AVAHO

A team at Lyon’s Cancer Research Center (CRCL) has revealed the role of an enzyme, PRMT5, in the response to tamoxifen, a drug used to prevent relapse in premenopausal women with breast cancer. The protein could become the first predictive marker of response to tamoxifen.

Muriel Le Romancer, MD, director of research at France’s Institute of Health and Medical Research, explained the issues involved in this discovery in an interview. She jointly led this research along with Olivier Trédan, MD, PhD, oncologist at Lyon’s Léon Bérard Clinic. The research concluded with the publication of a study in EMBO Molecular Medicine. The researchers both head up the CRCL’s hormone resistance, methylation, and breast cancer team.

Although the enzyme’s involvement in the mode of action of tamoxifen has been observed in close to 900 patients with breast cancer, these results need to be validated in other at-risk patient cohorts before the biomarker can be considered for routine use, said Dr. Le Romancer. She estimated that 2 more years of research are needed.

Can you tell us which cases involve the use of tamoxifen and what its mode of action is?

Dr. Le Romancer: Tamoxifen is a hormone therapy used to reduce the risk of breast cancer relapse. It is prescribed to premenopausal women with hormone-sensitive cancer, which equates to roughly 25% of women with breast cancer: 15,000 women each year. The drug, which is taken every day via oral administration, is an estrogen antagonist. By binding to these receptors, it blocks estrogen from mediating its biological effect in the breasts. Aromatase inhibitors are the preferred choice in postmenopausal women, as they have been shown to be more effective. These also have an antiestrogenic effect, but by inhibiting estrogen production.

Tamoxifen therapy is prescribed for a minimum period of 5 years. Despite this, 25% of women treated with tamoxifen relapse. Tamoxifen resistance is unique in that it occurs very late on, generally 10-15 years after starting treatment. This means that it’s really important for us to identify predictive markers of the response to hormone therapy to adapt treatment as best we can. For the moment, the only criteria used to prescribe tamoxifen are patient age and the presence of estrogen receptors within the tumor.

Exactly how would treatment be improved if a decisive predictive marker of response to tamoxifen could be identified?

Dr. Le Romancer: Currently, when a patient’s breast cancer relapses after several years of treatment with tamoxifen, we don’t know if the relapse is linked to tamoxifen resistance or not. This makes it difficult to choose the right treatment to manage such relapses, which remain complicated to treat. Lots of patients die because of metastases.

By predicting the response to tamoxifen using a marker, we will be able to either use another hormone therapy to prevent the relapse or prescribe tamoxifen alongside a molecule that stops resistance from developing. We hope that this will significantly reduce the rate of relapse.

You put forward PRMT5 as a potential predictive marker of response to tamoxifen. What makes you think it could be used in this way?

Dr. Le Romancer: Our research has allowed us to demonstrate that PRMT5, when present in the nuclei of tumor cells, is involved in the mechanisms of action of tamoxifen. Remember that estrogen receptors are located in cell nuclei. For tamoxifen to exert its antitumoral action, PRMT5, an enzyme, needs to enter the nucleus to modify the estrogen receptor. It’s this modification that allows tamoxifen to inhibit tumor growth. The proliferative effect induced by the estrogens is also blocked.

The results of our study showed that high nuclear expression of PRMT5, specifically in the nuclei of breast cancer cells, is associated with a prolonged survival of tamoxifen-treated patients. Until now, we thought this enzyme had an oncogenic role when present in the cytoplasm. It turns out that it also has the opposite effect when acting within the nucleus, at least in this patient cohort: women with hormone-sensitive breast cancer treated with tamoxifen.

What are the next steps in your research before we can begin to think about its use in clinical practice?

Dr. Le Romancer: Our next research will focus on understanding the circumstances surrounding PRMT5 entering and leaving the nucleus. We have also shown that in some patients, tamoxifen causes PRMT5 to enter the cell nucleus. This translocation is only seen in women who respond to tamoxifen, not in those who are resistant to treatment with the drug. All that remains is for us to work out how tamoxifen facilitates this translocation.

Once the elements promoting this translocation have been identified, we will be able to propose a treatment aimed at forcing the enzyme to enter the nucleus and stay there. Eventually, the idea is to combine treatment with antiestrogens with a medicinal product that promotes localization of PRMT5 in the nucleus to guarantee response to tamoxifen. It will be a few years of research before we can apply our findings to clinical practice.

Could we use this biomarker as is just to identify tamoxifen resistance?

Dr. Le Romancer: In the short term, yes, we could use this biomarker to better guide treatment choices at time of diagnosis. We have demonstrated the role of PRMT5 in response to tamoxifen by studying two cohorts of 900 patients with breast cancer receiving treatment at the Léon Bérard Center, Lyon. Before moving on to routine testing, we need to replicate these results in other cohorts, especially in high-risk patients with, for example, greater cell proliferation or those who experience relapse.

The use of this biomarker is based on histological examination of cancer tissue. Single antibody tissue staining targeting PRMT5 reveals the localization of the enzyme in the cells and provides a score evaluating its presence in the nucleus. Using this score, it would be possible to determine the level of response to tamoxifen and decide whether the treatment should be used. This biomarker is the first of its kind undergoing validation as part of the examination of resistance to hormone therapy. We should be able to confirm the findings within the next 2 years.

If clinical tests using this biomarker predict tamoxifen resistance, what alternative treatments are available to these patients?

Dr. Le Romancer: We could give them an aromatase inhibitor or one of the new estrogen antagonists that are currently in development. In a phase 3 study, fulvestrant (Faslodex), for example, demonstrated a significant benefit in treating women with hormone-sensitive advanced breast cancer when administered via injection. The same goes for oral treatment, elacestrant (Orserdu), which has recently been approved by the Food and Drug Administration. These treatments are usually deemed second line after tamoxifen, but they could certainly be used as first-line therapy in resistant patients.

The results obtained from research into novel estrogen antagonists are certainly encouraging. Can tamoxifen retain its prominent position while still ensuring its efficacy?

Dr. Le Romancer: Keeping in mind the current trend for personalized medicine, we should keep as many treatment options open as possible. When a patient relapses, there need to be other treatments available to them. Tamoxifen has been ousted in favor of aromatase inhibitors for postmenopausal women, but it’s still the gold standard for premenopausal women and has been for over 20 years. Despite having been replaced by a novel estrogen antagonist, it will still have a prominent place in the therapeutic arsenal of premenopausal women with breast cancer.

With the development of PRMT5 as a predictive biomarker, we could even see tamoxifen being proposed as first-line therapy for postmenopausal women in whom high levels of PRMT5 are found in the nuclei of their cancer cells. By predicting their response, we could achieve greater efficacy of tamoxifen, compared with aromatase inhibitors. For now, this remains a hypothesis and must be verified in further clinical studies.

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

A team at Lyon’s Cancer Research Center (CRCL) has revealed the role of an enzyme, PRMT5, in the response to tamoxifen, a drug used to prevent relapse in premenopausal women with breast cancer. The protein could become the first predictive marker of response to tamoxifen.

Muriel Le Romancer, MD, director of research at France’s Institute of Health and Medical Research, explained the issues involved in this discovery in an interview. She jointly led this research along with Olivier Trédan, MD, PhD, oncologist at Lyon’s Léon Bérard Clinic. The research concluded with the publication of a study in EMBO Molecular Medicine. The researchers both head up the CRCL’s hormone resistance, methylation, and breast cancer team.

Although the enzyme’s involvement in the mode of action of tamoxifen has been observed in close to 900 patients with breast cancer, these results need to be validated in other at-risk patient cohorts before the biomarker can be considered for routine use, said Dr. Le Romancer. She estimated that 2 more years of research are needed.

Can you tell us which cases involve the use of tamoxifen and what its mode of action is?

Dr. Le Romancer: Tamoxifen is a hormone therapy used to reduce the risk of breast cancer relapse. It is prescribed to premenopausal women with hormone-sensitive cancer, which equates to roughly 25% of women with breast cancer: 15,000 women each year. The drug, which is taken every day via oral administration, is an estrogen antagonist. By binding to these receptors, it blocks estrogen from mediating its biological effect in the breasts. Aromatase inhibitors are the preferred choice in postmenopausal women, as they have been shown to be more effective. These also have an antiestrogenic effect, but by inhibiting estrogen production.

Tamoxifen therapy is prescribed for a minimum period of 5 years. Despite this, 25% of women treated with tamoxifen relapse. Tamoxifen resistance is unique in that it occurs very late on, generally 10-15 years after starting treatment. This means that it’s really important for us to identify predictive markers of the response to hormone therapy to adapt treatment as best we can. For the moment, the only criteria used to prescribe tamoxifen are patient age and the presence of estrogen receptors within the tumor.

Exactly how would treatment be improved if a decisive predictive marker of response to tamoxifen could be identified?

Dr. Le Romancer: Currently, when a patient’s breast cancer relapses after several years of treatment with tamoxifen, we don’t know if the relapse is linked to tamoxifen resistance or not. This makes it difficult to choose the right treatment to manage such relapses, which remain complicated to treat. Lots of patients die because of metastases.

By predicting the response to tamoxifen using a marker, we will be able to either use another hormone therapy to prevent the relapse or prescribe tamoxifen alongside a molecule that stops resistance from developing. We hope that this will significantly reduce the rate of relapse.

You put forward PRMT5 as a potential predictive marker of response to tamoxifen. What makes you think it could be used in this way?

Dr. Le Romancer: Our research has allowed us to demonstrate that PRMT5, when present in the nuclei of tumor cells, is involved in the mechanisms of action of tamoxifen. Remember that estrogen receptors are located in cell nuclei. For tamoxifen to exert its antitumoral action, PRMT5, an enzyme, needs to enter the nucleus to modify the estrogen receptor. It’s this modification that allows tamoxifen to inhibit tumor growth. The proliferative effect induced by the estrogens is also blocked.

The results of our study showed that high nuclear expression of PRMT5, specifically in the nuclei of breast cancer cells, is associated with a prolonged survival of tamoxifen-treated patients. Until now, we thought this enzyme had an oncogenic role when present in the cytoplasm. It turns out that it also has the opposite effect when acting within the nucleus, at least in this patient cohort: women with hormone-sensitive breast cancer treated with tamoxifen.

What are the next steps in your research before we can begin to think about its use in clinical practice?

Dr. Le Romancer: Our next research will focus on understanding the circumstances surrounding PRMT5 entering and leaving the nucleus. We have also shown that in some patients, tamoxifen causes PRMT5 to enter the cell nucleus. This translocation is only seen in women who respond to tamoxifen, not in those who are resistant to treatment with the drug. All that remains is for us to work out how tamoxifen facilitates this translocation.

Once the elements promoting this translocation have been identified, we will be able to propose a treatment aimed at forcing the enzyme to enter the nucleus and stay there. Eventually, the idea is to combine treatment with antiestrogens with a medicinal product that promotes localization of PRMT5 in the nucleus to guarantee response to tamoxifen. It will be a few years of research before we can apply our findings to clinical practice.

Could we use this biomarker as is just to identify tamoxifen resistance?

Dr. Le Romancer: In the short term, yes, we could use this biomarker to better guide treatment choices at time of diagnosis. We have demonstrated the role of PRMT5 in response to tamoxifen by studying two cohorts of 900 patients with breast cancer receiving treatment at the Léon Bérard Center, Lyon. Before moving on to routine testing, we need to replicate these results in other cohorts, especially in high-risk patients with, for example, greater cell proliferation or those who experience relapse.

The use of this biomarker is based on histological examination of cancer tissue. Single antibody tissue staining targeting PRMT5 reveals the localization of the enzyme in the cells and provides a score evaluating its presence in the nucleus. Using this score, it would be possible to determine the level of response to tamoxifen and decide whether the treatment should be used. This biomarker is the first of its kind undergoing validation as part of the examination of resistance to hormone therapy. We should be able to confirm the findings within the next 2 years.

If clinical tests using this biomarker predict tamoxifen resistance, what alternative treatments are available to these patients?

Dr. Le Romancer: We could give them an aromatase inhibitor or one of the new estrogen antagonists that are currently in development. In a phase 3 study, fulvestrant (Faslodex), for example, demonstrated a significant benefit in treating women with hormone-sensitive advanced breast cancer when administered via injection. The same goes for oral treatment, elacestrant (Orserdu), which has recently been approved by the Food and Drug Administration. These treatments are usually deemed second line after tamoxifen, but they could certainly be used as first-line therapy in resistant patients.

The results obtained from research into novel estrogen antagonists are certainly encouraging. Can tamoxifen retain its prominent position while still ensuring its efficacy?

Dr. Le Romancer: Keeping in mind the current trend for personalized medicine, we should keep as many treatment options open as possible. When a patient relapses, there need to be other treatments available to them. Tamoxifen has been ousted in favor of aromatase inhibitors for postmenopausal women, but it’s still the gold standard for premenopausal women and has been for over 20 years. Despite having been replaced by a novel estrogen antagonist, it will still have a prominent place in the therapeutic arsenal of premenopausal women with breast cancer.

With the development of PRMT5 as a predictive biomarker, we could even see tamoxifen being proposed as first-line therapy for postmenopausal women in whom high levels of PRMT5 are found in the nuclei of their cancer cells. By predicting their response, we could achieve greater efficacy of tamoxifen, compared with aromatase inhibitors. For now, this remains a hypothesis and must be verified in further clinical studies.

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

A team at Lyon’s Cancer Research Center (CRCL) has revealed the role of an enzyme, PRMT5, in the response to tamoxifen, a drug used to prevent relapse in premenopausal women with breast cancer. The protein could become the first predictive marker of response to tamoxifen.

Muriel Le Romancer, MD, director of research at France’s Institute of Health and Medical Research, explained the issues involved in this discovery in an interview. She jointly led this research along with Olivier Trédan, MD, PhD, oncologist at Lyon’s Léon Bérard Clinic. The research concluded with the publication of a study in EMBO Molecular Medicine. The researchers both head up the CRCL’s hormone resistance, methylation, and breast cancer team.

Although the enzyme’s involvement in the mode of action of tamoxifen has been observed in close to 900 patients with breast cancer, these results need to be validated in other at-risk patient cohorts before the biomarker can be considered for routine use, said Dr. Le Romancer. She estimated that 2 more years of research are needed.

Can you tell us which cases involve the use of tamoxifen and what its mode of action is?

Dr. Le Romancer: Tamoxifen is a hormone therapy used to reduce the risk of breast cancer relapse. It is prescribed to premenopausal women with hormone-sensitive cancer, which equates to roughly 25% of women with breast cancer: 15,000 women each year. The drug, which is taken every day via oral administration, is an estrogen antagonist. By binding to these receptors, it blocks estrogen from mediating its biological effect in the breasts. Aromatase inhibitors are the preferred choice in postmenopausal women, as they have been shown to be more effective. These also have an antiestrogenic effect, but by inhibiting estrogen production.

Tamoxifen therapy is prescribed for a minimum period of 5 years. Despite this, 25% of women treated with tamoxifen relapse. Tamoxifen resistance is unique in that it occurs very late on, generally 10-15 years after starting treatment. This means that it’s really important for us to identify predictive markers of the response to hormone therapy to adapt treatment as best we can. For the moment, the only criteria used to prescribe tamoxifen are patient age and the presence of estrogen receptors within the tumor.

Exactly how would treatment be improved if a decisive predictive marker of response to tamoxifen could be identified?

Dr. Le Romancer: Currently, when a patient’s breast cancer relapses after several years of treatment with tamoxifen, we don’t know if the relapse is linked to tamoxifen resistance or not. This makes it difficult to choose the right treatment to manage such relapses, which remain complicated to treat. Lots of patients die because of metastases.

By predicting the response to tamoxifen using a marker, we will be able to either use another hormone therapy to prevent the relapse or prescribe tamoxifen alongside a molecule that stops resistance from developing. We hope that this will significantly reduce the rate of relapse.

You put forward PRMT5 as a potential predictive marker of response to tamoxifen. What makes you think it could be used in this way?

Dr. Le Romancer: Our research has allowed us to demonstrate that PRMT5, when present in the nuclei of tumor cells, is involved in the mechanisms of action of tamoxifen. Remember that estrogen receptors are located in cell nuclei. For tamoxifen to exert its antitumoral action, PRMT5, an enzyme, needs to enter the nucleus to modify the estrogen receptor. It’s this modification that allows tamoxifen to inhibit tumor growth. The proliferative effect induced by the estrogens is also blocked.

The results of our study showed that high nuclear expression of PRMT5, specifically in the nuclei of breast cancer cells, is associated with a prolonged survival of tamoxifen-treated patients. Until now, we thought this enzyme had an oncogenic role when present in the cytoplasm. It turns out that it also has the opposite effect when acting within the nucleus, at least in this patient cohort: women with hormone-sensitive breast cancer treated with tamoxifen.

What are the next steps in your research before we can begin to think about its use in clinical practice?

Dr. Le Romancer: Our next research will focus on understanding the circumstances surrounding PRMT5 entering and leaving the nucleus. We have also shown that in some patients, tamoxifen causes PRMT5 to enter the cell nucleus. This translocation is only seen in women who respond to tamoxifen, not in those who are resistant to treatment with the drug. All that remains is for us to work out how tamoxifen facilitates this translocation.

Once the elements promoting this translocation have been identified, we will be able to propose a treatment aimed at forcing the enzyme to enter the nucleus and stay there. Eventually, the idea is to combine treatment with antiestrogens with a medicinal product that promotes localization of PRMT5 in the nucleus to guarantee response to tamoxifen. It will be a few years of research before we can apply our findings to clinical practice.

Could we use this biomarker as is just to identify tamoxifen resistance?

Dr. Le Romancer: In the short term, yes, we could use this biomarker to better guide treatment choices at time of diagnosis. We have demonstrated the role of PRMT5 in response to tamoxifen by studying two cohorts of 900 patients with breast cancer receiving treatment at the Léon Bérard Center, Lyon. Before moving on to routine testing, we need to replicate these results in other cohorts, especially in high-risk patients with, for example, greater cell proliferation or those who experience relapse.

The use of this biomarker is based on histological examination of cancer tissue. Single antibody tissue staining targeting PRMT5 reveals the localization of the enzyme in the cells and provides a score evaluating its presence in the nucleus. Using this score, it would be possible to determine the level of response to tamoxifen and decide whether the treatment should be used. This biomarker is the first of its kind undergoing validation as part of the examination of resistance to hormone therapy. We should be able to confirm the findings within the next 2 years.

If clinical tests using this biomarker predict tamoxifen resistance, what alternative treatments are available to these patients?

Dr. Le Romancer: We could give them an aromatase inhibitor or one of the new estrogen antagonists that are currently in development. In a phase 3 study, fulvestrant (Faslodex), for example, demonstrated a significant benefit in treating women with hormone-sensitive advanced breast cancer when administered via injection. The same goes for oral treatment, elacestrant (Orserdu), which has recently been approved by the Food and Drug Administration. These treatments are usually deemed second line after tamoxifen, but they could certainly be used as first-line therapy in resistant patients.

The results obtained from research into novel estrogen antagonists are certainly encouraging. Can tamoxifen retain its prominent position while still ensuring its efficacy?

Dr. Le Romancer: Keeping in mind the current trend for personalized medicine, we should keep as many treatment options open as possible. When a patient relapses, there need to be other treatments available to them. Tamoxifen has been ousted in favor of aromatase inhibitors for postmenopausal women, but it’s still the gold standard for premenopausal women and has been for over 20 years. Despite having been replaced by a novel estrogen antagonist, it will still have a prominent place in the therapeutic arsenal of premenopausal women with breast cancer.

With the development of PRMT5 as a predictive biomarker, we could even see tamoxifen being proposed as first-line therapy for postmenopausal women in whom high levels of PRMT5 are found in the nuclei of their cancer cells. By predicting their response, we could achieve greater efficacy of tamoxifen, compared with aromatase inhibitors. For now, this remains a hypothesis and must be verified in further clinical studies.

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

Pediatric patients receiving donor stem cell transplantion with healthier pretransplant gut microbiota diversity show improved rates of survival and a lower risk of developing acute graft versus host disease (GvHD), similar to the patterns reported in adults.

“To the best of our knowledge, we present the first evidence of an association between pretransplantation lower gut microbiota diversity and poorer outcome in children undergoing allo-HSCT,” the authors report, in research published in the journal Blood. “Our findings underscore the importance of pre-transplant gut microbiota diversity and compositional structure in influencing allo-HSCT-related clinical outcomes in the pediatric setting.”

While allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be potentially curative of hematologic malignancies, the stem cell transplantation process can wreak havoc on gut microbiota, because of factors including the conditioning regimen, antibiotic exposure, and dietary changes.

Specifically, the process can cause a substantial decrease in necessary alpha diversity and a potential expansion of possibly pathogenic bacteria.

While poor gut microbiota diversity has been linked to higher mortality in adult patients receiving allo-HSCT, research on the effects in pediatric patients is lacking.

“The gut microbiota of children differs from adults’ one, and this accounts for the need for specific pediatric studies on the gut microbiota-to–allo-HSCT relationship,” the authors write.

For the multicenter study, first author Riccardo Masetti, MD, PhD, of the department of pediatric oncology and hematology at the University of Bologna, Italy, and colleagues analyzed the gut microbiota diversity of 90 pediatric allo-HSCT recipients at four centers in Italy and one in Poland, stratifying the patients into groups of higher and lower diversity pretransplantation and again at the time of neutrophil engraftment.

Overall, gut microbiota diversity significantly declined from before allo-HSCT to afterward, at the time of neutrophil engraftment (P < .0001), with lower diversity observed in patients 3 years of age or younger.

With a median follow-up of 52 months, compared with the lower diversity group, those with higher diversity prior to transplantation had a significantly higher probability of overall survival (hazard ratio, 0.26; P = .011), after adjustment for age, graft source, donor type, intensity of conditioning regimen, center, and type of disease, with estimated overall survival at 52 months after allo-HSCT of 88.9% for the higher diversity group and 62.7% for the lower diversity group.

The cumulative incidence of grade II-IV acute GvHD was significantly lower for the higher diversity group versus lower diversity (20.0 versus 44.4, respectively; P = .017), as were the incidence rates of grade III-IV acute GvHD (2.2 versus 20.0; P = .007).

There were, however, no significant differences between the low and high diversity gut microbiota groups in relapse-free survival (P = .091).

The higher diversity group notably had higher relative abundances of potentially health-related bacterial families, including Ruminococcaceae and Oscillospiraceae, while the lower diversity group showed an overabundance of Enterococcaceae and Enterobacteriaceae.

Of note, the results differ from those observed in adults, among whom gut microbiota diversity before as well as after transplantation has been significantly associated with transplant outcomes, whereas with children, the association was limited to diversity prior to transplant.

In general, children have significantly lower diversity of gut microbiota than adults, with varying functional properties, and microbiota that is more easily modified by environmental factors, with larger changes occurring upon exposure to external stressors, the authors explain.

“Considering these different ecological properties compared to adults, we hypothesize that allo-HSCT–induced dysbiosis in the pediatric setting may imply loss of age-related gut microbiota signatures, including alpha diversity, with high interpatient variability,” they say.

Characteristics that were associated with higher or lower gut microbiota diversity prior to allo-HSCT included the treating center, suggesting that the geographical region may affect the diversity and the type of antibiotic exposure prior to the transplant.

Limitations included that “we didn’t assess other pretransplant characteristics such as the type of chemotherapy received, or the lifestyle, and this should be addressed in future studies on larger cohorts,” Dr. Masetti said in an interview.

While lengthy delays in screening of samples are barriers in the use of the gut microbiome as a tool in clinical practice, he noted that clinicians can take key measures to improve the microbiota.

“[Preventive measures] include the avoidance of unnecessary antibiotic treatment, which has a detrimental effect on the microbiota,” he said. “Moreover, some dietary changes may promote microbiota health.”

In addition, key measures can be taken during the allo-HSCT to preserve the microbiota, he added.

“In our center, we use enteral nutrition with a nasogastric tube rather than parenteral nutrition, which helps the microbiota to recover faster,” Dr. Masetti explained. “Moreover, other interventional measures such as fecal microbiota transplantation or the use of probiotics are under testing.”

“In particular, our data emphasize the importance of an overall healthy network, rather than the abundance of specific families or genera, in preventing complications and unfavorable outcomes.”

Commenting on the study, Robert Jenq, MD, an assistant professor in the departments of genomic medicine and stem cell transplantation and cellular therapy at the University of Texas M.D. Anderson Cancer Center, Houston, noted that with the growing evidence of the effects of poor gut microbiota diversity on clinical outcomes, multiple early-phase clinical trials are being conducted to test various strategies to prevent or treat gut injury.

“I’m not aware of any one approach that has shown enough promise to warrant being tested in multicenter studies yet, but it’s still a bit early,” Dr. Jenq said.“In the meantime, discontinuing or de-escalating antibiotics when medically safe, and encouraging patients to eat as much as they’re able to is a reasonable recommendation.”

Dr. Jenq added that, with most of the data on the issue being retrospective, a causative role has not been established, and “the finding of an association between the gut microbiota composition and survival, while interesting and provocative, does not provide evidence that intervening on the gut microbiota will lead to a clinical benefit.”

“I’m hopeful that randomized clinical trials will eventually demonstrate that we can protect or restore the gut microbiota, and this will lead to substantial clinical benefits, but this remains to be seen,” he said.

The authors had no disclosures to report. Dr. Jenq is an advisor for Seres Therapeutics, Prolacta Biosciences, and MaaT Pharma.

Pediatric patients receiving donor stem cell transplantion with healthier pretransplant gut microbiota diversity show improved rates of survival and a lower risk of developing acute graft versus host disease (GvHD), similar to the patterns reported in adults.

“To the best of our knowledge, we present the first evidence of an association between pretransplantation lower gut microbiota diversity and poorer outcome in children undergoing allo-HSCT,” the authors report, in research published in the journal Blood. “Our findings underscore the importance of pre-transplant gut microbiota diversity and compositional structure in influencing allo-HSCT-related clinical outcomes in the pediatric setting.”

While allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be potentially curative of hematologic malignancies, the stem cell transplantation process can wreak havoc on gut microbiota, because of factors including the conditioning regimen, antibiotic exposure, and dietary changes.

Specifically, the process can cause a substantial decrease in necessary alpha diversity and a potential expansion of possibly pathogenic bacteria.

While poor gut microbiota diversity has been linked to higher mortality in adult patients receiving allo-HSCT, research on the effects in pediatric patients is lacking.

“The gut microbiota of children differs from adults’ one, and this accounts for the need for specific pediatric studies on the gut microbiota-to–allo-HSCT relationship,” the authors write.

For the multicenter study, first author Riccardo Masetti, MD, PhD, of the department of pediatric oncology and hematology at the University of Bologna, Italy, and colleagues analyzed the gut microbiota diversity of 90 pediatric allo-HSCT recipients at four centers in Italy and one in Poland, stratifying the patients into groups of higher and lower diversity pretransplantation and again at the time of neutrophil engraftment.

Overall, gut microbiota diversity significantly declined from before allo-HSCT to afterward, at the time of neutrophil engraftment (P < .0001), with lower diversity observed in patients 3 years of age or younger.

With a median follow-up of 52 months, compared with the lower diversity group, those with higher diversity prior to transplantation had a significantly higher probability of overall survival (hazard ratio, 0.26; P = .011), after adjustment for age, graft source, donor type, intensity of conditioning regimen, center, and type of disease, with estimated overall survival at 52 months after allo-HSCT of 88.9% for the higher diversity group and 62.7% for the lower diversity group.

The cumulative incidence of grade II-IV acute GvHD was significantly lower for the higher diversity group versus lower diversity (20.0 versus 44.4, respectively; P = .017), as were the incidence rates of grade III-IV acute GvHD (2.2 versus 20.0; P = .007).

There were, however, no significant differences between the low and high diversity gut microbiota groups in relapse-free survival (P = .091).

The higher diversity group notably had higher relative abundances of potentially health-related bacterial families, including Ruminococcaceae and Oscillospiraceae, while the lower diversity group showed an overabundance of Enterococcaceae and Enterobacteriaceae.

Of note, the results differ from those observed in adults, among whom gut microbiota diversity before as well as after transplantation has been significantly associated with transplant outcomes, whereas with children, the association was limited to diversity prior to transplant.

In general, children have significantly lower diversity of gut microbiota than adults, with varying functional properties, and microbiota that is more easily modified by environmental factors, with larger changes occurring upon exposure to external stressors, the authors explain.

“Considering these different ecological properties compared to adults, we hypothesize that allo-HSCT–induced dysbiosis in the pediatric setting may imply loss of age-related gut microbiota signatures, including alpha diversity, with high interpatient variability,” they say.

Characteristics that were associated with higher or lower gut microbiota diversity prior to allo-HSCT included the treating center, suggesting that the geographical region may affect the diversity and the type of antibiotic exposure prior to the transplant.

Limitations included that “we didn’t assess other pretransplant characteristics such as the type of chemotherapy received, or the lifestyle, and this should be addressed in future studies on larger cohorts,” Dr. Masetti said in an interview.

While lengthy delays in screening of samples are barriers in the use of the gut microbiome as a tool in clinical practice, he noted that clinicians can take key measures to improve the microbiota.

“[Preventive measures] include the avoidance of unnecessary antibiotic treatment, which has a detrimental effect on the microbiota,” he said. “Moreover, some dietary changes may promote microbiota health.”

In addition, key measures can be taken during the allo-HSCT to preserve the microbiota, he added.

“In our center, we use enteral nutrition with a nasogastric tube rather than parenteral nutrition, which helps the microbiota to recover faster,” Dr. Masetti explained. “Moreover, other interventional measures such as fecal microbiota transplantation or the use of probiotics are under testing.”

“In particular, our data emphasize the importance of an overall healthy network, rather than the abundance of specific families or genera, in preventing complications and unfavorable outcomes.”

Commenting on the study, Robert Jenq, MD, an assistant professor in the departments of genomic medicine and stem cell transplantation and cellular therapy at the University of Texas M.D. Anderson Cancer Center, Houston, noted that with the growing evidence of the effects of poor gut microbiota diversity on clinical outcomes, multiple early-phase clinical trials are being conducted to test various strategies to prevent or treat gut injury.

“I’m not aware of any one approach that has shown enough promise to warrant being tested in multicenter studies yet, but it’s still a bit early,” Dr. Jenq said.“In the meantime, discontinuing or de-escalating antibiotics when medically safe, and encouraging patients to eat as much as they’re able to is a reasonable recommendation.”

Dr. Jenq added that, with most of the data on the issue being retrospective, a causative role has not been established, and “the finding of an association between the gut microbiota composition and survival, while interesting and provocative, does not provide evidence that intervening on the gut microbiota will lead to a clinical benefit.”

“I’m hopeful that randomized clinical trials will eventually demonstrate that we can protect or restore the gut microbiota, and this will lead to substantial clinical benefits, but this remains to be seen,” he said.

The authors had no disclosures to report. Dr. Jenq is an advisor for Seres Therapeutics, Prolacta Biosciences, and MaaT Pharma.

Pediatric patients receiving donor stem cell transplantion with healthier pretransplant gut microbiota diversity show improved rates of survival and a lower risk of developing acute graft versus host disease (GvHD), similar to the patterns reported in adults.

“To the best of our knowledge, we present the first evidence of an association between pretransplantation lower gut microbiota diversity and poorer outcome in children undergoing allo-HSCT,” the authors report, in research published in the journal Blood. “Our findings underscore the importance of pre-transplant gut microbiota diversity and compositional structure in influencing allo-HSCT-related clinical outcomes in the pediatric setting.”

While allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be potentially curative of hematologic malignancies, the stem cell transplantation process can wreak havoc on gut microbiota, because of factors including the conditioning regimen, antibiotic exposure, and dietary changes.

Specifically, the process can cause a substantial decrease in necessary alpha diversity and a potential expansion of possibly pathogenic bacteria.

While poor gut microbiota diversity has been linked to higher mortality in adult patients receiving allo-HSCT, research on the effects in pediatric patients is lacking.

“The gut microbiota of children differs from adults’ one, and this accounts for the need for specific pediatric studies on the gut microbiota-to–allo-HSCT relationship,” the authors write.

For the multicenter study, first author Riccardo Masetti, MD, PhD, of the department of pediatric oncology and hematology at the University of Bologna, Italy, and colleagues analyzed the gut microbiota diversity of 90 pediatric allo-HSCT recipients at four centers in Italy and one in Poland, stratifying the patients into groups of higher and lower diversity pretransplantation and again at the time of neutrophil engraftment.

Overall, gut microbiota diversity significantly declined from before allo-HSCT to afterward, at the time of neutrophil engraftment (P < .0001), with lower diversity observed in patients 3 years of age or younger.

With a median follow-up of 52 months, compared with the lower diversity group, those with higher diversity prior to transplantation had a significantly higher probability of overall survival (hazard ratio, 0.26; P = .011), after adjustment for age, graft source, donor type, intensity of conditioning regimen, center, and type of disease, with estimated overall survival at 52 months after allo-HSCT of 88.9% for the higher diversity group and 62.7% for the lower diversity group.

The cumulative incidence of grade II-IV acute GvHD was significantly lower for the higher diversity group versus lower diversity (20.0 versus 44.4, respectively; P = .017), as were the incidence rates of grade III-IV acute GvHD (2.2 versus 20.0; P = .007).

There were, however, no significant differences between the low and high diversity gut microbiota groups in relapse-free survival (P = .091).

The higher diversity group notably had higher relative abundances of potentially health-related bacterial families, including Ruminococcaceae and Oscillospiraceae, while the lower diversity group showed an overabundance of Enterococcaceae and Enterobacteriaceae.

Of note, the results differ from those observed in adults, among whom gut microbiota diversity before as well as after transplantation has been significantly associated with transplant outcomes, whereas with children, the association was limited to diversity prior to transplant.

In general, children have significantly lower diversity of gut microbiota than adults, with varying functional properties, and microbiota that is more easily modified by environmental factors, with larger changes occurring upon exposure to external stressors, the authors explain.

“Considering these different ecological properties compared to adults, we hypothesize that allo-HSCT–induced dysbiosis in the pediatric setting may imply loss of age-related gut microbiota signatures, including alpha diversity, with high interpatient variability,” they say.

Characteristics that were associated with higher or lower gut microbiota diversity prior to allo-HSCT included the treating center, suggesting that the geographical region may affect the diversity and the type of antibiotic exposure prior to the transplant.

Limitations included that “we didn’t assess other pretransplant characteristics such as the type of chemotherapy received, or the lifestyle, and this should be addressed in future studies on larger cohorts,” Dr. Masetti said in an interview.

While lengthy delays in screening of samples are barriers in the use of the gut microbiome as a tool in clinical practice, he noted that clinicians can take key measures to improve the microbiota.

“[Preventive measures] include the avoidance of unnecessary antibiotic treatment, which has a detrimental effect on the microbiota,” he said. “Moreover, some dietary changes may promote microbiota health.”

In addition, key measures can be taken during the allo-HSCT to preserve the microbiota, he added.

“In our center, we use enteral nutrition with a nasogastric tube rather than parenteral nutrition, which helps the microbiota to recover faster,” Dr. Masetti explained. “Moreover, other interventional measures such as fecal microbiota transplantation or the use of probiotics are under testing.”

“In particular, our data emphasize the importance of an overall healthy network, rather than the abundance of specific families or genera, in preventing complications and unfavorable outcomes.”

Commenting on the study, Robert Jenq, MD, an assistant professor in the departments of genomic medicine and stem cell transplantation and cellular therapy at the University of Texas M.D. Anderson Cancer Center, Houston, noted that with the growing evidence of the effects of poor gut microbiota diversity on clinical outcomes, multiple early-phase clinical trials are being conducted to test various strategies to prevent or treat gut injury.

“I’m not aware of any one approach that has shown enough promise to warrant being tested in multicenter studies yet, but it’s still a bit early,” Dr. Jenq said.“In the meantime, discontinuing or de-escalating antibiotics when medically safe, and encouraging patients to eat as much as they’re able to is a reasonable recommendation.”

Dr. Jenq added that, with most of the data on the issue being retrospective, a causative role has not been established, and “the finding of an association between the gut microbiota composition and survival, while interesting and provocative, does not provide evidence that intervening on the gut microbiota will lead to a clinical benefit.”

“I’m hopeful that randomized clinical trials will eventually demonstrate that we can protect or restore the gut microbiota, and this will lead to substantial clinical benefits, but this remains to be seen,” he said.

The authors had no disclosures to report. Dr. Jenq is an advisor for Seres Therapeutics, Prolacta Biosciences, and MaaT Pharma.

Alcohol consumption, including risky drinking behaviors, is common among adult cancer survivors, even people currently receiving cancer treatment, new research shows.

An analysis of more than 15,000 adults with a cancer diagnosis revealed that nearly 80% were current drinkers. Among current drinkers, 13% consumed a moderate amount of alcohol in a typical day, while close to 40% engaged in hazardous drinking.

The numbers are “staggering,” Yin Cao, ScD, MPH, of Washington University in St. Louis, said in an interview. “Most concerning is that those on cancer treatment are engaged in a similar level of risky drinking.”

The study was published online in JAMA Network Open.

Drinking alcohol can increase a person’s risk for a variety of cancers, including oral and pharyngeal cancer as well as esophageal, colorectal, liver, and female breast cancers.

Consuming alcohol is also associated with numerous risks among people diagnosed with cancer. In the short term, alcohol consumption can worsen postsurgical outcomes as well as impair cognition and amplify cardiotoxicity in patients undergoing chemotherapy. In the long term, drinking alcohol can elevate a person’s risk of recurrence, secondary tumors, and mortality.

The American Society of Clinical Oncology recently issued a statement reinforcing the need to prioritize alcohol consumption as a key modifiable behavioral factor in the cancer control research agenda.

The current American Cancer Society guidelines indicate that it’s best to avoid or, at least, minimize alcohol consumption. Men should limit their intake to no more than two drinks per day and women should have no more than one drink per day.

Despite this data and guidelines, alcohol drinking patterns among cancer survivors in the United States remain poorly understood.

To explore further, the researchers identified 15,199 adult cancer survivors enrolled in the National Institutes of Health’s All of Us Research Program.

Overall, 78% of the cohort – more than 11,800 individuals – were current drinkers. In a typical day, 24% engaged in binge drinking – consuming six or more drinks on a single occasion – and 38% engaged in hazardous drinking. Using the Alcohol Use Disorders Identification Test–Consumption, the researchers classified hazardous drinking as scores of 4 or higher in men and 3 or higher in women.

Drinking patterns looked similar in the subset of 1,839 patients undergoing cancer treatment. In this group, 76% were current drinkers. Among current drinkers, 12% exceeded moderate drinking levels, 23% reported binge drinking, and 38% engaged in hazardous drinking. In this group, men, Hispanics, people diagnosed with cancer before age 18, and smokers were more likely to engage in risky drinking behaviors.

“We know that many people who are diagnosed with cancer continue to drink alcohol, but this study provides much more detailed information about that,” said Farhad Islami, MD, PhD, senior scientific director for cancer disparity research at the American Cancer Society, Atlanta, who was not involved in the study.

Given the degree of drinking identified in this population, Dr. Cao highlighted the importance of talking to patients about alcohol.

“Our findings highlight an opportunity for enhanced support and intervention concerning risky drinking behaviors” in oncology, Dr. Cao said. “Given the societal norms surrounding alcohol and the general lack of awareness of alcohol’s short- and long-term impact on cancer outcomes, gently educating patients/survivors about potential risks while understanding the cultural and societal contexts of drinking can make a difference.”

Dr. Islami agreed that oncologists should talk to their patients about alcohol, “especially those going through active treatment because alcohol may affect the treatment or may be associated with more complications of the treatment.”

“Many people now know that smoking causes cancer, but unfortunately, many people do not know about the association of alcohol with cancer,” he said.

Outside of an awareness gap, there are numerous risk factors for substance abuse among cancer survivors, Marleen Meyers, MD, director of the cancer survivorship program at NYU Langone Perlmutter Cancer Center, New York, explained.

Alcohol can help some cancer survivors dull feelings of isolation, fear, stress, and poor pain management that may accompany their diagnosis and treatment, said Dr. Meyers, who was not involved in the research. That is why “it is important for patients to be honest with their providers and for providers to ask about substance use in a nonjudgmental way.”

In these conversations, oncologists should educate patients about the safety risks associated with alcohol intake during or after treatment and that there is no established “safe” amount of alcohol. Incorporating a mental health screening and questions about a family history of substance abuse can also help identify patients “most at risk so providers can be proactive,” she said.

The study was supported by a grant from the NIH. Dr. Cao, Dr. Islami, and Dr. Meyers report no relevant financial relationships.

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

Alcohol consumption, including risky drinking behaviors, is common among adult cancer survivors, even people currently receiving cancer treatment, new research shows.

An analysis of more than 15,000 adults with a cancer diagnosis revealed that nearly 80% were current drinkers. Among current drinkers, 13% consumed a moderate amount of alcohol in a typical day, while close to 40% engaged in hazardous drinking.

The numbers are “staggering,” Yin Cao, ScD, MPH, of Washington University in St. Louis, said in an interview. “Most concerning is that those on cancer treatment are engaged in a similar level of risky drinking.”

The study was published online in JAMA Network Open.

Drinking alcohol can increase a person’s risk for a variety of cancers, including oral and pharyngeal cancer as well as esophageal, colorectal, liver, and female breast cancers.

Consuming alcohol is also associated with numerous risks among people diagnosed with cancer. In the short term, alcohol consumption can worsen postsurgical outcomes as well as impair cognition and amplify cardiotoxicity in patients undergoing chemotherapy. In the long term, drinking alcohol can elevate a person’s risk of recurrence, secondary tumors, and mortality.

The American Society of Clinical Oncology recently issued a statement reinforcing the need to prioritize alcohol consumption as a key modifiable behavioral factor in the cancer control research agenda.

The current American Cancer Society guidelines indicate that it’s best to avoid or, at least, minimize alcohol consumption. Men should limit their intake to no more than two drinks per day and women should have no more than one drink per day.

Despite this data and guidelines, alcohol drinking patterns among cancer survivors in the United States remain poorly understood.

To explore further, the researchers identified 15,199 adult cancer survivors enrolled in the National Institutes of Health’s All of Us Research Program.

Overall, 78% of the cohort – more than 11,800 individuals – were current drinkers. In a typical day, 24% engaged in binge drinking – consuming six or more drinks on a single occasion – and 38% engaged in hazardous drinking. Using the Alcohol Use Disorders Identification Test–Consumption, the researchers classified hazardous drinking as scores of 4 or higher in men and 3 or higher in women.

Drinking patterns looked similar in the subset of 1,839 patients undergoing cancer treatment. In this group, 76% were current drinkers. Among current drinkers, 12% exceeded moderate drinking levels, 23% reported binge drinking, and 38% engaged in hazardous drinking. In this group, men, Hispanics, people diagnosed with cancer before age 18, and smokers were more likely to engage in risky drinking behaviors.

“We know that many people who are diagnosed with cancer continue to drink alcohol, but this study provides much more detailed information about that,” said Farhad Islami, MD, PhD, senior scientific director for cancer disparity research at the American Cancer Society, Atlanta, who was not involved in the study.

Given the degree of drinking identified in this population, Dr. Cao highlighted the importance of talking to patients about alcohol.

“Our findings highlight an opportunity for enhanced support and intervention concerning risky drinking behaviors” in oncology, Dr. Cao said. “Given the societal norms surrounding alcohol and the general lack of awareness of alcohol’s short- and long-term impact on cancer outcomes, gently educating patients/survivors about potential risks while understanding the cultural and societal contexts of drinking can make a difference.”

Dr. Islami agreed that oncologists should talk to their patients about alcohol, “especially those going through active treatment because alcohol may affect the treatment or may be associated with more complications of the treatment.”

“Many people now know that smoking causes cancer, but unfortunately, many people do not know about the association of alcohol with cancer,” he said.

Outside of an awareness gap, there are numerous risk factors for substance abuse among cancer survivors, Marleen Meyers, MD, director of the cancer survivorship program at NYU Langone Perlmutter Cancer Center, New York, explained.

Alcohol can help some cancer survivors dull feelings of isolation, fear, stress, and poor pain management that may accompany their diagnosis and treatment, said Dr. Meyers, who was not involved in the research. That is why “it is important for patients to be honest with their providers and for providers to ask about substance use in a nonjudgmental way.”

In these conversations, oncologists should educate patients about the safety risks associated with alcohol intake during or after treatment and that there is no established “safe” amount of alcohol. Incorporating a mental health screening and questions about a family history of substance abuse can also help identify patients “most at risk so providers can be proactive,” she said.

The study was supported by a grant from the NIH. Dr. Cao, Dr. Islami, and Dr. Meyers report no relevant financial relationships.

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

Alcohol consumption, including risky drinking behaviors, is common among adult cancer survivors, even people currently receiving cancer treatment, new research shows.

An analysis of more than 15,000 adults with a cancer diagnosis revealed that nearly 80% were current drinkers. Among current drinkers, 13% consumed a moderate amount of alcohol in a typical day, while close to 40% engaged in hazardous drinking.

The numbers are “staggering,” Yin Cao, ScD, MPH, of Washington University in St. Louis, said in an interview. “Most concerning is that those on cancer treatment are engaged in a similar level of risky drinking.”

The study was published online in JAMA Network Open.

Drinking alcohol can increase a person’s risk for a variety of cancers, including oral and pharyngeal cancer as well as esophageal, colorectal, liver, and female breast cancers.

Consuming alcohol is also associated with numerous risks among people diagnosed with cancer. In the short term, alcohol consumption can worsen postsurgical outcomes as well as impair cognition and amplify cardiotoxicity in patients undergoing chemotherapy. In the long term, drinking alcohol can elevate a person’s risk of recurrence, secondary tumors, and mortality.

The American Society of Clinical Oncology recently issued a statement reinforcing the need to prioritize alcohol consumption as a key modifiable behavioral factor in the cancer control research agenda.

The current American Cancer Society guidelines indicate that it’s best to avoid or, at least, minimize alcohol consumption. Men should limit their intake to no more than two drinks per day and women should have no more than one drink per day.

Despite this data and guidelines, alcohol drinking patterns among cancer survivors in the United States remain poorly understood.

To explore further, the researchers identified 15,199 adult cancer survivors enrolled in the National Institutes of Health’s All of Us Research Program.

Overall, 78% of the cohort – more than 11,800 individuals – were current drinkers. In a typical day, 24% engaged in binge drinking – consuming six or more drinks on a single occasion – and 38% engaged in hazardous drinking. Using the Alcohol Use Disorders Identification Test–Consumption, the researchers classified hazardous drinking as scores of 4 or higher in men and 3 or higher in women.

Drinking patterns looked similar in the subset of 1,839 patients undergoing cancer treatment. In this group, 76% were current drinkers. Among current drinkers, 12% exceeded moderate drinking levels, 23% reported binge drinking, and 38% engaged in hazardous drinking. In this group, men, Hispanics, people diagnosed with cancer before age 18, and smokers were more likely to engage in risky drinking behaviors.

“We know that many people who are diagnosed with cancer continue to drink alcohol, but this study provides much more detailed information about that,” said Farhad Islami, MD, PhD, senior scientific director for cancer disparity research at the American Cancer Society, Atlanta, who was not involved in the study.

Given the degree of drinking identified in this population, Dr. Cao highlighted the importance of talking to patients about alcohol.

“Our findings highlight an opportunity for enhanced support and intervention concerning risky drinking behaviors” in oncology, Dr. Cao said. “Given the societal norms surrounding alcohol and the general lack of awareness of alcohol’s short- and long-term impact on cancer outcomes, gently educating patients/survivors about potential risks while understanding the cultural and societal contexts of drinking can make a difference.”

Dr. Islami agreed that oncologists should talk to their patients about alcohol, “especially those going through active treatment because alcohol may affect the treatment or may be associated with more complications of the treatment.”

“Many people now know that smoking causes cancer, but unfortunately, many people do not know about the association of alcohol with cancer,” he said.

Outside of an awareness gap, there are numerous risk factors for substance abuse among cancer survivors, Marleen Meyers, MD, director of the cancer survivorship program at NYU Langone Perlmutter Cancer Center, New York, explained.

Alcohol can help some cancer survivors dull feelings of isolation, fear, stress, and poor pain management that may accompany their diagnosis and treatment, said Dr. Meyers, who was not involved in the research. That is why “it is important for patients to be honest with their providers and for providers to ask about substance use in a nonjudgmental way.”

In these conversations, oncologists should educate patients about the safety risks associated with alcohol intake during or after treatment and that there is no established “safe” amount of alcohol. Incorporating a mental health screening and questions about a family history of substance abuse can also help identify patients “most at risk so providers can be proactive,” she said.

The study was supported by a grant from the NIH. Dr. Cao, Dr. Islami, and Dr. Meyers report no relevant financial relationships.

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

The results of a recent study in JAMA Oncology suggest that even short periods of intense, intermittent physical activity are associated with a lower risk for cancer. This activity could be a promising measure for cancer prevention in people who otherwise find it difficult to exercise regularly.

Periods of intense, intermittent physical activity are short phases of strenuous physical exercise that normally last for 1 or 2 minutes, such as a short sprint for the bus or walking up the stairs. In the prospective cohort study conducted in a large group of unathletic adults, researchers investigated a potential dose-effect relationship between intense and daily intermittent physical activity and the cancer incidence rate.

Using data gathered from wearable arm trackers, the researchers analyzed the physical activity of 22,398 people with an average age of 62 years from the UK Biobank. Of these participants, 54.8% were women. After a median follow-up of 6.7 years, corresponding to 149,650 person-years, they determined the general cancer incidence rate in this cohort and the incidence rate of 13 kinds of cancer associated with minimal physical activity (physical-activity related cancers).

Over the study period, 2,356 cancer events occurred, of which 1,084 could be attributed to kinds of cancer associated with minimal physical activity. Nearly all of the intense physical activity (92.3%) was achieved in bursts of up to 1 minute.
 

Four minutes

The daily duration of activity was almost linearly associated with the outcome, wrote Emmanuel Stamatakis, PhD, professor of physical activity, lifestyle, and population health at the University of Sydney. “The dose-effect curve was more vertical, and the extent of the risk reduction for kinds of cancer associated with minimal activity was larger than for the overall cancer incidence rate.”

For example, the lowest dose of intense, intermittent physical activity of up to 1 minute was generally 3.4 minutes per day for cancer in general and 3.7 minutes per day for cancer associated with minimal activity (hazard ratio, 0.83 and 0.72, respectively).

“The results of the study with an average follow-up time of almost 7 years suggest that people with a little less than 4 minutes per day of sporadic intense activity had an overall 17% lower risk of cancer,” wrote Yvonne Wengström, PhD, professor of nursing at Karolinska Institutet in Stockholm, in an accompanying editorial.

For kinds of cancer possibly associated with minimal activity, the researchers found the risk to be reduced by 28% through daily intermittent physical activity. “Even a few minutes of short, intense physical exercise in people with less leisure activity could lower their cancer risk,” wrote Dr. Wengström and colleagues.

Only at the end of 2022 did the data from Dr. Stamatakis and his colleagues suggest a correlation between a little more than 4 minutes of intense physical activity per day and a lower risk for cardiovascular diseases, cancer, and overall mortality in athletes and nonathletes.
 

Wearable arm trackers

The authors of the recent study used an existing cohort’s activity data from an earlier substudy of the UK Biobank that measured acceleration in the wrist. The movement behavior here was recorded over a period of 7 days in more than 90,000 people between 2013 and 2015.

Dr. Wengström and her colleagues rated the arm trackers to be more reliable than the questionnaires that were completed by the subjects. “One strength of the present study is that physical activity was evaluated with the help of wrist acceleration meters, even though nonathletes were defined using the questionnaire data.”

Information about the general lifestyle of healthy living people also had to be included. Dr. Wengström believes that the researchers succeeded in this, because they adjusted the analyses for the following important factors:

• Age.
• Sex.
• Body mass index.
• Level of education.
• Smoking status.
• Alcohol consumption.
• Duration of sleep.
• Fruit and vegetable consumption.
• Medication intake.
• Parental cancer history.

Clinical implications

According to Dr. Wengström, more studies are required to see whether the results of this study can also be transferred to patients who already have a cancer disease. This is because patients with cancer such as premenopausal and postmenopausal women with breast cancer diseases, who have different biologies and hormonal environments, are affected differently by physical activity.

However, physical activity does play a role in patients with cancer “since physical fitness improves muscle strength, cancer-related fatigue, and the survivors’ quality of life,” said Dr. Wengström. However, it is still important to find the correct amount of physical activity for each group of patients and for each patient. Nevertheless, “any physical activity is better than none,” wrote Dr. Wengström and her colleagues.

This article was translated from Medscape’s German edition. A version of this article appeared on Medscape.com.

The results of a recent study in JAMA Oncology suggest that even short periods of intense, intermittent physical activity are associated with a lower risk for cancer. This activity could be a promising measure for cancer prevention in people who otherwise find it difficult to exercise regularly.

Periods of intense, intermittent physical activity are short phases of strenuous physical exercise that normally last for 1 or 2 minutes, such as a short sprint for the bus or walking up the stairs. In the prospective cohort study conducted in a large group of unathletic adults, researchers investigated a potential dose-effect relationship between intense and daily intermittent physical activity and the cancer incidence rate.

Using data gathered from wearable arm trackers, the researchers analyzed the physical activity of 22,398 people with an average age of 62 years from the UK Biobank. Of these participants, 54.8% were women. After a median follow-up of 6.7 years, corresponding to 149,650 person-years, they determined the general cancer incidence rate in this cohort and the incidence rate of 13 kinds of cancer associated with minimal physical activity (physical-activity related cancers).

Over the study period, 2,356 cancer events occurred, of which 1,084 could be attributed to kinds of cancer associated with minimal physical activity. Nearly all of the intense physical activity (92.3%) was achieved in bursts of up to 1 minute.
 

Four minutes

The daily duration of activity was almost linearly associated with the outcome, wrote Emmanuel Stamatakis, PhD, professor of physical activity, lifestyle, and population health at the University of Sydney. “The dose-effect curve was more vertical, and the extent of the risk reduction for kinds of cancer associated with minimal activity was larger than for the overall cancer incidence rate.”

For example, the lowest dose of intense, intermittent physical activity of up to 1 minute was generally 3.4 minutes per day for cancer in general and 3.7 minutes per day for cancer associated with minimal activity (hazard ratio, 0.83 and 0.72, respectively).

“The results of the study with an average follow-up time of almost 7 years suggest that people with a little less than 4 minutes per day of sporadic intense activity had an overall 17% lower risk of cancer,” wrote Yvonne Wengström, PhD, professor of nursing at Karolinska Institutet in Stockholm, in an accompanying editorial.

For kinds of cancer possibly associated with minimal activity, the researchers found the risk to be reduced by 28% through daily intermittent physical activity. “Even a few minutes of short, intense physical exercise in people with less leisure activity could lower their cancer risk,” wrote Dr. Wengström and colleagues.

Only at the end of 2022 did the data from Dr. Stamatakis and his colleagues suggest a correlation between a little more than 4 minutes of intense physical activity per day and a lower risk for cardiovascular diseases, cancer, and overall mortality in athletes and nonathletes.
 

Wearable arm trackers

The authors of the recent study used an existing cohort’s activity data from an earlier substudy of the UK Biobank that measured acceleration in the wrist. The movement behavior here was recorded over a period of 7 days in more than 90,000 people between 2013 and 2015.

Dr. Wengström and her colleagues rated the arm trackers to be more reliable than the questionnaires that were completed by the subjects. “One strength of the present study is that physical activity was evaluated with the help of wrist acceleration meters, even though nonathletes were defined using the questionnaire data.”

Information about the general lifestyle of healthy living people also had to be included. Dr. Wengström believes that the researchers succeeded in this, because they adjusted the analyses for the following important factors:

• Age.
• Sex.
• Body mass index.
• Level of education.
• Smoking status.
• Alcohol consumption.
• Duration of sleep.
• Fruit and vegetable consumption.
• Medication intake.
• Parental cancer history.

Clinical implications

According to Dr. Wengström, more studies are required to see whether the results of this study can also be transferred to patients who already have a cancer disease. This is because patients with cancer such as premenopausal and postmenopausal women with breast cancer diseases, who have different biologies and hormonal environments, are affected differently by physical activity.

However, physical activity does play a role in patients with cancer “since physical fitness improves muscle strength, cancer-related fatigue, and the survivors’ quality of life,” said Dr. Wengström. However, it is still important to find the correct amount of physical activity for each group of patients and for each patient. Nevertheless, “any physical activity is better than none,” wrote Dr. Wengström and her colleagues.

This article was translated from Medscape’s German edition. A version of this article appeared on Medscape.com.

The results of a recent study in JAMA Oncology suggest that even short periods of intense, intermittent physical activity are associated with a lower risk for cancer. This activity could be a promising measure for cancer prevention in people who otherwise find it difficult to exercise regularly.

Periods of intense, intermittent physical activity are short phases of strenuous physical exercise that normally last for 1 or 2 minutes, such as a short sprint for the bus or walking up the stairs. In the prospective cohort study conducted in a large group of unathletic adults, researchers investigated a potential dose-effect relationship between intense and daily intermittent physical activity and the cancer incidence rate.

Using data gathered from wearable arm trackers, the researchers analyzed the physical activity of 22,398 people with an average age of 62 years from the UK Biobank. Of these participants, 54.8% were women. After a median follow-up of 6.7 years, corresponding to 149,650 person-years, they determined the general cancer incidence rate in this cohort and the incidence rate of 13 kinds of cancer associated with minimal physical activity (physical-activity related cancers).

Over the study period, 2,356 cancer events occurred, of which 1,084 could be attributed to kinds of cancer associated with minimal physical activity. Nearly all of the intense physical activity (92.3%) was achieved in bursts of up to 1 minute.
 

Four minutes

The daily duration of activity was almost linearly associated with the outcome, wrote Emmanuel Stamatakis, PhD, professor of physical activity, lifestyle, and population health at the University of Sydney. “The dose-effect curve was more vertical, and the extent of the risk reduction for kinds of cancer associated with minimal activity was larger than for the overall cancer incidence rate.”

For example, the lowest dose of intense, intermittent physical activity of up to 1 minute was generally 3.4 minutes per day for cancer in general and 3.7 minutes per day for cancer associated with minimal activity (hazard ratio, 0.83 and 0.72, respectively).

“The results of the study with an average follow-up time of almost 7 years suggest that people with a little less than 4 minutes per day of sporadic intense activity had an overall 17% lower risk of cancer,” wrote Yvonne Wengström, PhD, professor of nursing at Karolinska Institutet in Stockholm, in an accompanying editorial.

For kinds of cancer possibly associated with minimal activity, the researchers found the risk to be reduced by 28% through daily intermittent physical activity. “Even a few minutes of short, intense physical exercise in people with less leisure activity could lower their cancer risk,” wrote Dr. Wengström and colleagues.

Only at the end of 2022 did the data from Dr. Stamatakis and his colleagues suggest a correlation between a little more than 4 minutes of intense physical activity per day and a lower risk for cardiovascular diseases, cancer, and overall mortality in athletes and nonathletes.
 

Wearable arm trackers

The authors of the recent study used an existing cohort’s activity data from an earlier substudy of the UK Biobank that measured acceleration in the wrist. The movement behavior here was recorded over a period of 7 days in more than 90,000 people between 2013 and 2015.

Dr. Wengström and her colleagues rated the arm trackers to be more reliable than the questionnaires that were completed by the subjects. “One strength of the present study is that physical activity was evaluated with the help of wrist acceleration meters, even though nonathletes were defined using the questionnaire data.”

Information about the general lifestyle of healthy living people also had to be included. Dr. Wengström believes that the researchers succeeded in this, because they adjusted the analyses for the following important factors:

• Age.
• Sex.
• Body mass index.
• Level of education.
• Smoking status.
• Alcohol consumption.
• Duration of sleep.
• Fruit and vegetable consumption.
• Medication intake.
• Parental cancer history.

Clinical implications

According to Dr. Wengström, more studies are required to see whether the results of this study can also be transferred to patients who already have a cancer disease. This is because patients with cancer such as premenopausal and postmenopausal women with breast cancer diseases, who have different biologies and hormonal environments, are affected differently by physical activity.

However, physical activity does play a role in patients with cancer “since physical fitness improves muscle strength, cancer-related fatigue, and the survivors’ quality of life,” said Dr. Wengström. However, it is still important to find the correct amount of physical activity for each group of patients and for each patient. Nevertheless, “any physical activity is better than none,” wrote Dr. Wengström and her colleagues.

This article was translated from Medscape’s German edition. A version of this article appeared on Medscape.com.

People under the age of 50 are becoming more likely to be diagnosed with cancer, according to comprehensive new data.

From 2010 to 2019, the rate of cancer diagnoses rose from 100 to 103 cases per 100,000 people, according to the study, published in JAMA Network Open. The increases were driven by jumps in certain types of cancer and within specific age, racial, and ethnic groups. Researchers analyzed data for more than 560,000 people under age 50 who were diagnosed with cancer during the 9-year period.

Breast cancer remained the most common type of cancer to affect younger people, while the most striking increase was seen in gastrointestinal cancers. The rate of people with GI cancers rose 15%.

Women were more likely to be diagnosed with cancer, whereas the rate of cancer among men under age 50 declined by 5%. When the researchers analyzed the data based on a person’s race or ethnicity, they found that cancer rates were increasing among people who are Asian, Pacific Islander, Hispanic, American Indian, or Alaska Native. The rate of cancer among Black people declined and was steady among White people.

The only age group that saw cancer rates increase was 30- to 39-year-olds. One of the top concerns for younger people with cancer is that there is a greater risk for the cancer to spread.

The cancer rate has been declining among older people, the researchers noted. One doctor told The Washington Post that it’s urgent that the reasons for the increases among young people be understood.

“If we don’t understand what’s causing this risk and we can’t do something to change it, we’re afraid that as time goes on, it’s going to become a bigger and bigger challenge,” said Paul Oberstein, MD, director of the gastrointestinal medical oncology program at NYU Langone’s Perlmutter Cancer Center, New York. He was not involved in the study.

It’s unclear why cancer rates are rising among young people, but some possible reasons are obesity, alcohol use, smoking, poor sleep, sedentary lifestyle, and things in the environment like pollution and carcinogens, the Post reported.

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

People under the age of 50 are becoming more likely to be diagnosed with cancer, according to comprehensive new data.

From 2010 to 2019, the rate of cancer diagnoses rose from 100 to 103 cases per 100,000 people, according to the study, published in JAMA Network Open. The increases were driven by jumps in certain types of cancer and within specific age, racial, and ethnic groups. Researchers analyzed data for more than 560,000 people under age 50 who were diagnosed with cancer during the 9-year period.

Breast cancer remained the most common type of cancer to affect younger people, while the most striking increase was seen in gastrointestinal cancers. The rate of people with GI cancers rose 15%.

Women were more likely to be diagnosed with cancer, whereas the rate of cancer among men under age 50 declined by 5%. When the researchers analyzed the data based on a person’s race or ethnicity, they found that cancer rates were increasing among people who are Asian, Pacific Islander, Hispanic, American Indian, or Alaska Native. The rate of cancer among Black people declined and was steady among White people.

The only age group that saw cancer rates increase was 30- to 39-year-olds. One of the top concerns for younger people with cancer is that there is a greater risk for the cancer to spread.

The cancer rate has been declining among older people, the researchers noted. One doctor told The Washington Post that it’s urgent that the reasons for the increases among young people be understood.

“If we don’t understand what’s causing this risk and we can’t do something to change it, we’re afraid that as time goes on, it’s going to become a bigger and bigger challenge,” said Paul Oberstein, MD, director of the gastrointestinal medical oncology program at NYU Langone’s Perlmutter Cancer Center, New York. He was not involved in the study.

It’s unclear why cancer rates are rising among young people, but some possible reasons are obesity, alcohol use, smoking, poor sleep, sedentary lifestyle, and things in the environment like pollution and carcinogens, the Post reported.

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

People under the age of 50 are becoming more likely to be diagnosed with cancer, according to comprehensive new data.

From 2010 to 2019, the rate of cancer diagnoses rose from 100 to 103 cases per 100,000 people, according to the study, published in JAMA Network Open. The increases were driven by jumps in certain types of cancer and within specific age, racial, and ethnic groups. Researchers analyzed data for more than 560,000 people under age 50 who were diagnosed with cancer during the 9-year period.

Breast cancer remained the most common type of cancer to affect younger people, while the most striking increase was seen in gastrointestinal cancers. The rate of people with GI cancers rose 15%.

Women were more likely to be diagnosed with cancer, whereas the rate of cancer among men under age 50 declined by 5%. When the researchers analyzed the data based on a person’s race or ethnicity, they found that cancer rates were increasing among people who are Asian, Pacific Islander, Hispanic, American Indian, or Alaska Native. The rate of cancer among Black people declined and was steady among White people.

The only age group that saw cancer rates increase was 30- to 39-year-olds. One of the top concerns for younger people with cancer is that there is a greater risk for the cancer to spread.

The cancer rate has been declining among older people, the researchers noted. One doctor told The Washington Post that it’s urgent that the reasons for the increases among young people be understood.

“If we don’t understand what’s causing this risk and we can’t do something to change it, we’re afraid that as time goes on, it’s going to become a bigger and bigger challenge,” said Paul Oberstein, MD, director of the gastrointestinal medical oncology program at NYU Langone’s Perlmutter Cancer Center, New York. He was not involved in the study.

It’s unclear why cancer rates are rising among young people, but some possible reasons are obesity, alcohol use, smoking, poor sleep, sedentary lifestyle, and things in the environment like pollution and carcinogens, the Post reported.

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

For carefully selected patients with colorectal cancer (CRC), a liver transplant may offer long-term survival and potentially even cure unresectable liver metastases.

Findings from a Norwegian review of 61 patients who had liver transplants for unresectable colorectal liver metastases found half of patients were still alive at 5 years, and about one in five appeared to be cured at 10 years.

“It seems likely that there is a small group of patients with unresectable colorectal liver metastases who should be considered for transplant, and long-term survival and possibly cure are achievable in these patients with appropriate selection,” Ryan Ellis, MD, and Michael D’Angelica, MD, wrote in a commentary published alongside the study in JAMA Surgery.

The core question, however, is how to identify patients who will benefit the most from a liver transplant, said Dr. Ellis and Dr. D’Angelica, both surgical oncologists in the Hepatopancreatobiliary Service at Memorial Sloan Kettering Cancer Center, New York. Looking closely at who did well in this analysis can offer clues to appropriate patient selection, the editorialists said.

Three decades ago, the oncology community had largely abandoned liver transplant in this population after studies showed overall 5-year survival of less than 20%. Some patients, however, did better, which prompted the Norwegian investigators to attempt to refine patient selection.

In the current prospective nonrandomized study, 61 patients had liver transplants for unresectable metastases at Oslo University Hospital from 2006 to 2020.

The researchers reported a median overall survival of 60.3 months, with about half of patients (50.4%) alive at 5 years.

Most patients (78.3%) experienced a relapse after liver transplant, with a median time to relapse of 9 months and with most occurring within 2 years of transplant. Median overall survival from time of relapse was 37.1 months, with 5-year survival at nearly 35% in this group and with one patient still alive 156 months after relapse.

The remaining 21.7% of patients (n = 13) did not experience a relapse post-transplant at their last follow-up.

Given the variety of responses to liver transplant, how can experts differentiate patients who will benefit most from those who won’t?

The researchers looked at several factors, including Oslo score and Fong Clinical Risk Score. The Oslo score assesses overall survival among liver transplant patients, while the Fong score predicts recurrence risk for patients with CRC liver metastasis following resection. These scores assign one point for each adverse prognostic factor.

Among the 10 patients who had an Oslo Score of 0, median overall survival was 151.6 months, and the 5-year and 10-year survival rates reached nearly 89%. Among the 27 patients with an Oslo Score of 1, median overall survival was 60.3 months, and 5-year overall survival was 54.7%. No patients with an Oslo score of 4 lived for 5 years.

As for FCRS, median overall survival was 164.9 months among those with a score of 1, 90.5 months among those with a score of 2, 59.9 months for those with a score of 3, 32.8 months for those with a score of 4, and 25.3 months for those with the highest score of 5 (P < .001). Overall, these patients had 5-year overall survival of 100%, 63.9%, 49.4%, 33.3%, and 0%, respectively.

In addition to Oslo and Fong scores, metabolic tumor volume on PET scan (PET-MTV) was also a good prognostic factor for survival. Among the 40 patients with MTV values less than 70 cm³, median 5-year overall survival was nearly 67%, while those with values above 70 cm³ had a median 5-year overall survival of 23.3%.

Additional harbingers of low 5-year survival, in addition to higher Oslo and Fong scores and PET-MTV above 70 cm³, included a tumor size greater than 5.5 cm, progressive disease while receiving chemotherapy, primary tumors in the ascending colon, tumor burden scores of 9 or higher, and nine or more liver lesions.

Overall, the current analysis can help oncologists identify patients who may benefit from a liver transplant.

The findings indicate that “patients with liver-only metastases and favorable pretransplant prognostic scoring [have] long-term survival comparable with conventional indications for liver transplant, thus providing a potential curative treatment option in patients otherwise offered only palliative care,” said investigators led by Svein Dueland, MD, PhD, a member of the Transplant Oncology Research Group at Oslo University Hospital.

Perhaps “the most compelling argument in favor of liver transplant lies in the likely curative potential evidenced by the 13 disease-free patients,” Dr. Ellis and Dr. D’Angelica wrote.

But even some patients who had early recurrences did well following transplant. The investigators noted that early recurrences in this population aren’t as dire as in other settings because they generally manifest as slow growing lung metastases that can be caught early and resected with curative intent.

A major hurdle to broader use of liver transplants in this population is the scarcity of donor grafts. To manage demand, the investigators suggested “extended-criteria donor grafts” – grafts that don’t meet ideal criteria – and the use of the RAPID technique for liver transplant, which opens the door to using one graft for two patients and using living donors with low risk to the donor.

Another challenge will be identifying patients with unresectable colorectal liver metastases who may experience long-term survival following transplant and possibly a cure. “We all will need to keep a sharp eye out for these patients – they might be hard to find!” Dr. Ellis and Dr. D’Angelica wrote.

The study was supported by Oslo University Hospital, the Norwegian Cancer Society, and South-Eastern Norway Regional Health Authority. The investigators and editorialists report no relevant financial relationships.

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

For carefully selected patients with colorectal cancer (CRC), a liver transplant may offer long-term survival and potentially even cure unresectable liver metastases.

Findings from a Norwegian review of 61 patients who had liver transplants for unresectable colorectal liver metastases found half of patients were still alive at 5 years, and about one in five appeared to be cured at 10 years.

“It seems likely that there is a small group of patients with unresectable colorectal liver metastases who should be considered for transplant, and long-term survival and possibly cure are achievable in these patients with appropriate selection,” Ryan Ellis, MD, and Michael D’Angelica, MD, wrote in a commentary published alongside the study in JAMA Surgery.

The core question, however, is how to identify patients who will benefit the most from a liver transplant, said Dr. Ellis and Dr. D’Angelica, both surgical oncologists in the Hepatopancreatobiliary Service at Memorial Sloan Kettering Cancer Center, New York. Looking closely at who did well in this analysis can offer clues to appropriate patient selection, the editorialists said.

Three decades ago, the oncology community had largely abandoned liver transplant in this population after studies showed overall 5-year survival of less than 20%. Some patients, however, did better, which prompted the Norwegian investigators to attempt to refine patient selection.

In the current prospective nonrandomized study, 61 patients had liver transplants for unresectable metastases at Oslo University Hospital from 2006 to 2020.

The researchers reported a median overall survival of 60.3 months, with about half of patients (50.4%) alive at 5 years.

Most patients (78.3%) experienced a relapse after liver transplant, with a median time to relapse of 9 months and with most occurring within 2 years of transplant. Median overall survival from time of relapse was 37.1 months, with 5-year survival at nearly 35% in this group and with one patient still alive 156 months after relapse.

The remaining 21.7% of patients (n = 13) did not experience a relapse post-transplant at their last follow-up.

Given the variety of responses to liver transplant, how can experts differentiate patients who will benefit most from those who won’t?

The researchers looked at several factors, including Oslo score and Fong Clinical Risk Score. The Oslo score assesses overall survival among liver transplant patients, while the Fong score predicts recurrence risk for patients with CRC liver metastasis following resection. These scores assign one point for each adverse prognostic factor.

Among the 10 patients who had an Oslo Score of 0, median overall survival was 151.6 months, and the 5-year and 10-year survival rates reached nearly 89%. Among the 27 patients with an Oslo Score of 1, median overall survival was 60.3 months, and 5-year overall survival was 54.7%. No patients with an Oslo score of 4 lived for 5 years.

As for FCRS, median overall survival was 164.9 months among those with a score of 1, 90.5 months among those with a score of 2, 59.9 months for those with a score of 3, 32.8 months for those with a score of 4, and 25.3 months for those with the highest score of 5 (P < .001). Overall, these patients had 5-year overall survival of 100%, 63.9%, 49.4%, 33.3%, and 0%, respectively.

In addition to Oslo and Fong scores, metabolic tumor volume on PET scan (PET-MTV) was also a good prognostic factor for survival. Among the 40 patients with MTV values less than 70 cm³, median 5-year overall survival was nearly 67%, while those with values above 70 cm³ had a median 5-year overall survival of 23.3%.

Additional harbingers of low 5-year survival, in addition to higher Oslo and Fong scores and PET-MTV above 70 cm³, included a tumor size greater than 5.5 cm, progressive disease while receiving chemotherapy, primary tumors in the ascending colon, tumor burden scores of 9 or higher, and nine or more liver lesions.

Overall, the current analysis can help oncologists identify patients who may benefit from a liver transplant.

The findings indicate that “patients with liver-only metastases and favorable pretransplant prognostic scoring [have] long-term survival comparable with conventional indications for liver transplant, thus providing a potential curative treatment option in patients otherwise offered only palliative care,” said investigators led by Svein Dueland, MD, PhD, a member of the Transplant Oncology Research Group at Oslo University Hospital.

Perhaps “the most compelling argument in favor of liver transplant lies in the likely curative potential evidenced by the 13 disease-free patients,” Dr. Ellis and Dr. D’Angelica wrote.

But even some patients who had early recurrences did well following transplant. The investigators noted that early recurrences in this population aren’t as dire as in other settings because they generally manifest as slow growing lung metastases that can be caught early and resected with curative intent.

A major hurdle to broader use of liver transplants in this population is the scarcity of donor grafts. To manage demand, the investigators suggested “extended-criteria donor grafts” – grafts that don’t meet ideal criteria – and the use of the RAPID technique for liver transplant, which opens the door to using one graft for two patients and using living donors with low risk to the donor.

Another challenge will be identifying patients with unresectable colorectal liver metastases who may experience long-term survival following transplant and possibly a cure. “We all will need to keep a sharp eye out for these patients – they might be hard to find!” Dr. Ellis and Dr. D’Angelica wrote.

The study was supported by Oslo University Hospital, the Norwegian Cancer Society, and South-Eastern Norway Regional Health Authority. The investigators and editorialists report no relevant financial relationships.

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

For carefully selected patients with colorectal cancer (CRC), a liver transplant may offer long-term survival and potentially even cure unresectable liver metastases.

Findings from a Norwegian review of 61 patients who had liver transplants for unresectable colorectal liver metastases found half of patients were still alive at 5 years, and about one in five appeared to be cured at 10 years.

“It seems likely that there is a small group of patients with unresectable colorectal liver metastases who should be considered for transplant, and long-term survival and possibly cure are achievable in these patients with appropriate selection,” Ryan Ellis, MD, and Michael D’Angelica, MD, wrote in a commentary published alongside the study in JAMA Surgery.

The core question, however, is how to identify patients who will benefit the most from a liver transplant, said Dr. Ellis and Dr. D’Angelica, both surgical oncologists in the Hepatopancreatobiliary Service at Memorial Sloan Kettering Cancer Center, New York. Looking closely at who did well in this analysis can offer clues to appropriate patient selection, the editorialists said.

Three decades ago, the oncology community had largely abandoned liver transplant in this population after studies showed overall 5-year survival of less than 20%. Some patients, however, did better, which prompted the Norwegian investigators to attempt to refine patient selection.

In the current prospective nonrandomized study, 61 patients had liver transplants for unresectable metastases at Oslo University Hospital from 2006 to 2020.

The researchers reported a median overall survival of 60.3 months, with about half of patients (50.4%) alive at 5 years.

Most patients (78.3%) experienced a relapse after liver transplant, with a median time to relapse of 9 months and with most occurring within 2 years of transplant. Median overall survival from time of relapse was 37.1 months, with 5-year survival at nearly 35% in this group and with one patient still alive 156 months after relapse.

The remaining 21.7% of patients (n = 13) did not experience a relapse post-transplant at their last follow-up.

Given the variety of responses to liver transplant, how can experts differentiate patients who will benefit most from those who won’t?

The researchers looked at several factors, including Oslo score and Fong Clinical Risk Score. The Oslo score assesses overall survival among liver transplant patients, while the Fong score predicts recurrence risk for patients with CRC liver metastasis following resection. These scores assign one point for each adverse prognostic factor.

Among the 10 patients who had an Oslo Score of 0, median overall survival was 151.6 months, and the 5-year and 10-year survival rates reached nearly 89%. Among the 27 patients with an Oslo Score of 1, median overall survival was 60.3 months, and 5-year overall survival was 54.7%. No patients with an Oslo score of 4 lived for 5 years.

As for FCRS, median overall survival was 164.9 months among those with a score of 1, 90.5 months among those with a score of 2, 59.9 months for those with a score of 3, 32.8 months for those with a score of 4, and 25.3 months for those with the highest score of 5 (P < .001). Overall, these patients had 5-year overall survival of 100%, 63.9%, 49.4%, 33.3%, and 0%, respectively.

In addition to Oslo and Fong scores, metabolic tumor volume on PET scan (PET-MTV) was also a good prognostic factor for survival. Among the 40 patients with MTV values less than 70 cm³, median 5-year overall survival was nearly 67%, while those with values above 70 cm³ had a median 5-year overall survival of 23.3%.

Additional harbingers of low 5-year survival, in addition to higher Oslo and Fong scores and PET-MTV above 70 cm³, included a tumor size greater than 5.5 cm, progressive disease while receiving chemotherapy, primary tumors in the ascending colon, tumor burden scores of 9 or higher, and nine or more liver lesions.

Overall, the current analysis can help oncologists identify patients who may benefit from a liver transplant.

The findings indicate that “patients with liver-only metastases and favorable pretransplant prognostic scoring [have] long-term survival comparable with conventional indications for liver transplant, thus providing a potential curative treatment option in patients otherwise offered only palliative care,” said investigators led by Svein Dueland, MD, PhD, a member of the Transplant Oncology Research Group at Oslo University Hospital.

Perhaps “the most compelling argument in favor of liver transplant lies in the likely curative potential evidenced by the 13 disease-free patients,” Dr. Ellis and Dr. D’Angelica wrote.

But even some patients who had early recurrences did well following transplant. The investigators noted that early recurrences in this population aren’t as dire as in other settings because they generally manifest as slow growing lung metastases that can be caught early and resected with curative intent.

A major hurdle to broader use of liver transplants in this population is the scarcity of donor grafts. To manage demand, the investigators suggested “extended-criteria donor grafts” – grafts that don’t meet ideal criteria – and the use of the RAPID technique for liver transplant, which opens the door to using one graft for two patients and using living donors with low risk to the donor.

Another challenge will be identifying patients with unresectable colorectal liver metastases who may experience long-term survival following transplant and possibly a cure. “We all will need to keep a sharp eye out for these patients – they might be hard to find!” Dr. Ellis and Dr. D’Angelica wrote.

The study was supported by Oslo University Hospital, the Norwegian Cancer Society, and South-Eastern Norway Regional Health Authority. The investigators and editorialists report no relevant financial relationships.

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

Ethylene oxide is a compound used to sterilize more than 20 billion devices sold in the U.S. every year. Although this sterilization process helps keep medical devices – and patients – safe, the odorless, flammable gas may also be harming people who live near sterilization plants and who may inhale the compound, which has been linked to an elevated risk of cancer.

Regulatory agencies are currently feuding over the best way to address the dilemma: preserving patient safety versus protecting public health. Lawmakers are weighing in on the matter, which has been the source of multiple civil lawsuits filed by individuals who say they have suffered health problems as a result of exposure to ethylene oxide.

The Environmental Protection Agency and the U.S. Food and Drug Administration agree that use of the compound should be limited, but they are at odds about how quickly limits should be put in place, according to Axios.

A new commercial standard for ethylene oxide proposed by the EPA in April would impose stricter emission restrictions for sterilization facilities and chemical plants – a move that would cut ethylene oxide emissions by 80%, the EPA estimates.

While the FDA says it “shares concerns about the release of ethylene oxide at unsafe levels into the environment,” the agency cautions that moving too fast to cut emissions would disrupt the medical supply chain, which is already experiencing turbulence. The U.S. has been facing the worst drug supply shortages in a decade in addition to severe medical device shortages.

Currently, other methods of sterilization cannot replace the use of ethylene oxide for many devices. Ethylene oxide is used to sterilize about half of all medical devices in the U.S., the FDA says. Given the country’s reliance on this compound for sterilization, the FDA says it is “equally concerned about the potential impact of shortages of sterilized medical devices that would result from disruptions in commercial sterilizer facility operations.”

In 2019, Illinois temporarily closed a sterilization facility over concern regarding ethylene oxide emissions. The closure caused a shortage of a pediatric breathing tube.

Some lawmakers agree that an Interior-Environment bill would require FDA certification that any action by the EPA would not cause a medical device shortage.

The FDA has been working to identify safe alternatives to ethylene oxide for sterilizing medical supplies as well as strategies to reduce emissions of ethylene oxide by capturing the gas or by turning it into a harmless byproduct. In 2019, the FDA launched a pilot program to incentivize companies to develop new sterilization technologies.

“The FDA remains focused in our commitment to encourage novel ways to sterilize medical devices while reducing adverse impacts on the environment and public health and developing solutions to avoid potential shortages of devices that the American public relies upon,” the agency said.

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

Ethylene oxide is a compound used to sterilize more than 20 billion devices sold in the U.S. every year. Although this sterilization process helps keep medical devices – and patients – safe, the odorless, flammable gas may also be harming people who live near sterilization plants and who may inhale the compound, which has been linked to an elevated risk of cancer.

Regulatory agencies are currently feuding over the best way to address the dilemma: preserving patient safety versus protecting public health. Lawmakers are weighing in on the matter, which has been the source of multiple civil lawsuits filed by individuals who say they have suffered health problems as a result of exposure to ethylene oxide.

The Environmental Protection Agency and the U.S. Food and Drug Administration agree that use of the compound should be limited, but they are at odds about how quickly limits should be put in place, according to Axios.

A new commercial standard for ethylene oxide proposed by the EPA in April would impose stricter emission restrictions for sterilization facilities and chemical plants – a move that would cut ethylene oxide emissions by 80%, the EPA estimates.

While the FDA says it “shares concerns about the release of ethylene oxide at unsafe levels into the environment,” the agency cautions that moving too fast to cut emissions would disrupt the medical supply chain, which is already experiencing turbulence. The U.S. has been facing the worst drug supply shortages in a decade in addition to severe medical device shortages.

Currently, other methods of sterilization cannot replace the use of ethylene oxide for many devices. Ethylene oxide is used to sterilize about half of all medical devices in the U.S., the FDA says. Given the country’s reliance on this compound for sterilization, the FDA says it is “equally concerned about the potential impact of shortages of sterilized medical devices that would result from disruptions in commercial sterilizer facility operations.”

In 2019, Illinois temporarily closed a sterilization facility over concern regarding ethylene oxide emissions. The closure caused a shortage of a pediatric breathing tube.

Some lawmakers agree that an Interior-Environment bill would require FDA certification that any action by the EPA would not cause a medical device shortage.

The FDA has been working to identify safe alternatives to ethylene oxide for sterilizing medical supplies as well as strategies to reduce emissions of ethylene oxide by capturing the gas or by turning it into a harmless byproduct. In 2019, the FDA launched a pilot program to incentivize companies to develop new sterilization technologies.

“The FDA remains focused in our commitment to encourage novel ways to sterilize medical devices while reducing adverse impacts on the environment and public health and developing solutions to avoid potential shortages of devices that the American public relies upon,” the agency said.

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

Ethylene oxide is a compound used to sterilize more than 20 billion devices sold in the U.S. every year. Although this sterilization process helps keep medical devices – and patients – safe, the odorless, flammable gas may also be harming people who live near sterilization plants and who may inhale the compound, which has been linked to an elevated risk of cancer.

Regulatory agencies are currently feuding over the best way to address the dilemma: preserving patient safety versus protecting public health. Lawmakers are weighing in on the matter, which has been the source of multiple civil lawsuits filed by individuals who say they have suffered health problems as a result of exposure to ethylene oxide.

The Environmental Protection Agency and the U.S. Food and Drug Administration agree that use of the compound should be limited, but they are at odds about how quickly limits should be put in place, according to Axios.

A new commercial standard for ethylene oxide proposed by the EPA in April would impose stricter emission restrictions for sterilization facilities and chemical plants – a move that would cut ethylene oxide emissions by 80%, the EPA estimates.

While the FDA says it “shares concerns about the release of ethylene oxide at unsafe levels into the environment,” the agency cautions that moving too fast to cut emissions would disrupt the medical supply chain, which is already experiencing turbulence. The U.S. has been facing the worst drug supply shortages in a decade in addition to severe medical device shortages.

Currently, other methods of sterilization cannot replace the use of ethylene oxide for many devices. Ethylene oxide is used to sterilize about half of all medical devices in the U.S., the FDA says. Given the country’s reliance on this compound for sterilization, the FDA says it is “equally concerned about the potential impact of shortages of sterilized medical devices that would result from disruptions in commercial sterilizer facility operations.”

In 2019, Illinois temporarily closed a sterilization facility over concern regarding ethylene oxide emissions. The closure caused a shortage of a pediatric breathing tube.

Some lawmakers agree that an Interior-Environment bill would require FDA certification that any action by the EPA would not cause a medical device shortage.

The FDA has been working to identify safe alternatives to ethylene oxide for sterilizing medical supplies as well as strategies to reduce emissions of ethylene oxide by capturing the gas or by turning it into a harmless byproduct. In 2019, the FDA launched a pilot program to incentivize companies to develop new sterilization technologies.

“The FDA remains focused in our commitment to encourage novel ways to sterilize medical devices while reducing adverse impacts on the environment and public health and developing solutions to avoid potential shortages of devices that the American public relies upon,” the agency said.

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

Providing access to clinical trials for veteran and active-duty military patients can be a challenge, but many trials are now recruiting patients from those populations. Some trials explicitly recruit patients seeking care at the US Department of Veterans Affairs (VA), US Department of Defense (DoD) Military Health System, and Indian Health Service. The VA Office of Research and Development alone supported > 7260 research projects in 2022, and many more are sponsored by Walter Reed National Medical Center and other major defense and VA facilities. The clinical trials listed below are all open as of July 20, 2023; have at least 1 VA or DoD location recruiting patients; and are focused on treatments for lymphoma, leukemia, and esophageal cancer. For additional information and full inclusion/exclusion criteria, please consult clinicaltrials.gov.

Lymphoma

Study of a Triple Combination Therapy, DTRM-555, in Patients With R/R CLL or R/R Non-Hodgkin’s Lymphomas

Targeted drug therapies have greatly improved outcomes for patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma. However, single drug therapies have limitations, therefore, the current study is evaluating a novel oral combination of targeted drugs as a way of overcoming these limitations. This study will determine the efficacy of the triple combination therapy, DTRM-555, in patients with R/R CLL or R/R non-Hodgkin’s lymphoma.

ID: NCT04305444

Sponsor: Zhejiang DTRM Biopharma

Locations: 8 locations, including Memphis VA Medical Center

Randomized Phase IIB Trial of Oral Azacytidine Plus Romidepsin Versus Investigator’s Choice in PTCL (PTCL)

Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of non-Hodgkin lymphoma (NHL) originating from mature (or post-thymic or ‘peripheral’) T-lymphocytes and NK cells. They are considered very aggressive and are often resistant to conventional chemotherapy.

This study employs a stratified randomization with equal allocation within strata of patients to receive oral 5-azacytidine (AZA) plus romidepsin (ROMI) versus prespecified investigator choice (ROMI, belinostat, pralatrexate or gemcitabine), for the treatment of relapsed or refractory (R/R) PTCL. The dose and schedule of AZA/ROMI has been determined from a phase I clinical trial of the combination. The primary objective of this study is to estimate the progression-free survival (PFS) among patients receiving the combination compared to single agent of choice.

ID: NCT04747236

Sponsor: Collaborator: University of Virginia; Celgene

Locations: 4 locations, including VA Long Beach Health Care System

Connect® Lymphoma Disease Registry: A US-Based Prospective Observational Cohort Study

This Disease Registry is designed to capture the patient characteristics, practice patterns, and therapeutic strategies evaluated in community and academic centers when treating relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), and R/R follicular lymphoma (FL). The data collected in this Registry will facilitate the evaluation of the current treatment landscape for non-Hodgkin lymphoma (NHL), including the clinical effectiveness, safety. No investigational product or drug will be administered as part of this study. Enrolled patients will receive treatment and evaluations for their disease according to the standard of care and routine clinical practice at each study site. All treatments that patients receive for their disease will be recorded, including any previous lymphoma treatments. Clinical outcomes will be documented as part of an objective clinical assessment. In addition, patient-reported health-related quality of life (HRQoL) outcomes data will be collected from patients using various validated instruments. Social support data will also be collected.

ID: NCT04982471

Sponsor: Celgene

Locations: 60 locations, including VA Central California Health Care System, Harry S. Truman Memorial Veterans’ Hospital, and Brooke Army Medical Center

Obinutuzumab With or Without Umbralisib,Lenalidomide, or Combination Chemotherapy in Treating Patients With Relapsed or Refractory Grade I-IIIa Follicular Lymphoma

This phase II trial studies how well obinutuzumab with or without umbralisib, lenalidomide, or combination chemotherapy work in treating patients with grade I-IIIa follicular lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Immunotherapy with obinutuzumab, may induce changes in the body’s immune system and may interfere with the ability of tumor cells to grow and spread. Umbralisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Biological therapies, such as lenalidomide, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Chemotherapy drugs, such as cyclophosphamide, doxorubicin, vincristine, prednisone, and bendamustine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving obinutuzumab with or without umbralisib, lenalidomide, or combination chemotherapy will work better in treating patients with grade I-IIIa follicular lymphoma.

ID: NCT03269669

Sponsor: National Cancer Institute (NCI)

Locations: 427 locations, including VA Palo Alto Health Care System

Brentuximab Vedotin and Nivolumab With or Without Ipilimumab in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma

This phase I/II trial studies the side effects and best dose of ipilimumab and nivolumab when given together with brentuximab vedotin, and how well they work in treating patients with Hodgkin lymphoma that has returned after a period of improvement (recurrent) or has not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body’s immune system attack the cancer and may interfere with the ability of cancer cells to grow and spread. Brentuximab vedotin is a monoclonal antibody, brentuximab, linked to a toxic agent called vedotin. Brentuximab attaches to CD30-positive cancer cells in a targeted way and delivers vedotin to kill them. It is not known whether giving brentuximab vedotin and nivolumab with or without ipilimumab may kill more cancer cells.

ID: NCT01896999

Sponsor: National Cancer Institute (NCI)

Locations: 486 locations, including Walter Reed National Military Medical Center

Testing Early Treatment for Patients With High-Risk Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Leukemia (SLL), EVOLVE CLL/SLL Study

This phase III trial compares early treatment with venetoclax and obinutuzumab versus delayed treatment with venetoclax and obinutuzumab in patients with newly diagnosed high-risk chronic lymphocytic leukemia or small lymphocytic lymphoma. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Immunotherapy with monoclonal antibodies, such as obinutuzumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Starting treatment with the venetoclax and obinutuzumab early (before patients have symptoms) may have better outcomes for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma compared to starting treatment with the venetoclax and obinutuzumab after patients show symptoms.

ID: NCT04269902

Sponsor: National Cancer Institute (NCI)

Locations: 545 locations, Tibor Rubin VA Medical Center, Minneapolis VA Medical Center, and Durham VA Medical Center

Testing the Use of Steroids and TyrosineKinase Inhibitors With Blinatumomab or Chemotherapy for Newly Diagnosed BCR-ABL-Positive Acute Lymphoblastic Leukemia in Adults

This phase III trial compares the effect of usual treatment of chemotherapy and steroids and a tyrosine kinase inhibitor (TKI) to the same treatment plus blinatumomab. Blinatumomab is a Bi-specific T-cell Engager (‘BiTE’) that may interfere with the ability of cancer cells to grow and spread. The information gained from this study may help researchers determine if combination therapy with steroids, TKIs, and blinatumomab work better than the standard of care.

ID: NCT04530565

Sponsor: National Cancer Institute (NCI)

Locations: 180 locations, including Walter Reed National Military Medical Center

Asciminib Monotherapy, With Dose Escalation, for 2nd and 1st Line Chronic Myelogenous Leukemia (ASC2ESCALATE)

This will be a multicenter Phase II open-label study of asciminib in CML-CP patients who have been previously treated with one prior ATP-binding site TKI with discontinuation due to treatment failure, warning or intolerance. (2L patient cohort). In addition, newly diagnosed CML-CP patients who may have received up to 4 weeks of prior TKI are included in a separate 1L patient cohort.

ID: NCT05384587

Sponsor: Novartis

Locations: 26 locations, including VA Puget Sound Health Care System

Connect® Myeloid Disease Registry

This Disease Registry will collect data on patient characteristics, treatment patterns and clinical outcomes. The objective is to describe how patients with myeloid diseases are treated; and to build a knowledge base regarding the effectiveness and safety of first-line and subsequent treatment regimens in both community and academic settings. Enrolled patients will receive treatment and evaluations for their disease according to the standard of care and routine clinical practice at each study site. All treatments that patients receive for their disease will be recorded, including initial treatment and any subsequent therapy. Data on treatment outcomes, including response rates as measured by the treating physician, evidence of progression, survival, and patient-reported outcomes will be collected quarterly on the electronic CRF.

ID: NCT01688011

Sponsor: Celgene

Locations: 240 locations, including VA Central California Health Care System, John D. Dingell VA Medical Center, Manchester VA Medical Center, Dallas VA Medical Center, White River Junction VA Medical Center, and VA Caribbean Healthcare System

Esophageal Cancer

Non-endoscopic Esophageal Sampling to Detect Barrett’s Esophagus and Esophageal Cancer in Veterans

This study seeks to incorporate non-endoscopic detection method (Esocheck/Esoguard) in primary care practice and test whether this screening modality increases the positive predictive value of upper endoscopy and increases the detection of Barrett’s esophagus and esophageal cancer.

Currently, BE is diagnosed only when patients undergo endoscopy with esophagogastroduodenoscopy (EGD). However, due to the high cost of EGD and the lack of a randomized controlled trials supporting its efficacy, endoscopy to screen for BE is not routinely recommended. Current guidelines do recommend sedated EGD in patients with multiple BE risk factors, refractory GERD, or alarm symptoms. This strategy fails to detect BE in patients whose symptoms are well controlled with either over the counter medications or physician prescribed therapies. It also fails to detect BE in asymptomatic subjects who comprise 40% of those that develop EAC. Thus, < 10% of EACs are diagnosed as early stage lesions caught by surveillance of patients with previously detected BE. Ablative nonsurgical therapies that have been developed for preventing cancer in patients with BE with high-grade dysplasia over the past decade will have little impact and the 5-year survival for EACs will remain a dismal 18% unless more effective programs for identifying BE and early EAC are developed.

Esocheck/Esoguard is a FDA approved device designed to sample the distal esophagus and analyze the collected material for presence of two methylated DNA markers. The Specific Aims of this study are:

To determine sensitivity, specificity, positive and negative predictive value of Esocheck/Esoguard performed in routine practice for detecting BE in an at risk Veteran population

To compare the yield of detected BE using EGD alone vs. stepwise molecular diagnostics(Esocheck/Esoguard) and endoscopic screening strategy (EGD) in at risk Veteran population.

ID: NCT05210049

Sponsor: Cleveland VA Medical Research and Education Foundation

Location: Louis Stokes Cleveland VA Medical Center

Progression of Gastroesophageal Reflux Disease and Barrett’s Esophagus and the Creation of a Barrett’s Registry

The purpose of this study is to determine or evaluate the risk factors such as smoking, family history etc. that cause esophageal cancer and to determine the genetic changes that lead to esophageal cancer. The investigators hypothesis is that systematic collection of data on the natural history of GERD and BE patients and risk factors for development of BE in patients with chronic GERD and progression of BE to dysplasia and adenocarcinoma will provide useful information to develop a decision model for risk stratification and risk reduction strategies in these patients.

ID: NCT00574327

Sponsor: Midwest Biomedical Research Foundation

Location: Kansas City VA Medical Center

Providing access to clinical trials for veteran and active-duty military patients can be a challenge, but many trials are now recruiting patients from those populations. Some trials explicitly recruit patients seeking care at the US Department of Veterans Affairs (VA), US Department of Defense (DoD) Military Health System, and Indian Health Service. The VA Office of Research and Development alone supported > 7260 research projects in 2022, and many more are sponsored by Walter Reed National Medical Center and other major defense and VA facilities. The clinical trials listed below are all open as of July 20, 2023; have at least 1 VA or DoD location recruiting patients; and are focused on treatments for lymphoma, leukemia, and esophageal cancer. For additional information and full inclusion/exclusion criteria, please consult clinicaltrials.gov.

Lymphoma

Study of a Triple Combination Therapy, DTRM-555, in Patients With R/R CLL or R/R Non-Hodgkin’s Lymphomas

Targeted drug therapies have greatly improved outcomes for patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma. However, single drug therapies have limitations, therefore, the current study is evaluating a novel oral combination of targeted drugs as a way of overcoming these limitations. This study will determine the efficacy of the triple combination therapy, DTRM-555, in patients with R/R CLL or R/R non-Hodgkin’s lymphoma.

ID: NCT04305444

Sponsor: Zhejiang DTRM Biopharma

Locations: 8 locations, including Memphis VA Medical Center

Randomized Phase IIB Trial of Oral Azacytidine Plus Romidepsin Versus Investigator’s Choice in PTCL (PTCL)

Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of non-Hodgkin lymphoma (NHL) originating from mature (or post-thymic or ‘peripheral’) T-lymphocytes and NK cells. They are considered very aggressive and are often resistant to conventional chemotherapy.

This study employs a stratified randomization with equal allocation within strata of patients to receive oral 5-azacytidine (AZA) plus romidepsin (ROMI) versus prespecified investigator choice (ROMI, belinostat, pralatrexate or gemcitabine), for the treatment of relapsed or refractory (R/R) PTCL. The dose and schedule of AZA/ROMI has been determined from a phase I clinical trial of the combination. The primary objective of this study is to estimate the progression-free survival (PFS) among patients receiving the combination compared to single agent of choice.

ID: NCT04747236

Sponsor: Collaborator: University of Virginia; Celgene

Locations: 4 locations, including VA Long Beach Health Care System

Connect® Lymphoma Disease Registry: A US-Based Prospective Observational Cohort Study

This Disease Registry is designed to capture the patient characteristics, practice patterns, and therapeutic strategies evaluated in community and academic centers when treating relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), and R/R follicular lymphoma (FL). The data collected in this Registry will facilitate the evaluation of the current treatment landscape for non-Hodgkin lymphoma (NHL), including the clinical effectiveness, safety. No investigational product or drug will be administered as part of this study. Enrolled patients will receive treatment and evaluations for their disease according to the standard of care and routine clinical practice at each study site. All treatments that patients receive for their disease will be recorded, including any previous lymphoma treatments. Clinical outcomes will be documented as part of an objective clinical assessment. In addition, patient-reported health-related quality of life (HRQoL) outcomes data will be collected from patients using various validated instruments. Social support data will also be collected.

ID: NCT04982471

Sponsor: Celgene

Locations: 60 locations, including VA Central California Health Care System, Harry S. Truman Memorial Veterans’ Hospital, and Brooke Army Medical Center

Obinutuzumab With or Without Umbralisib,Lenalidomide, or Combination Chemotherapy in Treating Patients With Relapsed or Refractory Grade I-IIIa Follicular Lymphoma

This phase II trial studies how well obinutuzumab with or without umbralisib, lenalidomide, or combination chemotherapy work in treating patients with grade I-IIIa follicular lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Immunotherapy with obinutuzumab, may induce changes in the body’s immune system and may interfere with the ability of tumor cells to grow and spread. Umbralisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Biological therapies, such as lenalidomide, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Chemotherapy drugs, such as cyclophosphamide, doxorubicin, vincristine, prednisone, and bendamustine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving obinutuzumab with or without umbralisib, lenalidomide, or combination chemotherapy will work better in treating patients with grade I-IIIa follicular lymphoma.

ID: NCT03269669

Sponsor: National Cancer Institute (NCI)

Locations: 427 locations, including VA Palo Alto Health Care System

Brentuximab Vedotin and Nivolumab With or Without Ipilimumab in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma

This phase I/II trial studies the side effects and best dose of ipilimumab and nivolumab when given together with brentuximab vedotin, and how well they work in treating patients with Hodgkin lymphoma that has returned after a period of improvement (recurrent) or has not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body’s immune system attack the cancer and may interfere with the ability of cancer cells to grow and spread. Brentuximab vedotin is a monoclonal antibody, brentuximab, linked to a toxic agent called vedotin. Brentuximab attaches to CD30-positive cancer cells in a targeted way and delivers vedotin to kill them. It is not known whether giving brentuximab vedotin and nivolumab with or without ipilimumab may kill more cancer cells.

ID: NCT01896999

Sponsor: National Cancer Institute (NCI)

Locations: 486 locations, including Walter Reed National Military Medical Center

Testing Early Treatment for Patients With High-Risk Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Leukemia (SLL), EVOLVE CLL/SLL Study

This phase III trial compares early treatment with venetoclax and obinutuzumab versus delayed treatment with venetoclax and obinutuzumab in patients with newly diagnosed high-risk chronic lymphocytic leukemia or small lymphocytic lymphoma. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Immunotherapy with monoclonal antibodies, such as obinutuzumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Starting treatment with the venetoclax and obinutuzumab early (before patients have symptoms) may have better outcomes for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma compared to starting treatment with the venetoclax and obinutuzumab after patients show symptoms.

ID: NCT04269902

Sponsor: National Cancer Institute (NCI)

Locations: 545 locations, Tibor Rubin VA Medical Center, Minneapolis VA Medical Center, and Durham VA Medical Center

Testing the Use of Steroids and TyrosineKinase Inhibitors With Blinatumomab or Chemotherapy for Newly Diagnosed BCR-ABL-Positive Acute Lymphoblastic Leukemia in Adults

This phase III trial compares the effect of usual treatment of chemotherapy and steroids and a tyrosine kinase inhibitor (TKI) to the same treatment plus blinatumomab. Blinatumomab is a Bi-specific T-cell Engager (‘BiTE’) that may interfere with the ability of cancer cells to grow and spread. The information gained from this study may help researchers determine if combination therapy with steroids, TKIs, and blinatumomab work better than the standard of care.

ID: NCT04530565

Sponsor: National Cancer Institute (NCI)

Locations: 180 locations, including Walter Reed National Military Medical Center

Asciminib Monotherapy, With Dose Escalation, for 2nd and 1st Line Chronic Myelogenous Leukemia (ASC2ESCALATE)

This will be a multicenter Phase II open-label study of asciminib in CML-CP patients who have been previously treated with one prior ATP-binding site TKI with discontinuation due to treatment failure, warning or intolerance. (2L patient cohort). In addition, newly diagnosed CML-CP patients who may have received up to 4 weeks of prior TKI are included in a separate 1L patient cohort.

ID: NCT05384587

Sponsor: Novartis

Locations: 26 locations, including VA Puget Sound Health Care System

Connect® Myeloid Disease Registry

This Disease Registry will collect data on patient characteristics, treatment patterns and clinical outcomes. The objective is to describe how patients with myeloid diseases are treated; and to build a knowledge base regarding the effectiveness and safety of first-line and subsequent treatment regimens in both community and academic settings. Enrolled patients will receive treatment and evaluations for their disease according to the standard of care and routine clinical practice at each study site. All treatments that patients receive for their disease will be recorded, including initial treatment and any subsequent therapy. Data on treatment outcomes, including response rates as measured by the treating physician, evidence of progression, survival, and patient-reported outcomes will be collected quarterly on the electronic CRF.

ID: NCT01688011

Sponsor: Celgene

Locations: 240 locations, including VA Central California Health Care System, John D. Dingell VA Medical Center, Manchester VA Medical Center, Dallas VA Medical Center, White River Junction VA Medical Center, and VA Caribbean Healthcare System

Esophageal Cancer

Non-endoscopic Esophageal Sampling to Detect Barrett’s Esophagus and Esophageal Cancer in Veterans

This study seeks to incorporate non-endoscopic detection method (Esocheck/Esoguard) in primary care practice and test whether this screening modality increases the positive predictive value of upper endoscopy and increases the detection of Barrett’s esophagus and esophageal cancer.

Currently, BE is diagnosed only when patients undergo endoscopy with esophagogastroduodenoscopy (EGD). However, due to the high cost of EGD and the lack of a randomized controlled trials supporting its efficacy, endoscopy to screen for BE is not routinely recommended. Current guidelines do recommend sedated EGD in patients with multiple BE risk factors, refractory GERD, or alarm symptoms. This strategy fails to detect BE in patients whose symptoms are well controlled with either over the counter medications or physician prescribed therapies. It also fails to detect BE in asymptomatic subjects who comprise 40% of those that develop EAC. Thus, < 10% of EACs are diagnosed as early stage lesions caught by surveillance of patients with previously detected BE. Ablative nonsurgical therapies that have been developed for preventing cancer in patients with BE with high-grade dysplasia over the past decade will have little impact and the 5-year survival for EACs will remain a dismal 18% unless more effective programs for identifying BE and early EAC are developed.

Esocheck/Esoguard is a FDA approved device designed to sample the distal esophagus and analyze the collected material for presence of two methylated DNA markers. The Specific Aims of this study are:

To determine sensitivity, specificity, positive and negative predictive value of Esocheck/Esoguard performed in routine practice for detecting BE in an at risk Veteran population

To compare the yield of detected BE using EGD alone vs. stepwise molecular diagnostics(Esocheck/Esoguard) and endoscopic screening strategy (EGD) in at risk Veteran population.

ID: NCT05210049

Sponsor: Cleveland VA Medical Research and Education Foundation

Location: Louis Stokes Cleveland VA Medical Center

Progression of Gastroesophageal Reflux Disease and Barrett’s Esophagus and the Creation of a Barrett’s Registry

The purpose of this study is to determine or evaluate the risk factors such as smoking, family history etc. that cause esophageal cancer and to determine the genetic changes that lead to esophageal cancer. The investigators hypothesis is that systematic collection of data on the natural history of GERD and BE patients and risk factors for development of BE in patients with chronic GERD and progression of BE to dysplasia and adenocarcinoma will provide useful information to develop a decision model for risk stratification and risk reduction strategies in these patients.

ID: NCT00574327

Sponsor: Midwest Biomedical Research Foundation

Location: Kansas City VA Medical Center

Providing access to clinical trials for veteran and active-duty military patients can be a challenge, but many trials are now recruiting patients from those populations. Some trials explicitly recruit patients seeking care at the US Department of Veterans Affairs (VA), US Department of Defense (DoD) Military Health System, and Indian Health Service. The VA Office of Research and Development alone supported > 7260 research projects in 2022, and many more are sponsored by Walter Reed National Medical Center and other major defense and VA facilities. The clinical trials listed below are all open as of July 20, 2023; have at least 1 VA or DoD location recruiting patients; and are focused on treatments for lymphoma, leukemia, and esophageal cancer. For additional information and full inclusion/exclusion criteria, please consult clinicaltrials.gov.

Lymphoma

Study of a Triple Combination Therapy, DTRM-555, in Patients With R/R CLL or R/R Non-Hodgkin’s Lymphomas

Targeted drug therapies have greatly improved outcomes for patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma. However, single drug therapies have limitations, therefore, the current study is evaluating a novel oral combination of targeted drugs as a way of overcoming these limitations. This study will determine the efficacy of the triple combination therapy, DTRM-555, in patients with R/R CLL or R/R non-Hodgkin’s lymphoma.

ID: NCT04305444

Sponsor: Zhejiang DTRM Biopharma

Locations: 8 locations, including Memphis VA Medical Center

Randomized Phase IIB Trial of Oral Azacytidine Plus Romidepsin Versus Investigator’s Choice in PTCL (PTCL)

Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of non-Hodgkin lymphoma (NHL) originating from mature (or post-thymic or ‘peripheral’) T-lymphocytes and NK cells. They are considered very aggressive and are often resistant to conventional chemotherapy.

This study employs a stratified randomization with equal allocation within strata of patients to receive oral 5-azacytidine (AZA) plus romidepsin (ROMI) versus prespecified investigator choice (ROMI, belinostat, pralatrexate or gemcitabine), for the treatment of relapsed or refractory (R/R) PTCL. The dose and schedule of AZA/ROMI has been determined from a phase I clinical trial of the combination. The primary objective of this study is to estimate the progression-free survival (PFS) among patients receiving the combination compared to single agent of choice.

ID: NCT04747236

Sponsor: Collaborator: University of Virginia; Celgene

Locations: 4 locations, including VA Long Beach Health Care System

Connect® Lymphoma Disease Registry: A US-Based Prospective Observational Cohort Study

This Disease Registry is designed to capture the patient characteristics, practice patterns, and therapeutic strategies evaluated in community and academic centers when treating relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), and R/R follicular lymphoma (FL). The data collected in this Registry will facilitate the evaluation of the current treatment landscape for non-Hodgkin lymphoma (NHL), including the clinical effectiveness, safety. No investigational product or drug will be administered as part of this study. Enrolled patients will receive treatment and evaluations for their disease according to the standard of care and routine clinical practice at each study site. All treatments that patients receive for their disease will be recorded, including any previous lymphoma treatments. Clinical outcomes will be documented as part of an objective clinical assessment. In addition, patient-reported health-related quality of life (HRQoL) outcomes data will be collected from patients using various validated instruments. Social support data will also be collected.

ID: NCT04982471

Sponsor: Celgene

Locations: 60 locations, including VA Central California Health Care System, Harry S. Truman Memorial Veterans’ Hospital, and Brooke Army Medical Center

Obinutuzumab With or Without Umbralisib,Lenalidomide, or Combination Chemotherapy in Treating Patients With Relapsed or Refractory Grade I-IIIa Follicular Lymphoma

This phase II trial studies how well obinutuzumab with or without umbralisib, lenalidomide, or combination chemotherapy work in treating patients with grade I-IIIa follicular lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Immunotherapy with obinutuzumab, may induce changes in the body’s immune system and may interfere with the ability of tumor cells to grow and spread. Umbralisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Biological therapies, such as lenalidomide, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Chemotherapy drugs, such as cyclophosphamide, doxorubicin, vincristine, prednisone, and bendamustine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving obinutuzumab with or without umbralisib, lenalidomide, or combination chemotherapy will work better in treating patients with grade I-IIIa follicular lymphoma.

ID: NCT03269669

Sponsor: National Cancer Institute (NCI)

Locations: 427 locations, including VA Palo Alto Health Care System

Brentuximab Vedotin and Nivolumab With or Without Ipilimumab in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma

This phase I/II trial studies the side effects and best dose of ipilimumab and nivolumab when given together with brentuximab vedotin, and how well they work in treating patients with Hodgkin lymphoma that has returned after a period of improvement (recurrent) or has not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body’s immune system attack the cancer and may interfere with the ability of cancer cells to grow and spread. Brentuximab vedotin is a monoclonal antibody, brentuximab, linked to a toxic agent called vedotin. Brentuximab attaches to CD30-positive cancer cells in a targeted way and delivers vedotin to kill them. It is not known whether giving brentuximab vedotin and nivolumab with or without ipilimumab may kill more cancer cells.

ID: NCT01896999

Sponsor: National Cancer Institute (NCI)

Locations: 486 locations, including Walter Reed National Military Medical Center

Testing Early Treatment for Patients With High-Risk Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Leukemia (SLL), EVOLVE CLL/SLL Study

This phase III trial compares early treatment with venetoclax and obinutuzumab versus delayed treatment with venetoclax and obinutuzumab in patients with newly diagnosed high-risk chronic lymphocytic leukemia or small lymphocytic lymphoma. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Immunotherapy with monoclonal antibodies, such as obinutuzumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Starting treatment with the venetoclax and obinutuzumab early (before patients have symptoms) may have better outcomes for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma compared to starting treatment with the venetoclax and obinutuzumab after patients show symptoms.

ID: NCT04269902

Sponsor: National Cancer Institute (NCI)

Locations: 545 locations, Tibor Rubin VA Medical Center, Minneapolis VA Medical Center, and Durham VA Medical Center

Testing the Use of Steroids and TyrosineKinase Inhibitors With Blinatumomab or Chemotherapy for Newly Diagnosed BCR-ABL-Positive Acute Lymphoblastic Leukemia in Adults

This phase III trial compares the effect of usual treatment of chemotherapy and steroids and a tyrosine kinase inhibitor (TKI) to the same treatment plus blinatumomab. Blinatumomab is a Bi-specific T-cell Engager (‘BiTE’) that may interfere with the ability of cancer cells to grow and spread. The information gained from this study may help researchers determine if combination therapy with steroids, TKIs, and blinatumomab work better than the standard of care.

ID: NCT04530565

Sponsor: National Cancer Institute (NCI)

Locations: 180 locations, including Walter Reed National Military Medical Center

Asciminib Monotherapy, With Dose Escalation, for 2nd and 1st Line Chronic Myelogenous Leukemia (ASC2ESCALATE)

This will be a multicenter Phase II open-label study of asciminib in CML-CP patients who have been previously treated with one prior ATP-binding site TKI with discontinuation due to treatment failure, warning or intolerance. (2L patient cohort). In addition, newly diagnosed CML-CP patients who may have received up to 4 weeks of prior TKI are included in a separate 1L patient cohort.

ID: NCT05384587

Sponsor: Novartis

Locations: 26 locations, including VA Puget Sound Health Care System

Connect® Myeloid Disease Registry

This Disease Registry will collect data on patient characteristics, treatment patterns and clinical outcomes. The objective is to describe how patients with myeloid diseases are treated; and to build a knowledge base regarding the effectiveness and safety of first-line and subsequent treatment regimens in both community and academic settings. Enrolled patients will receive treatment and evaluations for their disease according to the standard of care and routine clinical practice at each study site. All treatments that patients receive for their disease will be recorded, including initial treatment and any subsequent therapy. Data on treatment outcomes, including response rates as measured by the treating physician, evidence of progression, survival, and patient-reported outcomes will be collected quarterly on the electronic CRF.

ID: NCT01688011

Sponsor: Celgene

Locations: 240 locations, including VA Central California Health Care System, John D. Dingell VA Medical Center, Manchester VA Medical Center, Dallas VA Medical Center, White River Junction VA Medical Center, and VA Caribbean Healthcare System

Esophageal Cancer

Non-endoscopic Esophageal Sampling to Detect Barrett’s Esophagus and Esophageal Cancer in Veterans

This study seeks to incorporate non-endoscopic detection method (Esocheck/Esoguard) in primary care practice and test whether this screening modality increases the positive predictive value of upper endoscopy and increases the detection of Barrett’s esophagus and esophageal cancer.

Currently, BE is diagnosed only when patients undergo endoscopy with esophagogastroduodenoscopy (EGD). However, due to the high cost of EGD and the lack of a randomized controlled trials supporting its efficacy, endoscopy to screen for BE is not routinely recommended. Current guidelines do recommend sedated EGD in patients with multiple BE risk factors, refractory GERD, or alarm symptoms. This strategy fails to detect BE in patients whose symptoms are well controlled with either over the counter medications or physician prescribed therapies. It also fails to detect BE in asymptomatic subjects who comprise 40% of those that develop EAC. Thus, < 10% of EACs are diagnosed as early stage lesions caught by surveillance of patients with previously detected BE. Ablative nonsurgical therapies that have been developed for preventing cancer in patients with BE with high-grade dysplasia over the past decade will have little impact and the 5-year survival for EACs will remain a dismal 18% unless more effective programs for identifying BE and early EAC are developed.

Esocheck/Esoguard is a FDA approved device designed to sample the distal esophagus and analyze the collected material for presence of two methylated DNA markers. The Specific Aims of this study are:

To determine sensitivity, specificity, positive and negative predictive value of Esocheck/Esoguard performed in routine practice for detecting BE in an at risk Veteran population

To compare the yield of detected BE using EGD alone vs. stepwise molecular diagnostics(Esocheck/Esoguard) and endoscopic screening strategy (EGD) in at risk Veteran population.

ID: NCT05210049

Sponsor: Cleveland VA Medical Research and Education Foundation

Location: Louis Stokes Cleveland VA Medical Center

Progression of Gastroesophageal Reflux Disease and Barrett’s Esophagus and the Creation of a Barrett’s Registry

The purpose of this study is to determine or evaluate the risk factors such as smoking, family history etc. that cause esophageal cancer and to determine the genetic changes that lead to esophageal cancer. The investigators hypothesis is that systematic collection of data on the natural history of GERD and BE patients and risk factors for development of BE in patients with chronic GERD and progression of BE to dysplasia and adenocarcinoma will provide useful information to develop a decision model for risk stratification and risk reduction strategies in these patients.

ID: NCT00574327

Sponsor: Midwest Biomedical Research Foundation

Location: Kansas City VA Medical Center

Complementary and alternative medicine (CAM) is a therapeutic approach to health care used in association with or in place of standard medical therapeutic approaches. When describing CAM, the terms complementary and alternative are often used interchangeably, but the terms refer to different concepts. A nonmainstream approach used together with conventional medicine is considered complementary, whereas an approach used in place of conventional medicine is considered alternative. Most people who use nonmainstream approaches also use conventional health care.¹

Integrative medicine represents therapeutic interventions that bring conventional and complementary approaches together in a coordinated way. Integrative health also emphasizes multimodal interventions, which are ≥ 2 interventions such as conventional (eg, medication, physical rehabilitation, psychotherapy) and complementary health approaches (eg, acupuncture, yoga, and probiotics) in various combinations, with an emphasis on treating the whole person rather than 1 organ system. Integrative health aims for well-coordinated care among different practitioners and institutions.¹

Functional medicine requires an individualized assessment and therapeutic plan for each patient, including optimizing the function of each organ system. It uses research to understand a patient’s unique needs and formulates a plan that often uses diet, exercise, and stress reduction methods. Functional medicine may use combinations of naturopathic, osteopathic, and chiropractic medicine, among other therapies. Functional medicine has been called a systems biology model, and patients and practitioners work together to achieve the highest expression of health by addressing the underlying causes of disease.^2,3

According to a 2012 national survey, more than 30% of adults and about 12% of children use health care approaches that are not part of conventional medical care or that may have unconventional origins. A National Center for Health Statistics study found that the most common complementary medical interventions from 2002 to 2012 included natural products, deep breathing, yoga and other movement programs, and chiropractic, among others. Magnets, magnetic fields, and copper devices (MMFC), which are the focus of this study, were not among the top listed interventions.⁴ Recent data showed that individuals in the United States are high users of CAM, including many patients who have neoplastic disease.^5,6

MMFCs are a part of CAM and are reported to be a billion-dollar industry worldwide, although it is not well studied.^7,8 In our study, magnet refers to the use of a magnet in contact with the body, magnetic field refers to exposure to a magnetic field administered without direct contact with the body, and copper devices refer to devices that are in contact with the body, such as bracelets, necklaces, wraps, and joint braces. These devices are often constructed using copper mesh, or weaved copper wires. Advertising has helped to increase interest in the use of these devices for musculoskeletal pain and restricted joint movement therapies. However, it is less clear whether MMFCs are being used to provide therapy for other medical conditions, such as neoplastic disease.

It is unclear how widespread MMFC use is or how it is accessed. A 2016 study of veterans and CAM use did not specifically address MMFCs.⁹ A Japanese study of the use of CAM provided or prescribed by a physician found that just 12 of 1575 respondents (0.7%) described using magnetic therapy.¹⁰ A Korean internet study that assessed the use of CAM found that of 1668 respondents who received CAM therapy by practice or advice of a physician, 1.2% used magnet therapy.^11,12 An online study of CAM use in patients with multiple sclerosis found that 9 of 1286 respondents (0.7%) had used magnetic field therapy in the previous 3 months.¹³

In this study, we aimed to assess MMFC use and perspectives in a veteran population at the Carl T. Hayden Veterans Affairs Medical Center (CTHVAMC) in Phoenix, Arizona.

METHODS

We created a brief questionnaire regarding MMFC use and perspectives and distributed it to veteran patients at the infusion center at the CTHVAMC. The study was approved by the CTHVAMC department of research, and the institutional review board determined that informed consent was not required. The questionnaire did not collect any specific personal identifying data but included the participant’s sex, age, and diagnosis. Although there are standardized questionnaires concerning the use of CAM, we designed a new survey for MMFCs. The participants in the study were consecutive patients referred to the CTHVAMC infusion center for IV or other nonoral therapies. Referrals came from endocrinology, gastroenterology, hematology/oncology, neurology, rheumatology, and other specialties (eg, allergy/immunology).

The questionnaire was 1 page (front and back) and was completed anonymously without involvement by the study investigators or infusion center staff. Dated and consecutively numbered questionnaires were given to patients receiving therapy regardless of their diagnosis. Ages were categorized into groups: 18 to 30 years; 31 to 50 years; 51 to 65 years; and ≥ 66 years. Diagnoses were categorized by specialty: endocrinology, gastroenterology, hematology/oncology, neurology, rheumatology, and other. We noted in a previous similar study that the exact diagnosis was often left blank, but the specialty was more often completed.⁹ Since some patients required multiple visits to the infusion center, respondents were asked whether they had previously answered the questionnaire; there were no duplications.

The population we studied was under stress while receiving therapy for underlying illnesses. To improve the response rate and accuracy of the responses, we limited the number of survey questions. Since many of the respondents in the infusion center for therapy received medications that could alter their ability to respond, all questionnaires were administered prior to therapeutic intervention. In addition to the background data, respondents were asked: Do you apply magnets to your body, use magnetic field therapy, or copper devices? If you use any of these therapies, is it for pain, your diagnosis, or other? Would you consider participating in a clinical trial using magnets applied to the body or magnetic therapy?

RESULTS

We collected 210 surveys. Four surveys were missing data and were excluded. The majority of respondents (n = 133, 64%) were in the hematology/oncology diagnostic group and 121 (59%) were aged ≥ 66 years (Table 1).

Respondents were asked whether they were using MMFC therapies. The results from all age groups showed an 18% overall use and in the diagnosis groups an overall use of 23%. Eighteen respondents (35%) aged 51 to 65 years reported using MMFC, followed by 6 respondents (21%) aged 31 to 50 years. Patients with an endocrinology diagnosis had the highest rate of MMFC use (6 of 11 patients; 55%) but more patients (33 of 133 [25%]) with a hematology/oncology diagnosis used MMFCs.

Copper was the most widely used MMFC therapy among individuals who used a single MMFC therapy. Twenty respondents reported copper use, 6 used magnets, and no respondents used magnetic field therapy (Table 2).

DISCUSSION

We surveyed a population of veterans at the CTHVAMC infusion center who were receiving antineoplastic chemotherapy, biologic therapy, immunomodulatory therapy, transfusion, and other therapies to evaluate their use of MMFC. We chose this group to sample because of how accessible this group was and the belief that there would be an adequate survey response. We hypothesized that by asking about a specific group of CAM therapies and not, as in many surveys, multiple CAM therapies, there would be an improved response rate. We expected that very few respondents would indicate MMFC use because in a similar study conducted in 2003 to 2004 at CTHVAMC, none of the 380 survey respondents (all with a hematology/oncology diagnosis) indicated magnet or magnetic field use (JR Salvatore, unpublished data). Although copper devices were available at that time, they were not included in that study. The current survey added copper devices and showed a greater use of MMFC, including copper devices. We identified veterans who used either 1 MMFC or multiple therapies. In both groups, copper devices were the most common. This may be due to the ubiquity and availability of copper devices. These devices are highly visible and promoted by professional athletes and other well-known personalities.

Our findings showed 2 unexpected results. First, there was greater than expected use of magnets and copper devices. Second, an even less expected result that there was considerable interest in participating in clinical research that used magnets or magnetic fields.

Respondents indicated a high interest in participating in clinical trials using magnets or magnetic fields regardless of their history of MMFC use. We did not ask about a trial using copper devices because there is less scientific/medical research to justify studying those devices as opposed to data that support the use of magnets or magnetic fields. The data presented in this study suggest interest in participating in clinical trials using magnets or magnetic field therapy. One clinical trial combined static magnets as an adjuvant to antineoplastic chemotherapy.¹⁴ We believe this is the first publication to specifically quantify both MMFC use in a veteran (or any) population, and to identify the desire to participate in clinical studies that would utilize magnets or magnetic fields, whether or not they currently use magnets or magnetic fields. Based on current knowledge, it is not clear whether use of MMFC by patients represents a risk or a benefit to the population studied, and seeking that information is part of the continuation of our work. We also believe that the data in this study will help practitioners to consider asking patients specifically whether they are using these therapies, and if so why and with what result. We are extending our work to a more generalized patient population.

The use of copper devices relates to beliefs (dating to the mid-1800s) that there was a relationship between copper deficiency and rheumatologic disorders. Copper devices are used as therapies because of the belief that small amounts of copper are absorbed through the skin, decreasing inflammation, particularly around joint spaces.¹⁵ Recent data suggest a mechanism for copper-induced cell death.¹⁶ Although this recent research suggests a mechanism for how copper might induce cell death, it is unclear how this would be applied to establishing a mechanism for the health effects of wearing copper devices. Since copper devices are thought to decrease inflammation, they may have a theoretical function by decreasing the number of inflammatory cells in an affected space.

CAM magnetics are typically of lower strength. The field generated by magnets is measured and reported in Tesla. Magnetic resonance imaging typically generates from 1.5 to 3 Tesla. A refrigerator magnet is about 1 milliTesla.¹⁷ In a study conducted at the CTHVAMC, the strength of the magnets used was measured at distances from the magnet. For example, at 2 cm from the magnet, the measured strength was 18 milliTesla.¹⁴ Many MMFC devices approved by the US Food and Drug Administration are pulsed electromagnetic fields (PEMF) devices for healing of nonunion fractures (approved in 1979); cervical and lumbar fusion therapies (approved in 2004); and therapy for anxiety and depression (approved in 2006).¹⁸

Limitations

Patients with endocrinology diagnoses were the most likely to use MMFCs but were a very small percentage of the infusion center population, which could skew the data. The surveyed individuals may not have been representative of the overall patient population. Similarly, the patient population at CTHVAMC, which is primarily male and aged ≥ 66 years, may not be representative of other veteran and nonveteran patient populations.

Conclusions

MMFC devices are being used regularly by patients as a form of CAM therapy, but few studies researching the use of CAM therapy have generated data that are as specific as this study is about the use of these MMFC devices. Although there is considerable general public awareness of MMFC therapies and devices, we believe that there is a need to quantify the use of these devices. We further believe that our study is one of the first to look specifically at the use of MMFCs in a veteran population. We have found a considerable use of MMFCs in the veteran population studied, and we also showed that whether or not veterans are using these devices, they are willing to be part of research that uses the devices. Further studies would look at a more general veteran population, look more in depth at the way and for what purpose these devices are being used, and consider the development of clinical research studies that use MMFCs.

Complementary and alternative medicine (CAM) is a therapeutic approach to health care used in association with or in place of standard medical therapeutic approaches. When describing CAM, the terms complementary and alternative are often used interchangeably, but the terms refer to different concepts. A nonmainstream approach used together with conventional medicine is considered complementary, whereas an approach used in place of conventional medicine is considered alternative. Most people who use nonmainstream approaches also use conventional health care.¹

Integrative medicine represents therapeutic interventions that bring conventional and complementary approaches together in a coordinated way. Integrative health also emphasizes multimodal interventions, which are ≥ 2 interventions such as conventional (eg, medication, physical rehabilitation, psychotherapy) and complementary health approaches (eg, acupuncture, yoga, and probiotics) in various combinations, with an emphasis on treating the whole person rather than 1 organ system. Integrative health aims for well-coordinated care among different practitioners and institutions.¹

Functional medicine requires an individualized assessment and therapeutic plan for each patient, including optimizing the function of each organ system. It uses research to understand a patient’s unique needs and formulates a plan that often uses diet, exercise, and stress reduction methods. Functional medicine may use combinations of naturopathic, osteopathic, and chiropractic medicine, among other therapies. Functional medicine has been called a systems biology model, and patients and practitioners work together to achieve the highest expression of health by addressing the underlying causes of disease.^2,3

According to a 2012 national survey, more than 30% of adults and about 12% of children use health care approaches that are not part of conventional medical care or that may have unconventional origins. A National Center for Health Statistics study found that the most common complementary medical interventions from 2002 to 2012 included natural products, deep breathing, yoga and other movement programs, and chiropractic, among others. Magnets, magnetic fields, and copper devices (MMFC), which are the focus of this study, were not among the top listed interventions.⁴ Recent data showed that individuals in the United States are high users of CAM, including many patients who have neoplastic disease.^5,6

MMFCs are a part of CAM and are reported to be a billion-dollar industry worldwide, although it is not well studied.^7,8 In our study, magnet refers to the use of a magnet in contact with the body, magnetic field refers to exposure to a magnetic field administered without direct contact with the body, and copper devices refer to devices that are in contact with the body, such as bracelets, necklaces, wraps, and joint braces. These devices are often constructed using copper mesh, or weaved copper wires. Advertising has helped to increase interest in the use of these devices for musculoskeletal pain and restricted joint movement therapies. However, it is less clear whether MMFCs are being used to provide therapy for other medical conditions, such as neoplastic disease.

It is unclear how widespread MMFC use is or how it is accessed. A 2016 study of veterans and CAM use did not specifically address MMFCs.⁹ A Japanese study of the use of CAM provided or prescribed by a physician found that just 12 of 1575 respondents (0.7%) described using magnetic therapy.¹⁰ A Korean internet study that assessed the use of CAM found that of 1668 respondents who received CAM therapy by practice or advice of a physician, 1.2% used magnet therapy.^11,12 An online study of CAM use in patients with multiple sclerosis found that 9 of 1286 respondents (0.7%) had used magnetic field therapy in the previous 3 months.¹³

In this study, we aimed to assess MMFC use and perspectives in a veteran population at the Carl T. Hayden Veterans Affairs Medical Center (CTHVAMC) in Phoenix, Arizona.

METHODS

We created a brief questionnaire regarding MMFC use and perspectives and distributed it to veteran patients at the infusion center at the CTHVAMC. The study was approved by the CTHVAMC department of research, and the institutional review board determined that informed consent was not required. The questionnaire did not collect any specific personal identifying data but included the participant’s sex, age, and diagnosis. Although there are standardized questionnaires concerning the use of CAM, we designed a new survey for MMFCs. The participants in the study were consecutive patients referred to the CTHVAMC infusion center for IV or other nonoral therapies. Referrals came from endocrinology, gastroenterology, hematology/oncology, neurology, rheumatology, and other specialties (eg, allergy/immunology).

The questionnaire was 1 page (front and back) and was completed anonymously without involvement by the study investigators or infusion center staff. Dated and consecutively numbered questionnaires were given to patients receiving therapy regardless of their diagnosis. Ages were categorized into groups: 18 to 30 years; 31 to 50 years; 51 to 65 years; and ≥ 66 years. Diagnoses were categorized by specialty: endocrinology, gastroenterology, hematology/oncology, neurology, rheumatology, and other. We noted in a previous similar study that the exact diagnosis was often left blank, but the specialty was more often completed.⁹ Since some patients required multiple visits to the infusion center, respondents were asked whether they had previously answered the questionnaire; there were no duplications.

The population we studied was under stress while receiving therapy for underlying illnesses. To improve the response rate and accuracy of the responses, we limited the number of survey questions. Since many of the respondents in the infusion center for therapy received medications that could alter their ability to respond, all questionnaires were administered prior to therapeutic intervention. In addition to the background data, respondents were asked: Do you apply magnets to your body, use magnetic field therapy, or copper devices? If you use any of these therapies, is it for pain, your diagnosis, or other? Would you consider participating in a clinical trial using magnets applied to the body or magnetic therapy?

RESULTS

We collected 210 surveys. Four surveys were missing data and were excluded. The majority of respondents (n = 133, 64%) were in the hematology/oncology diagnostic group and 121 (59%) were aged ≥ 66 years (Table 1).

Respondents were asked whether they were using MMFC therapies. The results from all age groups showed an 18% overall use and in the diagnosis groups an overall use of 23%. Eighteen respondents (35%) aged 51 to 65 years reported using MMFC, followed by 6 respondents (21%) aged 31 to 50 years. Patients with an endocrinology diagnosis had the highest rate of MMFC use (6 of 11 patients; 55%) but more patients (33 of 133 [25%]) with a hematology/oncology diagnosis used MMFCs.

Copper was the most widely used MMFC therapy among individuals who used a single MMFC therapy. Twenty respondents reported copper use, 6 used magnets, and no respondents used magnetic field therapy (Table 2).

DISCUSSION

We surveyed a population of veterans at the CTHVAMC infusion center who were receiving antineoplastic chemotherapy, biologic therapy, immunomodulatory therapy, transfusion, and other therapies to evaluate their use of MMFC. We chose this group to sample because of how accessible this group was and the belief that there would be an adequate survey response. We hypothesized that by asking about a specific group of CAM therapies and not, as in many surveys, multiple CAM therapies, there would be an improved response rate. We expected that very few respondents would indicate MMFC use because in a similar study conducted in 2003 to 2004 at CTHVAMC, none of the 380 survey respondents (all with a hematology/oncology diagnosis) indicated magnet or magnetic field use (JR Salvatore, unpublished data). Although copper devices were available at that time, they were not included in that study. The current survey added copper devices and showed a greater use of MMFC, including copper devices. We identified veterans who used either 1 MMFC or multiple therapies. In both groups, copper devices were the most common. This may be due to the ubiquity and availability of copper devices. These devices are highly visible and promoted by professional athletes and other well-known personalities.

Our findings showed 2 unexpected results. First, there was greater than expected use of magnets and copper devices. Second, an even less expected result that there was considerable interest in participating in clinical research that used magnets or magnetic fields.

Respondents indicated a high interest in participating in clinical trials using magnets or magnetic fields regardless of their history of MMFC use. We did not ask about a trial using copper devices because there is less scientific/medical research to justify studying those devices as opposed to data that support the use of magnets or magnetic fields. The data presented in this study suggest interest in participating in clinical trials using magnets or magnetic field therapy. One clinical trial combined static magnets as an adjuvant to antineoplastic chemotherapy.¹⁴ We believe this is the first publication to specifically quantify both MMFC use in a veteran (or any) population, and to identify the desire to participate in clinical studies that would utilize magnets or magnetic fields, whether or not they currently use magnets or magnetic fields. Based on current knowledge, it is not clear whether use of MMFC by patients represents a risk or a benefit to the population studied, and seeking that information is part of the continuation of our work. We also believe that the data in this study will help practitioners to consider asking patients specifically whether they are using these therapies, and if so why and with what result. We are extending our work to a more generalized patient population.

The use of copper devices relates to beliefs (dating to the mid-1800s) that there was a relationship between copper deficiency and rheumatologic disorders. Copper devices are used as therapies because of the belief that small amounts of copper are absorbed through the skin, decreasing inflammation, particularly around joint spaces.¹⁵ Recent data suggest a mechanism for copper-induced cell death.¹⁶ Although this recent research suggests a mechanism for how copper might induce cell death, it is unclear how this would be applied to establishing a mechanism for the health effects of wearing copper devices. Since copper devices are thought to decrease inflammation, they may have a theoretical function by decreasing the number of inflammatory cells in an affected space.

CAM magnetics are typically of lower strength. The field generated by magnets is measured and reported in Tesla. Magnetic resonance imaging typically generates from 1.5 to 3 Tesla. A refrigerator magnet is about 1 milliTesla.¹⁷ In a study conducted at the CTHVAMC, the strength of the magnets used was measured at distances from the magnet. For example, at 2 cm from the magnet, the measured strength was 18 milliTesla.¹⁴ Many MMFC devices approved by the US Food and Drug Administration are pulsed electromagnetic fields (PEMF) devices for healing of nonunion fractures (approved in 1979); cervical and lumbar fusion therapies (approved in 2004); and therapy for anxiety and depression (approved in 2006).¹⁸

Limitations

Patients with endocrinology diagnoses were the most likely to use MMFCs but were a very small percentage of the infusion center population, which could skew the data. The surveyed individuals may not have been representative of the overall patient population. Similarly, the patient population at CTHVAMC, which is primarily male and aged ≥ 66 years, may not be representative of other veteran and nonveteran patient populations.

Conclusions

MMFC devices are being used regularly by patients as a form of CAM therapy, but few studies researching the use of CAM therapy have generated data that are as specific as this study is about the use of these MMFC devices. Although there is considerable general public awareness of MMFC therapies and devices, we believe that there is a need to quantify the use of these devices. We further believe that our study is one of the first to look specifically at the use of MMFCs in a veteran population. We have found a considerable use of MMFCs in the veteran population studied, and we also showed that whether or not veterans are using these devices, they are willing to be part of research that uses the devices. Further studies would look at a more general veteran population, look more in depth at the way and for what purpose these devices are being used, and consider the development of clinical research studies that use MMFCs.

Complementary and alternative medicine (CAM) is a therapeutic approach to health care used in association with or in place of standard medical therapeutic approaches. When describing CAM, the terms complementary and alternative are often used interchangeably, but the terms refer to different concepts. A nonmainstream approach used together with conventional medicine is considered complementary, whereas an approach used in place of conventional medicine is considered alternative. Most people who use nonmainstream approaches also use conventional health care.¹

Integrative medicine represents therapeutic interventions that bring conventional and complementary approaches together in a coordinated way. Integrative health also emphasizes multimodal interventions, which are ≥ 2 interventions such as conventional (eg, medication, physical rehabilitation, psychotherapy) and complementary health approaches (eg, acupuncture, yoga, and probiotics) in various combinations, with an emphasis on treating the whole person rather than 1 organ system. Integrative health aims for well-coordinated care among different practitioners and institutions.¹

Functional medicine requires an individualized assessment and therapeutic plan for each patient, including optimizing the function of each organ system. It uses research to understand a patient’s unique needs and formulates a plan that often uses diet, exercise, and stress reduction methods. Functional medicine may use combinations of naturopathic, osteopathic, and chiropractic medicine, among other therapies. Functional medicine has been called a systems biology model, and patients and practitioners work together to achieve the highest expression of health by addressing the underlying causes of disease.^2,3

According to a 2012 national survey, more than 30% of adults and about 12% of children use health care approaches that are not part of conventional medical care or that may have unconventional origins. A National Center for Health Statistics study found that the most common complementary medical interventions from 2002 to 2012 included natural products, deep breathing, yoga and other movement programs, and chiropractic, among others. Magnets, magnetic fields, and copper devices (MMFC), which are the focus of this study, were not among the top listed interventions.⁴ Recent data showed that individuals in the United States are high users of CAM, including many patients who have neoplastic disease.^5,6

MMFCs are a part of CAM and are reported to be a billion-dollar industry worldwide, although it is not well studied.^7,8 In our study, magnet refers to the use of a magnet in contact with the body, magnetic field refers to exposure to a magnetic field administered without direct contact with the body, and copper devices refer to devices that are in contact with the body, such as bracelets, necklaces, wraps, and joint braces. These devices are often constructed using copper mesh, or weaved copper wires. Advertising has helped to increase interest in the use of these devices for musculoskeletal pain and restricted joint movement therapies. However, it is less clear whether MMFCs are being used to provide therapy for other medical conditions, such as neoplastic disease.

It is unclear how widespread MMFC use is or how it is accessed. A 2016 study of veterans and CAM use did not specifically address MMFCs.⁹ A Japanese study of the use of CAM provided or prescribed by a physician found that just 12 of 1575 respondents (0.7%) described using magnetic therapy.¹⁰ A Korean internet study that assessed the use of CAM found that of 1668 respondents who received CAM therapy by practice or advice of a physician, 1.2% used magnet therapy.^11,12 An online study of CAM use in patients with multiple sclerosis found that 9 of 1286 respondents (0.7%) had used magnetic field therapy in the previous 3 months.¹³

In this study, we aimed to assess MMFC use and perspectives in a veteran population at the Carl T. Hayden Veterans Affairs Medical Center (CTHVAMC) in Phoenix, Arizona.

METHODS

We created a brief questionnaire regarding MMFC use and perspectives and distributed it to veteran patients at the infusion center at the CTHVAMC. The study was approved by the CTHVAMC department of research, and the institutional review board determined that informed consent was not required. The questionnaire did not collect any specific personal identifying data but included the participant’s sex, age, and diagnosis. Although there are standardized questionnaires concerning the use of CAM, we designed a new survey for MMFCs. The participants in the study were consecutive patients referred to the CTHVAMC infusion center for IV or other nonoral therapies. Referrals came from endocrinology, gastroenterology, hematology/oncology, neurology, rheumatology, and other specialties (eg, allergy/immunology).

The questionnaire was 1 page (front and back) and was completed anonymously without involvement by the study investigators or infusion center staff. Dated and consecutively numbered questionnaires were given to patients receiving therapy regardless of their diagnosis. Ages were categorized into groups: 18 to 30 years; 31 to 50 years; 51 to 65 years; and ≥ 66 years. Diagnoses were categorized by specialty: endocrinology, gastroenterology, hematology/oncology, neurology, rheumatology, and other. We noted in a previous similar study that the exact diagnosis was often left blank, but the specialty was more often completed.⁹ Since some patients required multiple visits to the infusion center, respondents were asked whether they had previously answered the questionnaire; there were no duplications.

The population we studied was under stress while receiving therapy for underlying illnesses. To improve the response rate and accuracy of the responses, we limited the number of survey questions. Since many of the respondents in the infusion center for therapy received medications that could alter their ability to respond, all questionnaires were administered prior to therapeutic intervention. In addition to the background data, respondents were asked: Do you apply magnets to your body, use magnetic field therapy, or copper devices? If you use any of these therapies, is it for pain, your diagnosis, or other? Would you consider participating in a clinical trial using magnets applied to the body or magnetic therapy?

RESULTS

We collected 210 surveys. Four surveys were missing data and were excluded. The majority of respondents (n = 133, 64%) were in the hematology/oncology diagnostic group and 121 (59%) were aged ≥ 66 years (Table 1).

Respondents were asked whether they were using MMFC therapies. The results from all age groups showed an 18% overall use and in the diagnosis groups an overall use of 23%. Eighteen respondents (35%) aged 51 to 65 years reported using MMFC, followed by 6 respondents (21%) aged 31 to 50 years. Patients with an endocrinology diagnosis had the highest rate of MMFC use (6 of 11 patients; 55%) but more patients (33 of 133 [25%]) with a hematology/oncology diagnosis used MMFCs.

Copper was the most widely used MMFC therapy among individuals who used a single MMFC therapy. Twenty respondents reported copper use, 6 used magnets, and no respondents used magnetic field therapy (Table 2).

DISCUSSION

We surveyed a population of veterans at the CTHVAMC infusion center who were receiving antineoplastic chemotherapy, biologic therapy, immunomodulatory therapy, transfusion, and other therapies to evaluate their use of MMFC. We chose this group to sample because of how accessible this group was and the belief that there would be an adequate survey response. We hypothesized that by asking about a specific group of CAM therapies and not, as in many surveys, multiple CAM therapies, there would be an improved response rate. We expected that very few respondents would indicate MMFC use because in a similar study conducted in 2003 to 2004 at CTHVAMC, none of the 380 survey respondents (all with a hematology/oncology diagnosis) indicated magnet or magnetic field use (JR Salvatore, unpublished data). Although copper devices were available at that time, they were not included in that study. The current survey added copper devices and showed a greater use of MMFC, including copper devices. We identified veterans who used either 1 MMFC or multiple therapies. In both groups, copper devices were the most common. This may be due to the ubiquity and availability of copper devices. These devices are highly visible and promoted by professional athletes and other well-known personalities.

Our findings showed 2 unexpected results. First, there was greater than expected use of magnets and copper devices. Second, an even less expected result that there was considerable interest in participating in clinical research that used magnets or magnetic fields.

Respondents indicated a high interest in participating in clinical trials using magnets or magnetic fields regardless of their history of MMFC use. We did not ask about a trial using copper devices because there is less scientific/medical research to justify studying those devices as opposed to data that support the use of magnets or magnetic fields. The data presented in this study suggest interest in participating in clinical trials using magnets or magnetic field therapy. One clinical trial combined static magnets as an adjuvant to antineoplastic chemotherapy.¹⁴ We believe this is the first publication to specifically quantify both MMFC use in a veteran (or any) population, and to identify the desire to participate in clinical studies that would utilize magnets or magnetic fields, whether or not they currently use magnets or magnetic fields. Based on current knowledge, it is not clear whether use of MMFC by patients represents a risk or a benefit to the population studied, and seeking that information is part of the continuation of our work. We also believe that the data in this study will help practitioners to consider asking patients specifically whether they are using these therapies, and if so why and with what result. We are extending our work to a more generalized patient population.

The use of copper devices relates to beliefs (dating to the mid-1800s) that there was a relationship between copper deficiency and rheumatologic disorders. Copper devices are used as therapies because of the belief that small amounts of copper are absorbed through the skin, decreasing inflammation, particularly around joint spaces.¹⁵ Recent data suggest a mechanism for copper-induced cell death.¹⁶ Although this recent research suggests a mechanism for how copper might induce cell death, it is unclear how this would be applied to establishing a mechanism for the health effects of wearing copper devices. Since copper devices are thought to decrease inflammation, they may have a theoretical function by decreasing the number of inflammatory cells in an affected space.

CAM magnetics are typically of lower strength. The field generated by magnets is measured and reported in Tesla. Magnetic resonance imaging typically generates from 1.5 to 3 Tesla. A refrigerator magnet is about 1 milliTesla.¹⁷ In a study conducted at the CTHVAMC, the strength of the magnets used was measured at distances from the magnet. For example, at 2 cm from the magnet, the measured strength was 18 milliTesla.¹⁴ Many MMFC devices approved by the US Food and Drug Administration are pulsed electromagnetic fields (PEMF) devices for healing of nonunion fractures (approved in 1979); cervical and lumbar fusion therapies (approved in 2004); and therapy for anxiety and depression (approved in 2006).¹⁸

Limitations

Patients with endocrinology diagnoses were the most likely to use MMFCs but were a very small percentage of the infusion center population, which could skew the data. The surveyed individuals may not have been representative of the overall patient population. Similarly, the patient population at CTHVAMC, which is primarily male and aged ≥ 66 years, may not be representative of other veteran and nonveteran patient populations.

Conclusions

MMFC devices are being used regularly by patients as a form of CAM therapy, but few studies researching the use of CAM therapy have generated data that are as specific as this study is about the use of these MMFC devices. Although there is considerable general public awareness of MMFC therapies and devices, we believe that there is a need to quantify the use of these devices. We further believe that our study is one of the first to look specifically at the use of MMFCs in a veteran population. We have found a considerable use of MMFCs in the veteran population studied, and we also showed that whether or not veterans are using these devices, they are willing to be part of research that uses the devices. Further studies would look at a more general veteran population, look more in depth at the way and for what purpose these devices are being used, and consider the development of clinical research studies that use MMFCs.

Originally developed for the treatment of refractory epilepsy, the ketogenic diet is distinguished by its high-fat, moderate-protein, and low-carbohydrate food program. Preclinical models provide emerging evidence that a ketogenic diet can have therapeutic potential for a broad range of cancers. The Warburg effect is a condition where cancer cells increase the uptake and fermentation of glucose to produce lactate for their metabolism, which is called aerobic glycolysis. Lactate is the key driver of cancer angiogenesis and proliferation.^1,2

The ketogenic diet promotes a metabolic shift from glycolysis to mitochondrial metabolism in normal cells while cancer cells have dysfunction in their mitochondria due to damage in cellular respiration. The ketogenic diet creates a metabolic state whereby blood glucose levels are reduced, and blood ketone bodies (D-β-hydroxybutyrate and acetoacetate) are elevated. In normal cells, the ketogenic diet causes a decrease in glucose intake for glycolysis, which makes them unable to produce enough substrate to enter the tricarboxylic acid (TCA) cycle for adenosine triphosphate (ATP) production. Fatty acid oxidation plays a key role in ketone body synthesis as a “super fuel” that enter the TCA cycle as an alternative pathway to generate ATP. On the other hand, cancer cells are unable to use ketone bodies to produce ATP for energy and metabolism due to mitochondrial defects. Lack of energy subsequently leads to the inhibition of proliferation and survival of cancer cells.^3,4

CASE PRESENTATION

A 69-year-old veteran had iron deficiency anemia (hemoglobin, 6.5 g/dL) about 5 years previously. He underwent a colonoscopy that revealed a near circumferential ulcerated mass measuring 7 cm in the transverse colon. Biopsy results showed mucinous adenocarcinoma of the colon with a foci of signet ring cells (Figure 2).

The patient received adjuvant treatment with FOLFOX (fluorouracil, leucovorin calcium, and oxaliplatin), but within several months he developed pancreatic and worsening omental metastasis seen on PET/CT. He was then started on FOLFIRI (fluorouracil, leucovorin calcium, and irinotecan hydrochloride) plus bevacizumab 16 months after his initial diagnosis. He underwent a pancreatic mastectomy that confirmed adenocarcinoma 9 months later. Afterward, he briefly resumed FOLFIRI and bevacizumab. Next-generation sequencing testing with Foundation One CDx revealed a wild-type (WT) KRAS with a high degree of tumor mutation burden of 37 muts/Mb, BRAF V600E mutation, and high microsatellite instability (MSI-H).

The purpose of this case report is to describe whether a patient receiving active cancer treatment was able to tolerate the ketogenic diet in conjunction with chemotherapy or immunotherapy. Most literature published on the subject evaluated the tolerability and response of the ketogenic diet after the failure of standard therapy. Our patient was diagnosed with stage III mucinous colon adenocarcinoma. He received adjuvant chemotherapy but quickly developed metastatic disease to the pancreas and omentum. We started him on encorafenib and cetuximab based on the BEACON study that showed improvement in response rate and survival when compared with standard chemotherapy for patients with BRAF V600E mutation.⁵ Unfortunately, his cancer quickly progressed within 4 months and again did not respond to pembrolizumab despite MSI-H, which lasted for another 4 months.

We suggested the ketogenic diet and the patient agreed. He started the diet along with trifluridine/tipiracil, and bevacizumab in January 2021. The patient’s metastatic cancer stabilized for 9 months until his disease progressed again. He was started on doublet immune checkpoint inhibitors ipilimumab and nivolumab based on his MSI-H and high tumor mutation burden with the continuation of the ketogenic diet until now. The CheckMate 142 study revealed that the combination of ipilimumab and nivolumab in patients with MSI-H previously treated for metastatic colon cancer showed some benefit.⁶

Our patient had the loss of nuclear expression of MLH1 and PMS2 (zero tumor stained) but no evidence of the loss expression of MSH2 and MSH6 genes (99% tumor stained). About 8% to 12% of patients with metastatic colon cancer have BRAF V600E mutations that are usually mucinous type, poorly differentiated, and located in the right side of the colon, which portends to a poor prognosis. Tumor DNA mismatch repair damage results in genetic hypermutability and leads to MSI that is sensitive to treatment with checkpoint inhibitors, as in our patient. Only about 3% of MSI-H tumors are due to germline mutations such as Lynch syndrome (hereditary nonpolyposis colorectal cancer). The presence of both MLH1 hypermethylation and BRAF mutation, as in our patient, is a strong indication of somatic rather than germline mutation.⁷

GKI, which represents the ratio of glucose to ketone, was developed to evaluate the efficacy of the ketogenic diet. This index measures the degree of metabolic stress on tumor cells through the decrease of glucose levels and increase of ketone bodies. A GKI of ≤ 1.0 has been suggested as the ideal therapeutic goal for cancer management.⁸ As levels of blood glucose decline, the blood levels of ketone bodies should rise. These 2 lines should eventually intersect at a certain point beyond which one enters the therapeutic zone or therapeutic ketosis zone. This is when tumor growth is expected to slow or cease.⁹ The patient’s ketone (β-hydroxybutyrate) level was initially high (0.71 mmol/L) with a GKI of 8.2. (low ketotic level), which meant he tolerated a rather strict diet for the first several months. This was also reflected in his 18 lb weight loss (almost 10% of body weight) and cancer stabilization, as in our previous publication.¹ Unfortunately, the patient was unable to maintain high ketone and lower GKI levels due to fatigue from depleted carbohydrate intake. He added some carbohydrate snacks in between meals, which improved the fatigue. His ketone level has been < 0.5 mmol/L ever since, albeit his disease continues to be stable. The patient continues his daily work and reports a better QOL, based on the ECOG QLC-C30 form that he completed every 3 months.¹⁰ Currently, the patient is still receiving ipilimumab and nivolumab while maintaining the ketogenic diet with stable metastatic disease on PET/CT.

Ketogenic Diet and Cellular Mechanism of Action

PI3K/Akt (phosphatidylinositol-3-kinase) signaling is one of the most important intracellular pathways for tumor cells. It leads to the inhibition of apoptosis and the promotion of cell proliferation, metabolism, and angiogenesis. Deregulation of the PI3K pathway either via amplification of PI3K by tyrosine kinase growth factor receptors or inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN), which is the negative regulator of the PI3K pathway, contributes to the development of cancer cells.¹¹

A study by Goncalves and colleagues revealed an interesting relationship between the PI3K pathway and the benefit of the ketogenic diet to slow tumor growth. PI3K inhibitors inhibit glucose uptake into skeletal muscle and adipose tissue that activate hepatic glycogenolysis. This event results in hyperglycemia due to the pancreas releasing very high levels of insulin into the blood (hyperinsulinemia) that subsequently reactivate PI3K signaling and cause resistance to PI3K inhibitors. The ketogenic diet reportedly minimized the hyperglycemia and hyperinsulinemia induced by the PI3K inhibitor and enhanced the efficacy of PI3K inhibitors in tumor models. Studies combining PI3K inhibitors and ketogenic diet are underway. Hence, combining the ketogenic diet with chemotherapy or other novel treatment should be the focus of ketogenic diet trials.^12,13

The impact of the ketogenic diet on the growth of murine pancreatic tumors was evaluated by Yang and colleagues. The ketogenic diet decreased glucose concentration that enters the TCA cycle and increased fatty acid oxidation that produces β-hydroxybutyrate. This event promotes the generation of ATP, although with only modest elevations of NADH with less impact on tumor growth. The combination of ketogenic diet and standard chemotherapy substantially raised tumor NADH and suppressed the growth of murine tumor cells, they noted.¹⁴ Furukawa and colleagues compared 10 patients with metastatic colon cancer receiving chemotherapy plus the modified medium-chain triglyceride ketogenic diet for 1 year with 14 patients receiving chemotherapy only. The ketogenic diet group exhibited a response rate of 60% with 5 patients achieving a complete response and a disease control rate of 70%, while the chemotherapy-alone group showed a response rate of only 21% with no complete response and a disease control rate of 64%.¹⁵

The ketogenic diet also reportedly stimulates cytokine and CD4+ and CD8+ T-cell production that stimulates T-cell killing activity. The ketogenic diet may overcome several immune escape mechanisms by downregulating the expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on tumor-infiltrating lymphocytes.¹⁶ Our patient tolerated the combination of the ketogenic diet with ipilimumab (CTLA-4 inhibitor) and nivolumab (PD-1 inhibitor) without significant toxicities and stabilization of his disease.

Future Directions

We originally presented the abstract and poster of this case report at the Association of VA Hematology/Oncology annual meeting in San Diego, California, in September 2022.¹⁷ Based on our previous experience, we are now using a modified Atkins diet, which is a less strict diet consisting of 60% fat, 30% protein, and 10% carbohydrates combined with chemotherapy and/or immunotherapy. The composition of fat to carbohydrate plus protein in the traditional ketogenic diet is usually 4:1 or 3:1, while in modified Atkins diet the ratio is 1:1 or 2:1. The benefit of the modified Atkins diet is that patients can consume more protein than a strict ketogenic diet and they can be more liberal in carbohydrate allowances. We are about to open a study protocol of combining a modified Atkin diet and chemotherapy and/or immunotherapy as a first-line treatment for veterans with all types of advanced or metastatic solid tumors at VACCHCS. The study protocol was approved by the VA Office of Research and Development and has been submitted to the VACCHCS Institutional Review Board for review. Once approved, we will start patient recruitment.

CONCLUSIONS

Cancer cells have defects in their mitochondria that prevent them from generating energy for metabolism in the absence of glucose. They also depend on the PI3K signaling pathway to survive. The ketogenic diet has the advantage of affecting cancer cell growth by exploiting these mitochondrial defects and blocking hyperglycemia. There is growing evidence that the ketogenic diet is feasible, tolerable, and reportedly inhibits cancer growth. Our case report and previous publications suggest that the ketogenic diet can be added to chemotherapy and/or immunotherapy as an adjunct to standard-of-care cancer treatment while maintaining good QOL. We are planning to open a clinical trial using the modified Atkins diet in conjunction with active cancer treatments as first-line therapy for metastatic solid tumors at the VACCHCS. We are also working closely with researchers from several veteran hospitals to do a diet collaborative study. We believe the ketogenic diet is an important part of cancer treatment and has a promising future. More research should be dedicated to this very interesting field.

Acknowledgments

We previously presented this case report in an abstract and poster at the September 2022 AVAHO meeting in San Diego, California.

Originally developed for the treatment of refractory epilepsy, the ketogenic diet is distinguished by its high-fat, moderate-protein, and low-carbohydrate food program. Preclinical models provide emerging evidence that a ketogenic diet can have therapeutic potential for a broad range of cancers. The Warburg effect is a condition where cancer cells increase the uptake and fermentation of glucose to produce lactate for their metabolism, which is called aerobic glycolysis. Lactate is the key driver of cancer angiogenesis and proliferation.^1,2

The ketogenic diet promotes a metabolic shift from glycolysis to mitochondrial metabolism in normal cells while cancer cells have dysfunction in their mitochondria due to damage in cellular respiration. The ketogenic diet creates a metabolic state whereby blood glucose levels are reduced, and blood ketone bodies (D-β-hydroxybutyrate and acetoacetate) are elevated. In normal cells, the ketogenic diet causes a decrease in glucose intake for glycolysis, which makes them unable to produce enough substrate to enter the tricarboxylic acid (TCA) cycle for adenosine triphosphate (ATP) production. Fatty acid oxidation plays a key role in ketone body synthesis as a “super fuel” that enter the TCA cycle as an alternative pathway to generate ATP. On the other hand, cancer cells are unable to use ketone bodies to produce ATP for energy and metabolism due to mitochondrial defects. Lack of energy subsequently leads to the inhibition of proliferation and survival of cancer cells.^3,4

CASE PRESENTATION

A 69-year-old veteran had iron deficiency anemia (hemoglobin, 6.5 g/dL) about 5 years previously. He underwent a colonoscopy that revealed a near circumferential ulcerated mass measuring 7 cm in the transverse colon. Biopsy results showed mucinous adenocarcinoma of the colon with a foci of signet ring cells (Figure 2).

The patient received adjuvant treatment with FOLFOX (fluorouracil, leucovorin calcium, and oxaliplatin), but within several months he developed pancreatic and worsening omental metastasis seen on PET/CT. He was then started on FOLFIRI (fluorouracil, leucovorin calcium, and irinotecan hydrochloride) plus bevacizumab 16 months after his initial diagnosis. He underwent a pancreatic mastectomy that confirmed adenocarcinoma 9 months later. Afterward, he briefly resumed FOLFIRI and bevacizumab. Next-generation sequencing testing with Foundation One CDx revealed a wild-type (WT) KRAS with a high degree of tumor mutation burden of 37 muts/Mb, BRAF V600E mutation, and high microsatellite instability (MSI-H).

The purpose of this case report is to describe whether a patient receiving active cancer treatment was able to tolerate the ketogenic diet in conjunction with chemotherapy or immunotherapy. Most literature published on the subject evaluated the tolerability and response of the ketogenic diet after the failure of standard therapy. Our patient was diagnosed with stage III mucinous colon adenocarcinoma. He received adjuvant chemotherapy but quickly developed metastatic disease to the pancreas and omentum. We started him on encorafenib and cetuximab based on the BEACON study that showed improvement in response rate and survival when compared with standard chemotherapy for patients with BRAF V600E mutation.⁵ Unfortunately, his cancer quickly progressed within 4 months and again did not respond to pembrolizumab despite MSI-H, which lasted for another 4 months.

We suggested the ketogenic diet and the patient agreed. He started the diet along with trifluridine/tipiracil, and bevacizumab in January 2021. The patient’s metastatic cancer stabilized for 9 months until his disease progressed again. He was started on doublet immune checkpoint inhibitors ipilimumab and nivolumab based on his MSI-H and high tumor mutation burden with the continuation of the ketogenic diet until now. The CheckMate 142 study revealed that the combination of ipilimumab and nivolumab in patients with MSI-H previously treated for metastatic colon cancer showed some benefit.⁶

Our patient had the loss of nuclear expression of MLH1 and PMS2 (zero tumor stained) but no evidence of the loss expression of MSH2 and MSH6 genes (99% tumor stained). About 8% to 12% of patients with metastatic colon cancer have BRAF V600E mutations that are usually mucinous type, poorly differentiated, and located in the right side of the colon, which portends to a poor prognosis. Tumor DNA mismatch repair damage results in genetic hypermutability and leads to MSI that is sensitive to treatment with checkpoint inhibitors, as in our patient. Only about 3% of MSI-H tumors are due to germline mutations such as Lynch syndrome (hereditary nonpolyposis colorectal cancer). The presence of both MLH1 hypermethylation and BRAF mutation, as in our patient, is a strong indication of somatic rather than germline mutation.⁷

GKI, which represents the ratio of glucose to ketone, was developed to evaluate the efficacy of the ketogenic diet. This index measures the degree of metabolic stress on tumor cells through the decrease of glucose levels and increase of ketone bodies. A GKI of ≤ 1.0 has been suggested as the ideal therapeutic goal for cancer management.⁸ As levels of blood glucose decline, the blood levels of ketone bodies should rise. These 2 lines should eventually intersect at a certain point beyond which one enters the therapeutic zone or therapeutic ketosis zone. This is when tumor growth is expected to slow or cease.⁹ The patient’s ketone (β-hydroxybutyrate) level was initially high (0.71 mmol/L) with a GKI of 8.2. (low ketotic level), which meant he tolerated a rather strict diet for the first several months. This was also reflected in his 18 lb weight loss (almost 10% of body weight) and cancer stabilization, as in our previous publication.¹ Unfortunately, the patient was unable to maintain high ketone and lower GKI levels due to fatigue from depleted carbohydrate intake. He added some carbohydrate snacks in between meals, which improved the fatigue. His ketone level has been < 0.5 mmol/L ever since, albeit his disease continues to be stable. The patient continues his daily work and reports a better QOL, based on the ECOG QLC-C30 form that he completed every 3 months.¹⁰ Currently, the patient is still receiving ipilimumab and nivolumab while maintaining the ketogenic diet with stable metastatic disease on PET/CT.

Ketogenic Diet and Cellular Mechanism of Action

PI3K/Akt (phosphatidylinositol-3-kinase) signaling is one of the most important intracellular pathways for tumor cells. It leads to the inhibition of apoptosis and the promotion of cell proliferation, metabolism, and angiogenesis. Deregulation of the PI3K pathway either via amplification of PI3K by tyrosine kinase growth factor receptors or inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN), which is the negative regulator of the PI3K pathway, contributes to the development of cancer cells.¹¹

A study by Goncalves and colleagues revealed an interesting relationship between the PI3K pathway and the benefit of the ketogenic diet to slow tumor growth. PI3K inhibitors inhibit glucose uptake into skeletal muscle and adipose tissue that activate hepatic glycogenolysis. This event results in hyperglycemia due to the pancreas releasing very high levels of insulin into the blood (hyperinsulinemia) that subsequently reactivate PI3K signaling and cause resistance to PI3K inhibitors. The ketogenic diet reportedly minimized the hyperglycemia and hyperinsulinemia induced by the PI3K inhibitor and enhanced the efficacy of PI3K inhibitors in tumor models. Studies combining PI3K inhibitors and ketogenic diet are underway. Hence, combining the ketogenic diet with chemotherapy or other novel treatment should be the focus of ketogenic diet trials.^12,13

The impact of the ketogenic diet on the growth of murine pancreatic tumors was evaluated by Yang and colleagues. The ketogenic diet decreased glucose concentration that enters the TCA cycle and increased fatty acid oxidation that produces β-hydroxybutyrate. This event promotes the generation of ATP, although with only modest elevations of NADH with less impact on tumor growth. The combination of ketogenic diet and standard chemotherapy substantially raised tumor NADH and suppressed the growth of murine tumor cells, they noted.¹⁴ Furukawa and colleagues compared 10 patients with metastatic colon cancer receiving chemotherapy plus the modified medium-chain triglyceride ketogenic diet for 1 year with 14 patients receiving chemotherapy only. The ketogenic diet group exhibited a response rate of 60% with 5 patients achieving a complete response and a disease control rate of 70%, while the chemotherapy-alone group showed a response rate of only 21% with no complete response and a disease control rate of 64%.¹⁵

The ketogenic diet also reportedly stimulates cytokine and CD4+ and CD8+ T-cell production that stimulates T-cell killing activity. The ketogenic diet may overcome several immune escape mechanisms by downregulating the expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on tumor-infiltrating lymphocytes.¹⁶ Our patient tolerated the combination of the ketogenic diet with ipilimumab (CTLA-4 inhibitor) and nivolumab (PD-1 inhibitor) without significant toxicities and stabilization of his disease.

Future Directions

We originally presented the abstract and poster of this case report at the Association of VA Hematology/Oncology annual meeting in San Diego, California, in September 2022.¹⁷ Based on our previous experience, we are now using a modified Atkins diet, which is a less strict diet consisting of 60% fat, 30% protein, and 10% carbohydrates combined with chemotherapy and/or immunotherapy. The composition of fat to carbohydrate plus protein in the traditional ketogenic diet is usually 4:1 or 3:1, while in modified Atkins diet the ratio is 1:1 or 2:1. The benefit of the modified Atkins diet is that patients can consume more protein than a strict ketogenic diet and they can be more liberal in carbohydrate allowances. We are about to open a study protocol of combining a modified Atkin diet and chemotherapy and/or immunotherapy as a first-line treatment for veterans with all types of advanced or metastatic solid tumors at VACCHCS. The study protocol was approved by the VA Office of Research and Development and has been submitted to the VACCHCS Institutional Review Board for review. Once approved, we will start patient recruitment.

CONCLUSIONS

Cancer cells have defects in their mitochondria that prevent them from generating energy for metabolism in the absence of glucose. They also depend on the PI3K signaling pathway to survive. The ketogenic diet has the advantage of affecting cancer cell growth by exploiting these mitochondrial defects and blocking hyperglycemia. There is growing evidence that the ketogenic diet is feasible, tolerable, and reportedly inhibits cancer growth. Our case report and previous publications suggest that the ketogenic diet can be added to chemotherapy and/or immunotherapy as an adjunct to standard-of-care cancer treatment while maintaining good QOL. We are planning to open a clinical trial using the modified Atkins diet in conjunction with active cancer treatments as first-line therapy for metastatic solid tumors at the VACCHCS. We are also working closely with researchers from several veteran hospitals to do a diet collaborative study. We believe the ketogenic diet is an important part of cancer treatment and has a promising future. More research should be dedicated to this very interesting field.

Acknowledgments

We previously presented this case report in an abstract and poster at the September 2022 AVAHO meeting in San Diego, California.

Originally developed for the treatment of refractory epilepsy, the ketogenic diet is distinguished by its high-fat, moderate-protein, and low-carbohydrate food program. Preclinical models provide emerging evidence that a ketogenic diet can have therapeutic potential for a broad range of cancers. The Warburg effect is a condition where cancer cells increase the uptake and fermentation of glucose to produce lactate for their metabolism, which is called aerobic glycolysis. Lactate is the key driver of cancer angiogenesis and proliferation.^1,2

The ketogenic diet promotes a metabolic shift from glycolysis to mitochondrial metabolism in normal cells while cancer cells have dysfunction in their mitochondria due to damage in cellular respiration. The ketogenic diet creates a metabolic state whereby blood glucose levels are reduced, and blood ketone bodies (D-β-hydroxybutyrate and acetoacetate) are elevated. In normal cells, the ketogenic diet causes a decrease in glucose intake for glycolysis, which makes them unable to produce enough substrate to enter the tricarboxylic acid (TCA) cycle for adenosine triphosphate (ATP) production. Fatty acid oxidation plays a key role in ketone body synthesis as a “super fuel” that enter the TCA cycle as an alternative pathway to generate ATP. On the other hand, cancer cells are unable to use ketone bodies to produce ATP for energy and metabolism due to mitochondrial defects. Lack of energy subsequently leads to the inhibition of proliferation and survival of cancer cells.^3,4

CASE PRESENTATION

A 69-year-old veteran had iron deficiency anemia (hemoglobin, 6.5 g/dL) about 5 years previously. He underwent a colonoscopy that revealed a near circumferential ulcerated mass measuring 7 cm in the transverse colon. Biopsy results showed mucinous adenocarcinoma of the colon with a foci of signet ring cells (Figure 2).

The patient received adjuvant treatment with FOLFOX (fluorouracil, leucovorin calcium, and oxaliplatin), but within several months he developed pancreatic and worsening omental metastasis seen on PET/CT. He was then started on FOLFIRI (fluorouracil, leucovorin calcium, and irinotecan hydrochloride) plus bevacizumab 16 months after his initial diagnosis. He underwent a pancreatic mastectomy that confirmed adenocarcinoma 9 months later. Afterward, he briefly resumed FOLFIRI and bevacizumab. Next-generation sequencing testing with Foundation One CDx revealed a wild-type (WT) KRAS with a high degree of tumor mutation burden of 37 muts/Mb, BRAF V600E mutation, and high microsatellite instability (MSI-H).

The purpose of this case report is to describe whether a patient receiving active cancer treatment was able to tolerate the ketogenic diet in conjunction with chemotherapy or immunotherapy. Most literature published on the subject evaluated the tolerability and response of the ketogenic diet after the failure of standard therapy. Our patient was diagnosed with stage III mucinous colon adenocarcinoma. He received adjuvant chemotherapy but quickly developed metastatic disease to the pancreas and omentum. We started him on encorafenib and cetuximab based on the BEACON study that showed improvement in response rate and survival when compared with standard chemotherapy for patients with BRAF V600E mutation.⁵ Unfortunately, his cancer quickly progressed within 4 months and again did not respond to pembrolizumab despite MSI-H, which lasted for another 4 months.

We suggested the ketogenic diet and the patient agreed. He started the diet along with trifluridine/tipiracil, and bevacizumab in January 2021. The patient’s metastatic cancer stabilized for 9 months until his disease progressed again. He was started on doublet immune checkpoint inhibitors ipilimumab and nivolumab based on his MSI-H and high tumor mutation burden with the continuation of the ketogenic diet until now. The CheckMate 142 study revealed that the combination of ipilimumab and nivolumab in patients with MSI-H previously treated for metastatic colon cancer showed some benefit.⁶

Our patient had the loss of nuclear expression of MLH1 and PMS2 (zero tumor stained) but no evidence of the loss expression of MSH2 and MSH6 genes (99% tumor stained). About 8% to 12% of patients with metastatic colon cancer have BRAF V600E mutations that are usually mucinous type, poorly differentiated, and located in the right side of the colon, which portends to a poor prognosis. Tumor DNA mismatch repair damage results in genetic hypermutability and leads to MSI that is sensitive to treatment with checkpoint inhibitors, as in our patient. Only about 3% of MSI-H tumors are due to germline mutations such as Lynch syndrome (hereditary nonpolyposis colorectal cancer). The presence of both MLH1 hypermethylation and BRAF mutation, as in our patient, is a strong indication of somatic rather than germline mutation.⁷

GKI, which represents the ratio of glucose to ketone, was developed to evaluate the efficacy of the ketogenic diet. This index measures the degree of metabolic stress on tumor cells through the decrease of glucose levels and increase of ketone bodies. A GKI of ≤ 1.0 has been suggested as the ideal therapeutic goal for cancer management.⁸ As levels of blood glucose decline, the blood levels of ketone bodies should rise. These 2 lines should eventually intersect at a certain point beyond which one enters the therapeutic zone or therapeutic ketosis zone. This is when tumor growth is expected to slow or cease.⁹ The patient’s ketone (β-hydroxybutyrate) level was initially high (0.71 mmol/L) with a GKI of 8.2. (low ketotic level), which meant he tolerated a rather strict diet for the first several months. This was also reflected in his 18 lb weight loss (almost 10% of body weight) and cancer stabilization, as in our previous publication.¹ Unfortunately, the patient was unable to maintain high ketone and lower GKI levels due to fatigue from depleted carbohydrate intake. He added some carbohydrate snacks in between meals, which improved the fatigue. His ketone level has been < 0.5 mmol/L ever since, albeit his disease continues to be stable. The patient continues his daily work and reports a better QOL, based on the ECOG QLC-C30 form that he completed every 3 months.¹⁰ Currently, the patient is still receiving ipilimumab and nivolumab while maintaining the ketogenic diet with stable metastatic disease on PET/CT.

Ketogenic Diet and Cellular Mechanism of Action

PI3K/Akt (phosphatidylinositol-3-kinase) signaling is one of the most important intracellular pathways for tumor cells. It leads to the inhibition of apoptosis and the promotion of cell proliferation, metabolism, and angiogenesis. Deregulation of the PI3K pathway either via amplification of PI3K by tyrosine kinase growth factor receptors or inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN), which is the negative regulator of the PI3K pathway, contributes to the development of cancer cells.¹¹

A study by Goncalves and colleagues revealed an interesting relationship between the PI3K pathway and the benefit of the ketogenic diet to slow tumor growth. PI3K inhibitors inhibit glucose uptake into skeletal muscle and adipose tissue that activate hepatic glycogenolysis. This event results in hyperglycemia due to the pancreas releasing very high levels of insulin into the blood (hyperinsulinemia) that subsequently reactivate PI3K signaling and cause resistance to PI3K inhibitors. The ketogenic diet reportedly minimized the hyperglycemia and hyperinsulinemia induced by the PI3K inhibitor and enhanced the efficacy of PI3K inhibitors in tumor models. Studies combining PI3K inhibitors and ketogenic diet are underway. Hence, combining the ketogenic diet with chemotherapy or other novel treatment should be the focus of ketogenic diet trials.^12,13

The impact of the ketogenic diet on the growth of murine pancreatic tumors was evaluated by Yang and colleagues. The ketogenic diet decreased glucose concentration that enters the TCA cycle and increased fatty acid oxidation that produces β-hydroxybutyrate. This event promotes the generation of ATP, although with only modest elevations of NADH with less impact on tumor growth. The combination of ketogenic diet and standard chemotherapy substantially raised tumor NADH and suppressed the growth of murine tumor cells, they noted.¹⁴ Furukawa and colleagues compared 10 patients with metastatic colon cancer receiving chemotherapy plus the modified medium-chain triglyceride ketogenic diet for 1 year with 14 patients receiving chemotherapy only. The ketogenic diet group exhibited a response rate of 60% with 5 patients achieving a complete response and a disease control rate of 70%, while the chemotherapy-alone group showed a response rate of only 21% with no complete response and a disease control rate of 64%.¹⁵

The ketogenic diet also reportedly stimulates cytokine and CD4+ and CD8+ T-cell production that stimulates T-cell killing activity. The ketogenic diet may overcome several immune escape mechanisms by downregulating the expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on tumor-infiltrating lymphocytes.¹⁶ Our patient tolerated the combination of the ketogenic diet with ipilimumab (CTLA-4 inhibitor) and nivolumab (PD-1 inhibitor) without significant toxicities and stabilization of his disease.

Future Directions

We originally presented the abstract and poster of this case report at the Association of VA Hematology/Oncology annual meeting in San Diego, California, in September 2022.¹⁷ Based on our previous experience, we are now using a modified Atkins diet, which is a less strict diet consisting of 60% fat, 30% protein, and 10% carbohydrates combined with chemotherapy and/or immunotherapy. The composition of fat to carbohydrate plus protein in the traditional ketogenic diet is usually 4:1 or 3:1, while in modified Atkins diet the ratio is 1:1 or 2:1. The benefit of the modified Atkins diet is that patients can consume more protein than a strict ketogenic diet and they can be more liberal in carbohydrate allowances. We are about to open a study protocol of combining a modified Atkin diet and chemotherapy and/or immunotherapy as a first-line treatment for veterans with all types of advanced or metastatic solid tumors at VACCHCS. The study protocol was approved by the VA Office of Research and Development and has been submitted to the VACCHCS Institutional Review Board for review. Once approved, we will start patient recruitment.

CONCLUSIONS

Cancer cells have defects in their mitochondria that prevent them from generating energy for metabolism in the absence of glucose. They also depend on the PI3K signaling pathway to survive. The ketogenic diet has the advantage of affecting cancer cell growth by exploiting these mitochondrial defects and blocking hyperglycemia. There is growing evidence that the ketogenic diet is feasible, tolerable, and reportedly inhibits cancer growth. Our case report and previous publications suggest that the ketogenic diet can be added to chemotherapy and/or immunotherapy as an adjunct to standard-of-care cancer treatment while maintaining good QOL. We are planning to open a clinical trial using the modified Atkins diet in conjunction with active cancer treatments as first-line therapy for metastatic solid tumors at the VACCHCS. We are also working closely with researchers from several veteran hospitals to do a diet collaborative study. We believe the ketogenic diet is an important part of cancer treatment and has a promising future. More research should be dedicated to this very interesting field.

Acknowledgments

We previously presented this case report in an abstract and poster at the September 2022 AVAHO meeting in San Diego, California.