”

Although DRE performed better in higher-grade tumors, 80% of the tumors in the PROBASE participants were ISUP grade 1 or 2 and were likely to be undetected by DRE, she added.

“In Germany, the recommendations for the screening still include 45-year-olds to go with annual DRE. The PROBASE trial allowed us to evaluate for the first time what was the diagnostic performance for DRE at such a young age, and we see that 99% of men undergoing DRE have no suspicious findings, and among the 1% of suspicious findings having cancers extremely unlikely,” she said.

The study was supported by Deutsche Krebshilfe (German Cancer Aid). Dr. Krilaviciute and Dr. Pow-Sang reported having no relevant conflicts of interest.

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

A simple urine test for genetic mutations in urine-derived DNA can predict urothelial cancer up to 12 years before patients develop symptoms, an international team of researchers claims.

The test, if validated in further studies, has the potential to serve as a cancer screening tool for individuals at elevated risk for bladder cancer due to genetics, smoking, or from environmental exposures to known carcinogens, and it could help to reduce the frequency of unnecessary cystoscopies, say urologists who were not involved in the research.

The test involved was performed using a next-generation sequencing assay (UroAmp, Convergent Genomics, based in San Francisco) that identifies mutations in 60 genes associated with bladder cancer. New research reported at the annual congress of the European Association of Urology described the screening model that focused on 10 key genes covered in the assay.

In training and validation cohorts, the urinary comprehensive genomic profiling test accurately predicted future bladder cancer in 66% of patient urine samples, including some that had been collected more than a decade prior to being tested, reported Florence Le Calvez-Kelm, PhD, MSc, from the International Agency for Research on Cancer, Lyon, France.

“Our results provide first evidence from a population-based cohort study of preclinical urothelial cancer detection with urinary comprehensive genomic profiling,” she told the meeting.

The results were consistent both in individuals with known risk factors for bladder cancer who were undergoing cystoscopy and in those with no evidence of disease, she said.

“Research of this nature is very encouraging, as it shows that our ability to identify molecular alterations in liquid biopsies such as urine that might indicate cancer is constantly improving,” commented Joost Boormans, MD, PhD, a urologist at the Erasmus University Medical Center, Rotterdam, Netherlands, and a member of the EAU Scientific Congress Office.

“While we do need to develop more accurate diagnostics, it’s unlikely that we’ll have a mass screening program for bladder cancer in the near future,” he continued. “Where a urine test for genetic mutations could show its value is in reducing cystoscopies and scans in bladder cancer patients who are being monitored for recurrence, as well as those referred for blood in their urine. A simple urine test would be far easier for patients to undergo than invasive procedures or scans, as well as being less costly for health services.”

Dr. Le Calvez-Kelm and colleagues had previously shown that promoter mutations in the gene encoding for the enzyme telomerase reverse transcriptase (TERT) identified in urine were “promising noninvasive biomarkers” for early detection of bladder cancer.

They found that TERT mutations in urine could predict which patients were likely to develop urothelial cancer with 48% sensitivity and 100% specificity.

In the study presented at EAU23, they hypothesized that uCGP of DNA in urine could offer enhanced sensitivity for early detection of urothelial cancer.

They first used the 60-gene assay to create a training set using urine samples from 46 patients with de novo urothelial cancer, 40 with recurrent cancer, and 140 healthy controls.

They then tested the model in two validation cohorts. The first validation cohort consisted of samples from 22 patients with de novo cancer, 48 with recurrent urothelial cancer, and 96 controls from a case-control study conducted at Massachusetts General Hospital, Boston, and Ohio State University, Columbus.

The second validation cohort included 29 patients from the prospective Golestan Cohort Study who subsequently developed urothelial cancer, with 98 controls.

In all, 10 genes were identified as optimal for inclusion in a screening model, which was trained to an overall sensitivity of 88% and a 97% sensitivity for high-grade tumors, with a specificity of 94%.

In the MGH/OSU validation cohort the sensitivity of the models was 71%, and the specificity was 94%. In the Golestan cohort, the sensitivity was 66%, with a specificity of 94%. This compared favorably with the performance of the TERT-only screening model, which, as noted before, had a sensitivity of 48%, albeit with 100% specificity.

“Interestingly, when we broke down the analysis according to the lag time between urine collection and diagnosis, sensitivity increased as the time to diagnosis decreased, so the closer we got to the diagnosis, the higher was the sensitivity,” Dr. Le Calvez-Kelm said.

When the analysis was limited to urothelial cancers diagnosed within 7 years of sample collection, the sensitivity for detecting preclinical cancer improved to 86%, compared with 57% for a test of TERT promoter mutations alone. 

Among the patients in the Golestan cohort, uCGP-predicted positive results were associated with a more than eightfold higher risk for worse cancer-free survival, compared with uCGP-predicted negatives (hazard ratio 8.5, P < .0001).

“Of course, further studies are needed to validate this finding and to assess the clinical utility in other longitudinal cohorts,” Dr. Le Calvez-Kelm concluded.

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

A simple urine test for genetic mutations in urine-derived DNA can predict urothelial cancer up to 12 years before patients develop symptoms, an international team of researchers claims.

The test, if validated in further studies, has the potential to serve as a cancer screening tool for individuals at elevated risk for bladder cancer due to genetics, smoking, or from environmental exposures to known carcinogens, and it could help to reduce the frequency of unnecessary cystoscopies, say urologists who were not involved in the research.

The test involved was performed using a next-generation sequencing assay (UroAmp, Convergent Genomics, based in San Francisco) that identifies mutations in 60 genes associated with bladder cancer. New research reported at the annual congress of the European Association of Urology described the screening model that focused on 10 key genes covered in the assay.

In training and validation cohorts, the urinary comprehensive genomic profiling test accurately predicted future bladder cancer in 66% of patient urine samples, including some that had been collected more than a decade prior to being tested, reported Florence Le Calvez-Kelm, PhD, MSc, from the International Agency for Research on Cancer, Lyon, France.

“Our results provide first evidence from a population-based cohort study of preclinical urothelial cancer detection with urinary comprehensive genomic profiling,” she told the meeting.

The results were consistent both in individuals with known risk factors for bladder cancer who were undergoing cystoscopy and in those with no evidence of disease, she said.

“Research of this nature is very encouraging, as it shows that our ability to identify molecular alterations in liquid biopsies such as urine that might indicate cancer is constantly improving,” commented Joost Boormans, MD, PhD, a urologist at the Erasmus University Medical Center, Rotterdam, Netherlands, and a member of the EAU Scientific Congress Office.

“While we do need to develop more accurate diagnostics, it’s unlikely that we’ll have a mass screening program for bladder cancer in the near future,” he continued. “Where a urine test for genetic mutations could show its value is in reducing cystoscopies and scans in bladder cancer patients who are being monitored for recurrence, as well as those referred for blood in their urine. A simple urine test would be far easier for patients to undergo than invasive procedures or scans, as well as being less costly for health services.”

Dr. Le Calvez-Kelm and colleagues had previously shown that promoter mutations in the gene encoding for the enzyme telomerase reverse transcriptase (TERT) identified in urine were “promising noninvasive biomarkers” for early detection of bladder cancer.

They found that TERT mutations in urine could predict which patients were likely to develop urothelial cancer with 48% sensitivity and 100% specificity.

In the study presented at EAU23, they hypothesized that uCGP of DNA in urine could offer enhanced sensitivity for early detection of urothelial cancer.

They first used the 60-gene assay to create a training set using urine samples from 46 patients with de novo urothelial cancer, 40 with recurrent cancer, and 140 healthy controls.

They then tested the model in two validation cohorts. The first validation cohort consisted of samples from 22 patients with de novo cancer, 48 with recurrent urothelial cancer, and 96 controls from a case-control study conducted at Massachusetts General Hospital, Boston, and Ohio State University, Columbus.

The second validation cohort included 29 patients from the prospective Golestan Cohort Study who subsequently developed urothelial cancer, with 98 controls.

In all, 10 genes were identified as optimal for inclusion in a screening model, which was trained to an overall sensitivity of 88% and a 97% sensitivity for high-grade tumors, with a specificity of 94%.

In the MGH/OSU validation cohort the sensitivity of the models was 71%, and the specificity was 94%. In the Golestan cohort, the sensitivity was 66%, with a specificity of 94%. This compared favorably with the performance of the TERT-only screening model, which, as noted before, had a sensitivity of 48%, albeit with 100% specificity.

“Interestingly, when we broke down the analysis according to the lag time between urine collection and diagnosis, sensitivity increased as the time to diagnosis decreased, so the closer we got to the diagnosis, the higher was the sensitivity,” Dr. Le Calvez-Kelm said.

When the analysis was limited to urothelial cancers diagnosed within 7 years of sample collection, the sensitivity for detecting preclinical cancer improved to 86%, compared with 57% for a test of TERT promoter mutations alone. 

Among the patients in the Golestan cohort, uCGP-predicted positive results were associated with a more than eightfold higher risk for worse cancer-free survival, compared with uCGP-predicted negatives (hazard ratio 8.5, P < .0001).

“Of course, further studies are needed to validate this finding and to assess the clinical utility in other longitudinal cohorts,” Dr. Le Calvez-Kelm concluded.

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

A simple urine test for genetic mutations in urine-derived DNA can predict urothelial cancer up to 12 years before patients develop symptoms, an international team of researchers claims.

The test, if validated in further studies, has the potential to serve as a cancer screening tool for individuals at elevated risk for bladder cancer due to genetics, smoking, or from environmental exposures to known carcinogens, and it could help to reduce the frequency of unnecessary cystoscopies, say urologists who were not involved in the research.

The test involved was performed using a next-generation sequencing assay (UroAmp, Convergent Genomics, based in San Francisco) that identifies mutations in 60 genes associated with bladder cancer. New research reported at the annual congress of the European Association of Urology described the screening model that focused on 10 key genes covered in the assay.

In training and validation cohorts, the urinary comprehensive genomic profiling test accurately predicted future bladder cancer in 66% of patient urine samples, including some that had been collected more than a decade prior to being tested, reported Florence Le Calvez-Kelm, PhD, MSc, from the International Agency for Research on Cancer, Lyon, France.

“Our results provide first evidence from a population-based cohort study of preclinical urothelial cancer detection with urinary comprehensive genomic profiling,” she told the meeting.

The results were consistent both in individuals with known risk factors for bladder cancer who were undergoing cystoscopy and in those with no evidence of disease, she said.

“Research of this nature is very encouraging, as it shows that our ability to identify molecular alterations in liquid biopsies such as urine that might indicate cancer is constantly improving,” commented Joost Boormans, MD, PhD, a urologist at the Erasmus University Medical Center, Rotterdam, Netherlands, and a member of the EAU Scientific Congress Office.

“While we do need to develop more accurate diagnostics, it’s unlikely that we’ll have a mass screening program for bladder cancer in the near future,” he continued. “Where a urine test for genetic mutations could show its value is in reducing cystoscopies and scans in bladder cancer patients who are being monitored for recurrence, as well as those referred for blood in their urine. A simple urine test would be far easier for patients to undergo than invasive procedures or scans, as well as being less costly for health services.”

Dr. Le Calvez-Kelm and colleagues had previously shown that promoter mutations in the gene encoding for the enzyme telomerase reverse transcriptase (TERT) identified in urine were “promising noninvasive biomarkers” for early detection of bladder cancer.

They found that TERT mutations in urine could predict which patients were likely to develop urothelial cancer with 48% sensitivity and 100% specificity.

In the study presented at EAU23, they hypothesized that uCGP of DNA in urine could offer enhanced sensitivity for early detection of urothelial cancer.

They first used the 60-gene assay to create a training set using urine samples from 46 patients with de novo urothelial cancer, 40 with recurrent cancer, and 140 healthy controls.

They then tested the model in two validation cohorts. The first validation cohort consisted of samples from 22 patients with de novo cancer, 48 with recurrent urothelial cancer, and 96 controls from a case-control study conducted at Massachusetts General Hospital, Boston, and Ohio State University, Columbus.

The second validation cohort included 29 patients from the prospective Golestan Cohort Study who subsequently developed urothelial cancer, with 98 controls.

In all, 10 genes were identified as optimal for inclusion in a screening model, which was trained to an overall sensitivity of 88% and a 97% sensitivity for high-grade tumors, with a specificity of 94%.

In the MGH/OSU validation cohort the sensitivity of the models was 71%, and the specificity was 94%. In the Golestan cohort, the sensitivity was 66%, with a specificity of 94%. This compared favorably with the performance of the TERT-only screening model, which, as noted before, had a sensitivity of 48%, albeit with 100% specificity.

“Interestingly, when we broke down the analysis according to the lag time between urine collection and diagnosis, sensitivity increased as the time to diagnosis decreased, so the closer we got to the diagnosis, the higher was the sensitivity,” Dr. Le Calvez-Kelm said.

When the analysis was limited to urothelial cancers diagnosed within 7 years of sample collection, the sensitivity for detecting preclinical cancer improved to 86%, compared with 57% for a test of TERT promoter mutations alone. 

Among the patients in the Golestan cohort, uCGP-predicted positive results were associated with a more than eightfold higher risk for worse cancer-free survival, compared with uCGP-predicted negatives (hazard ratio 8.5, P < .0001).

“Of course, further studies are needed to validate this finding and to assess the clinical utility in other longitudinal cohorts,” Dr. Le Calvez-Kelm concluded.

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

A growing body of evidence shows that deeper and larger tumors can be safely removed with endoscopy instead of surgery when individual patient risk is taken into account, according to a review by Eva P.D. Verheij, a doctoral candidate at Amsterdam University Medical Center, and colleagues.

“Management of patients with superficial esophageal adenocarcinoma (EAC) is becoming less invasive and more patient-tailored,” the researchers wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “In the future, watchful waiting may be a valid alternative to surgery in selected cases.”

Courtesy Eva P. D. Verheij

The investigators examined new advances that have been made in the management of superficial esophageal adenocarcinomas by endoscopy, and they address how guidelines may be falling short in light of newly published evidence.

Surgery is usually the first choice for the management of advanced esophageal adenocarcinoma. “Endoscopic treatment has become the cornerstone for early cancer confined to the mucosa,” the authors wrote.

“For low-risk submucosal EAC, which only invades the superficial submucosa (sm1, i.e. less than 500 mcm) without any other risk factors, endoscopic treatment as an alternative to surgery is gaining acceptance because multiple studies have demonstrated a very low risk of lymph node metastases (less than 2% for these lesions),” the investigators wrote. Although surgical resection with lymphadenectomy is currently the recommended treatment for cases with deep submucosal invasion, poor differentiation, or lymphovascular invasion, the investigators suggested that even these tumors may be within an endoscopist’s reach.

While the rate of lymph node metastasis for such patients has been reported to be as high as 46%, more recent endoscopic studies show a metastasis rate range of up to 20% after 23-63 months of follow-up.

“One possible explanation for the discrepancy in lymph node metastases rates between surgical and endoscopic studies could be the different preparation of slides for histopathological assessment,” the investigators wrote. “In general, the cuts in surgical specimen are made with wider intervals (±5 mm) than the cuts in endoscopic resection specimens (2-3 mm), with additional cuts in case of submucosal invasion. The hypothesis is that this wider interval may result in missing the area with the deepest tumor infiltration. This could result in an underdiagnosis of the actual invasion depth, and therefore an overestimation of the associated lymph node metastases risk.” A study published in August 2022 in Gastrointestinal Endoscopy found an annual metastases risk of 6.9% in patients with high-risk T1a EAC.

“Given its invasiveness and associated morbidity and mortality, esophagectomy may be overtreatment in those patients who will not develop lymph node metastases,” the investigators wrote. “Given the technical advances in endoscopy that enable us to radically remove large EACs, and to perform more meticulous follow-up, it might be time to swing the pendulum and only send those patients for surgery who have an indisputable indication for surgery, instead of performing esophagectomy as a prophylactic treatment.”

To truly find the limits of endoscopic resection for EAC, however, more research is needed.

“Ongoing studies are necessary to evaluate the lymph node metastases risk on an individual basis, using presence of histological risk factors. By predicting the risk of lymph node metastases, and considering patients’ wishes and condition, one might decide to perform esophagectomy or watchful waiting with strict endoscopic follow-up. In high-risk cases, we may use sentinel node navigated surgery in the future as an extra safety check before deciding on optimal management,” the authors wrote.

The investigators disclosed relationships Medtronic, C2 Therapeutics/Pentax Medical, MicroTech, and Aqua Medical.

A growing body of evidence shows that deeper and larger tumors can be safely removed with endoscopy instead of surgery when individual patient risk is taken into account, according to a review by Eva P.D. Verheij, a doctoral candidate at Amsterdam University Medical Center, and colleagues.

“Management of patients with superficial esophageal adenocarcinoma (EAC) is becoming less invasive and more patient-tailored,” the researchers wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “In the future, watchful waiting may be a valid alternative to surgery in selected cases.”

Courtesy Eva P. D. Verheij

The investigators examined new advances that have been made in the management of superficial esophageal adenocarcinomas by endoscopy, and they address how guidelines may be falling short in light of newly published evidence.

Surgery is usually the first choice for the management of advanced esophageal adenocarcinoma. “Endoscopic treatment has become the cornerstone for early cancer confined to the mucosa,” the authors wrote.

“For low-risk submucosal EAC, which only invades the superficial submucosa (sm1, i.e. less than 500 mcm) without any other risk factors, endoscopic treatment as an alternative to surgery is gaining acceptance because multiple studies have demonstrated a very low risk of lymph node metastases (less than 2% for these lesions),” the investigators wrote. Although surgical resection with lymphadenectomy is currently the recommended treatment for cases with deep submucosal invasion, poor differentiation, or lymphovascular invasion, the investigators suggested that even these tumors may be within an endoscopist’s reach.

While the rate of lymph node metastasis for such patients has been reported to be as high as 46%, more recent endoscopic studies show a metastasis rate range of up to 20% after 23-63 months of follow-up.

“One possible explanation for the discrepancy in lymph node metastases rates between surgical and endoscopic studies could be the different preparation of slides for histopathological assessment,” the investigators wrote. “In general, the cuts in surgical specimen are made with wider intervals (±5 mm) than the cuts in endoscopic resection specimens (2-3 mm), with additional cuts in case of submucosal invasion. The hypothesis is that this wider interval may result in missing the area with the deepest tumor infiltration. This could result in an underdiagnosis of the actual invasion depth, and therefore an overestimation of the associated lymph node metastases risk.” A study published in August 2022 in Gastrointestinal Endoscopy found an annual metastases risk of 6.9% in patients with high-risk T1a EAC.

“Given its invasiveness and associated morbidity and mortality, esophagectomy may be overtreatment in those patients who will not develop lymph node metastases,” the investigators wrote. “Given the technical advances in endoscopy that enable us to radically remove large EACs, and to perform more meticulous follow-up, it might be time to swing the pendulum and only send those patients for surgery who have an indisputable indication for surgery, instead of performing esophagectomy as a prophylactic treatment.”

To truly find the limits of endoscopic resection for EAC, however, more research is needed.

“Ongoing studies are necessary to evaluate the lymph node metastases risk on an individual basis, using presence of histological risk factors. By predicting the risk of lymph node metastases, and considering patients’ wishes and condition, one might decide to perform esophagectomy or watchful waiting with strict endoscopic follow-up. In high-risk cases, we may use sentinel node navigated surgery in the future as an extra safety check before deciding on optimal management,” the authors wrote.

The investigators disclosed relationships Medtronic, C2 Therapeutics/Pentax Medical, MicroTech, and Aqua Medical.

A growing body of evidence shows that deeper and larger tumors can be safely removed with endoscopy instead of surgery when individual patient risk is taken into account, according to a review by Eva P.D. Verheij, a doctoral candidate at Amsterdam University Medical Center, and colleagues.

“Management of patients with superficial esophageal adenocarcinoma (EAC) is becoming less invasive and more patient-tailored,” the researchers wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “In the future, watchful waiting may be a valid alternative to surgery in selected cases.”

Courtesy Eva P. D. Verheij

The investigators examined new advances that have been made in the management of superficial esophageal adenocarcinomas by endoscopy, and they address how guidelines may be falling short in light of newly published evidence.

Surgery is usually the first choice for the management of advanced esophageal adenocarcinoma. “Endoscopic treatment has become the cornerstone for early cancer confined to the mucosa,” the authors wrote.

“For low-risk submucosal EAC, which only invades the superficial submucosa (sm1, i.e. less than 500 mcm) without any other risk factors, endoscopic treatment as an alternative to surgery is gaining acceptance because multiple studies have demonstrated a very low risk of lymph node metastases (less than 2% for these lesions),” the investigators wrote. Although surgical resection with lymphadenectomy is currently the recommended treatment for cases with deep submucosal invasion, poor differentiation, or lymphovascular invasion, the investigators suggested that even these tumors may be within an endoscopist’s reach.

While the rate of lymph node metastasis for such patients has been reported to be as high as 46%, more recent endoscopic studies show a metastasis rate range of up to 20% after 23-63 months of follow-up.

“One possible explanation for the discrepancy in lymph node metastases rates between surgical and endoscopic studies could be the different preparation of slides for histopathological assessment,” the investigators wrote. “In general, the cuts in surgical specimen are made with wider intervals (±5 mm) than the cuts in endoscopic resection specimens (2-3 mm), with additional cuts in case of submucosal invasion. The hypothesis is that this wider interval may result in missing the area with the deepest tumor infiltration. This could result in an underdiagnosis of the actual invasion depth, and therefore an overestimation of the associated lymph node metastases risk.” A study published in August 2022 in Gastrointestinal Endoscopy found an annual metastases risk of 6.9% in patients with high-risk T1a EAC.

“Given its invasiveness and associated morbidity and mortality, esophagectomy may be overtreatment in those patients who will not develop lymph node metastases,” the investigators wrote. “Given the technical advances in endoscopy that enable us to radically remove large EACs, and to perform more meticulous follow-up, it might be time to swing the pendulum and only send those patients for surgery who have an indisputable indication for surgery, instead of performing esophagectomy as a prophylactic treatment.”

To truly find the limits of endoscopic resection for EAC, however, more research is needed.

“Ongoing studies are necessary to evaluate the lymph node metastases risk on an individual basis, using presence of histological risk factors. By predicting the risk of lymph node metastases, and considering patients’ wishes and condition, one might decide to perform esophagectomy or watchful waiting with strict endoscopic follow-up. In high-risk cases, we may use sentinel node navigated surgery in the future as an extra safety check before deciding on optimal management,” the authors wrote.

The investigators disclosed relationships Medtronic, C2 Therapeutics/Pentax Medical, MicroTech, and Aqua Medical.

Radiation dermatitis is one of the most common side effects of radiotherapy for women with breast cancer. Results from a phase 3 trial add to previous evidence from smaller trials that show that a silicone-based film can protect skin from this side effect. 

But it is not being used much in clinical practice. Instead, radiation dermatitis is usually treated after the fact, most often with aqueous creams.

The product is Mepitel film, from Swedish medical device company Mölnlycke Health Care.

It should be used for women who are at high risk for developing radiation dermatitis, said Edward Chow, MBBS, PhD, of the department of radiation oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, who was the senior author of the phase 3 study published recently in the Journal of Clinical Oncology.

“Other doctors think that because radiation dermatitis isn’t life-threatening it isn’t as important, but the condition does affect the quality of life for patients,” Dr. Chow said. “If we can lessen the pain and discomfort, why wouldn’t we as physicians?”

Dr. Chow’s open-label, multicenter trial was conducted in 376 women with large breasts (bra cup size C or larger) who were undergoing radiotherapy after lumpectomy or mastectomy. The primary endpoint was grade 2 or 3 radiation dermatitis using the Common Terminology Criteria for Adverse Events. (Grade 2 is described as moderate, whereas grade 3 is severe.) 

The film significantly reduced the incidence of grade 2 or 3 radiation dermatitis, down to  15.5% compared with 45.6% in patients receiving standard care (odds ratio, 0.20, 95% confidence interval, 0.12-0.34, P < .0001). 

There was also a significant reduction in grade 3 radiation dermatitis (2.8% vs. 13.6%; OR, 0.19; P < .0002) and moist desquamation (8% vs. 19.2%; OR, 0.36; P = .002).

“The film was remarkably effective and helped protect patients from potentially debilitating side effects,” commented Corey Speers, MD, PhD, a radiation oncologist with University Hospitals, Cleveland, who saw the study data presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.

He believes that preventing radiation dermatitis before it develops is the best way to care for patients. 

“[Radiation dermatitis] is usually associated with pain and discomfort and can lead to more serious issues like infection or delayed wound healing, and unfortunately, there aren’t effective treatments for it once it’s developed, so preventing it is our most effective strategy,” Dr. Speers said. 

One reason for the film not being used much could be that it takes time apply the film, suggested Patries Herst, PhD, department of radiation therapy, University of Otago, Wellington, New Zealand. She was the lead author of a study published in 2014 that also analyzed the effectiveness of the film in preventing radiation dermatitis.

In their trial, a research radiation therapist applied the film to women when they were starting their radiotherapy. The film is applied to a portion of the breast or chest wall, and Dr. Herst emphasized the importance of applying the film correctly, making sure the film is not stretched during application and not overlapping other pieces of the film, while also making sure that it conforms to the breast shape. The film was replaced when it would curl too much around the sides, approximately every 1 or 2 weeks. 

“Radiation therapy itself is very short. And so you have about 10 minutes for every patient,” she explained.

“But applying the film adds 20-30 minutes and it’s really awkward to apply properly,” Dr. Herst said. “You have to tap it in and then have to maybe cut it so that it fits better. And hospitals say, ‘We don’t have the time’ and that is still the biggest issue that we’re seeing right now.”

In Dr. Chow’s study, the average time spent applying the film on lumpectomy patients was 55 minutes and was slightly shorter at 45 minutes for mastectomy patients. He acknowledged that it does take time that staff at most hospitals and clinics simply don’t have.

Dr. Chow suggested that perhaps a family member or other caregiver could apply the film, and he referenced an educational video from the manufacturer that provides in-depth instructions on the correct way to apply the film for radiotherapy patients. However, this could lead to errors and a waste of product if not the film was not applied properly. 

The cost of Mepitel film may also be a deterrent. Dr. Chow’s study noted that, during the entire course of radiotherapy, the cost for the film was about $80-$100 per patient. However, he believes the benefits outweigh the cost. 

In addition, there have been issues with supplies, and it has been difficult for people to get their hands on the actual product.

Currently, the Mayo Clinic is also conducting a study testing Mepitel Film for radiation dermatitis in breast cancer patients following mastectomy. Mayo Clinic principal investigator Kimberly Corbin, MD, could not go into great detail about the ongoing trial, but she said it has been difficult to get the product. 

“We have been using the film at Mayo for a number of years,” Dr. Corbin said, but we “have found that it is challenging to get supplies.”

“While we have generally been able to have some supply established through our store here, we know that is not typical and it is difficult for patients to access,” she said. In addition, “there are not a ton of centers with experience in application.”

A representative with Mölnlycke Health Care, Allyson Bower-Willner, could not comment on the distribution of Mepitel film in the United States or if the company plans to increase the amount of product shipped. The film is available “to a limited set of customers,” she said.

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

Radiation dermatitis is one of the most common side effects of radiotherapy for women with breast cancer. Results from a phase 3 trial add to previous evidence from smaller trials that show that a silicone-based film can protect skin from this side effect. 

But it is not being used much in clinical practice. Instead, radiation dermatitis is usually treated after the fact, most often with aqueous creams.

The product is Mepitel film, from Swedish medical device company Mölnlycke Health Care.

It should be used for women who are at high risk for developing radiation dermatitis, said Edward Chow, MBBS, PhD, of the department of radiation oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, who was the senior author of the phase 3 study published recently in the Journal of Clinical Oncology.

“Other doctors think that because radiation dermatitis isn’t life-threatening it isn’t as important, but the condition does affect the quality of life for patients,” Dr. Chow said. “If we can lessen the pain and discomfort, why wouldn’t we as physicians?”

Dr. Chow’s open-label, multicenter trial was conducted in 376 women with large breasts (bra cup size C or larger) who were undergoing radiotherapy after lumpectomy or mastectomy. The primary endpoint was grade 2 or 3 radiation dermatitis using the Common Terminology Criteria for Adverse Events. (Grade 2 is described as moderate, whereas grade 3 is severe.) 

The film significantly reduced the incidence of grade 2 or 3 radiation dermatitis, down to  15.5% compared with 45.6% in patients receiving standard care (odds ratio, 0.20, 95% confidence interval, 0.12-0.34, P < .0001). 

There was also a significant reduction in grade 3 radiation dermatitis (2.8% vs. 13.6%; OR, 0.19; P < .0002) and moist desquamation (8% vs. 19.2%; OR, 0.36; P = .002).

“The film was remarkably effective and helped protect patients from potentially debilitating side effects,” commented Corey Speers, MD, PhD, a radiation oncologist with University Hospitals, Cleveland, who saw the study data presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.

He believes that preventing radiation dermatitis before it develops is the best way to care for patients. 

“[Radiation dermatitis] is usually associated with pain and discomfort and can lead to more serious issues like infection or delayed wound healing, and unfortunately, there aren’t effective treatments for it once it’s developed, so preventing it is our most effective strategy,” Dr. Speers said. 

One reason for the film not being used much could be that it takes time apply the film, suggested Patries Herst, PhD, department of radiation therapy, University of Otago, Wellington, New Zealand. She was the lead author of a study published in 2014 that also analyzed the effectiveness of the film in preventing radiation dermatitis.

In their trial, a research radiation therapist applied the film to women when they were starting their radiotherapy. The film is applied to a portion of the breast or chest wall, and Dr. Herst emphasized the importance of applying the film correctly, making sure the film is not stretched during application and not overlapping other pieces of the film, while also making sure that it conforms to the breast shape. The film was replaced when it would curl too much around the sides, approximately every 1 or 2 weeks. 

“Radiation therapy itself is very short. And so you have about 10 minutes for every patient,” she explained.

“But applying the film adds 20-30 minutes and it’s really awkward to apply properly,” Dr. Herst said. “You have to tap it in and then have to maybe cut it so that it fits better. And hospitals say, ‘We don’t have the time’ and that is still the biggest issue that we’re seeing right now.”

In Dr. Chow’s study, the average time spent applying the film on lumpectomy patients was 55 minutes and was slightly shorter at 45 minutes for mastectomy patients. He acknowledged that it does take time that staff at most hospitals and clinics simply don’t have.

Dr. Chow suggested that perhaps a family member or other caregiver could apply the film, and he referenced an educational video from the manufacturer that provides in-depth instructions on the correct way to apply the film for radiotherapy patients. However, this could lead to errors and a waste of product if not the film was not applied properly. 

The cost of Mepitel film may also be a deterrent. Dr. Chow’s study noted that, during the entire course of radiotherapy, the cost for the film was about $80-$100 per patient. However, he believes the benefits outweigh the cost. 

In addition, there have been issues with supplies, and it has been difficult for people to get their hands on the actual product.

Currently, the Mayo Clinic is also conducting a study testing Mepitel Film for radiation dermatitis in breast cancer patients following mastectomy. Mayo Clinic principal investigator Kimberly Corbin, MD, could not go into great detail about the ongoing trial, but she said it has been difficult to get the product. 

“We have been using the film at Mayo for a number of years,” Dr. Corbin said, but we “have found that it is challenging to get supplies.”

“While we have generally been able to have some supply established through our store here, we know that is not typical and it is difficult for patients to access,” she said. In addition, “there are not a ton of centers with experience in application.”

A representative with Mölnlycke Health Care, Allyson Bower-Willner, could not comment on the distribution of Mepitel film in the United States or if the company plans to increase the amount of product shipped. The film is available “to a limited set of customers,” she said.

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

Radiation dermatitis is one of the most common side effects of radiotherapy for women with breast cancer. Results from a phase 3 trial add to previous evidence from smaller trials that show that a silicone-based film can protect skin from this side effect. 

But it is not being used much in clinical practice. Instead, radiation dermatitis is usually treated after the fact, most often with aqueous creams.

The product is Mepitel film, from Swedish medical device company Mölnlycke Health Care.

It should be used for women who are at high risk for developing radiation dermatitis, said Edward Chow, MBBS, PhD, of the department of radiation oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, who was the senior author of the phase 3 study published recently in the Journal of Clinical Oncology.

“Other doctors think that because radiation dermatitis isn’t life-threatening it isn’t as important, but the condition does affect the quality of life for patients,” Dr. Chow said. “If we can lessen the pain and discomfort, why wouldn’t we as physicians?”

Dr. Chow’s open-label, multicenter trial was conducted in 376 women with large breasts (bra cup size C or larger) who were undergoing radiotherapy after lumpectomy or mastectomy. The primary endpoint was grade 2 or 3 radiation dermatitis using the Common Terminology Criteria for Adverse Events. (Grade 2 is described as moderate, whereas grade 3 is severe.) 

The film significantly reduced the incidence of grade 2 or 3 radiation dermatitis, down to  15.5% compared with 45.6% in patients receiving standard care (odds ratio, 0.20, 95% confidence interval, 0.12-0.34, P < .0001). 

There was also a significant reduction in grade 3 radiation dermatitis (2.8% vs. 13.6%; OR, 0.19; P < .0002) and moist desquamation (8% vs. 19.2%; OR, 0.36; P = .002).

“The film was remarkably effective and helped protect patients from potentially debilitating side effects,” commented Corey Speers, MD, PhD, a radiation oncologist with University Hospitals, Cleveland, who saw the study data presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.

He believes that preventing radiation dermatitis before it develops is the best way to care for patients. 

“[Radiation dermatitis] is usually associated with pain and discomfort and can lead to more serious issues like infection or delayed wound healing, and unfortunately, there aren’t effective treatments for it once it’s developed, so preventing it is our most effective strategy,” Dr. Speers said. 

One reason for the film not being used much could be that it takes time apply the film, suggested Patries Herst, PhD, department of radiation therapy, University of Otago, Wellington, New Zealand. She was the lead author of a study published in 2014 that also analyzed the effectiveness of the film in preventing radiation dermatitis.

In their trial, a research radiation therapist applied the film to women when they were starting their radiotherapy. The film is applied to a portion of the breast or chest wall, and Dr. Herst emphasized the importance of applying the film correctly, making sure the film is not stretched during application and not overlapping other pieces of the film, while also making sure that it conforms to the breast shape. The film was replaced when it would curl too much around the sides, approximately every 1 or 2 weeks. 

“Radiation therapy itself is very short. And so you have about 10 minutes for every patient,” she explained.

“But applying the film adds 20-30 minutes and it’s really awkward to apply properly,” Dr. Herst said. “You have to tap it in and then have to maybe cut it so that it fits better. And hospitals say, ‘We don’t have the time’ and that is still the biggest issue that we’re seeing right now.”

In Dr. Chow’s study, the average time spent applying the film on lumpectomy patients was 55 minutes and was slightly shorter at 45 minutes for mastectomy patients. He acknowledged that it does take time that staff at most hospitals and clinics simply don’t have.

Dr. Chow suggested that perhaps a family member or other caregiver could apply the film, and he referenced an educational video from the manufacturer that provides in-depth instructions on the correct way to apply the film for radiotherapy patients. However, this could lead to errors and a waste of product if not the film was not applied properly. 

The cost of Mepitel film may also be a deterrent. Dr. Chow’s study noted that, during the entire course of radiotherapy, the cost for the film was about $80-$100 per patient. However, he believes the benefits outweigh the cost. 

In addition, there have been issues with supplies, and it has been difficult for people to get their hands on the actual product.

Currently, the Mayo Clinic is also conducting a study testing Mepitel Film for radiation dermatitis in breast cancer patients following mastectomy. Mayo Clinic principal investigator Kimberly Corbin, MD, could not go into great detail about the ongoing trial, but she said it has been difficult to get the product. 

“We have been using the film at Mayo for a number of years,” Dr. Corbin said, but we “have found that it is challenging to get supplies.”

“While we have generally been able to have some supply established through our store here, we know that is not typical and it is difficult for patients to access,” she said. In addition, “there are not a ton of centers with experience in application.”

A representative with Mölnlycke Health Care, Allyson Bower-Willner, could not comment on the distribution of Mepitel film in the United States or if the company plans to increase the amount of product shipped. The film is available “to a limited set of customers,” she said.

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

Researchers are calling for the extent of skin erythema to be considered as an outcome measure in patients who develop chronic cutaneous graft-versus-host disease (ccGVHD) after allogeneic stem cell transplants for various blood cancers.

“There is value in collecting erythema serially over time as a continuous variable on a scale of 0%-100%” to identify high-risk patients for prophylactic and preemptive treatment, say investigators led by dermatologist Emily Baumrin, MD, director of the GVHD clinic at the University of Pennsylvania, Philadelphia.

They report a study of more than 300 patients with ccGVHD, which found that the extent of skin erythema strongly predicted the risk for death from GVHD.

Of the 267 patients with cutaneous GVHD at baseline, 103 patients died, the majority without a relapse of their blood cancer.

With additional research, erythema body surface area (BSA) should be “introduced as an outcome measure in clinical practice and trials,” they conclude.

At the moment, the NIH Skin Score is commonly used for risk assessment in cutaneous GVHD, but the researchers found that erythema BSA out-predicts this score.

The investigators explain that the NIH Skin Score does incorporate erythema surface area, but it does so as a categorical variable, not a continuous variable. Among other additional factors, it also includes assessments of skin sclerosis, which the investigators found was not associated with GVHD mortality.

Overall, the composite score waters down the weight given to erythema BSA because the score is “driven by stable sclerotic features, and erythema changes are missed,” they explain.

The study was published online in JAMA Dermatology.
 

Study details

The study included 469 patients with chronic GVHD (cGVHD), of whom 267 (57%) had cutaneous cGVHD at enrollment and 89 (19%) developed skin involvement subsequently.

All of the patients were on systemic immunosuppression for GVHD after allogeneic stem cell transplants for various blood cancers.

They were enrolled from 2007 through 2012 at nine U.S. medical centers – all members of the Chronic Graft Versus Host Disease Consortium – and they were followed until 2018.

Erythema BSA and NIH Skin Score were assessed at baseline and then every 3-6 months. Erythema was the first manifestation of skin involvement in the majority of patients, with a median surface area involvement of 11% at baseline.

The study team found that the extent of erythema at first follow-up visit was associated with both nonrelapse mortality (hazard ratio, 1.33 per 10% BSA increase; P < .001) and overall survival (HR, 1.28 per 10% BSA increase; P < .001), whereas extent of sclerotic skin involvement was not associated with either.

Participants in the study were predominantly White. The investigators note that “BSA assessments of erythema may be less reliable in patients with darker skin.”

The work was funded by the Department of Veterans Affairs and the National Institutes of Health. Dr. Baumrin had no disclosures; one coauthor is an employee of CorEvitas, and two others reported grants/adviser fees from several companies, including Janssen, Mallinckrodt, and Pfizer.

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

Researchers are calling for the extent of skin erythema to be considered as an outcome measure in patients who develop chronic cutaneous graft-versus-host disease (ccGVHD) after allogeneic stem cell transplants for various blood cancers.

“There is value in collecting erythema serially over time as a continuous variable on a scale of 0%-100%” to identify high-risk patients for prophylactic and preemptive treatment, say investigators led by dermatologist Emily Baumrin, MD, director of the GVHD clinic at the University of Pennsylvania, Philadelphia.

They report a study of more than 300 patients with ccGVHD, which found that the extent of skin erythema strongly predicted the risk for death from GVHD.

Of the 267 patients with cutaneous GVHD at baseline, 103 patients died, the majority without a relapse of their blood cancer.

With additional research, erythema body surface area (BSA) should be “introduced as an outcome measure in clinical practice and trials,” they conclude.

At the moment, the NIH Skin Score is commonly used for risk assessment in cutaneous GVHD, but the researchers found that erythema BSA out-predicts this score.

The investigators explain that the NIH Skin Score does incorporate erythema surface area, but it does so as a categorical variable, not a continuous variable. Among other additional factors, it also includes assessments of skin sclerosis, which the investigators found was not associated with GVHD mortality.

Overall, the composite score waters down the weight given to erythema BSA because the score is “driven by stable sclerotic features, and erythema changes are missed,” they explain.

The study was published online in JAMA Dermatology.
 

Study details

The study included 469 patients with chronic GVHD (cGVHD), of whom 267 (57%) had cutaneous cGVHD at enrollment and 89 (19%) developed skin involvement subsequently.

All of the patients were on systemic immunosuppression for GVHD after allogeneic stem cell transplants for various blood cancers.

They were enrolled from 2007 through 2012 at nine U.S. medical centers – all members of the Chronic Graft Versus Host Disease Consortium – and they were followed until 2018.

Erythema BSA and NIH Skin Score were assessed at baseline and then every 3-6 months. Erythema was the first manifestation of skin involvement in the majority of patients, with a median surface area involvement of 11% at baseline.

The study team found that the extent of erythema at first follow-up visit was associated with both nonrelapse mortality (hazard ratio, 1.33 per 10% BSA increase; P < .001) and overall survival (HR, 1.28 per 10% BSA increase; P < .001), whereas extent of sclerotic skin involvement was not associated with either.

Participants in the study were predominantly White. The investigators note that “BSA assessments of erythema may be less reliable in patients with darker skin.”

The work was funded by the Department of Veterans Affairs and the National Institutes of Health. Dr. Baumrin had no disclosures; one coauthor is an employee of CorEvitas, and two others reported grants/adviser fees from several companies, including Janssen, Mallinckrodt, and Pfizer.

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

Researchers are calling for the extent of skin erythema to be considered as an outcome measure in patients who develop chronic cutaneous graft-versus-host disease (ccGVHD) after allogeneic stem cell transplants for various blood cancers.

“There is value in collecting erythema serially over time as a continuous variable on a scale of 0%-100%” to identify high-risk patients for prophylactic and preemptive treatment, say investigators led by dermatologist Emily Baumrin, MD, director of the GVHD clinic at the University of Pennsylvania, Philadelphia.

They report a study of more than 300 patients with ccGVHD, which found that the extent of skin erythema strongly predicted the risk for death from GVHD.

Of the 267 patients with cutaneous GVHD at baseline, 103 patients died, the majority without a relapse of their blood cancer.

With additional research, erythema body surface area (BSA) should be “introduced as an outcome measure in clinical practice and trials,” they conclude.

At the moment, the NIH Skin Score is commonly used for risk assessment in cutaneous GVHD, but the researchers found that erythema BSA out-predicts this score.

The investigators explain that the NIH Skin Score does incorporate erythema surface area, but it does so as a categorical variable, not a continuous variable. Among other additional factors, it also includes assessments of skin sclerosis, which the investigators found was not associated with GVHD mortality.

Overall, the composite score waters down the weight given to erythema BSA because the score is “driven by stable sclerotic features, and erythema changes are missed,” they explain.

The study was published online in JAMA Dermatology.
 

Study details

The study included 469 patients with chronic GVHD (cGVHD), of whom 267 (57%) had cutaneous cGVHD at enrollment and 89 (19%) developed skin involvement subsequently.

All of the patients were on systemic immunosuppression for GVHD after allogeneic stem cell transplants for various blood cancers.

They were enrolled from 2007 through 2012 at nine U.S. medical centers – all members of the Chronic Graft Versus Host Disease Consortium – and they were followed until 2018.

Erythema BSA and NIH Skin Score were assessed at baseline and then every 3-6 months. Erythema was the first manifestation of skin involvement in the majority of patients, with a median surface area involvement of 11% at baseline.

The study team found that the extent of erythema at first follow-up visit was associated with both nonrelapse mortality (hazard ratio, 1.33 per 10% BSA increase; P < .001) and overall survival (HR, 1.28 per 10% BSA increase; P < .001), whereas extent of sclerotic skin involvement was not associated with either.

Participants in the study were predominantly White. The investigators note that “BSA assessments of erythema may be less reliable in patients with darker skin.”

The work was funded by the Department of Veterans Affairs and the National Institutes of Health. Dr. Baumrin had no disclosures; one coauthor is an employee of CorEvitas, and two others reported grants/adviser fees from several companies, including Janssen, Mallinckrodt, and Pfizer.

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

Venetoclax (Venclexta) shows promise as salvage therapy for patients with relapsed or refractory hairy cell leukemia (HCL), according to a small study in which five of six patients responded to the drug when used alone or in combination with rituximab.

Venetoclax is already approved for adults with chronic lymphocytic leukemia, small lymphocytic leukemia, and as part of a treatment combination in certain patients with acute myeloid leukemia.

The new findings suggest that the drug could also be a chemotherapy-free treatment option for HCL patients after the failure of multiple prior lines of therapy, including vemurafenib plus rituximab, the investigators wrote in a letter to the editor published in the New England Journal of Medicine.

Treatment options for such patients are limited, they noted.

Enrico Tiacci, MD, of the University of Perugia (Italy), and colleagues decided to explore the use of venetoclax in this patient population after reports of in vitro findings showing a possible benefit.

The investigators administered the drug off-label to six patients who had received vemurafenib plus rituximab as their most recent prior therapy; one was resistant and five relapsed after that therapy, they reported. Venetoclax was delivered in 29-day cycles.

After 6 or 12 cycles, two patients experienced complete remission with minimal residual disease (MRD), and one had partial remission, although each had incomplete platelet recovery.

Adding rituximab at a dose of 375 mg per square meter of body-surface area for three to eight cycles improved the depth of response in a patient who had a previous minor response, further reduced MRD in one who had a complete remission to venetoclax, and led to hematologic remission in one who had no response to venetoclax, they noted.

Progression-free survival ranged from 23 to 53-plus months in all five patients who did not have early progression and was similar or better than PFS seen after vemurafenib plus rituximab.

The main toxic effect of venetoclax was worsening of baseline neutropenia, which was sometimes complicated by infections or febrile neutropenia and was managed by dose reductions and granulocyte colony-stimulating factor.

“Thus, venetoclax with or without rituximab may serve as a safe and effective salvage option after failure of vemurafenib plus rituximab treatment, especially in patients who do not require a rapid recovery of blood count,” they concluded.

The study was supported by grants from Fondazione Associazione Italiana per la Ricerca sul Cancro and the Italian Ministry of Health.

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

Venetoclax (Venclexta) shows promise as salvage therapy for patients with relapsed or refractory hairy cell leukemia (HCL), according to a small study in which five of six patients responded to the drug when used alone or in combination with rituximab.

Venetoclax is already approved for adults with chronic lymphocytic leukemia, small lymphocytic leukemia, and as part of a treatment combination in certain patients with acute myeloid leukemia.

The new findings suggest that the drug could also be a chemotherapy-free treatment option for HCL patients after the failure of multiple prior lines of therapy, including vemurafenib plus rituximab, the investigators wrote in a letter to the editor published in the New England Journal of Medicine.

Treatment options for such patients are limited, they noted.

Enrico Tiacci, MD, of the University of Perugia (Italy), and colleagues decided to explore the use of venetoclax in this patient population after reports of in vitro findings showing a possible benefit.

The investigators administered the drug off-label to six patients who had received vemurafenib plus rituximab as their most recent prior therapy; one was resistant and five relapsed after that therapy, they reported. Venetoclax was delivered in 29-day cycles.

After 6 or 12 cycles, two patients experienced complete remission with minimal residual disease (MRD), and one had partial remission, although each had incomplete platelet recovery.

Adding rituximab at a dose of 375 mg per square meter of body-surface area for three to eight cycles improved the depth of response in a patient who had a previous minor response, further reduced MRD in one who had a complete remission to venetoclax, and led to hematologic remission in one who had no response to venetoclax, they noted.

Progression-free survival ranged from 23 to 53-plus months in all five patients who did not have early progression and was similar or better than PFS seen after vemurafenib plus rituximab.

The main toxic effect of venetoclax was worsening of baseline neutropenia, which was sometimes complicated by infections or febrile neutropenia and was managed by dose reductions and granulocyte colony-stimulating factor.

“Thus, venetoclax with or without rituximab may serve as a safe and effective salvage option after failure of vemurafenib plus rituximab treatment, especially in patients who do not require a rapid recovery of blood count,” they concluded.

The study was supported by grants from Fondazione Associazione Italiana per la Ricerca sul Cancro and the Italian Ministry of Health.

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

Venetoclax (Venclexta) shows promise as salvage therapy for patients with relapsed or refractory hairy cell leukemia (HCL), according to a small study in which five of six patients responded to the drug when used alone or in combination with rituximab.

Venetoclax is already approved for adults with chronic lymphocytic leukemia, small lymphocytic leukemia, and as part of a treatment combination in certain patients with acute myeloid leukemia.

The new findings suggest that the drug could also be a chemotherapy-free treatment option for HCL patients after the failure of multiple prior lines of therapy, including vemurafenib plus rituximab, the investigators wrote in a letter to the editor published in the New England Journal of Medicine.

Treatment options for such patients are limited, they noted.

Enrico Tiacci, MD, of the University of Perugia (Italy), and colleagues decided to explore the use of venetoclax in this patient population after reports of in vitro findings showing a possible benefit.

The investigators administered the drug off-label to six patients who had received vemurafenib plus rituximab as their most recent prior therapy; one was resistant and five relapsed after that therapy, they reported. Venetoclax was delivered in 29-day cycles.

After 6 or 12 cycles, two patients experienced complete remission with minimal residual disease (MRD), and one had partial remission, although each had incomplete platelet recovery.

Adding rituximab at a dose of 375 mg per square meter of body-surface area for three to eight cycles improved the depth of response in a patient who had a previous minor response, further reduced MRD in one who had a complete remission to venetoclax, and led to hematologic remission in one who had no response to venetoclax, they noted.

Progression-free survival ranged from 23 to 53-plus months in all five patients who did not have early progression and was similar or better than PFS seen after vemurafenib plus rituximab.

The main toxic effect of venetoclax was worsening of baseline neutropenia, which was sometimes complicated by infections or febrile neutropenia and was managed by dose reductions and granulocyte colony-stimulating factor.

“Thus, venetoclax with or without rituximab may serve as a safe and effective salvage option after failure of vemurafenib plus rituximab treatment, especially in patients who do not require a rapid recovery of blood count,” they concluded.

The study was supported by grants from Fondazione Associazione Italiana per la Ricerca sul Cancro and the Italian Ministry of Health.

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

The Food and Drug Administration has made changes to existing mammography regulations.

A final rule, updating the regulations issued under the Mammography Quality Standards Act of 1992, requires that mammography facilities notify patients about the density of their breasts, strengthens the FDA’s oversight of facilities, and provides guidance to help physicians better categorize and assess mammograms, according to a March 9 press release.

The rule requires implementation of the changes within 18 months.

According to the final rule document, the updates are “intended to improve the delivery of mammography services” in ways that reflect changes in mammography technology, quality standards, and the way results are categorized, reported, and communicated to patients and providers.

For instance, mammography reports must include an assessment of breast density to provide greater detail on the potential limitations of the mammogram results and allow patients and physicians to make more informed decisions, such as the possibility of additional imaging for women with dense breast tissue.

“Today’s action represents the agency’s broader commitment to support innovation to prevent, detect and treat cancer,” said Hilary Marston, MD, MPH, FDA’s chief medical officer, in the agency’s press release. The FDA remains “committed to advancing efforts to improve the health of women and strengthen the fight against breast cancer.”

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

The Food and Drug Administration has made changes to existing mammography regulations.

A final rule, updating the regulations issued under the Mammography Quality Standards Act of 1992, requires that mammography facilities notify patients about the density of their breasts, strengthens the FDA’s oversight of facilities, and provides guidance to help physicians better categorize and assess mammograms, according to a March 9 press release.

The rule requires implementation of the changes within 18 months.

According to the final rule document, the updates are “intended to improve the delivery of mammography services” in ways that reflect changes in mammography technology, quality standards, and the way results are categorized, reported, and communicated to patients and providers.

For instance, mammography reports must include an assessment of breast density to provide greater detail on the potential limitations of the mammogram results and allow patients and physicians to make more informed decisions, such as the possibility of additional imaging for women with dense breast tissue.

“Today’s action represents the agency’s broader commitment to support innovation to prevent, detect and treat cancer,” said Hilary Marston, MD, MPH, FDA’s chief medical officer, in the agency’s press release. The FDA remains “committed to advancing efforts to improve the health of women and strengthen the fight against breast cancer.”

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

The Food and Drug Administration has made changes to existing mammography regulations.

A final rule, updating the regulations issued under the Mammography Quality Standards Act of 1992, requires that mammography facilities notify patients about the density of their breasts, strengthens the FDA’s oversight of facilities, and provides guidance to help physicians better categorize and assess mammograms, according to a March 9 press release.

The rule requires implementation of the changes within 18 months.

According to the final rule document, the updates are “intended to improve the delivery of mammography services” in ways that reflect changes in mammography technology, quality standards, and the way results are categorized, reported, and communicated to patients and providers.

For instance, mammography reports must include an assessment of breast density to provide greater detail on the potential limitations of the mammogram results and allow patients and physicians to make more informed decisions, such as the possibility of additional imaging for women with dense breast tissue.

“Today’s action represents the agency’s broader commitment to support innovation to prevent, detect and treat cancer,” said Hilary Marston, MD, MPH, FDA’s chief medical officer, in the agency’s press release. The FDA remains “committed to advancing efforts to improve the health of women and strengthen the fight against breast cancer.”

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

A year before the COVID-19 pandemic began, a team of clinical statisticians at the University of Texas MD Anderson Cancer Center sat together in small office for a year, painstakingly hand coding data from the U.S. clinical trials database, www.clinicaltrials.gov.

They were trying to answer a simple question: Why are cancer-drug trials enrolling too few patients over the age of 65?

More than 300 trials and 262,354 patients later, the research team confirmed that participants in clinical trials were, on average, 6.5 years younger than the population for whom the drug was intended.

Ethan Ludmir

“We found marked disparities across different disease sites. ... The patients that are enrolling on studies are markedly younger than the average patient seen in the population with those same conditions,” said team leader Ethan Ludmir, MD, assistant professor, Division of Radiation Oncology at the University of Texas.

And this age disparity was significantly greater in industry-funded trials.

Researchers have known for 20 years that cancer trial participants are not representative of the wider cancer population, and numerous government guidance documents have been issued on the matter. However, this Texas team’s findings were the first unambiguous evidence that pharmaceutical companies seem to be selecting younger patients to test their drugs.

“If we’re being generous then perhaps the answer is: They’re looking for some element of homogeneity, which is to say they don’t want competing risks to make the signal-to-noise ratio uninterpretable,” said Dr. Ludmir.

Dr. Laura Bothwell, PhD, assistant professor, Yale School of Public Health, recently coauthored a 259-page consensus report for the National Academies of Sciences, Engineering and Medicine on how to increase the research involvement of under-represented groups.

Dr. Bothwell said, “The problem with industry funded research is that ... it’s an inevitable conflict of interest that exists. They want the research to show that their products work. And older populations ... have a lot more complications, which leads to potentially less favorable results.”

The MD Anderson findings were published in JAMA Oncology. “That was the starting point in our journey,” said Dr. Ludmir. For the next 3 years, the researchers mined their painstakingly constructed database to understand what was preventing greater numbers of older patients from enrollment in cancer trials.

Meanwhile, answers were coming from elsewhere. In parallel with the work at MD Anderson, a team in California led by Mina Sedrak, MD, a medical oncologist at the City of Hope National Medical Center, had also started investigating age disparities in clinical trials.

COH

Dr. Sedrak, who also serves as deputy director of Clinical Trials at the Center for Cancer and Aging, said he had become increasingly concerned that he did not have adequate information on new cancer therapies for his older patients.

“I was caring for a large number of people who were ... older adults,” said Dr. Sedrak, “But the data that was being used to get the standard-of-care treatment for cancer did not include older adults. And so there was this lack of applicability.”

He summed up the challenges in a 2021 review paper: “Most of what we know about cancer therapeutics is based on clinical trials conducted in younger, healthier patients.”

By 2030, it is estimated that 70% of all new cancer diagnoses will be in patients 65 years old and older. By contrast, patients over age 65 still account for only 40% of patients in cancer trials registered with the FDA (2015 figures) and older adults make up only 44% of participants in practice-changing cancer trials, according to a 2022 study.

So what is going on? Are studies specifically designed to squeeze out older patients?

Surprisingly, patients are not being kept out of trials by formal age limits, according to Dr. Ludmir. His team found that only 10% of phase 3 trials over the past 30 years had an upper limit for age, and age restrictions have been dropping by 1% a year. (For example, 16% of trials that enrolled in 2002-2005 had an upper age limit, compared with just 8% of trials that started in 2010-2014.)

Dr. Sedrak’s team found that “clinician bias” may be a factor, a situation in which trial investigators – particularly academic oncologists – are subconsciously picking younger, healthier patients for trials and excluding older, sicker patients to protect them from drug toxicities.

Dr. Ludmir said this was understandable, especially in the case of industry-driven trials, which tend to have demanding endpoints and “an overall posture of more treatment aggressiveness.”

“These are typically not trials where they’re saying, `Hey, if we add acupuncture ... are we going to see improved patient reported outcomes?’” Dr. Ludmir explained. “You’re asking ... I’ve got this cocktail of two pretty rough chemos: I want to see what happens if I add an immunotherapy to that. If I’m the clinician in clinic, I might reasonably, subconsciously, say, is the 75-year-old really who I want on this?”

What about patient bias? Perhaps fewer older patients wish to join clinical trials?

Not so, at least not at community cancer centers, said Dr. Sedrak. His team’s analysis of the National Cancer Institute Community Oncology Research Program database for 2016-2019 revealed that older patients were just as keen as the younger patients to participate in trials (68% of patients aged 50-69 years and 65% of patients 70+; P = .28).

However, drug companies may be excluding older patients by more subtle means. One-fifth of patients over 65 have had a prior cancer. Dr. Ludmir and coauthor Roshal Patel, MD, used their hand-coded www.clinicaltrials.gov database to look at prior malignancy exclusion criteria (PMEC). The analysis found “pervasive utilization” of PMEC in phase 3 trials, cropping up in 41% of studies over the past 30 years.

PMEC was significantly associated with age disparities and was significantly more common in industry-funded trials.

When asked whether PMEC are “age restriction by stealth” on the part of drug companies, Dr. Ludmir was reluctant to assign blame, but stood by his data: “The wider you restrict people in terms of having a prior cancer, the wider the age disparities in the subsequent studies, which to me is about as strong, in terms of causal understanding of these phenomena, as you can reasonably get at this level.”

In March the FDA released a guidance document titled Inclusion of Older Adults in Cancer Clinical Trials. However, its recommendations are “nonbinding” and “do not have the force and effect of law.”

To fix the issues, said Dr. Sedrak, the FDA must be given teeth.

“Okay, you write guidelines,” he said. “But if you don’t actually hold people accountable to following the guidelines, how are we going to implement and make sure that we’re transforming policy into action?”

Dr. Bothwell of Yale’s School of Public Health agreed. “Accountability has been the weakest link for decades now.”

She concluded, “In medicine there’s a tendency to believe that a therapy, because it exists and it has been tested and it’s shown some efficacy, it’s useful. But we don’t know the answer to that question unless we have statistically valid research in the population that we’re using it in.”

Dr. Bothwell and Dr. Ludmir report no conflicts of interest. In his publications, Dr. Sedrak reports industry grants from Seattle Genetics, Eli Lilly, Novartis, and Pfizer Foundation.
 

A year before the COVID-19 pandemic began, a team of clinical statisticians at the University of Texas MD Anderson Cancer Center sat together in small office for a year, painstakingly hand coding data from the U.S. clinical trials database, www.clinicaltrials.gov.

They were trying to answer a simple question: Why are cancer-drug trials enrolling too few patients over the age of 65?

More than 300 trials and 262,354 patients later, the research team confirmed that participants in clinical trials were, on average, 6.5 years younger than the population for whom the drug was intended.

Ethan Ludmir

“We found marked disparities across different disease sites. ... The patients that are enrolling on studies are markedly younger than the average patient seen in the population with those same conditions,” said team leader Ethan Ludmir, MD, assistant professor, Division of Radiation Oncology at the University of Texas.

And this age disparity was significantly greater in industry-funded trials.

Researchers have known for 20 years that cancer trial participants are not representative of the wider cancer population, and numerous government guidance documents have been issued on the matter. However, this Texas team’s findings were the first unambiguous evidence that pharmaceutical companies seem to be selecting younger patients to test their drugs.

“If we’re being generous then perhaps the answer is: They’re looking for some element of homogeneity, which is to say they don’t want competing risks to make the signal-to-noise ratio uninterpretable,” said Dr. Ludmir.

Dr. Laura Bothwell, PhD, assistant professor, Yale School of Public Health, recently coauthored a 259-page consensus report for the National Academies of Sciences, Engineering and Medicine on how to increase the research involvement of under-represented groups.

Dr. Bothwell said, “The problem with industry funded research is that ... it’s an inevitable conflict of interest that exists. They want the research to show that their products work. And older populations ... have a lot more complications, which leads to potentially less favorable results.”

The MD Anderson findings were published in JAMA Oncology. “That was the starting point in our journey,” said Dr. Ludmir. For the next 3 years, the researchers mined their painstakingly constructed database to understand what was preventing greater numbers of older patients from enrollment in cancer trials.

Meanwhile, answers were coming from elsewhere. In parallel with the work at MD Anderson, a team in California led by Mina Sedrak, MD, a medical oncologist at the City of Hope National Medical Center, had also started investigating age disparities in clinical trials.

COH

Dr. Sedrak, who also serves as deputy director of Clinical Trials at the Center for Cancer and Aging, said he had become increasingly concerned that he did not have adequate information on new cancer therapies for his older patients.

“I was caring for a large number of people who were ... older adults,” said Dr. Sedrak, “But the data that was being used to get the standard-of-care treatment for cancer did not include older adults. And so there was this lack of applicability.”

He summed up the challenges in a 2021 review paper: “Most of what we know about cancer therapeutics is based on clinical trials conducted in younger, healthier patients.”

By 2030, it is estimated that 70% of all new cancer diagnoses will be in patients 65 years old and older. By contrast, patients over age 65 still account for only 40% of patients in cancer trials registered with the FDA (2015 figures) and older adults make up only 44% of participants in practice-changing cancer trials, according to a 2022 study.

So what is going on? Are studies specifically designed to squeeze out older patients?

Surprisingly, patients are not being kept out of trials by formal age limits, according to Dr. Ludmir. His team found that only 10% of phase 3 trials over the past 30 years had an upper limit for age, and age restrictions have been dropping by 1% a year. (For example, 16% of trials that enrolled in 2002-2005 had an upper age limit, compared with just 8% of trials that started in 2010-2014.)

Dr. Sedrak’s team found that “clinician bias” may be a factor, a situation in which trial investigators – particularly academic oncologists – are subconsciously picking younger, healthier patients for trials and excluding older, sicker patients to protect them from drug toxicities.

Dr. Ludmir said this was understandable, especially in the case of industry-driven trials, which tend to have demanding endpoints and “an overall posture of more treatment aggressiveness.”

“These are typically not trials where they’re saying, `Hey, if we add acupuncture ... are we going to see improved patient reported outcomes?’” Dr. Ludmir explained. “You’re asking ... I’ve got this cocktail of two pretty rough chemos: I want to see what happens if I add an immunotherapy to that. If I’m the clinician in clinic, I might reasonably, subconsciously, say, is the 75-year-old really who I want on this?”

What about patient bias? Perhaps fewer older patients wish to join clinical trials?

Not so, at least not at community cancer centers, said Dr. Sedrak. His team’s analysis of the National Cancer Institute Community Oncology Research Program database for 2016-2019 revealed that older patients were just as keen as the younger patients to participate in trials (68% of patients aged 50-69 years and 65% of patients 70+; P = .28).

However, drug companies may be excluding older patients by more subtle means. One-fifth of patients over 65 have had a prior cancer. Dr. Ludmir and coauthor Roshal Patel, MD, used their hand-coded www.clinicaltrials.gov database to look at prior malignancy exclusion criteria (PMEC). The analysis found “pervasive utilization” of PMEC in phase 3 trials, cropping up in 41% of studies over the past 30 years.

PMEC was significantly associated with age disparities and was significantly more common in industry-funded trials.

When asked whether PMEC are “age restriction by stealth” on the part of drug companies, Dr. Ludmir was reluctant to assign blame, but stood by his data: “The wider you restrict people in terms of having a prior cancer, the wider the age disparities in the subsequent studies, which to me is about as strong, in terms of causal understanding of these phenomena, as you can reasonably get at this level.”

In March the FDA released a guidance document titled Inclusion of Older Adults in Cancer Clinical Trials. However, its recommendations are “nonbinding” and “do not have the force and effect of law.”

To fix the issues, said Dr. Sedrak, the FDA must be given teeth.

“Okay, you write guidelines,” he said. “But if you don’t actually hold people accountable to following the guidelines, how are we going to implement and make sure that we’re transforming policy into action?”

Dr. Bothwell of Yale’s School of Public Health agreed. “Accountability has been the weakest link for decades now.”

She concluded, “In medicine there’s a tendency to believe that a therapy, because it exists and it has been tested and it’s shown some efficacy, it’s useful. But we don’t know the answer to that question unless we have statistically valid research in the population that we’re using it in.”

Dr. Bothwell and Dr. Ludmir report no conflicts of interest. In his publications, Dr. Sedrak reports industry grants from Seattle Genetics, Eli Lilly, Novartis, and Pfizer Foundation.
 

A year before the COVID-19 pandemic began, a team of clinical statisticians at the University of Texas MD Anderson Cancer Center sat together in small office for a year, painstakingly hand coding data from the U.S. clinical trials database, www.clinicaltrials.gov.

They were trying to answer a simple question: Why are cancer-drug trials enrolling too few patients over the age of 65?

More than 300 trials and 262,354 patients later, the research team confirmed that participants in clinical trials were, on average, 6.5 years younger than the population for whom the drug was intended.

Ethan Ludmir

“We found marked disparities across different disease sites. ... The patients that are enrolling on studies are markedly younger than the average patient seen in the population with those same conditions,” said team leader Ethan Ludmir, MD, assistant professor, Division of Radiation Oncology at the University of Texas.

And this age disparity was significantly greater in industry-funded trials.

Researchers have known for 20 years that cancer trial participants are not representative of the wider cancer population, and numerous government guidance documents have been issued on the matter. However, this Texas team’s findings were the first unambiguous evidence that pharmaceutical companies seem to be selecting younger patients to test their drugs.

“If we’re being generous then perhaps the answer is: They’re looking for some element of homogeneity, which is to say they don’t want competing risks to make the signal-to-noise ratio uninterpretable,” said Dr. Ludmir.

Dr. Laura Bothwell, PhD, assistant professor, Yale School of Public Health, recently coauthored a 259-page consensus report for the National Academies of Sciences, Engineering and Medicine on how to increase the research involvement of under-represented groups.

Dr. Bothwell said, “The problem with industry funded research is that ... it’s an inevitable conflict of interest that exists. They want the research to show that their products work. And older populations ... have a lot more complications, which leads to potentially less favorable results.”

The MD Anderson findings were published in JAMA Oncology. “That was the starting point in our journey,” said Dr. Ludmir. For the next 3 years, the researchers mined their painstakingly constructed database to understand what was preventing greater numbers of older patients from enrollment in cancer trials.

Meanwhile, answers were coming from elsewhere. In parallel with the work at MD Anderson, a team in California led by Mina Sedrak, MD, a medical oncologist at the City of Hope National Medical Center, had also started investigating age disparities in clinical trials.

COH

Dr. Sedrak, who also serves as deputy director of Clinical Trials at the Center for Cancer and Aging, said he had become increasingly concerned that he did not have adequate information on new cancer therapies for his older patients.

“I was caring for a large number of people who were ... older adults,” said Dr. Sedrak, “But the data that was being used to get the standard-of-care treatment for cancer did not include older adults. And so there was this lack of applicability.”

He summed up the challenges in a 2021 review paper: “Most of what we know about cancer therapeutics is based on clinical trials conducted in younger, healthier patients.”

By 2030, it is estimated that 70% of all new cancer diagnoses will be in patients 65 years old and older. By contrast, patients over age 65 still account for only 40% of patients in cancer trials registered with the FDA (2015 figures) and older adults make up only 44% of participants in practice-changing cancer trials, according to a 2022 study.

So what is going on? Are studies specifically designed to squeeze out older patients?

Surprisingly, patients are not being kept out of trials by formal age limits, according to Dr. Ludmir. His team found that only 10% of phase 3 trials over the past 30 years had an upper limit for age, and age restrictions have been dropping by 1% a year. (For example, 16% of trials that enrolled in 2002-2005 had an upper age limit, compared with just 8% of trials that started in 2010-2014.)

Dr. Sedrak’s team found that “clinician bias” may be a factor, a situation in which trial investigators – particularly academic oncologists – are subconsciously picking younger, healthier patients for trials and excluding older, sicker patients to protect them from drug toxicities.

Dr. Ludmir said this was understandable, especially in the case of industry-driven trials, which tend to have demanding endpoints and “an overall posture of more treatment aggressiveness.”

“These are typically not trials where they’re saying, `Hey, if we add acupuncture ... are we going to see improved patient reported outcomes?’” Dr. Ludmir explained. “You’re asking ... I’ve got this cocktail of two pretty rough chemos: I want to see what happens if I add an immunotherapy to that. If I’m the clinician in clinic, I might reasonably, subconsciously, say, is the 75-year-old really who I want on this?”

What about patient bias? Perhaps fewer older patients wish to join clinical trials?

Not so, at least not at community cancer centers, said Dr. Sedrak. His team’s analysis of the National Cancer Institute Community Oncology Research Program database for 2016-2019 revealed that older patients were just as keen as the younger patients to participate in trials (68% of patients aged 50-69 years and 65% of patients 70+; P = .28).

However, drug companies may be excluding older patients by more subtle means. One-fifth of patients over 65 have had a prior cancer. Dr. Ludmir and coauthor Roshal Patel, MD, used their hand-coded www.clinicaltrials.gov database to look at prior malignancy exclusion criteria (PMEC). The analysis found “pervasive utilization” of PMEC in phase 3 trials, cropping up in 41% of studies over the past 30 years.

PMEC was significantly associated with age disparities and was significantly more common in industry-funded trials.

When asked whether PMEC are “age restriction by stealth” on the part of drug companies, Dr. Ludmir was reluctant to assign blame, but stood by his data: “The wider you restrict people in terms of having a prior cancer, the wider the age disparities in the subsequent studies, which to me is about as strong, in terms of causal understanding of these phenomena, as you can reasonably get at this level.”

In March the FDA released a guidance document titled Inclusion of Older Adults in Cancer Clinical Trials. However, its recommendations are “nonbinding” and “do not have the force and effect of law.”

To fix the issues, said Dr. Sedrak, the FDA must be given teeth.

“Okay, you write guidelines,” he said. “But if you don’t actually hold people accountable to following the guidelines, how are we going to implement and make sure that we’re transforming policy into action?”

Dr. Bothwell of Yale’s School of Public Health agreed. “Accountability has been the weakest link for decades now.”

She concluded, “In medicine there’s a tendency to believe that a therapy, because it exists and it has been tested and it’s shown some efficacy, it’s useful. But we don’t know the answer to that question unless we have statistically valid research in the population that we’re using it in.”

Dr. Bothwell and Dr. Ludmir report no conflicts of interest. In his publications, Dr. Sedrak reports industry grants from Seattle Genetics, Eli Lilly, Novartis, and Pfizer Foundation.
 

An Irish study attempting to get at the root of why men and women delay colon cancer screening found that, despite an uptick in colon cancer cases among younger adults, screening isn’t a priority for some adults while others are under the impression that a healthy diet with regular bowel movements negates the need for regular screening.

The findings are based on a survey of over 2,000 adults who participated in a population-based fecal immunochemical test (FIT) screening program. The authors found that denying the immediacy of the need to be tested and self-exempting from screening because of a belief in a healthy lifestyle were key drivers for opting out of FIT screening.

“What we found was that people who didn’t take part [in the survey] responded much more defensively to the invitation,” said Nicholas Clarke, PhD, a researcher at Dublin City University, who served as the lead author of the study published in the journal Cancer.

The domain of denying immediacy, which covers decisions like putting off a test because of more pressing life events, was associated with a 47% reduction in screening probability. “That’s quite a high percentage. They’re not saying I won’t do it. They’re saying: ‘I’ll wait to get tested for colon cancer until my other health concerns are under control, or until there’s a better test,’ ” he said.

The other suppression category of self-exempting was associated with a 20% reduction in the odds of participation. “They’re saying: ‘I don’t need to be tested because I have enough vegetables in my diet or because I have regular bowel movements,’ ” Dr. Clarke said.

Despite the proven efficacy of screening, many individuals still resist screening. In previous research, Dr. Clarke found that men in Ireland were less likely than women to undergo screening.

FIT works by identifying small amounts of blood in the stool that could suggest the presence of a tumor or precancerous polyps. The test also looks for methylation and DNA mutations that are indicative of precancer polyps or tumors. A positive test calls for a follow-up procedure such as a colonoscopy, where precancerous polyps can be removed to prevent them from developing into tumors.

FIT has similar sensitivity to colonoscopy in detecting cancers (93% vs. 95%), but is less effective with respect to polyps (42% vs. 75%-93%). For average risk adults between 50-75 years old, the U.S Preventive Services Task Force recommends colonoscopy every 10 years; flexible sigmoidoscopy or CT colonography every 5 years, or flexible sigmoidoscopy every 10 years plus fecal immunochemical test (FIT) every year; FIT DNA test every 3 years; guaiac-based fecal occult blood test or FIT test annually.
 

Findings from the new study

In the new study, researchers contacted both 2,299 responders and nonresponders to FIT tests that had been mailed out as part of a Dublin colorectal cancer screening program between 2008 and 2012. Researchers employed the McQueen defensive information processing (DIP) measure, which includes four domains of defensive attitudes that include information avoidance, mental disengagement or denial, suppression through belief that one is immune, and arguing against the evidence.

In this study, 7,476 men and women in Dublin were invited to participate in a population‐based FIT screening program. In follow-up questionnaires sent to those who did or did not complete FIT, 53% of those who completed FIT screening answered the questionnaire, while 8% of those who did not complete the screening returned the questionnaire. Those who didn’t complete the FIT test had higher DIP scores suggesting more rates of opting out of receiving health information, avoiding doctor visits, prevention avoidance, continually delaying screening, either claiming colon cancer is rare or normalizing cancer risk, and falsely aligning regular bowel movements with good health which was directly associated with less screening.
 

Increasing rates of early onset colorectal cancer

The research may shed light on reasons for increasing rates of early-onset colorectal cancer. “Often younger people feel invincible and as Beverly Green, MD, MPH, pointed out in an editorial on defensive information processing, invincibility is a good example of self-exemption DIP,” Dr. Clarke said.

“I think what’s underlying these two pieces is a lack of awareness of the trajectory of colorectal cancer, but it’s also the future consequences of not taking part [in screening]. A person can have their colorectal cancer for about 10 years before they begin to feel any symptoms from it, and usually at that point, the disease has gone to an advanced stage, so it’s much more difficult to treat, and the person will have much poorer outcomes. If it’s detected at stage 1, the outcomes are far better,” Dr. Clarke said.

Doctors should react calmly to defensiveness and listen to the patient’s concerns. “Informing them of the aim of screening, i.e. to detect it when its precancerous or at the earliest possible stage, is very important. Letting them know they are taking responsibility for their own health and giving them the best chance of a healthy old age may be a good way of counteracting defensiveness,” he said.

Dr. Green noted that nonresponders claiming lack of immediacy could be swayed with the right approach. She has conducted similar research and subjects themselves suggested the use of marketing techniques “like what happens on Amazon. People remind you frequently the same thing when they get a clue that you have an interest in that behavior. Or, they tell you it’s on sale, and you might lose out from that big bargain if you don’t buy it now. There’s a deadline. I think a lot of the things we might do to nudge people are similar to what’s already happening in marketing,” said Dr. Green, who is a family physician and a researcher at the Kaiser Permanente Washington Health Research Institute.

Dr. Clarke and Dr. Green have no relevant financial disclosures.

An Irish study attempting to get at the root of why men and women delay colon cancer screening found that, despite an uptick in colon cancer cases among younger adults, screening isn’t a priority for some adults while others are under the impression that a healthy diet with regular bowel movements negates the need for regular screening.

The findings are based on a survey of over 2,000 adults who participated in a population-based fecal immunochemical test (FIT) screening program. The authors found that denying the immediacy of the need to be tested and self-exempting from screening because of a belief in a healthy lifestyle were key drivers for opting out of FIT screening.

“What we found was that people who didn’t take part [in the survey] responded much more defensively to the invitation,” said Nicholas Clarke, PhD, a researcher at Dublin City University, who served as the lead author of the study published in the journal Cancer.

The domain of denying immediacy, which covers decisions like putting off a test because of more pressing life events, was associated with a 47% reduction in screening probability. “That’s quite a high percentage. They’re not saying I won’t do it. They’re saying: ‘I’ll wait to get tested for colon cancer until my other health concerns are under control, or until there’s a better test,’ ” he said.

The other suppression category of self-exempting was associated with a 20% reduction in the odds of participation. “They’re saying: ‘I don’t need to be tested because I have enough vegetables in my diet or because I have regular bowel movements,’ ” Dr. Clarke said.

Despite the proven efficacy of screening, many individuals still resist screening. In previous research, Dr. Clarke found that men in Ireland were less likely than women to undergo screening.

FIT works by identifying small amounts of blood in the stool that could suggest the presence of a tumor or precancerous polyps. The test also looks for methylation and DNA mutations that are indicative of precancer polyps or tumors. A positive test calls for a follow-up procedure such as a colonoscopy, where precancerous polyps can be removed to prevent them from developing into tumors.

FIT has similar sensitivity to colonoscopy in detecting cancers (93% vs. 95%), but is less effective with respect to polyps (42% vs. 75%-93%). For average risk adults between 50-75 years old, the U.S Preventive Services Task Force recommends colonoscopy every 10 years; flexible sigmoidoscopy or CT colonography every 5 years, or flexible sigmoidoscopy every 10 years plus fecal immunochemical test (FIT) every year; FIT DNA test every 3 years; guaiac-based fecal occult blood test or FIT test annually.
 

Findings from the new study

In the new study, researchers contacted both 2,299 responders and nonresponders to FIT tests that had been mailed out as part of a Dublin colorectal cancer screening program between 2008 and 2012. Researchers employed the McQueen defensive information processing (DIP) measure, which includes four domains of defensive attitudes that include information avoidance, mental disengagement or denial, suppression through belief that one is immune, and arguing against the evidence.

In this study, 7,476 men and women in Dublin were invited to participate in a population‐based FIT screening program. In follow-up questionnaires sent to those who did or did not complete FIT, 53% of those who completed FIT screening answered the questionnaire, while 8% of those who did not complete the screening returned the questionnaire. Those who didn’t complete the FIT test had higher DIP scores suggesting more rates of opting out of receiving health information, avoiding doctor visits, prevention avoidance, continually delaying screening, either claiming colon cancer is rare or normalizing cancer risk, and falsely aligning regular bowel movements with good health which was directly associated with less screening.
 

Increasing rates of early onset colorectal cancer

The research may shed light on reasons for increasing rates of early-onset colorectal cancer. “Often younger people feel invincible and as Beverly Green, MD, MPH, pointed out in an editorial on defensive information processing, invincibility is a good example of self-exemption DIP,” Dr. Clarke said.

“I think what’s underlying these two pieces is a lack of awareness of the trajectory of colorectal cancer, but it’s also the future consequences of not taking part [in screening]. A person can have their colorectal cancer for about 10 years before they begin to feel any symptoms from it, and usually at that point, the disease has gone to an advanced stage, so it’s much more difficult to treat, and the person will have much poorer outcomes. If it’s detected at stage 1, the outcomes are far better,” Dr. Clarke said.

Doctors should react calmly to defensiveness and listen to the patient’s concerns. “Informing them of the aim of screening, i.e. to detect it when its precancerous or at the earliest possible stage, is very important. Letting them know they are taking responsibility for their own health and giving them the best chance of a healthy old age may be a good way of counteracting defensiveness,” he said.

Dr. Green noted that nonresponders claiming lack of immediacy could be swayed with the right approach. She has conducted similar research and subjects themselves suggested the use of marketing techniques “like what happens on Amazon. People remind you frequently the same thing when they get a clue that you have an interest in that behavior. Or, they tell you it’s on sale, and you might lose out from that big bargain if you don’t buy it now. There’s a deadline. I think a lot of the things we might do to nudge people are similar to what’s already happening in marketing,” said Dr. Green, who is a family physician and a researcher at the Kaiser Permanente Washington Health Research Institute.

Dr. Clarke and Dr. Green have no relevant financial disclosures.

An Irish study attempting to get at the root of why men and women delay colon cancer screening found that, despite an uptick in colon cancer cases among younger adults, screening isn’t a priority for some adults while others are under the impression that a healthy diet with regular bowel movements negates the need for regular screening.

The findings are based on a survey of over 2,000 adults who participated in a population-based fecal immunochemical test (FIT) screening program. The authors found that denying the immediacy of the need to be tested and self-exempting from screening because of a belief in a healthy lifestyle were key drivers for opting out of FIT screening.

“What we found was that people who didn’t take part [in the survey] responded much more defensively to the invitation,” said Nicholas Clarke, PhD, a researcher at Dublin City University, who served as the lead author of the study published in the journal Cancer.

The domain of denying immediacy, which covers decisions like putting off a test because of more pressing life events, was associated with a 47% reduction in screening probability. “That’s quite a high percentage. They’re not saying I won’t do it. They’re saying: ‘I’ll wait to get tested for colon cancer until my other health concerns are under control, or until there’s a better test,’ ” he said.

The other suppression category of self-exempting was associated with a 20% reduction in the odds of participation. “They’re saying: ‘I don’t need to be tested because I have enough vegetables in my diet or because I have regular bowel movements,’ ” Dr. Clarke said.

Despite the proven efficacy of screening, many individuals still resist screening. In previous research, Dr. Clarke found that men in Ireland were less likely than women to undergo screening.

FIT works by identifying small amounts of blood in the stool that could suggest the presence of a tumor or precancerous polyps. The test also looks for methylation and DNA mutations that are indicative of precancer polyps or tumors. A positive test calls for a follow-up procedure such as a colonoscopy, where precancerous polyps can be removed to prevent them from developing into tumors.

FIT has similar sensitivity to colonoscopy in detecting cancers (93% vs. 95%), but is less effective with respect to polyps (42% vs. 75%-93%). For average risk adults between 50-75 years old, the U.S Preventive Services Task Force recommends colonoscopy every 10 years; flexible sigmoidoscopy or CT colonography every 5 years, or flexible sigmoidoscopy every 10 years plus fecal immunochemical test (FIT) every year; FIT DNA test every 3 years; guaiac-based fecal occult blood test or FIT test annually.
 

Findings from the new study

In the new study, researchers contacted both 2,299 responders and nonresponders to FIT tests that had been mailed out as part of a Dublin colorectal cancer screening program between 2008 and 2012. Researchers employed the McQueen defensive information processing (DIP) measure, which includes four domains of defensive attitudes that include information avoidance, mental disengagement or denial, suppression through belief that one is immune, and arguing against the evidence.

In this study, 7,476 men and women in Dublin were invited to participate in a population‐based FIT screening program. In follow-up questionnaires sent to those who did or did not complete FIT, 53% of those who completed FIT screening answered the questionnaire, while 8% of those who did not complete the screening returned the questionnaire. Those who didn’t complete the FIT test had higher DIP scores suggesting more rates of opting out of receiving health information, avoiding doctor visits, prevention avoidance, continually delaying screening, either claiming colon cancer is rare or normalizing cancer risk, and falsely aligning regular bowel movements with good health which was directly associated with less screening.
 

Increasing rates of early onset colorectal cancer

The research may shed light on reasons for increasing rates of early-onset colorectal cancer. “Often younger people feel invincible and as Beverly Green, MD, MPH, pointed out in an editorial on defensive information processing, invincibility is a good example of self-exemption DIP,” Dr. Clarke said.

“I think what’s underlying these two pieces is a lack of awareness of the trajectory of colorectal cancer, but it’s also the future consequences of not taking part [in screening]. A person can have their colorectal cancer for about 10 years before they begin to feel any symptoms from it, and usually at that point, the disease has gone to an advanced stage, so it’s much more difficult to treat, and the person will have much poorer outcomes. If it’s detected at stage 1, the outcomes are far better,” Dr. Clarke said.

Doctors should react calmly to defensiveness and listen to the patient’s concerns. “Informing them of the aim of screening, i.e. to detect it when its precancerous or at the earliest possible stage, is very important. Letting them know they are taking responsibility for their own health and giving them the best chance of a healthy old age may be a good way of counteracting defensiveness,” he said.

Dr. Green noted that nonresponders claiming lack of immediacy could be swayed with the right approach. She has conducted similar research and subjects themselves suggested the use of marketing techniques “like what happens on Amazon. People remind you frequently the same thing when they get a clue that you have an interest in that behavior. Or, they tell you it’s on sale, and you might lose out from that big bargain if you don’t buy it now. There’s a deadline. I think a lot of the things we might do to nudge people are similar to what’s already happening in marketing,” said Dr. Green, who is a family physician and a researcher at the Kaiser Permanente Washington Health Research Institute.

Dr. Clarke and Dr. Green have no relevant financial disclosures.