News

TOPLINE:

For patients with early-stage ERBB2 (formerly HER2)–positive breast cancer, injections of increasing doses of autologous conventional type 1 dendritic cells (cDC1) combined with ERBB2-targeted antibodies demonstrate safety and effectiveness in enhancing immune response. The higher dose (100 million cells) shows enhanced immune effector recruitment and significant tumor regression before chemotherapy initiation.

METHODOLOGY:

• ERBB2-positive breast cancer survival has improved with anti-ERBB2 antibodies trastuzumab and pertuzumab, but for a pathologic complete response, chemotherapy remains necessary, which comes with significant toxic effects.
• A phase 1, nonrandomized clinical trial enrolled 12 patients with early-stage ERBB2-positive breast cancer in Tampa, Florida, from October 2021 to October 2022.
• Participants received intratumoral (IT) cDC1 injections weekly for 6 weeks at two dose levels (50 million cells for dose level 1 and 100 million cells for dose level 2), with six patients in each group.
• Starting from day 1 of the cDC1 injections, treatment included trastuzumab (8-mg/kg loading dose, then 6 mg/kg) and pertuzumab (840-mg loading dose, then 420 mg) administered intravenously every 3 weeks for six cycles, followed by paclitaxel (80 mg/m²) weekly for 12 weeks and surgery with lumpectomy or mastectomy.
• Primary outcomes measured safety and immune response of increasing doses of cDC1 combined with anti-ERBB2 antibodies before neoadjuvant chemotherapy; secondary outcomes assessed antitumor efficacy through breast MRI and residual cancer burden at surgery.

TAKEAWAY:

• IT delivery of ERBB2 cDC1 was safe and not associated with any dose-limiting toxic effects. The most frequent adverse events attributed to cDC1 were grade 1-2 chills (50%), fatigue (41.7%), headache (33%), and injection-site reactions (33%).
• Dose level 2 showed enhanced recruitment of adaptive CD3, CD4, and CD8 T cells and B cells within the tumor microenvironment (TME), along with increased innate gamma delta T cells and natural killer T cells.
• Breast MRI revealed nine objective responses, including six partial responses and three complete responses, with three cases of stable disease.
• Following surgery, 7 of 12 patients (58%) achieved a pathologic complete response, including all 3 hormone receptor–negative patients and 4 of the 9 hormone receptor–positive patients.

IN PRACTICE:

“Overall, the clinical data shown here demonstrate the effects of combining ERBB2 antibodies with IT [intratumoral] delivery of targeted cDC1 to enhance immune cell infiltration within the TME [tumor microenvironment] and subsequently induce tumor regression before chemotherapy,” wrote the authors, who noted they will be testing the higher dose for an ongoing phase 2 trial with an additional 41 patients.

SOURCE:

The study was led by Hyo S. Han, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. It was published online on December 5, 2024, in JAMA Oncology.

LIMITATIONS:

Because only two dose levels of cDC1 were tested, it remains unclear whether higher doses or different administration schedules could further enhance immune response. Additionally, the nonrandomized design prevents definitive conclusions about whether the clinical benefits were solely from the anti-ERBB2 antibodies. The small sample size also makes it difficult to determine if the pathologic complete responses were primarily due to the 12 weeks of trastuzumab/pertuzumab/paclitaxel treatment.

DISCLOSURES:

This study was funded by the Moffitt Breast Cancer Research Fund, Shula Fund, and Pennies in Action. Several authors reported research support and personal and consulting fees from US funding agencies and multiple pharmaceutical companies outside of the submitted work, as well as related intellectual property and patents.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

For patients with early-stage ERBB2 (formerly HER2)–positive breast cancer, injections of increasing doses of autologous conventional type 1 dendritic cells (cDC1) combined with ERBB2-targeted antibodies demonstrate safety and effectiveness in enhancing immune response. The higher dose (100 million cells) shows enhanced immune effector recruitment and significant tumor regression before chemotherapy initiation.

METHODOLOGY:

• ERBB2-positive breast cancer survival has improved with anti-ERBB2 antibodies trastuzumab and pertuzumab, but for a pathologic complete response, chemotherapy remains necessary, which comes with significant toxic effects.
• A phase 1, nonrandomized clinical trial enrolled 12 patients with early-stage ERBB2-positive breast cancer in Tampa, Florida, from October 2021 to October 2022.
• Participants received intratumoral (IT) cDC1 injections weekly for 6 weeks at two dose levels (50 million cells for dose level 1 and 100 million cells for dose level 2), with six patients in each group.
• Starting from day 1 of the cDC1 injections, treatment included trastuzumab (8-mg/kg loading dose, then 6 mg/kg) and pertuzumab (840-mg loading dose, then 420 mg) administered intravenously every 3 weeks for six cycles, followed by paclitaxel (80 mg/m²) weekly for 12 weeks and surgery with lumpectomy or mastectomy.
• Primary outcomes measured safety and immune response of increasing doses of cDC1 combined with anti-ERBB2 antibodies before neoadjuvant chemotherapy; secondary outcomes assessed antitumor efficacy through breast MRI and residual cancer burden at surgery.

TAKEAWAY:

• IT delivery of ERBB2 cDC1 was safe and not associated with any dose-limiting toxic effects. The most frequent adverse events attributed to cDC1 were grade 1-2 chills (50%), fatigue (41.7%), headache (33%), and injection-site reactions (33%).
• Dose level 2 showed enhanced recruitment of adaptive CD3, CD4, and CD8 T cells and B cells within the tumor microenvironment (TME), along with increased innate gamma delta T cells and natural killer T cells.
• Breast MRI revealed nine objective responses, including six partial responses and three complete responses, with three cases of stable disease.
• Following surgery, 7 of 12 patients (58%) achieved a pathologic complete response, including all 3 hormone receptor–negative patients and 4 of the 9 hormone receptor–positive patients.

IN PRACTICE:

“Overall, the clinical data shown here demonstrate the effects of combining ERBB2 antibodies with IT [intratumoral] delivery of targeted cDC1 to enhance immune cell infiltration within the TME [tumor microenvironment] and subsequently induce tumor regression before chemotherapy,” wrote the authors, who noted they will be testing the higher dose for an ongoing phase 2 trial with an additional 41 patients.

SOURCE:

The study was led by Hyo S. Han, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. It was published online on December 5, 2024, in JAMA Oncology.

LIMITATIONS:

Because only two dose levels of cDC1 were tested, it remains unclear whether higher doses or different administration schedules could further enhance immune response. Additionally, the nonrandomized design prevents definitive conclusions about whether the clinical benefits were solely from the anti-ERBB2 antibodies. The small sample size also makes it difficult to determine if the pathologic complete responses were primarily due to the 12 weeks of trastuzumab/pertuzumab/paclitaxel treatment.

DISCLOSURES:

This study was funded by the Moffitt Breast Cancer Research Fund, Shula Fund, and Pennies in Action. Several authors reported research support and personal and consulting fees from US funding agencies and multiple pharmaceutical companies outside of the submitted work, as well as related intellectual property and patents.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

For patients with early-stage ERBB2 (formerly HER2)–positive breast cancer, injections of increasing doses of autologous conventional type 1 dendritic cells (cDC1) combined with ERBB2-targeted antibodies demonstrate safety and effectiveness in enhancing immune response. The higher dose (100 million cells) shows enhanced immune effector recruitment and significant tumor regression before chemotherapy initiation.

METHODOLOGY:

• ERBB2-positive breast cancer survival has improved with anti-ERBB2 antibodies trastuzumab and pertuzumab, but for a pathologic complete response, chemotherapy remains necessary, which comes with significant toxic effects.
• A phase 1, nonrandomized clinical trial enrolled 12 patients with early-stage ERBB2-positive breast cancer in Tampa, Florida, from October 2021 to October 2022.
• Participants received intratumoral (IT) cDC1 injections weekly for 6 weeks at two dose levels (50 million cells for dose level 1 and 100 million cells for dose level 2), with six patients in each group.
• Starting from day 1 of the cDC1 injections, treatment included trastuzumab (8-mg/kg loading dose, then 6 mg/kg) and pertuzumab (840-mg loading dose, then 420 mg) administered intravenously every 3 weeks for six cycles, followed by paclitaxel (80 mg/m²) weekly for 12 weeks and surgery with lumpectomy or mastectomy.
• Primary outcomes measured safety and immune response of increasing doses of cDC1 combined with anti-ERBB2 antibodies before neoadjuvant chemotherapy; secondary outcomes assessed antitumor efficacy through breast MRI and residual cancer burden at surgery.

TAKEAWAY:

• IT delivery of ERBB2 cDC1 was safe and not associated with any dose-limiting toxic effects. The most frequent adverse events attributed to cDC1 were grade 1-2 chills (50%), fatigue (41.7%), headache (33%), and injection-site reactions (33%).
• Dose level 2 showed enhanced recruitment of adaptive CD3, CD4, and CD8 T cells and B cells within the tumor microenvironment (TME), along with increased innate gamma delta T cells and natural killer T cells.
• Breast MRI revealed nine objective responses, including six partial responses and three complete responses, with three cases of stable disease.
• Following surgery, 7 of 12 patients (58%) achieved a pathologic complete response, including all 3 hormone receptor–negative patients and 4 of the 9 hormone receptor–positive patients.

IN PRACTICE:

“Overall, the clinical data shown here demonstrate the effects of combining ERBB2 antibodies with IT [intratumoral] delivery of targeted cDC1 to enhance immune cell infiltration within the TME [tumor microenvironment] and subsequently induce tumor regression before chemotherapy,” wrote the authors, who noted they will be testing the higher dose for an ongoing phase 2 trial with an additional 41 patients.

SOURCE:

The study was led by Hyo S. Han, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. It was published online on December 5, 2024, in JAMA Oncology.

LIMITATIONS:

Because only two dose levels of cDC1 were tested, it remains unclear whether higher doses or different administration schedules could further enhance immune response. Additionally, the nonrandomized design prevents definitive conclusions about whether the clinical benefits were solely from the anti-ERBB2 antibodies. The small sample size also makes it difficult to determine if the pathologic complete responses were primarily due to the 12 weeks of trastuzumab/pertuzumab/paclitaxel treatment.

DISCLOSURES:

This study was funded by the Moffitt Breast Cancer Research Fund, Shula Fund, and Pennies in Action. Several authors reported research support and personal and consulting fees from US funding agencies and multiple pharmaceutical companies outside of the submitted work, as well as related intellectual property and patents.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Vaccines for treating and preventing cancer have long been considered a holy grail in oncology.

But aside from a few notable exceptions — including the human papillomavirus (HPV) vaccine, which has dramatically reduced the incidence of HPV-related cancers, and a Bacillus Calmette-Guerin vaccine, which helps prevent early-stage bladder cancer recurrence — most have failed to deliver.

Following a string of disappointments over the past decade, recent advances in the immunotherapy space are bringing renewed hope for progress.

In an American Association for Cancer Research (AACR) series earlier in 2024, Catherine J. Wu, MD, predicted big strides for cancer vaccines, especially for personalized vaccines that target patient-specific neoantigens — the proteins that form on cancer cells — as well as vaccines that can treat diverse tumor types.

“A focus on neoantigens that arise from driver mutations in different tumor types could allow us to make progress in creating off-the-shelf vaccines,” said Wu, the Lavine Family Chair of Preventative Cancer Therapies at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

A prime example is a personalized, messenger RNA (mRNA)–based vaccine designed to prevent melanoma recurrence. The mRNA-4157 vaccine encodes up to 34 different patient-specific neoantigens.

“This is one of the most exciting developments in modern cancer therapy,” said Lawrence Young, a virologist and professor of molecular oncology at the University of Warwick, Coventry, England, who commented on the investigational vaccine via the UK-based Science Media Centre.

Other promising options are on the horizon as well. In August, BioNTech announced a phase 1 global trial to study BNT116 — a vaccine to treat non–small cell lung cancer (NSCLC). BNT116, like mRNA-4157, targets specific antigens in the lung cancer cells.

“This technology is the next big phase of cancer treatment,” Siow Ming Lee, MD, a consultant medical oncologist at University College London Hospitals in England, which is leading the UK trial for the lung cancer and melanoma vaccines, told The Guardian. “We are now entering this very exciting new era of mRNA-based immunotherapy clinical trials to investigate the treatment of lung cancer.”

Still, these predictions have a familiar ring. While the prospects are exciting, delivering on them is another story. There are simply no guarantees these strategies will work as hoped.

 

Then: Where We Were

Cancer vaccine research began to ramp up in the 2000s, and in 2006, the first-generation HPV vaccine, Gardasil, was approved. Gardasil prevents infection from four strains of HPV that cause about 80% of cervical cancer cases.

In 2010, the Food and Drug Administration approved sipuleucel-T, the first therapeutic cancer vaccine, which improved overall survival in patients with hormone-refractory prostate cancer.

Researchers predicted this approval would “pave the way for developing innovative, next generation of vaccines with enhanced antitumor potency.”

In a 2015 AACR research forecast report, Drew Pardoll, MD, PhD, co-director of the Cancer Immunology and Hematopoiesis Program at Johns Hopkins University, Baltimore, Maryland, said that “we can expect to see encouraging results from studies using cancer vaccines.”

Despite the excitement surrounding cancer vaccines alongside a few successes, the next decade brought a longer string of late-phase disappointments.

In 2016, the phase 3 ACT IV trial of a therapeutic vaccine to treat glioblastoma multiforme (CDX-110) was terminated after it failed to demonstrate improved survival.

In 2017, a phase 3 trial of the therapeutic pancreatic cancer vaccine, GVAX, was stopped early for lack of efficacy.

That year, an attenuated Listeria monocytogenes vaccine to treat pancreatic cancer and mesothelioma also failed to come to fruition. In late 2017, concerns over listeria infections prompted Aduro Biotech to cancel its listeria-based cancer treatment program.

In 2018, a phase 3 trial of belagenpumatucel-L, a therapeutic NSCLC vaccine, failed to demonstrate a significant improvement in survival and further study was discontinued.

And in 2019, a vaccine targeting MAGE-A3, a cancer-testis antigen present in multiple tumor types, failed to meet endpoints for improved survival in a phase 3 trial, leading to discontinuation of the vaccine program.

But these disappointments and failures are normal parts of medical research and drug development and have allowed for incremental advances that helped fuel renewed interest and hope for cancer vaccines, when the timing was right, explained vaccine pioneer Larry W. Kwak, MD, PhD, deputy director of the Comprehensive Cancer Center at City of Hope, Duarte, California.

When it comes to vaccine progress, timing makes a difference. In 2011, Kwak and colleagues published promising phase 3 trial results on a personalized vaccine. The vaccine was a patient-specific tumor-derived antigen for patients with follicular lymphoma in their first remission following chemotherapy. Patients who received the vaccine demonstrated significantly longer disease-free survival.

But, at the time, personalized vaccines faced strong headwinds due, largely, to high costs, and commercial interest failed to materialize. “That’s been the major hurdle for a long time,” said Kwak.

Now, however, interest has returned alongside advances in technology and research. The big shift has been the emergence of lower-cost rapid-production mRNA and DNA platforms and a better understanding of how vaccines and potent immune stimulants, like checkpoint inhibitors, can work together to improve outcomes, he explained.

“The timing wasn’t right” back then, Kwak noted. “Now, it’s a different environment and a different time.”

 

A Turning Point?

Indeed, a decade later, cancer vaccine development appears to be headed in a more promising direction.

Among key cancer vaccines to watch is the mRNA-4157 vaccine, developed by Merck and Moderna, designed to prevent melanoma recurrence. In a recent phase 2 study, patients receiving the mRNA-4157 vaccine alongside pembrolizumab had nearly half the risk for melanoma recurrence or death at 3 years compared with those receiving pembrolizumab alone. Investigators are now evaluating the vaccine in a global phase 3 study in patients with high-risk, stage IIB to IV melanoma following surgery.

Another one to watch is the BNT116 NSCLC vaccine from BioNTech. This vaccine presents the immune system with NSCLC tumor markers to encourage the body to fight cancer cells expressing those markers while ignoring healthy cells. BioNTech also launched a global clinical trial for its vaccine this year.

Other notables include a pancreatic cancer mRNA vaccine, which has shown promising early results in a small trial of 16 patients. Of 16 patients who received the vaccine alongside chemotherapy and after surgery and immunotherapy, 8 responded. Of these eight, six remained recurrence free at 3 years. Investigators noted that the vaccine appeared to stimulate a durable T-cell response in patients who responded.

Kwak has also continued his work on lymphoma vaccines. In August, his team published promising first-in-human data on the use of personalized neoantigen vaccines as an early intervention in untreated patients with lymphoplasmacytic lymphoma. Among nine asymptomatic patients who received the vaccine, all achieved stable disease or better, with no dose-limiting toxicities. One patient had a minor response, and the median time to progression was greater than 72 months.

“The current setting is more for advanced disease,” Kwak explained. “It’s a tougher task, but combined with checkpoint blockade, it may be potent enough to work.” 

Still, caution is important. Despite early promise, it’s too soon to tell which, if any, of these investigational vaccines will pan out in the long run. Like investigational drugs, cancer vaccines may show big promising initially but then fail in larger trials.

One key to success, according to Kwak, is to design trials so that even negative results will inform next steps.

But, he noted, failures in large clinical trials will “put a chilling effect on cancer vaccine research again.”

“That’s what keeps me up at night,” he said. “We know the science is fundamentally sound and we have seen glimpses over decades of research that cancer vaccines can work, so it’s really just a matter of tweaking things to optimize trial design.”

Companies tend to design trials to test if a vaccine works or not, without trying to understand why, he said.

“What we need to do is design those so that we can learn from negative results,” he said. That’s what he and his colleagues attempted to do in their recent trial. “We didn’t just look at clinical results; we’re interrogating the actual tumor environment to understand what worked and didn’t and how to tweak that for the next trial.”

Kwak and his colleagues found, for instance, that the vaccine had a greater effect on B cell–derived tumor cells than on cells of plasma origin, so “the most rational design for the next iteration is to combine the vaccine with agents that work directly against plasma cells,” he explained.

As for what’s next, Kwak said: “We’re just focused on trying to do good science and understand. We’ve seen glimpses of success. That’s where we are.”

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

Vaccines for treating and preventing cancer have long been considered a holy grail in oncology.

But aside from a few notable exceptions — including the human papillomavirus (HPV) vaccine, which has dramatically reduced the incidence of HPV-related cancers, and a Bacillus Calmette-Guerin vaccine, which helps prevent early-stage bladder cancer recurrence — most have failed to deliver.

Following a string of disappointments over the past decade, recent advances in the immunotherapy space are bringing renewed hope for progress.

In an American Association for Cancer Research (AACR) series earlier in 2024, Catherine J. Wu, MD, predicted big strides for cancer vaccines, especially for personalized vaccines that target patient-specific neoantigens — the proteins that form on cancer cells — as well as vaccines that can treat diverse tumor types.

“A focus on neoantigens that arise from driver mutations in different tumor types could allow us to make progress in creating off-the-shelf vaccines,” said Wu, the Lavine Family Chair of Preventative Cancer Therapies at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

A prime example is a personalized, messenger RNA (mRNA)–based vaccine designed to prevent melanoma recurrence. The mRNA-4157 vaccine encodes up to 34 different patient-specific neoantigens.

“This is one of the most exciting developments in modern cancer therapy,” said Lawrence Young, a virologist and professor of molecular oncology at the University of Warwick, Coventry, England, who commented on the investigational vaccine via the UK-based Science Media Centre.

Other promising options are on the horizon as well. In August, BioNTech announced a phase 1 global trial to study BNT116 — a vaccine to treat non–small cell lung cancer (NSCLC). BNT116, like mRNA-4157, targets specific antigens in the lung cancer cells.

“This technology is the next big phase of cancer treatment,” Siow Ming Lee, MD, a consultant medical oncologist at University College London Hospitals in England, which is leading the UK trial for the lung cancer and melanoma vaccines, told The Guardian. “We are now entering this very exciting new era of mRNA-based immunotherapy clinical trials to investigate the treatment of lung cancer.”

Still, these predictions have a familiar ring. While the prospects are exciting, delivering on them is another story. There are simply no guarantees these strategies will work as hoped.

 

Then: Where We Were

Cancer vaccine research began to ramp up in the 2000s, and in 2006, the first-generation HPV vaccine, Gardasil, was approved. Gardasil prevents infection from four strains of HPV that cause about 80% of cervical cancer cases.

In 2010, the Food and Drug Administration approved sipuleucel-T, the first therapeutic cancer vaccine, which improved overall survival in patients with hormone-refractory prostate cancer.

Researchers predicted this approval would “pave the way for developing innovative, next generation of vaccines with enhanced antitumor potency.”

In a 2015 AACR research forecast report, Drew Pardoll, MD, PhD, co-director of the Cancer Immunology and Hematopoiesis Program at Johns Hopkins University, Baltimore, Maryland, said that “we can expect to see encouraging results from studies using cancer vaccines.”

Despite the excitement surrounding cancer vaccines alongside a few successes, the next decade brought a longer string of late-phase disappointments.

In 2016, the phase 3 ACT IV trial of a therapeutic vaccine to treat glioblastoma multiforme (CDX-110) was terminated after it failed to demonstrate improved survival.

In 2017, a phase 3 trial of the therapeutic pancreatic cancer vaccine, GVAX, was stopped early for lack of efficacy.

That year, an attenuated Listeria monocytogenes vaccine to treat pancreatic cancer and mesothelioma also failed to come to fruition. In late 2017, concerns over listeria infections prompted Aduro Biotech to cancel its listeria-based cancer treatment program.

In 2018, a phase 3 trial of belagenpumatucel-L, a therapeutic NSCLC vaccine, failed to demonstrate a significant improvement in survival and further study was discontinued.

And in 2019, a vaccine targeting MAGE-A3, a cancer-testis antigen present in multiple tumor types, failed to meet endpoints for improved survival in a phase 3 trial, leading to discontinuation of the vaccine program.

But these disappointments and failures are normal parts of medical research and drug development and have allowed for incremental advances that helped fuel renewed interest and hope for cancer vaccines, when the timing was right, explained vaccine pioneer Larry W. Kwak, MD, PhD, deputy director of the Comprehensive Cancer Center at City of Hope, Duarte, California.

When it comes to vaccine progress, timing makes a difference. In 2011, Kwak and colleagues published promising phase 3 trial results on a personalized vaccine. The vaccine was a patient-specific tumor-derived antigen for patients with follicular lymphoma in their first remission following chemotherapy. Patients who received the vaccine demonstrated significantly longer disease-free survival.

But, at the time, personalized vaccines faced strong headwinds due, largely, to high costs, and commercial interest failed to materialize. “That’s been the major hurdle for a long time,” said Kwak.

Now, however, interest has returned alongside advances in technology and research. The big shift has been the emergence of lower-cost rapid-production mRNA and DNA platforms and a better understanding of how vaccines and potent immune stimulants, like checkpoint inhibitors, can work together to improve outcomes, he explained.

“The timing wasn’t right” back then, Kwak noted. “Now, it’s a different environment and a different time.”

 

A Turning Point?

Indeed, a decade later, cancer vaccine development appears to be headed in a more promising direction.

Among key cancer vaccines to watch is the mRNA-4157 vaccine, developed by Merck and Moderna, designed to prevent melanoma recurrence. In a recent phase 2 study, patients receiving the mRNA-4157 vaccine alongside pembrolizumab had nearly half the risk for melanoma recurrence or death at 3 years compared with those receiving pembrolizumab alone. Investigators are now evaluating the vaccine in a global phase 3 study in patients with high-risk, stage IIB to IV melanoma following surgery.

Another one to watch is the BNT116 NSCLC vaccine from BioNTech. This vaccine presents the immune system with NSCLC tumor markers to encourage the body to fight cancer cells expressing those markers while ignoring healthy cells. BioNTech also launched a global clinical trial for its vaccine this year.

Other notables include a pancreatic cancer mRNA vaccine, which has shown promising early results in a small trial of 16 patients. Of 16 patients who received the vaccine alongside chemotherapy and after surgery and immunotherapy, 8 responded. Of these eight, six remained recurrence free at 3 years. Investigators noted that the vaccine appeared to stimulate a durable T-cell response in patients who responded.

Kwak has also continued his work on lymphoma vaccines. In August, his team published promising first-in-human data on the use of personalized neoantigen vaccines as an early intervention in untreated patients with lymphoplasmacytic lymphoma. Among nine asymptomatic patients who received the vaccine, all achieved stable disease or better, with no dose-limiting toxicities. One patient had a minor response, and the median time to progression was greater than 72 months.

“The current setting is more for advanced disease,” Kwak explained. “It’s a tougher task, but combined with checkpoint blockade, it may be potent enough to work.” 

Still, caution is important. Despite early promise, it’s too soon to tell which, if any, of these investigational vaccines will pan out in the long run. Like investigational drugs, cancer vaccines may show big promising initially but then fail in larger trials.

One key to success, according to Kwak, is to design trials so that even negative results will inform next steps.

But, he noted, failures in large clinical trials will “put a chilling effect on cancer vaccine research again.”

“That’s what keeps me up at night,” he said. “We know the science is fundamentally sound and we have seen glimpses over decades of research that cancer vaccines can work, so it’s really just a matter of tweaking things to optimize trial design.”

Companies tend to design trials to test if a vaccine works or not, without trying to understand why, he said.

“What we need to do is design those so that we can learn from negative results,” he said. That’s what he and his colleagues attempted to do in their recent trial. “We didn’t just look at clinical results; we’re interrogating the actual tumor environment to understand what worked and didn’t and how to tweak that for the next trial.”

Kwak and his colleagues found, for instance, that the vaccine had a greater effect on B cell–derived tumor cells than on cells of plasma origin, so “the most rational design for the next iteration is to combine the vaccine with agents that work directly against plasma cells,” he explained.

As for what’s next, Kwak said: “We’re just focused on trying to do good science and understand. We’ve seen glimpses of success. That’s where we are.”

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

Vaccines for treating and preventing cancer have long been considered a holy grail in oncology.

But aside from a few notable exceptions — including the human papillomavirus (HPV) vaccine, which has dramatically reduced the incidence of HPV-related cancers, and a Bacillus Calmette-Guerin vaccine, which helps prevent early-stage bladder cancer recurrence — most have failed to deliver.

Following a string of disappointments over the past decade, recent advances in the immunotherapy space are bringing renewed hope for progress.

In an American Association for Cancer Research (AACR) series earlier in 2024, Catherine J. Wu, MD, predicted big strides for cancer vaccines, especially for personalized vaccines that target patient-specific neoantigens — the proteins that form on cancer cells — as well as vaccines that can treat diverse tumor types.

“A focus on neoantigens that arise from driver mutations in different tumor types could allow us to make progress in creating off-the-shelf vaccines,” said Wu, the Lavine Family Chair of Preventative Cancer Therapies at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

A prime example is a personalized, messenger RNA (mRNA)–based vaccine designed to prevent melanoma recurrence. The mRNA-4157 vaccine encodes up to 34 different patient-specific neoantigens.

“This is one of the most exciting developments in modern cancer therapy,” said Lawrence Young, a virologist and professor of molecular oncology at the University of Warwick, Coventry, England, who commented on the investigational vaccine via the UK-based Science Media Centre.

Other promising options are on the horizon as well. In August, BioNTech announced a phase 1 global trial to study BNT116 — a vaccine to treat non–small cell lung cancer (NSCLC). BNT116, like mRNA-4157, targets specific antigens in the lung cancer cells.

“This technology is the next big phase of cancer treatment,” Siow Ming Lee, MD, a consultant medical oncologist at University College London Hospitals in England, which is leading the UK trial for the lung cancer and melanoma vaccines, told The Guardian. “We are now entering this very exciting new era of mRNA-based immunotherapy clinical trials to investigate the treatment of lung cancer.”

Still, these predictions have a familiar ring. While the prospects are exciting, delivering on them is another story. There are simply no guarantees these strategies will work as hoped.

 

Then: Where We Were

Cancer vaccine research began to ramp up in the 2000s, and in 2006, the first-generation HPV vaccine, Gardasil, was approved. Gardasil prevents infection from four strains of HPV that cause about 80% of cervical cancer cases.

In 2010, the Food and Drug Administration approved sipuleucel-T, the first therapeutic cancer vaccine, which improved overall survival in patients with hormone-refractory prostate cancer.

Researchers predicted this approval would “pave the way for developing innovative, next generation of vaccines with enhanced antitumor potency.”

In a 2015 AACR research forecast report, Drew Pardoll, MD, PhD, co-director of the Cancer Immunology and Hematopoiesis Program at Johns Hopkins University, Baltimore, Maryland, said that “we can expect to see encouraging results from studies using cancer vaccines.”

Despite the excitement surrounding cancer vaccines alongside a few successes, the next decade brought a longer string of late-phase disappointments.

In 2016, the phase 3 ACT IV trial of a therapeutic vaccine to treat glioblastoma multiforme (CDX-110) was terminated after it failed to demonstrate improved survival.

In 2017, a phase 3 trial of the therapeutic pancreatic cancer vaccine, GVAX, was stopped early for lack of efficacy.

That year, an attenuated Listeria monocytogenes vaccine to treat pancreatic cancer and mesothelioma also failed to come to fruition. In late 2017, concerns over listeria infections prompted Aduro Biotech to cancel its listeria-based cancer treatment program.

In 2018, a phase 3 trial of belagenpumatucel-L, a therapeutic NSCLC vaccine, failed to demonstrate a significant improvement in survival and further study was discontinued.

And in 2019, a vaccine targeting MAGE-A3, a cancer-testis antigen present in multiple tumor types, failed to meet endpoints for improved survival in a phase 3 trial, leading to discontinuation of the vaccine program.

But these disappointments and failures are normal parts of medical research and drug development and have allowed for incremental advances that helped fuel renewed interest and hope for cancer vaccines, when the timing was right, explained vaccine pioneer Larry W. Kwak, MD, PhD, deputy director of the Comprehensive Cancer Center at City of Hope, Duarte, California.

When it comes to vaccine progress, timing makes a difference. In 2011, Kwak and colleagues published promising phase 3 trial results on a personalized vaccine. The vaccine was a patient-specific tumor-derived antigen for patients with follicular lymphoma in their first remission following chemotherapy. Patients who received the vaccine demonstrated significantly longer disease-free survival.

But, at the time, personalized vaccines faced strong headwinds due, largely, to high costs, and commercial interest failed to materialize. “That’s been the major hurdle for a long time,” said Kwak.

Now, however, interest has returned alongside advances in technology and research. The big shift has been the emergence of lower-cost rapid-production mRNA and DNA platforms and a better understanding of how vaccines and potent immune stimulants, like checkpoint inhibitors, can work together to improve outcomes, he explained.

“The timing wasn’t right” back then, Kwak noted. “Now, it’s a different environment and a different time.”

 

A Turning Point?

Indeed, a decade later, cancer vaccine development appears to be headed in a more promising direction.

Among key cancer vaccines to watch is the mRNA-4157 vaccine, developed by Merck and Moderna, designed to prevent melanoma recurrence. In a recent phase 2 study, patients receiving the mRNA-4157 vaccine alongside pembrolizumab had nearly half the risk for melanoma recurrence or death at 3 years compared with those receiving pembrolizumab alone. Investigators are now evaluating the vaccine in a global phase 3 study in patients with high-risk, stage IIB to IV melanoma following surgery.

Another one to watch is the BNT116 NSCLC vaccine from BioNTech. This vaccine presents the immune system with NSCLC tumor markers to encourage the body to fight cancer cells expressing those markers while ignoring healthy cells. BioNTech also launched a global clinical trial for its vaccine this year.

Other notables include a pancreatic cancer mRNA vaccine, which has shown promising early results in a small trial of 16 patients. Of 16 patients who received the vaccine alongside chemotherapy and after surgery and immunotherapy, 8 responded. Of these eight, six remained recurrence free at 3 years. Investigators noted that the vaccine appeared to stimulate a durable T-cell response in patients who responded.

Kwak has also continued his work on lymphoma vaccines. In August, his team published promising first-in-human data on the use of personalized neoantigen vaccines as an early intervention in untreated patients with lymphoplasmacytic lymphoma. Among nine asymptomatic patients who received the vaccine, all achieved stable disease or better, with no dose-limiting toxicities. One patient had a minor response, and the median time to progression was greater than 72 months.

“The current setting is more for advanced disease,” Kwak explained. “It’s a tougher task, but combined with checkpoint blockade, it may be potent enough to work.” 

Still, caution is important. Despite early promise, it’s too soon to tell which, if any, of these investigational vaccines will pan out in the long run. Like investigational drugs, cancer vaccines may show big promising initially but then fail in larger trials.

One key to success, according to Kwak, is to design trials so that even negative results will inform next steps.

But, he noted, failures in large clinical trials will “put a chilling effect on cancer vaccine research again.”

“That’s what keeps me up at night,” he said. “We know the science is fundamentally sound and we have seen glimpses over decades of research that cancer vaccines can work, so it’s really just a matter of tweaking things to optimize trial design.”

Companies tend to design trials to test if a vaccine works or not, without trying to understand why, he said.

“What we need to do is design those so that we can learn from negative results,” he said. That’s what he and his colleagues attempted to do in their recent trial. “We didn’t just look at clinical results; we’re interrogating the actual tumor environment to understand what worked and didn’t and how to tweak that for the next trial.”

Kwak and his colleagues found, for instance, that the vaccine had a greater effect on B cell–derived tumor cells than on cells of plasma origin, so “the most rational design for the next iteration is to combine the vaccine with agents that work directly against plasma cells,” he explained.

As for what’s next, Kwak said: “We’re just focused on trying to do good science and understand. We’ve seen glimpses of success. That’s where we are.”

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

TOPLINE:

Consuming five or more servings per week of dark chocolate is associated with a lower risk for type 2 diabetes (T2D), compared with infrequent or no consumption. Conversely, a higher consumption of milk chocolate does not significantly affect the risk for diabetes and may contribute to greater weight gain.

METHODOLOGY:

• Chocolate is rich in flavanols, natural compounds known to support heart health and lower the risk for T2D. However, the link between chocolate consumption and the risk for T2D is uncertain, with inconsistent research findings that don’t distinguish between dark or milk chocolate.
• Researchers conducted a prospective cohort study to investigate the associations between dark, milk, and total chocolate consumption and the risk for T2D in three long-term US studies of female nurses and male healthcare professionals with no history of diabetes, cardiovascular disease, or cancer at baseline.
• The relationship between total chocolate consumption and the risk for diabetes was investigated in 192,208 individuals who reported their chocolate consumption using validated food frequency questionnaires every 4 years from 1986 onward.
• Information on chocolate subtypes was assessed from 2006/2007 onward in 111,654 participants.
• Participants self-reported T2D through biennial questionnaires, which was confirmed via supplementary questionnaires collecting data on glucose levels, hemoglobin A1c concentration, symptoms, and treatments; they also self-reported their body weight at baseline and during follow-ups.

TAKEAWAY:

• During 4,829,175 person-years of follow-up, researchers identified 18,862 individuals with incident T2D in the total chocolate analysis cohort.
• In the chocolate subtype cohort, 4771 incident T2D cases were identified during 1,270,348 person-years of follow-up. Having at least five servings per week of dark chocolate was associated with a 21% lower risk for T2D (adjusted hazard ratio, 0.79; P for trend = .006), while milk chocolate consumption showed no significant link (P for trend = .75).
• The risk for T2D decreased by 3% for each additional serving of dark chocolate consumed weekly, indicating a dose-response effect.
• Compared with individuals who did not change their chocolate intake, those who had an increased milk chocolate intake had greater weight gain over 4-year periods (mean difference, 0.35 kg; 95% CI, 0.27-0.43); dark chocolate showed no significant association with weight change.

IN PRACTICE:

“Even though dark and milk chocolate have similar levels of calories and saturated fat, it appears that the rich polyphenols in dark chocolate might offset the effects of saturated fat and sugar on weight gain and diabetes. It’s an intriguing difference that’s worth exploring more,” corresponding author Qi Sun from the Departments of Nutrition and Epidemiology, Harvard TH Chan School of Public Health, Boston, Massachusetts, said in a press release.

SOURCE:

This study was led by Binkai Liu, Harvard TH Chan School of Public Health. It was published online in The BMJ.

LIMITATIONS:

The relatively limited number of participants in the higher chocolate consumption groups may have reduced the statistical power for detecting modest associations between dark chocolate consumption and the risk for T2D. Additionally, the study population primarily consisted of non-Hispanic White adults older than 50 years at baseline, which, along with their professional backgrounds, may have limited the generalizability of the study findings to other populations with different socioeconomic or personal characteristics. Chocolate consumption in this study was lower than the national average of three servings per week, which may have limited the ability to assess the dose-response relationship at higher intake levels.

DISCLOSURES:

This study was supported by grants from the National Institutes of Health. Some authors reported receiving investigator-initiated grants, being on scientific advisory boards, and receiving research funding from certain institutions.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Consuming five or more servings per week of dark chocolate is associated with a lower risk for type 2 diabetes (T2D), compared with infrequent or no consumption. Conversely, a higher consumption of milk chocolate does not significantly affect the risk for diabetes and may contribute to greater weight gain.

METHODOLOGY:

• Chocolate is rich in flavanols, natural compounds known to support heart health and lower the risk for T2D. However, the link between chocolate consumption and the risk for T2D is uncertain, with inconsistent research findings that don’t distinguish between dark or milk chocolate.
• Researchers conducted a prospective cohort study to investigate the associations between dark, milk, and total chocolate consumption and the risk for T2D in three long-term US studies of female nurses and male healthcare professionals with no history of diabetes, cardiovascular disease, or cancer at baseline.
• The relationship between total chocolate consumption and the risk for diabetes was investigated in 192,208 individuals who reported their chocolate consumption using validated food frequency questionnaires every 4 years from 1986 onward.
• Information on chocolate subtypes was assessed from 2006/2007 onward in 111,654 participants.
• Participants self-reported T2D through biennial questionnaires, which was confirmed via supplementary questionnaires collecting data on glucose levels, hemoglobin A1c concentration, symptoms, and treatments; they also self-reported their body weight at baseline and during follow-ups.

TAKEAWAY:

• During 4,829,175 person-years of follow-up, researchers identified 18,862 individuals with incident T2D in the total chocolate analysis cohort.
• In the chocolate subtype cohort, 4771 incident T2D cases were identified during 1,270,348 person-years of follow-up. Having at least five servings per week of dark chocolate was associated with a 21% lower risk for T2D (adjusted hazard ratio, 0.79; P for trend = .006), while milk chocolate consumption showed no significant link (P for trend = .75).
• The risk for T2D decreased by 3% for each additional serving of dark chocolate consumed weekly, indicating a dose-response effect.
• Compared with individuals who did not change their chocolate intake, those who had an increased milk chocolate intake had greater weight gain over 4-year periods (mean difference, 0.35 kg; 95% CI, 0.27-0.43); dark chocolate showed no significant association with weight change.

IN PRACTICE:

“Even though dark and milk chocolate have similar levels of calories and saturated fat, it appears that the rich polyphenols in dark chocolate might offset the effects of saturated fat and sugar on weight gain and diabetes. It’s an intriguing difference that’s worth exploring more,” corresponding author Qi Sun from the Departments of Nutrition and Epidemiology, Harvard TH Chan School of Public Health, Boston, Massachusetts, said in a press release.

SOURCE:

This study was led by Binkai Liu, Harvard TH Chan School of Public Health. It was published online in The BMJ.

LIMITATIONS:

The relatively limited number of participants in the higher chocolate consumption groups may have reduced the statistical power for detecting modest associations between dark chocolate consumption and the risk for T2D. Additionally, the study population primarily consisted of non-Hispanic White adults older than 50 years at baseline, which, along with their professional backgrounds, may have limited the generalizability of the study findings to other populations with different socioeconomic or personal characteristics. Chocolate consumption in this study was lower than the national average of three servings per week, which may have limited the ability to assess the dose-response relationship at higher intake levels.

DISCLOSURES:

This study was supported by grants from the National Institutes of Health. Some authors reported receiving investigator-initiated grants, being on scientific advisory boards, and receiving research funding from certain institutions.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Consuming five or more servings per week of dark chocolate is associated with a lower risk for type 2 diabetes (T2D), compared with infrequent or no consumption. Conversely, a higher consumption of milk chocolate does not significantly affect the risk for diabetes and may contribute to greater weight gain.

METHODOLOGY:

• Chocolate is rich in flavanols, natural compounds known to support heart health and lower the risk for T2D. However, the link between chocolate consumption and the risk for T2D is uncertain, with inconsistent research findings that don’t distinguish between dark or milk chocolate.
• Researchers conducted a prospective cohort study to investigate the associations between dark, milk, and total chocolate consumption and the risk for T2D in three long-term US studies of female nurses and male healthcare professionals with no history of diabetes, cardiovascular disease, or cancer at baseline.
• The relationship between total chocolate consumption and the risk for diabetes was investigated in 192,208 individuals who reported their chocolate consumption using validated food frequency questionnaires every 4 years from 1986 onward.
• Information on chocolate subtypes was assessed from 2006/2007 onward in 111,654 participants.
• Participants self-reported T2D through biennial questionnaires, which was confirmed via supplementary questionnaires collecting data on glucose levels, hemoglobin A1c concentration, symptoms, and treatments; they also self-reported their body weight at baseline and during follow-ups.

TAKEAWAY:

• During 4,829,175 person-years of follow-up, researchers identified 18,862 individuals with incident T2D in the total chocolate analysis cohort.
• In the chocolate subtype cohort, 4771 incident T2D cases were identified during 1,270,348 person-years of follow-up. Having at least five servings per week of dark chocolate was associated with a 21% lower risk for T2D (adjusted hazard ratio, 0.79; P for trend = .006), while milk chocolate consumption showed no significant link (P for trend = .75).
• The risk for T2D decreased by 3% for each additional serving of dark chocolate consumed weekly, indicating a dose-response effect.
• Compared with individuals who did not change their chocolate intake, those who had an increased milk chocolate intake had greater weight gain over 4-year periods (mean difference, 0.35 kg; 95% CI, 0.27-0.43); dark chocolate showed no significant association with weight change.

IN PRACTICE:

“Even though dark and milk chocolate have similar levels of calories and saturated fat, it appears that the rich polyphenols in dark chocolate might offset the effects of saturated fat and sugar on weight gain and diabetes. It’s an intriguing difference that’s worth exploring more,” corresponding author Qi Sun from the Departments of Nutrition and Epidemiology, Harvard TH Chan School of Public Health, Boston, Massachusetts, said in a press release.

SOURCE:

This study was led by Binkai Liu, Harvard TH Chan School of Public Health. It was published online in The BMJ.

LIMITATIONS:

The relatively limited number of participants in the higher chocolate consumption groups may have reduced the statistical power for detecting modest associations between dark chocolate consumption and the risk for T2D. Additionally, the study population primarily consisted of non-Hispanic White adults older than 50 years at baseline, which, along with their professional backgrounds, may have limited the generalizability of the study findings to other populations with different socioeconomic or personal characteristics. Chocolate consumption in this study was lower than the national average of three servings per week, which may have limited the ability to assess the dose-response relationship at higher intake levels.

DISCLOSURES:

This study was supported by grants from the National Institutes of Health. Some authors reported receiving investigator-initiated grants, being on scientific advisory boards, and receiving research funding from certain institutions.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Merkel cell polyomavirus (MCPyV) and ambient ultraviolet radiation (UVR) exposure account for most Merkel cell carcinoma (MCC) cases in the United States.

METHODOLOGY:

• Researchers evaluated 38,020 MCC cases (38% women; 93% non-Hispanic White, 4% Hispanic, 1% non-Hispanic Black) diagnosed in the United States from 2001 to 2019 to estimate the contribution of potentially modifiable risk factors to the burden of MCC.
• Population-based cancer registries and linkages with HIV and transplant registries were utilized to identify MCC cases in patients with HIV, solid organ transplant recipients, and patients with chronic lymphocytic leukemia (CLL).
• Data on cloud-adjusted daily ambient UVR irradiance were merged with cancer registry information on the county of residence at diagnosis to assess UVR exposure. Studies reporting the prevalence of MCPyV in MCC specimens collected in the United States were combined via a meta-analysis.
• The study assessed population attributable fractions of MCC cases that were attributable to major immunosuppressive conditions (HIV, solid organ transplant, and chronic CLL), ambient UVR exposure, and MCPyV.

TAKEAWAY:

• The incidence of MCC was higher in people with HIV (standardized incidence ratio [SIR], 2.78), organ transplant recipients (SIR, 13.1), and patients with CLL (SIR, 5.75) than in the general US population. However, only 2.5% of MCC cases were attributable to these immunosuppressive conditions.
• Non-Hispanic White individuals showed elevated MCC incidence at both lower and higher ambient UVR exposure levels, with incidence rate ratios of 4.05 and 4.91, respectively, for MCC on the head and neck.
• A meta-analysis of 19 case series revealed that 63.8% of MCC cases were attributable to MCPyV, with a similar prevalence observed between immunocompromised and immunocompetent patients.
• Overall, 65.1% of MCC cases were attributable to ambient UVR exposure, with higher attribution for cases diagnosed on the head and neck than those diagnosed on other sites (72.1% vs 60.2%).

IN PRACTICE:

“The results of this study suggest that most MCC cases in the US are attributable to MCPyV and/or ambient UVR [UV radiation] exposure, with a smaller fraction attributable to three major immunosuppressive conditions,” the authors wrote. “Future studies should investigate UVR mutational signature, TMB [tumor mutational burden], and MCPyV prevalence according to race and ethnicity and patient immune status to help clarify the overlap between MCC risk factors.”

SOURCE:

The study was led by Jacob T. Tribble, BA, Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), Rockville, Maryland. It was published online on November 27, 2024, in JAMA Dermatology.

LIMITATIONS:

Incidences of MCC may have been inflated because of increased medical surveillance in immunosuppressed populations. The analysis assumed that only cases among non-Hispanic White individuals were associated with UVR. Additionally, the meta-analysis of MCPyV prevalence primarily included studies from large academic institutions, which may not be representative of the entire US population.

DISCLOSURES:

This study was supported in part by the Intramural Research Program of the NCI and the National Institutes of Health Medical Research Scholars Program. Additional funding was provided through a public-private partnership with contributions from the American Association for Dental Research and the Colgate-Palmolive Company to the Foundation for the National Institutes of Health. The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Merkel cell polyomavirus (MCPyV) and ambient ultraviolet radiation (UVR) exposure account for most Merkel cell carcinoma (MCC) cases in the United States.

METHODOLOGY:

• Researchers evaluated 38,020 MCC cases (38% women; 93% non-Hispanic White, 4% Hispanic, 1% non-Hispanic Black) diagnosed in the United States from 2001 to 2019 to estimate the contribution of potentially modifiable risk factors to the burden of MCC.
• Population-based cancer registries and linkages with HIV and transplant registries were utilized to identify MCC cases in patients with HIV, solid organ transplant recipients, and patients with chronic lymphocytic leukemia (CLL).
• Data on cloud-adjusted daily ambient UVR irradiance were merged with cancer registry information on the county of residence at diagnosis to assess UVR exposure. Studies reporting the prevalence of MCPyV in MCC specimens collected in the United States were combined via a meta-analysis.
• The study assessed population attributable fractions of MCC cases that were attributable to major immunosuppressive conditions (HIV, solid organ transplant, and chronic CLL), ambient UVR exposure, and MCPyV.

TAKEAWAY:

• The incidence of MCC was higher in people with HIV (standardized incidence ratio [SIR], 2.78), organ transplant recipients (SIR, 13.1), and patients with CLL (SIR, 5.75) than in the general US population. However, only 2.5% of MCC cases were attributable to these immunosuppressive conditions.
• Non-Hispanic White individuals showed elevated MCC incidence at both lower and higher ambient UVR exposure levels, with incidence rate ratios of 4.05 and 4.91, respectively, for MCC on the head and neck.
• A meta-analysis of 19 case series revealed that 63.8% of MCC cases were attributable to MCPyV, with a similar prevalence observed between immunocompromised and immunocompetent patients.
• Overall, 65.1% of MCC cases were attributable to ambient UVR exposure, with higher attribution for cases diagnosed on the head and neck than those diagnosed on other sites (72.1% vs 60.2%).

IN PRACTICE:

“The results of this study suggest that most MCC cases in the US are attributable to MCPyV and/or ambient UVR [UV radiation] exposure, with a smaller fraction attributable to three major immunosuppressive conditions,” the authors wrote. “Future studies should investigate UVR mutational signature, TMB [tumor mutational burden], and MCPyV prevalence according to race and ethnicity and patient immune status to help clarify the overlap between MCC risk factors.”

SOURCE:

The study was led by Jacob T. Tribble, BA, Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), Rockville, Maryland. It was published online on November 27, 2024, in JAMA Dermatology.

LIMITATIONS:

Incidences of MCC may have been inflated because of increased medical surveillance in immunosuppressed populations. The analysis assumed that only cases among non-Hispanic White individuals were associated with UVR. Additionally, the meta-analysis of MCPyV prevalence primarily included studies from large academic institutions, which may not be representative of the entire US population.

DISCLOSURES:

This study was supported in part by the Intramural Research Program of the NCI and the National Institutes of Health Medical Research Scholars Program. Additional funding was provided through a public-private partnership with contributions from the American Association for Dental Research and the Colgate-Palmolive Company to the Foundation for the National Institutes of Health. The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Merkel cell polyomavirus (MCPyV) and ambient ultraviolet radiation (UVR) exposure account for most Merkel cell carcinoma (MCC) cases in the United States.

METHODOLOGY:

• Researchers evaluated 38,020 MCC cases (38% women; 93% non-Hispanic White, 4% Hispanic, 1% non-Hispanic Black) diagnosed in the United States from 2001 to 2019 to estimate the contribution of potentially modifiable risk factors to the burden of MCC.
• Population-based cancer registries and linkages with HIV and transplant registries were utilized to identify MCC cases in patients with HIV, solid organ transplant recipients, and patients with chronic lymphocytic leukemia (CLL).
• Data on cloud-adjusted daily ambient UVR irradiance were merged with cancer registry information on the county of residence at diagnosis to assess UVR exposure. Studies reporting the prevalence of MCPyV in MCC specimens collected in the United States were combined via a meta-analysis.
• The study assessed population attributable fractions of MCC cases that were attributable to major immunosuppressive conditions (HIV, solid organ transplant, and chronic CLL), ambient UVR exposure, and MCPyV.

TAKEAWAY:

• The incidence of MCC was higher in people with HIV (standardized incidence ratio [SIR], 2.78), organ transplant recipients (SIR, 13.1), and patients with CLL (SIR, 5.75) than in the general US population. However, only 2.5% of MCC cases were attributable to these immunosuppressive conditions.
• Non-Hispanic White individuals showed elevated MCC incidence at both lower and higher ambient UVR exposure levels, with incidence rate ratios of 4.05 and 4.91, respectively, for MCC on the head and neck.
• A meta-analysis of 19 case series revealed that 63.8% of MCC cases were attributable to MCPyV, with a similar prevalence observed between immunocompromised and immunocompetent patients.
• Overall, 65.1% of MCC cases were attributable to ambient UVR exposure, with higher attribution for cases diagnosed on the head and neck than those diagnosed on other sites (72.1% vs 60.2%).

IN PRACTICE:

“The results of this study suggest that most MCC cases in the US are attributable to MCPyV and/or ambient UVR [UV radiation] exposure, with a smaller fraction attributable to three major immunosuppressive conditions,” the authors wrote. “Future studies should investigate UVR mutational signature, TMB [tumor mutational burden], and MCPyV prevalence according to race and ethnicity and patient immune status to help clarify the overlap between MCC risk factors.”

SOURCE:

The study was led by Jacob T. Tribble, BA, Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), Rockville, Maryland. It was published online on November 27, 2024, in JAMA Dermatology.

LIMITATIONS:

Incidences of MCC may have been inflated because of increased medical surveillance in immunosuppressed populations. The analysis assumed that only cases among non-Hispanic White individuals were associated with UVR. Additionally, the meta-analysis of MCPyV prevalence primarily included studies from large academic institutions, which may not be representative of the entire US population.

DISCLOSURES:

This study was supported in part by the Intramural Research Program of the NCI and the National Institutes of Health Medical Research Scholars Program. Additional funding was provided through a public-private partnership with contributions from the American Association for Dental Research and the Colgate-Palmolive Company to the Foundation for the National Institutes of Health. The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

VANCOUVER, BRITISH COLUMBIA — Canadian women aged 40-49 years at no or moderate risk for breast cancer who participated in organized mammography screening programs had a significantly greater breast cancer 10-year net survival than that of similar women who did not participate in such programs, according to data presented here at the Family Medicine Forum 2024. 

The data call into question draft guidelines from the Canadian Task Force on Preventive Health Care, which suggest not systematically screening women in this age group with mammography.

 

Overdiagnosis Challenged

Given that some jurisdictions in Canada have organized screening programs and some do not, there was an opportunity to compare breast cancer 10-year net survival of women who lived in jurisdictions with and without such programs, explained family physician Anna N. Wilkinson, MD, Ottawa regional cancer primary care lead and associate professor at the University of Ottawa in Ontario, Canada.

“The question was [whether] we could use big cancer data to figure out what’s going on,” she told this news organization. 

To investigate, Wilkinson and co-investigators reviewed data from the Canadian Cancer Registry linked to mortality information and assessed outcomes for women aged 40-49 and 50-59 years diagnosed with breast cancer from 2002 to 2007. They compared 10-year net survival estimates in jurisdictions with organized screening programs for those aged 40-49 years with the jurisdictions without them. 

“Net survival is important because it’s a survival measure that looks at only the cancer in question,” Wilkinson explained.

Investigators determined breast cancer to be the primary cause of 10-year mortality in women aged 40-49 years diagnosed with the disease (90.7% of deaths). 

Furthermore, the 10-year net survival in jurisdictions that screened these women (84.8%) was 1.9 percentage points higher than for jurisdictions that did not (82.9%). 

The difference in 10-year net survival favoring jurisdictions that offered screening was significant for women aged 45-49 years (2.6 percentage points) but not for those aged 40-44 years (0.9 percentage points).

Given that 90% of the deaths in women in their 40s who had a breast cancer diagnosis were due to breast cancer, Wilkinson challenged the concept of women in their 40s being overdiagnosed with breast cancer, meaning that the cancers detected were indolent and did not require treatment nor result in death.

Earlier detection would generally mean finding disease at an earlier stage and the need for less invasive treatment, she noted. “And one of the biggest benefits [of screening women in their 40s] is that you have diagnosis at earlier stage disease, which means fewer intensive therapies, less time off work, less long-term morbidity, and less cost to our healthcare system.”

 

Modeling Shows Little Screening Benefit

The task force’s draft guidelines, released earlier this year, were based on evidence from 165 studies including randomized, controlled trials, observational studies, time-trend studies and modeling. They suggest not systematically screening women 40-49 with mammography who are not high risk.

Family physician Guylène Thériault, MD, chair of the task force and its breast cancer working group, and director of the Pedagogy Center at the Outaouais Campus, McGill University, Montreal, Quebec, Canada, explained that to come to that conclusion, the task force had assessed the impact of organized screening for women in Canada aged 40-49 years and calculated the impact of mammography for every 1000 women over 10 years.

The model suggested that screening would yield 368 false positives, leading to 55 biopsies, and then to a breast cancer diagnosis in 19 women. Of those 19, the task force estimated 17 or 18 would not die of breast cancer over 10 years, two would be treated for breast cancer that would not have caused problems, ie, overdiagnosis, and one to two would die of breast cancer.

Without screening, on the other hand, the model suggested that 983 of 1000 women aged 40-49 years would not be diagnosed with breast cancer, and 17 would be, 15 of whom would not die from breast cancer over 10 years (no overdiagnosis, no deaths prevented) and two would die.

It is important that family physicians provide their patients with this information to assist in shared decision making about screening, Thériault said.

Wilkinson concluded that screening programs that included women in their 40s were associated with a significantly higher breast cancer 10-year survival, without an increased rate of diagnosis. She suggested that the study findings can inform the screening guidelines for women aged 40-49 years. 

The study was supported by the University of Ottawa’s department of family medicine. 

Wilkinson, MD, is a consultant for Thrive Health. Thériault, MD, disclosed no relevant financial relationships.

 

A version of this article appeared on Medscape.com.

VANCOUVER, BRITISH COLUMBIA — Canadian women aged 40-49 years at no or moderate risk for breast cancer who participated in organized mammography screening programs had a significantly greater breast cancer 10-year net survival than that of similar women who did not participate in such programs, according to data presented here at the Family Medicine Forum 2024. 

The data call into question draft guidelines from the Canadian Task Force on Preventive Health Care, which suggest not systematically screening women in this age group with mammography.

 

Overdiagnosis Challenged

Given that some jurisdictions in Canada have organized screening programs and some do not, there was an opportunity to compare breast cancer 10-year net survival of women who lived in jurisdictions with and without such programs, explained family physician Anna N. Wilkinson, MD, Ottawa regional cancer primary care lead and associate professor at the University of Ottawa in Ontario, Canada.

“The question was [whether] we could use big cancer data to figure out what’s going on,” she told this news organization. 

To investigate, Wilkinson and co-investigators reviewed data from the Canadian Cancer Registry linked to mortality information and assessed outcomes for women aged 40-49 and 50-59 years diagnosed with breast cancer from 2002 to 2007. They compared 10-year net survival estimates in jurisdictions with organized screening programs for those aged 40-49 years with the jurisdictions without them. 

“Net survival is important because it’s a survival measure that looks at only the cancer in question,” Wilkinson explained.

Investigators determined breast cancer to be the primary cause of 10-year mortality in women aged 40-49 years diagnosed with the disease (90.7% of deaths). 

Furthermore, the 10-year net survival in jurisdictions that screened these women (84.8%) was 1.9 percentage points higher than for jurisdictions that did not (82.9%). 

The difference in 10-year net survival favoring jurisdictions that offered screening was significant for women aged 45-49 years (2.6 percentage points) but not for those aged 40-44 years (0.9 percentage points).

Given that 90% of the deaths in women in their 40s who had a breast cancer diagnosis were due to breast cancer, Wilkinson challenged the concept of women in their 40s being overdiagnosed with breast cancer, meaning that the cancers detected were indolent and did not require treatment nor result in death.

Earlier detection would generally mean finding disease at an earlier stage and the need for less invasive treatment, she noted. “And one of the biggest benefits [of screening women in their 40s] is that you have diagnosis at earlier stage disease, which means fewer intensive therapies, less time off work, less long-term morbidity, and less cost to our healthcare system.”

 

Modeling Shows Little Screening Benefit

The task force’s draft guidelines, released earlier this year, were based on evidence from 165 studies including randomized, controlled trials, observational studies, time-trend studies and modeling. They suggest not systematically screening women 40-49 with mammography who are not high risk.

Family physician Guylène Thériault, MD, chair of the task force and its breast cancer working group, and director of the Pedagogy Center at the Outaouais Campus, McGill University, Montreal, Quebec, Canada, explained that to come to that conclusion, the task force had assessed the impact of organized screening for women in Canada aged 40-49 years and calculated the impact of mammography for every 1000 women over 10 years.

The model suggested that screening would yield 368 false positives, leading to 55 biopsies, and then to a breast cancer diagnosis in 19 women. Of those 19, the task force estimated 17 or 18 would not die of breast cancer over 10 years, two would be treated for breast cancer that would not have caused problems, ie, overdiagnosis, and one to two would die of breast cancer.

Without screening, on the other hand, the model suggested that 983 of 1000 women aged 40-49 years would not be diagnosed with breast cancer, and 17 would be, 15 of whom would not die from breast cancer over 10 years (no overdiagnosis, no deaths prevented) and two would die.

It is important that family physicians provide their patients with this information to assist in shared decision making about screening, Thériault said.

Wilkinson concluded that screening programs that included women in their 40s were associated with a significantly higher breast cancer 10-year survival, without an increased rate of diagnosis. She suggested that the study findings can inform the screening guidelines for women aged 40-49 years. 

The study was supported by the University of Ottawa’s department of family medicine. 

Wilkinson, MD, is a consultant for Thrive Health. Thériault, MD, disclosed no relevant financial relationships.

 

A version of this article appeared on Medscape.com.

VANCOUVER, BRITISH COLUMBIA — Canadian women aged 40-49 years at no or moderate risk for breast cancer who participated in organized mammography screening programs had a significantly greater breast cancer 10-year net survival than that of similar women who did not participate in such programs, according to data presented here at the Family Medicine Forum 2024. 

The data call into question draft guidelines from the Canadian Task Force on Preventive Health Care, which suggest not systematically screening women in this age group with mammography.

 

Overdiagnosis Challenged

Given that some jurisdictions in Canada have organized screening programs and some do not, there was an opportunity to compare breast cancer 10-year net survival of women who lived in jurisdictions with and without such programs, explained family physician Anna N. Wilkinson, MD, Ottawa regional cancer primary care lead and associate professor at the University of Ottawa in Ontario, Canada.

“The question was [whether] we could use big cancer data to figure out what’s going on,” she told this news organization. 

To investigate, Wilkinson and co-investigators reviewed data from the Canadian Cancer Registry linked to mortality information and assessed outcomes for women aged 40-49 and 50-59 years diagnosed with breast cancer from 2002 to 2007. They compared 10-year net survival estimates in jurisdictions with organized screening programs for those aged 40-49 years with the jurisdictions without them. 

“Net survival is important because it’s a survival measure that looks at only the cancer in question,” Wilkinson explained.

Investigators determined breast cancer to be the primary cause of 10-year mortality in women aged 40-49 years diagnosed with the disease (90.7% of deaths). 

Furthermore, the 10-year net survival in jurisdictions that screened these women (84.8%) was 1.9 percentage points higher than for jurisdictions that did not (82.9%). 

The difference in 10-year net survival favoring jurisdictions that offered screening was significant for women aged 45-49 years (2.6 percentage points) but not for those aged 40-44 years (0.9 percentage points).

Given that 90% of the deaths in women in their 40s who had a breast cancer diagnosis were due to breast cancer, Wilkinson challenged the concept of women in their 40s being overdiagnosed with breast cancer, meaning that the cancers detected were indolent and did not require treatment nor result in death.

Earlier detection would generally mean finding disease at an earlier stage and the need for less invasive treatment, she noted. “And one of the biggest benefits [of screening women in their 40s] is that you have diagnosis at earlier stage disease, which means fewer intensive therapies, less time off work, less long-term morbidity, and less cost to our healthcare system.”

 

Modeling Shows Little Screening Benefit

The task force’s draft guidelines, released earlier this year, were based on evidence from 165 studies including randomized, controlled trials, observational studies, time-trend studies and modeling. They suggest not systematically screening women 40-49 with mammography who are not high risk.

Family physician Guylène Thériault, MD, chair of the task force and its breast cancer working group, and director of the Pedagogy Center at the Outaouais Campus, McGill University, Montreal, Quebec, Canada, explained that to come to that conclusion, the task force had assessed the impact of organized screening for women in Canada aged 40-49 years and calculated the impact of mammography for every 1000 women over 10 years.

The model suggested that screening would yield 368 false positives, leading to 55 biopsies, and then to a breast cancer diagnosis in 19 women. Of those 19, the task force estimated 17 or 18 would not die of breast cancer over 10 years, two would be treated for breast cancer that would not have caused problems, ie, overdiagnosis, and one to two would die of breast cancer.

Without screening, on the other hand, the model suggested that 983 of 1000 women aged 40-49 years would not be diagnosed with breast cancer, and 17 would be, 15 of whom would not die from breast cancer over 10 years (no overdiagnosis, no deaths prevented) and two would die.

It is important that family physicians provide their patients with this information to assist in shared decision making about screening, Thériault said.

Wilkinson concluded that screening programs that included women in their 40s were associated with a significantly higher breast cancer 10-year survival, without an increased rate of diagnosis. She suggested that the study findings can inform the screening guidelines for women aged 40-49 years. 

The study was supported by the University of Ottawa’s department of family medicine. 

Wilkinson, MD, is a consultant for Thrive Health. Thériault, MD, disclosed no relevant financial relationships.

 

A version of this article appeared on Medscape.com.

The emergence of vorasidenib, the first targeted therapy for certain gliomas with IDH mutations, has ignited a wave of excitement in both patient and physician spaces.

After years with limited treatment options, experts hailed vorasidenib “a promising breakthrough,” “a paradigm shift,” a “new hope,” and “probably the most important advance in the treatment of low-grade gliomas in the last decade.”

Promising results from vorasidenib’s pivotal INDIGO trial fueled petitions and patient advocacy circles to push for the drug’s approval. And, in August 2024, the Food and Drug Administration (FDA) approved vorasidenib for grade 2 astrocytomas or oligodendrogliomas with an IDH1 or IDH2 mutation.

But following the approval, some experts expressed concerns and doubts about the drug and the INDIGO trial, bringing a host of unanswered questions into sharper focus.

In an editorial, Stanislav Lazarev, MD, and Kunal K. Sindhu, MD, both radiation oncologists from Icahn School of Medicine at Mount Sinai, New York City, suggest that the FDA approval “might be premature given the high cost of this drug and lack of clear benefit over standard treatments.”

Another recent critique also pointed to the lack of clear evidence that vorasidenib is superior to the prevailing standard of care, despite the drug’s high cost. These authors noted that “patients want to live longer, and if not, at least live better,” but “based on the INDIGO study, it is impossible to say whether vorasidenib can provide either.”

Vorasidenib is now one of the most expensive cancer therapies, with an annual cost of nearly $500,000, but the INDIGO trial did not explore whether the drug led to improved overall survival or better quality of life. Among the trial’s design flaws, experts called out the use of progression-free survival as the primary outcome, instead of overall survival, and the use of an inappropriate comparator group.

INDIGO was a phase 3 trial that included 331 adult patients (median age, 40.5 years) with grade-2 IDH-mutant recurrent or residual glioma after surgery. To be eligible, patients had to be followed for at least 1 year, and up to 5 years, post surgery and had to be considered appropriate candidates for a watch-and-wait approach.

Participants were randomly assigned to receive either 40 mg of vorasidenib or a matching placebo orally, once daily, in continuous 28-day cycles until imaging-confirmed tumor disease progression or unacceptable toxicity, at which point crossover to vorasidenib from placebo was permitted. Over one third (n = 58) of patients in the placebo group crossed over and 90% of them (n = 52) received vorasidenib.

Median progression-free survival was significantly better in the vorasidenib group at 27.7 months vs 11.1 months in the placebo group (hazard ratio [HR], 0.39).

A key secondary endpoint — time to next intervention — was also significant; the likelihood of being alive and not receiving further treatment at 18 months was 85.6% in the vorasidenib group and 47.4% in the placebo group (HR, 0.26). This finding indicates that most patients receiving vorasidenib could delay chemoradiation for 18 months or longer.

Despite these impressive outcomes, some experts noted that using progression-free survival as the primary endpoint was a major flaw of the INDIGO trial because, currently, there is no evidence that progression-free survival is a reliable surrogate endpoint for overall survival in this setting.

The high rate of crossover to vorasidenib is another issue because it may limit a longer-term analysis of overall survival. If, for instance, overall survival is the same between the groups, it could signal that the drug is effective in both groups or, alternatively, that the drug has no effect on survival in either group.

“That is a legitimate concern,” Seema Nagpal, MD, a neuro-oncologist at Stanford University in California, and a site principal investigator for the INDIGO trial, said in an interview. “We don’t know that this drug changes overall survival, and I think we’re not going to get a super clean answer on that.”

Another major issue centers on the standard of care assigned to control patients in the INDIGO trial.

In the trial, vorasidenib was compared with placebo — an appropriate standard-of-care comparison for patients with low-risk gliomas. These patients often initially undergo watch-and-wait to delay chemoradiation. But Lazarev and Sindhu argue that the patients in INDIGO were really high risk, which means the control group should have received the standard of care for these patients: Chemoradiation following surgery.

This question about the appropriate standard of care stems from ongoing uncertainty about the distinction between high- and low-risk gliomas.

The classification for gliomas falls into either low risk or high risk for early disease progression. The RTOG 9802 criteria, often used for glioma risk stratification, defines low-risk patients as those younger than 40 years with gross total resection and high-risk patients as those aged 40 years or older with any extent of resection or those younger than 40 years with subtotal or biopsy resection.

But an evolving understanding of genetic anomalies that affect prognoses in this tumor type has muddied the current high- and low-risk distinctions.

“People haven’t totally figured out what high and low risk means,” Nagpal acknowledged.

This uncertainty has spilled over into the INDIGO trial.

While the trial excluded patients who had any features indicating high risk, such as brain stem involvement or neurocognitive deficits, the researchers also did not explicitly define patients as low risk. However, the inclusion criteria specified that patients had to be observed for at least 1 year after surgery and be considered appropriate for a watch-and-wait protocol, which does suggest patients were considered low risk, said Nagpal.

Still, some experts argue that the patients in INDIGO were not low risk.

Patients had residual or recurrent disease so “wouldn’t be classified as low risk,” said Sindhu in an interview. The standard of care for these patients is chemoradiation, Lazarev added.

“The definition of a phase 3 clinical trial is that you compare the novel intervention to the standard of care,” said Lazarev. “Level 1 evidence clearly shows that omitting chemoradiation leads to worse outcomes, with patients literally dying sooner. For the investigators to knowingly exclude this proven treatment raises serious ethical and methodological questions about the study’s design.” 

In a recent opinion piece, Nagpal agreed that most patients selected for INDIGO would not have been considered low risk by many providers. All patients selected for INDIGO had postoperative residual/recurrent disease and many were older than 40 years.

But, Nagpal explained, the risk stratification of the INDIGO patients was still lower than what is commonly considered high risk. The patients had all been observed for a year or more already, “so by definition, the clinician treating them already decided they were not high risk,” she said.

In another recent opinion piece, oncologists suggested that, because patients in the INDIGO trial do not squarely fall into either category, instead representing a “grey area,” it’s time to create a new risk category.

“Perhaps the time has come to abandon the old binary risk stratification (“low risk” vs “high risk”), which still contains arbitrary elements (such as the age cutoff), proving impractical in real-world clinical decision-making, and to adopt a new one, also taking into account many emerging prognostic biomarkers,” the authors wrote.

Despite the uncertainty surrounding risk categories, the INDIGO authors justified their study design.

A watch-and-wait period for patients in the trial, which “represents the earliest clinical phase in tumorigenesis of IDH-mutant WHO grade 2 glioma,” is “an opportunity to detect a clear signal of antitumor activity for new therapies in placebo-controlled trials” and “postpone the use of radiation therapy and chemotherapy,” the authors explained.

Lazarev, however, questioned the premise that chemoradiation should be delayed.

Oncologists’ desire to delay chemoradiation for their patients reflects “a limited understanding of modern irradiation therapy,” Lazarev said. “Modern technology has improved dramatically. We’re more precise, our understanding about late side effects is better. So, the big picture is that the absolute risk of late neurocognitive affects that actually will affect patients’ quality of life, their ability to work, go to school, succeed on a personal or professional level is exceedingly low.”

Nagpal strongly disagreed.

“Please come to my clinic and ask an actual patient,” said Nagpal. “Once a radiation oncologist has irradiated the patient, they almost never seen them again. People who are on the medical side, who follow these patients from beginning to end, recognize that delaying radiation is a huge deal.”

Although vorasidenib isn’t a cure, Nagpal said, it is a less toxic way to delay radiation “because that is a real and disabling thing” for patients and is why neuro-oncologists are excited about alternative treatment options.

Another issue surrounding the vorasidenib approval lies in the FDA’s vague prescribing information. The prescribing information does not specify that patients should be followed for at least 1 year post surgery or that patients need to be lower risk. Prescribing physicians may, therefore, think vorasidenib is appropriate for any patient with a grade-2 IDH mutant glioma at any time and defer or not offer chemoradiation to high-risk patients.

Amid lingering questions about the INDIGO trial design and ongoing uncertainties about how to define and treat this patient population, experts remain divided on whether vorasidenib is worth it.

“If vorasidenib is truly transformative, it should be feasible to demonstrate its superiority over chemoradiotherapy,” Lazarev and Sindhu wrote. “For a drug with such a staggering price tag, an imperative should be placed on the investigators and manufacturer to provide clear evidence of efficacy, whether in terms of improved [overall survival] or quality of life, before vorasidenib is recommended for the treatment of IDH-mutant low-grade gliomas.”

The INDIGO trial was supported by Servier, the manufacturer of vorasidenib. Many of the study authors reported employment or support from the company. Nagpal reported consulting fees from Servier and AnHeart Therapeutics. Lazarev and Sindhu reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

The emergence of vorasidenib, the first targeted therapy for certain gliomas with IDH mutations, has ignited a wave of excitement in both patient and physician spaces.

After years with limited treatment options, experts hailed vorasidenib “a promising breakthrough,” “a paradigm shift,” a “new hope,” and “probably the most important advance in the treatment of low-grade gliomas in the last decade.”

Promising results from vorasidenib’s pivotal INDIGO trial fueled petitions and patient advocacy circles to push for the drug’s approval. And, in August 2024, the Food and Drug Administration (FDA) approved vorasidenib for grade 2 astrocytomas or oligodendrogliomas with an IDH1 or IDH2 mutation.

But following the approval, some experts expressed concerns and doubts about the drug and the INDIGO trial, bringing a host of unanswered questions into sharper focus.

In an editorial, Stanislav Lazarev, MD, and Kunal K. Sindhu, MD, both radiation oncologists from Icahn School of Medicine at Mount Sinai, New York City, suggest that the FDA approval “might be premature given the high cost of this drug and lack of clear benefit over standard treatments.”

Another recent critique also pointed to the lack of clear evidence that vorasidenib is superior to the prevailing standard of care, despite the drug’s high cost. These authors noted that “patients want to live longer, and if not, at least live better,” but “based on the INDIGO study, it is impossible to say whether vorasidenib can provide either.”

Vorasidenib is now one of the most expensive cancer therapies, with an annual cost of nearly $500,000, but the INDIGO trial did not explore whether the drug led to improved overall survival or better quality of life. Among the trial’s design flaws, experts called out the use of progression-free survival as the primary outcome, instead of overall survival, and the use of an inappropriate comparator group.

INDIGO was a phase 3 trial that included 331 adult patients (median age, 40.5 years) with grade-2 IDH-mutant recurrent or residual glioma after surgery. To be eligible, patients had to be followed for at least 1 year, and up to 5 years, post surgery and had to be considered appropriate candidates for a watch-and-wait approach.

Participants were randomly assigned to receive either 40 mg of vorasidenib or a matching placebo orally, once daily, in continuous 28-day cycles until imaging-confirmed tumor disease progression or unacceptable toxicity, at which point crossover to vorasidenib from placebo was permitted. Over one third (n = 58) of patients in the placebo group crossed over and 90% of them (n = 52) received vorasidenib.

Median progression-free survival was significantly better in the vorasidenib group at 27.7 months vs 11.1 months in the placebo group (hazard ratio [HR], 0.39).

A key secondary endpoint — time to next intervention — was also significant; the likelihood of being alive and not receiving further treatment at 18 months was 85.6% in the vorasidenib group and 47.4% in the placebo group (HR, 0.26). This finding indicates that most patients receiving vorasidenib could delay chemoradiation for 18 months or longer.

Despite these impressive outcomes, some experts noted that using progression-free survival as the primary endpoint was a major flaw of the INDIGO trial because, currently, there is no evidence that progression-free survival is a reliable surrogate endpoint for overall survival in this setting.

The high rate of crossover to vorasidenib is another issue because it may limit a longer-term analysis of overall survival. If, for instance, overall survival is the same between the groups, it could signal that the drug is effective in both groups or, alternatively, that the drug has no effect on survival in either group.

“That is a legitimate concern,” Seema Nagpal, MD, a neuro-oncologist at Stanford University in California, and a site principal investigator for the INDIGO trial, said in an interview. “We don’t know that this drug changes overall survival, and I think we’re not going to get a super clean answer on that.”

Another major issue centers on the standard of care assigned to control patients in the INDIGO trial.

In the trial, vorasidenib was compared with placebo — an appropriate standard-of-care comparison for patients with low-risk gliomas. These patients often initially undergo watch-and-wait to delay chemoradiation. But Lazarev and Sindhu argue that the patients in INDIGO were really high risk, which means the control group should have received the standard of care for these patients: Chemoradiation following surgery.

This question about the appropriate standard of care stems from ongoing uncertainty about the distinction between high- and low-risk gliomas.

The classification for gliomas falls into either low risk or high risk for early disease progression. The RTOG 9802 criteria, often used for glioma risk stratification, defines low-risk patients as those younger than 40 years with gross total resection and high-risk patients as those aged 40 years or older with any extent of resection or those younger than 40 years with subtotal or biopsy resection.

But an evolving understanding of genetic anomalies that affect prognoses in this tumor type has muddied the current high- and low-risk distinctions.

“People haven’t totally figured out what high and low risk means,” Nagpal acknowledged.

This uncertainty has spilled over into the INDIGO trial.

While the trial excluded patients who had any features indicating high risk, such as brain stem involvement or neurocognitive deficits, the researchers also did not explicitly define patients as low risk. However, the inclusion criteria specified that patients had to be observed for at least 1 year after surgery and be considered appropriate for a watch-and-wait protocol, which does suggest patients were considered low risk, said Nagpal.

Still, some experts argue that the patients in INDIGO were not low risk.

Patients had residual or recurrent disease so “wouldn’t be classified as low risk,” said Sindhu in an interview. The standard of care for these patients is chemoradiation, Lazarev added.

“The definition of a phase 3 clinical trial is that you compare the novel intervention to the standard of care,” said Lazarev. “Level 1 evidence clearly shows that omitting chemoradiation leads to worse outcomes, with patients literally dying sooner. For the investigators to knowingly exclude this proven treatment raises serious ethical and methodological questions about the study’s design.” 

In a recent opinion piece, Nagpal agreed that most patients selected for INDIGO would not have been considered low risk by many providers. All patients selected for INDIGO had postoperative residual/recurrent disease and many were older than 40 years.

But, Nagpal explained, the risk stratification of the INDIGO patients was still lower than what is commonly considered high risk. The patients had all been observed for a year or more already, “so by definition, the clinician treating them already decided they were not high risk,” she said.

In another recent opinion piece, oncologists suggested that, because patients in the INDIGO trial do not squarely fall into either category, instead representing a “grey area,” it’s time to create a new risk category.

“Perhaps the time has come to abandon the old binary risk stratification (“low risk” vs “high risk”), which still contains arbitrary elements (such as the age cutoff), proving impractical in real-world clinical decision-making, and to adopt a new one, also taking into account many emerging prognostic biomarkers,” the authors wrote.

Despite the uncertainty surrounding risk categories, the INDIGO authors justified their study design.

A watch-and-wait period for patients in the trial, which “represents the earliest clinical phase in tumorigenesis of IDH-mutant WHO grade 2 glioma,” is “an opportunity to detect a clear signal of antitumor activity for new therapies in placebo-controlled trials” and “postpone the use of radiation therapy and chemotherapy,” the authors explained.

Lazarev, however, questioned the premise that chemoradiation should be delayed.

Oncologists’ desire to delay chemoradiation for their patients reflects “a limited understanding of modern irradiation therapy,” Lazarev said. “Modern technology has improved dramatically. We’re more precise, our understanding about late side effects is better. So, the big picture is that the absolute risk of late neurocognitive affects that actually will affect patients’ quality of life, their ability to work, go to school, succeed on a personal or professional level is exceedingly low.”

Nagpal strongly disagreed.

“Please come to my clinic and ask an actual patient,” said Nagpal. “Once a radiation oncologist has irradiated the patient, they almost never seen them again. People who are on the medical side, who follow these patients from beginning to end, recognize that delaying radiation is a huge deal.”

Although vorasidenib isn’t a cure, Nagpal said, it is a less toxic way to delay radiation “because that is a real and disabling thing” for patients and is why neuro-oncologists are excited about alternative treatment options.

Another issue surrounding the vorasidenib approval lies in the FDA’s vague prescribing information. The prescribing information does not specify that patients should be followed for at least 1 year post surgery or that patients need to be lower risk. Prescribing physicians may, therefore, think vorasidenib is appropriate for any patient with a grade-2 IDH mutant glioma at any time and defer or not offer chemoradiation to high-risk patients.

Amid lingering questions about the INDIGO trial design and ongoing uncertainties about how to define and treat this patient population, experts remain divided on whether vorasidenib is worth it.

“If vorasidenib is truly transformative, it should be feasible to demonstrate its superiority over chemoradiotherapy,” Lazarev and Sindhu wrote. “For a drug with such a staggering price tag, an imperative should be placed on the investigators and manufacturer to provide clear evidence of efficacy, whether in terms of improved [overall survival] or quality of life, before vorasidenib is recommended for the treatment of IDH-mutant low-grade gliomas.”

The INDIGO trial was supported by Servier, the manufacturer of vorasidenib. Many of the study authors reported employment or support from the company. Nagpal reported consulting fees from Servier and AnHeart Therapeutics. Lazarev and Sindhu reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

The emergence of vorasidenib, the first targeted therapy for certain gliomas with IDH mutations, has ignited a wave of excitement in both patient and physician spaces.

After years with limited treatment options, experts hailed vorasidenib “a promising breakthrough,” “a paradigm shift,” a “new hope,” and “probably the most important advance in the treatment of low-grade gliomas in the last decade.”

Promising results from vorasidenib’s pivotal INDIGO trial fueled petitions and patient advocacy circles to push for the drug’s approval. And, in August 2024, the Food and Drug Administration (FDA) approved vorasidenib for grade 2 astrocytomas or oligodendrogliomas with an IDH1 or IDH2 mutation.

But following the approval, some experts expressed concerns and doubts about the drug and the INDIGO trial, bringing a host of unanswered questions into sharper focus.

In an editorial, Stanislav Lazarev, MD, and Kunal K. Sindhu, MD, both radiation oncologists from Icahn School of Medicine at Mount Sinai, New York City, suggest that the FDA approval “might be premature given the high cost of this drug and lack of clear benefit over standard treatments.”

Another recent critique also pointed to the lack of clear evidence that vorasidenib is superior to the prevailing standard of care, despite the drug’s high cost. These authors noted that “patients want to live longer, and if not, at least live better,” but “based on the INDIGO study, it is impossible to say whether vorasidenib can provide either.”

Vorasidenib is now one of the most expensive cancer therapies, with an annual cost of nearly $500,000, but the INDIGO trial did not explore whether the drug led to improved overall survival or better quality of life. Among the trial’s design flaws, experts called out the use of progression-free survival as the primary outcome, instead of overall survival, and the use of an inappropriate comparator group.

INDIGO was a phase 3 trial that included 331 adult patients (median age, 40.5 years) with grade-2 IDH-mutant recurrent or residual glioma after surgery. To be eligible, patients had to be followed for at least 1 year, and up to 5 years, post surgery and had to be considered appropriate candidates for a watch-and-wait approach.

Participants were randomly assigned to receive either 40 mg of vorasidenib or a matching placebo orally, once daily, in continuous 28-day cycles until imaging-confirmed tumor disease progression or unacceptable toxicity, at which point crossover to vorasidenib from placebo was permitted. Over one third (n = 58) of patients in the placebo group crossed over and 90% of them (n = 52) received vorasidenib.

Median progression-free survival was significantly better in the vorasidenib group at 27.7 months vs 11.1 months in the placebo group (hazard ratio [HR], 0.39).

A key secondary endpoint — time to next intervention — was also significant; the likelihood of being alive and not receiving further treatment at 18 months was 85.6% in the vorasidenib group and 47.4% in the placebo group (HR, 0.26). This finding indicates that most patients receiving vorasidenib could delay chemoradiation for 18 months or longer.

Despite these impressive outcomes, some experts noted that using progression-free survival as the primary endpoint was a major flaw of the INDIGO trial because, currently, there is no evidence that progression-free survival is a reliable surrogate endpoint for overall survival in this setting.

The high rate of crossover to vorasidenib is another issue because it may limit a longer-term analysis of overall survival. If, for instance, overall survival is the same between the groups, it could signal that the drug is effective in both groups or, alternatively, that the drug has no effect on survival in either group.

“That is a legitimate concern,” Seema Nagpal, MD, a neuro-oncologist at Stanford University in California, and a site principal investigator for the INDIGO trial, said in an interview. “We don’t know that this drug changes overall survival, and I think we’re not going to get a super clean answer on that.”

Another major issue centers on the standard of care assigned to control patients in the INDIGO trial.

In the trial, vorasidenib was compared with placebo — an appropriate standard-of-care comparison for patients with low-risk gliomas. These patients often initially undergo watch-and-wait to delay chemoradiation. But Lazarev and Sindhu argue that the patients in INDIGO were really high risk, which means the control group should have received the standard of care for these patients: Chemoradiation following surgery.

This question about the appropriate standard of care stems from ongoing uncertainty about the distinction between high- and low-risk gliomas.

The classification for gliomas falls into either low risk or high risk for early disease progression. The RTOG 9802 criteria, often used for glioma risk stratification, defines low-risk patients as those younger than 40 years with gross total resection and high-risk patients as those aged 40 years or older with any extent of resection or those younger than 40 years with subtotal or biopsy resection.

But an evolving understanding of genetic anomalies that affect prognoses in this tumor type has muddied the current high- and low-risk distinctions.

“People haven’t totally figured out what high and low risk means,” Nagpal acknowledged.

This uncertainty has spilled over into the INDIGO trial.

While the trial excluded patients who had any features indicating high risk, such as brain stem involvement or neurocognitive deficits, the researchers also did not explicitly define patients as low risk. However, the inclusion criteria specified that patients had to be observed for at least 1 year after surgery and be considered appropriate for a watch-and-wait protocol, which does suggest patients were considered low risk, said Nagpal.

Still, some experts argue that the patients in INDIGO were not low risk.

Patients had residual or recurrent disease so “wouldn’t be classified as low risk,” said Sindhu in an interview. The standard of care for these patients is chemoradiation, Lazarev added.

“The definition of a phase 3 clinical trial is that you compare the novel intervention to the standard of care,” said Lazarev. “Level 1 evidence clearly shows that omitting chemoradiation leads to worse outcomes, with patients literally dying sooner. For the investigators to knowingly exclude this proven treatment raises serious ethical and methodological questions about the study’s design.” 

In a recent opinion piece, Nagpal agreed that most patients selected for INDIGO would not have been considered low risk by many providers. All patients selected for INDIGO had postoperative residual/recurrent disease and many were older than 40 years.

But, Nagpal explained, the risk stratification of the INDIGO patients was still lower than what is commonly considered high risk. The patients had all been observed for a year or more already, “so by definition, the clinician treating them already decided they were not high risk,” she said.

In another recent opinion piece, oncologists suggested that, because patients in the INDIGO trial do not squarely fall into either category, instead representing a “grey area,” it’s time to create a new risk category.

“Perhaps the time has come to abandon the old binary risk stratification (“low risk” vs “high risk”), which still contains arbitrary elements (such as the age cutoff), proving impractical in real-world clinical decision-making, and to adopt a new one, also taking into account many emerging prognostic biomarkers,” the authors wrote.

Despite the uncertainty surrounding risk categories, the INDIGO authors justified their study design.

A watch-and-wait period for patients in the trial, which “represents the earliest clinical phase in tumorigenesis of IDH-mutant WHO grade 2 glioma,” is “an opportunity to detect a clear signal of antitumor activity for new therapies in placebo-controlled trials” and “postpone the use of radiation therapy and chemotherapy,” the authors explained.

Lazarev, however, questioned the premise that chemoradiation should be delayed.

Oncologists’ desire to delay chemoradiation for their patients reflects “a limited understanding of modern irradiation therapy,” Lazarev said. “Modern technology has improved dramatically. We’re more precise, our understanding about late side effects is better. So, the big picture is that the absolute risk of late neurocognitive affects that actually will affect patients’ quality of life, their ability to work, go to school, succeed on a personal or professional level is exceedingly low.”

Nagpal strongly disagreed.

“Please come to my clinic and ask an actual patient,” said Nagpal. “Once a radiation oncologist has irradiated the patient, they almost never seen them again. People who are on the medical side, who follow these patients from beginning to end, recognize that delaying radiation is a huge deal.”

Although vorasidenib isn’t a cure, Nagpal said, it is a less toxic way to delay radiation “because that is a real and disabling thing” for patients and is why neuro-oncologists are excited about alternative treatment options.

Another issue surrounding the vorasidenib approval lies in the FDA’s vague prescribing information. The prescribing information does not specify that patients should be followed for at least 1 year post surgery or that patients need to be lower risk. Prescribing physicians may, therefore, think vorasidenib is appropriate for any patient with a grade-2 IDH mutant glioma at any time and defer or not offer chemoradiation to high-risk patients.

Amid lingering questions about the INDIGO trial design and ongoing uncertainties about how to define and treat this patient population, experts remain divided on whether vorasidenib is worth it.

“If vorasidenib is truly transformative, it should be feasible to demonstrate its superiority over chemoradiotherapy,” Lazarev and Sindhu wrote. “For a drug with such a staggering price tag, an imperative should be placed on the investigators and manufacturer to provide clear evidence of efficacy, whether in terms of improved [overall survival] or quality of life, before vorasidenib is recommended for the treatment of IDH-mutant low-grade gliomas.”

The INDIGO trial was supported by Servier, the manufacturer of vorasidenib. Many of the study authors reported employment or support from the company. Nagpal reported consulting fees from Servier and AnHeart Therapeutics. Lazarev and Sindhu reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Rose Gerber was 39, mother to a third grader and a kindergartener, when the diagnosis came: Advanced HER2-positive breast cancer.

“On one of my first or second appointments, I took in a little picture of Alexander and Isabella,” Gerber said. Gerber showed her oncologist the picture and told her: “I’ll do anything. I just want to be there for them.”

That was 21 years ago. Today, her current cancer status is “no evidence of disease.”

Over the past 2 decades, Gerber has gotten to be there for her children. Her youngest is now a television producer and her oldest, a CPA.

In that time, Gerber has had one constant: Her oncologist, Kandhasamy Jagathambal, MD, or Dr. Jaga, as she’s often called. 

“I’ve seen multiple physicians over my 21 years, but my oncologist has always been the focal point, guiding me in the right direction,” Gerber said in an interview.

Over the years, Jaga guided Gerber through a range of treatment decisions, including a Herceptin clinical trial that the mom of two views as lifesaving. Jaga often took on the role of both doctor and therapist, even providing comfort in the smaller moments when Gerber would fret about her weight gain.

The oncologist-patient “bond is very, very, very special,” said Gerber, who now works as director of patient advocacy and education at the Community Oncology Alliance.

Gerber isn’t alone in calling out the depth of the oncologist-patient bond.

Over years, sometimes decades, patients and oncologists can experience a whole world together: The treatment successes, relapses, uncertainties, and tough calls. As a result, a deep therapeutic alliance often develops. And with each new hurdle or decision, that collaborative, human connection between doctor and patient continues to form new layers.

“It’s like a shared bonding experience over trauma, like strangers trapped on a subway and then we get out, and we’re now on the other side, celebrating together,” said Saad Khan, MD, an associate professor of medicine (oncology) at Stanford University in California.

 

Connecting Through Stress

Although studies exploring the oncologist-patient bond are limited, some research suggests that a strong therapeutic alliance between patients and oncologists not only provides a foundation for quality care but can also help improve patients’ quality of life, protect against suicidal ideation, and increase treatment adherence.

Because of how stressful and frightening a cancer diagnosis can be, creating “a trusting, uninterrupted, almost sacred environment for them” is paramount for Khan. “I have no doubt that the most important part of their treatment is that they find an oncologist in whom they have total confidence,” Khan wrote in a blog.

The stress that patients with cancer experience is well documented, but oncologists take on a lot themselves and can also experience intense stress (.

“I consider my patient’s battles to be my battles,” Khan wrote.

The stress can start with the daily schedule. Oncologists often have a high volume of patients and tend to spend more time with each individual than most.

According to a 2023 survey, oncologists see about 68 patients a week, on average, but some oncologists, like Khan, have many more. Khan typically sees 20-30 patients a day and continues to care for many over years.

The survey also found that oncologists tend to spend a lot of time with their patients. Compared with other physicians, oncologists are two times more likely to spend at least 25 minutes with each patient.

With this kind of patient volume and time, Khan said, “you’re going to be exhausted.”

What can compound the exhaustion are the occasions oncologists need to deliver bad news — this treatment isn’t working, your cancer has come roaring back and, perhaps the hardest, we have no therapeutic options left. The end-of-life conversations, in particular, can be heartbreaking, especially when a patient is young and not ready to stop trying.

“It can be hard for doctors to discuss the end of life,” Don Dizon, MD, director of the Pelvic Malignancies Program at Lifespan Cancer Institute and director of Medical Oncology at Rhode Island Hospital, Providence, wrote in a column in 2023. Instead, it can be tempting and is often easier to focus on the next treatment, “instilling hope that there’s more that can be done,” even if doing more will only do harm.

In the face of these challenging decisions, growing a personal connection with patients over time can help keep oncologists going.

“We’re not just chemotherapy salesmen,” Khan said in an interview. “We get to know their social support network, who’s going to be driving them [to and from appointments], where they go on vacation, their cat’s name, who their neighbors are.”

 

A ‘Special Relationship’

Ralph V. Boccia, MD, is often asked what he does.

The next question that often comes — “Why do I do what I do?” — is Boccia’s favorite.

“Someone needs to take these patients through their journey,” Boccia, the founder of The Center for Cancer and Blood Disorders, Bethesda, Maryland, typically responds. He also often notes that “it is a special relationship you develop with the patient and their families.”

Boccia thinks about one long-term patient who captures this bond.

Joan Pinson, 70, was diagnosed with multiple myeloma about 25 years ago, when patients’ average survival was about 4 years.

Over a quarter century, Pinson has pivoted to different treatments, amid multiple relapses and remissions. Throughout most of this cancer journey, Boccia has been her primary oncologist, performing a stem cell transplant in 2000 and steering her to six clinical trials.

Her last relapse was 2 years ago, and since then she has been doing well on oral chemotherapy.

“Every time I relapsed, by the next appointment, he’d say, ‘here is what we are going to do,’ ” Pinson recalled. “I never worried, I never panicked. I knew he would take care of me.”

Over the years, Pinson and Boccia have shared many personal moments, sometimes by accident. One special moment happened early on in Pinson’s cancer journey. During an appointment, Boccia had “one ear to the phone” as his wife was about to deliver their first baby, Pinson recalled.

Later, Pinson met that child as a young man working in Boccia’s lab. She has also met Boccia’s wife, a nurse, when she filled in one day in the chemotherapy room.

Boccia now also treats Pinson’s husband who has prostate cancer, and he ruled out cancer when Pinson’s son, now in his 40s, had some worrisome symptoms.

More than 2 decades ago, Pinson told Boccia her goal was to see her youngest child graduate from high school. Now, six grandsons later, she has lived far beyond that goal.

“He has kept me alive,” said Pinson.

 

The Dying Patient

Harsha Vyas, MD, FACP, remembers the first encounter his office had with a 29-year-old woman referred with a diagnosis of stage IV breast cancer.

After just 15 minutes in the waiting room, the woman announced she was leaving. Although office staff assured the woman that she was next, the patient walked out.

Several months later, Vyas was called for an inpatient consult. It was the same woman.

Her lungs were full of fluid, and she was struggling to breathe, said Vyas, president and CEO of the Cancer Center of Middle Georgia, Dublin, and assistant professor at Augusta University in Georgia.

The woman, a single mother, told Vyas about her three young kids at home and asked him, “Doc, do something, please help me,” he recalled.

“Absolutely,” Vyas told her. But he had to be brutally honest about her prognosis and firm that she needed to follow his instructions. “You have a breast cancer I cannot cure,” he said. “All I can do is control the disease.”

From that first day, until the day she died, she came to every appointment and followed the treatment plan Vyas laid out.

For about 2 years, she responded well to treatment. And as the time passed and the trust grew, she began to open up to him. She showed him pictures. She talked about her children and being a mother.

“I’ve got to get my kids in a better place. I’m going to be there for them,” he recalled her saying.

Vyas admired her resourcefulness. She held down a part-time job, working retail and at a local restaurant. She figured out childcare so she could get to her chemotherapy appointments every 3 weeks and manage the copays.

Several years later, when she knew she was approaching the end of her life, she asked Vyas a question that hit hard.

“Doc, I don’t want to die and my kids find me dead. What can we do about it?”

Vyas, who has three daughters, imagined how traumatic this would be for a child. She and Vyas made the shared decision to cease treatment and begin home hospice. When the end was approaching, a hospice worker took over, waiting for bodily functions to cease.

When news of a death comes, “I say a little prayer, it’s almost like a send-off for that soul. That helps me absorb the news ... and let it go.”

But when the bond grows strong over time, as with his patient with breast cancer, Vyas said, “a piece of her is still with me.”

Khan had no relevant disclosures. Boccia and Vyas had no disclosures.

A version of this article appeared on Medscape.com.

Rose Gerber was 39, mother to a third grader and a kindergartener, when the diagnosis came: Advanced HER2-positive breast cancer.

“On one of my first or second appointments, I took in a little picture of Alexander and Isabella,” Gerber said. Gerber showed her oncologist the picture and told her: “I’ll do anything. I just want to be there for them.”

That was 21 years ago. Today, her current cancer status is “no evidence of disease.”

Over the past 2 decades, Gerber has gotten to be there for her children. Her youngest is now a television producer and her oldest, a CPA.

In that time, Gerber has had one constant: Her oncologist, Kandhasamy Jagathambal, MD, or Dr. Jaga, as she’s often called. 

“I’ve seen multiple physicians over my 21 years, but my oncologist has always been the focal point, guiding me in the right direction,” Gerber said in an interview.

Over the years, Jaga guided Gerber through a range of treatment decisions, including a Herceptin clinical trial that the mom of two views as lifesaving. Jaga often took on the role of both doctor and therapist, even providing comfort in the smaller moments when Gerber would fret about her weight gain.

The oncologist-patient “bond is very, very, very special,” said Gerber, who now works as director of patient advocacy and education at the Community Oncology Alliance.

Gerber isn’t alone in calling out the depth of the oncologist-patient bond.

Over years, sometimes decades, patients and oncologists can experience a whole world together: The treatment successes, relapses, uncertainties, and tough calls. As a result, a deep therapeutic alliance often develops. And with each new hurdle or decision, that collaborative, human connection between doctor and patient continues to form new layers.

“It’s like a shared bonding experience over trauma, like strangers trapped on a subway and then we get out, and we’re now on the other side, celebrating together,” said Saad Khan, MD, an associate professor of medicine (oncology) at Stanford University in California.

 

Connecting Through Stress

Although studies exploring the oncologist-patient bond are limited, some research suggests that a strong therapeutic alliance between patients and oncologists not only provides a foundation for quality care but can also help improve patients’ quality of life, protect against suicidal ideation, and increase treatment adherence.

Because of how stressful and frightening a cancer diagnosis can be, creating “a trusting, uninterrupted, almost sacred environment for them” is paramount for Khan. “I have no doubt that the most important part of their treatment is that they find an oncologist in whom they have total confidence,” Khan wrote in a blog.

The stress that patients with cancer experience is well documented, but oncologists take on a lot themselves and can also experience intense stress (.

“I consider my patient’s battles to be my battles,” Khan wrote.

The stress can start with the daily schedule. Oncologists often have a high volume of patients and tend to spend more time with each individual than most.

According to a 2023 survey, oncologists see about 68 patients a week, on average, but some oncologists, like Khan, have many more. Khan typically sees 20-30 patients a day and continues to care for many over years.

The survey also found that oncologists tend to spend a lot of time with their patients. Compared with other physicians, oncologists are two times more likely to spend at least 25 minutes with each patient.

With this kind of patient volume and time, Khan said, “you’re going to be exhausted.”

What can compound the exhaustion are the occasions oncologists need to deliver bad news — this treatment isn’t working, your cancer has come roaring back and, perhaps the hardest, we have no therapeutic options left. The end-of-life conversations, in particular, can be heartbreaking, especially when a patient is young and not ready to stop trying.

“It can be hard for doctors to discuss the end of life,” Don Dizon, MD, director of the Pelvic Malignancies Program at Lifespan Cancer Institute and director of Medical Oncology at Rhode Island Hospital, Providence, wrote in a column in 2023. Instead, it can be tempting and is often easier to focus on the next treatment, “instilling hope that there’s more that can be done,” even if doing more will only do harm.

In the face of these challenging decisions, growing a personal connection with patients over time can help keep oncologists going.

“We’re not just chemotherapy salesmen,” Khan said in an interview. “We get to know their social support network, who’s going to be driving them [to and from appointments], where they go on vacation, their cat’s name, who their neighbors are.”

 

A ‘Special Relationship’

Ralph V. Boccia, MD, is often asked what he does.

The next question that often comes — “Why do I do what I do?” — is Boccia’s favorite.

“Someone needs to take these patients through their journey,” Boccia, the founder of The Center for Cancer and Blood Disorders, Bethesda, Maryland, typically responds. He also often notes that “it is a special relationship you develop with the patient and their families.”

Boccia thinks about one long-term patient who captures this bond.

Joan Pinson, 70, was diagnosed with multiple myeloma about 25 years ago, when patients’ average survival was about 4 years.

Over a quarter century, Pinson has pivoted to different treatments, amid multiple relapses and remissions. Throughout most of this cancer journey, Boccia has been her primary oncologist, performing a stem cell transplant in 2000 and steering her to six clinical trials.

Her last relapse was 2 years ago, and since then she has been doing well on oral chemotherapy.

“Every time I relapsed, by the next appointment, he’d say, ‘here is what we are going to do,’ ” Pinson recalled. “I never worried, I never panicked. I knew he would take care of me.”

Over the years, Pinson and Boccia have shared many personal moments, sometimes by accident. One special moment happened early on in Pinson’s cancer journey. During an appointment, Boccia had “one ear to the phone” as his wife was about to deliver their first baby, Pinson recalled.

Later, Pinson met that child as a young man working in Boccia’s lab. She has also met Boccia’s wife, a nurse, when she filled in one day in the chemotherapy room.

Boccia now also treats Pinson’s husband who has prostate cancer, and he ruled out cancer when Pinson’s son, now in his 40s, had some worrisome symptoms.

More than 2 decades ago, Pinson told Boccia her goal was to see her youngest child graduate from high school. Now, six grandsons later, she has lived far beyond that goal.

“He has kept me alive,” said Pinson.

 

The Dying Patient

Harsha Vyas, MD, FACP, remembers the first encounter his office had with a 29-year-old woman referred with a diagnosis of stage IV breast cancer.

After just 15 minutes in the waiting room, the woman announced she was leaving. Although office staff assured the woman that she was next, the patient walked out.

Several months later, Vyas was called for an inpatient consult. It was the same woman.

Her lungs were full of fluid, and she was struggling to breathe, said Vyas, president and CEO of the Cancer Center of Middle Georgia, Dublin, and assistant professor at Augusta University in Georgia.

The woman, a single mother, told Vyas about her three young kids at home and asked him, “Doc, do something, please help me,” he recalled.

“Absolutely,” Vyas told her. But he had to be brutally honest about her prognosis and firm that she needed to follow his instructions. “You have a breast cancer I cannot cure,” he said. “All I can do is control the disease.”

From that first day, until the day she died, she came to every appointment and followed the treatment plan Vyas laid out.

For about 2 years, she responded well to treatment. And as the time passed and the trust grew, she began to open up to him. She showed him pictures. She talked about her children and being a mother.

“I’ve got to get my kids in a better place. I’m going to be there for them,” he recalled her saying.

Vyas admired her resourcefulness. She held down a part-time job, working retail and at a local restaurant. She figured out childcare so she could get to her chemotherapy appointments every 3 weeks and manage the copays.

Several years later, when she knew she was approaching the end of her life, she asked Vyas a question that hit hard.

“Doc, I don’t want to die and my kids find me dead. What can we do about it?”

Vyas, who has three daughters, imagined how traumatic this would be for a child. She and Vyas made the shared decision to cease treatment and begin home hospice. When the end was approaching, a hospice worker took over, waiting for bodily functions to cease.

When news of a death comes, “I say a little prayer, it’s almost like a send-off for that soul. That helps me absorb the news ... and let it go.”

But when the bond grows strong over time, as with his patient with breast cancer, Vyas said, “a piece of her is still with me.”

Khan had no relevant disclosures. Boccia and Vyas had no disclosures.

A version of this article appeared on Medscape.com.

Rose Gerber was 39, mother to a third grader and a kindergartener, when the diagnosis came: Advanced HER2-positive breast cancer.

“On one of my first or second appointments, I took in a little picture of Alexander and Isabella,” Gerber said. Gerber showed her oncologist the picture and told her: “I’ll do anything. I just want to be there for them.”

That was 21 years ago. Today, her current cancer status is “no evidence of disease.”

Over the past 2 decades, Gerber has gotten to be there for her children. Her youngest is now a television producer and her oldest, a CPA.

In that time, Gerber has had one constant: Her oncologist, Kandhasamy Jagathambal, MD, or Dr. Jaga, as she’s often called. 

“I’ve seen multiple physicians over my 21 years, but my oncologist has always been the focal point, guiding me in the right direction,” Gerber said in an interview.

Over the years, Jaga guided Gerber through a range of treatment decisions, including a Herceptin clinical trial that the mom of two views as lifesaving. Jaga often took on the role of both doctor and therapist, even providing comfort in the smaller moments when Gerber would fret about her weight gain.

The oncologist-patient “bond is very, very, very special,” said Gerber, who now works as director of patient advocacy and education at the Community Oncology Alliance.

Gerber isn’t alone in calling out the depth of the oncologist-patient bond.

Over years, sometimes decades, patients and oncologists can experience a whole world together: The treatment successes, relapses, uncertainties, and tough calls. As a result, a deep therapeutic alliance often develops. And with each new hurdle or decision, that collaborative, human connection between doctor and patient continues to form new layers.

“It’s like a shared bonding experience over trauma, like strangers trapped on a subway and then we get out, and we’re now on the other side, celebrating together,” said Saad Khan, MD, an associate professor of medicine (oncology) at Stanford University in California.

 

Connecting Through Stress

Although studies exploring the oncologist-patient bond are limited, some research suggests that a strong therapeutic alliance between patients and oncologists not only provides a foundation for quality care but can also help improve patients’ quality of life, protect against suicidal ideation, and increase treatment adherence.

Because of how stressful and frightening a cancer diagnosis can be, creating “a trusting, uninterrupted, almost sacred environment for them” is paramount for Khan. “I have no doubt that the most important part of their treatment is that they find an oncologist in whom they have total confidence,” Khan wrote in a blog.

The stress that patients with cancer experience is well documented, but oncologists take on a lot themselves and can also experience intense stress (.

“I consider my patient’s battles to be my battles,” Khan wrote.

The stress can start with the daily schedule. Oncologists often have a high volume of patients and tend to spend more time with each individual than most.

According to a 2023 survey, oncologists see about 68 patients a week, on average, but some oncologists, like Khan, have many more. Khan typically sees 20-30 patients a day and continues to care for many over years.

The survey also found that oncologists tend to spend a lot of time with their patients. Compared with other physicians, oncologists are two times more likely to spend at least 25 minutes with each patient.

With this kind of patient volume and time, Khan said, “you’re going to be exhausted.”

What can compound the exhaustion are the occasions oncologists need to deliver bad news — this treatment isn’t working, your cancer has come roaring back and, perhaps the hardest, we have no therapeutic options left. The end-of-life conversations, in particular, can be heartbreaking, especially when a patient is young and not ready to stop trying.

“It can be hard for doctors to discuss the end of life,” Don Dizon, MD, director of the Pelvic Malignancies Program at Lifespan Cancer Institute and director of Medical Oncology at Rhode Island Hospital, Providence, wrote in a column in 2023. Instead, it can be tempting and is often easier to focus on the next treatment, “instilling hope that there’s more that can be done,” even if doing more will only do harm.

In the face of these challenging decisions, growing a personal connection with patients over time can help keep oncologists going.

“We’re not just chemotherapy salesmen,” Khan said in an interview. “We get to know their social support network, who’s going to be driving them [to and from appointments], where they go on vacation, their cat’s name, who their neighbors are.”

 

A ‘Special Relationship’

Ralph V. Boccia, MD, is often asked what he does.

The next question that often comes — “Why do I do what I do?” — is Boccia’s favorite.

“Someone needs to take these patients through their journey,” Boccia, the founder of The Center for Cancer and Blood Disorders, Bethesda, Maryland, typically responds. He also often notes that “it is a special relationship you develop with the patient and their families.”

Boccia thinks about one long-term patient who captures this bond.

Joan Pinson, 70, was diagnosed with multiple myeloma about 25 years ago, when patients’ average survival was about 4 years.

Over a quarter century, Pinson has pivoted to different treatments, amid multiple relapses and remissions. Throughout most of this cancer journey, Boccia has been her primary oncologist, performing a stem cell transplant in 2000 and steering her to six clinical trials.

Her last relapse was 2 years ago, and since then she has been doing well on oral chemotherapy.

“Every time I relapsed, by the next appointment, he’d say, ‘here is what we are going to do,’ ” Pinson recalled. “I never worried, I never panicked. I knew he would take care of me.”

Over the years, Pinson and Boccia have shared many personal moments, sometimes by accident. One special moment happened early on in Pinson’s cancer journey. During an appointment, Boccia had “one ear to the phone” as his wife was about to deliver their first baby, Pinson recalled.

Later, Pinson met that child as a young man working in Boccia’s lab. She has also met Boccia’s wife, a nurse, when she filled in one day in the chemotherapy room.

Boccia now also treats Pinson’s husband who has prostate cancer, and he ruled out cancer when Pinson’s son, now in his 40s, had some worrisome symptoms.

More than 2 decades ago, Pinson told Boccia her goal was to see her youngest child graduate from high school. Now, six grandsons later, she has lived far beyond that goal.

“He has kept me alive,” said Pinson.

 

The Dying Patient

Harsha Vyas, MD, FACP, remembers the first encounter his office had with a 29-year-old woman referred with a diagnosis of stage IV breast cancer.

After just 15 minutes in the waiting room, the woman announced she was leaving. Although office staff assured the woman that she was next, the patient walked out.

Several months later, Vyas was called for an inpatient consult. It was the same woman.

Her lungs were full of fluid, and she was struggling to breathe, said Vyas, president and CEO of the Cancer Center of Middle Georgia, Dublin, and assistant professor at Augusta University in Georgia.

The woman, a single mother, told Vyas about her three young kids at home and asked him, “Doc, do something, please help me,” he recalled.

“Absolutely,” Vyas told her. But he had to be brutally honest about her prognosis and firm that she needed to follow his instructions. “You have a breast cancer I cannot cure,” he said. “All I can do is control the disease.”

From that first day, until the day she died, she came to every appointment and followed the treatment plan Vyas laid out.

For about 2 years, she responded well to treatment. And as the time passed and the trust grew, she began to open up to him. She showed him pictures. She talked about her children and being a mother.

“I’ve got to get my kids in a better place. I’m going to be there for them,” he recalled her saying.

Vyas admired her resourcefulness. She held down a part-time job, working retail and at a local restaurant. She figured out childcare so she could get to her chemotherapy appointments every 3 weeks and manage the copays.

Several years later, when she knew she was approaching the end of her life, she asked Vyas a question that hit hard.

“Doc, I don’t want to die and my kids find me dead. What can we do about it?”

Vyas, who has three daughters, imagined how traumatic this would be for a child. She and Vyas made the shared decision to cease treatment and begin home hospice. When the end was approaching, a hospice worker took over, waiting for bodily functions to cease.

When news of a death comes, “I say a little prayer, it’s almost like a send-off for that soul. That helps me absorb the news ... and let it go.”

But when the bond grows strong over time, as with his patient with breast cancer, Vyas said, “a piece of her is still with me.”

Khan had no relevant disclosures. Boccia and Vyas had no disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Lichen planus (LP) affects an estimated 0.15% of US adults, and more than half of patients do not receive treatment within a year of diagnosis by a dermatologist.

METHODOLOGY:

• To evaluate the prevalence of LP, researchers analyzed 566,851 eligible patients from the Explorys database, comprising electronic medical records from over 40 healthcare networks and 53 million patients across the United States.
• They also assessed treatment plans separately among 1998 newly diagnosed patients with LP between October 2015 and January 2020, who required at least one dermatology encounter within the first year following diagnosis.
• The primary outcome was overall prevalence of LP in the United States, including prevalence across specific age, sex, and racial subgroups. Additionally, dermatologist-prescribed treatments for non-oral LP were also reported.

TAKEAWAY:

• Overall, there were 1098 cases of LP (median age, 66 years; 74% women); the crude prevalence of LP was 0.19% and the age- and sex-standardized overall prevalence was 0.15%. Prevalence in women was 1.77 times higher than in men.
• Asian patients showed the highest standardized prevalence (0.2%), followed by Black patients (0.16). Prevalence increased with age, ranging from 0.04% among those aged 18-29 years to 0.26% among those aged 60-69 years and 0.33% among those aged 70-79 years.

IN PRACTICE:

“LP is a fairly common disease, which disproportionately affects women and individuals older than 60 years of age,” the authors wrote. “Future research to help identify patients who may need systemic treatment and determine appropriate treatments for patients with LP to limit sequelae is important as no medication is currently FDA approved for LP.”

SOURCE:

The study was led by Natalia Pelet Del Toro, MD, Department of Dermatology, Northwell Health, New Hyde Park, New York, and was published online in The Journal of the American Academy of Dermatology.

LIMITATIONS:

The absence of a precise diagnosis code for non-oral LP introduces potential misclassification risks. Additionally, the study design did not allow for the establishment of disease severity levels, limiting the ability to correlate treatment choices with disease severity.

DISCLOSURES:

The study did not receive any funding. Two authors reported to have received advisory fees, grants, and/or honoraria from several pharmaceutical companies. Pelet Del Toro and another author did not declare any conflict of interests.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Lichen planus (LP) affects an estimated 0.15% of US adults, and more than half of patients do not receive treatment within a year of diagnosis by a dermatologist.

METHODOLOGY:

• To evaluate the prevalence of LP, researchers analyzed 566,851 eligible patients from the Explorys database, comprising electronic medical records from over 40 healthcare networks and 53 million patients across the United States.
• They also assessed treatment plans separately among 1998 newly diagnosed patients with LP between October 2015 and January 2020, who required at least one dermatology encounter within the first year following diagnosis.
• The primary outcome was overall prevalence of LP in the United States, including prevalence across specific age, sex, and racial subgroups. Additionally, dermatologist-prescribed treatments for non-oral LP were also reported.

TAKEAWAY:

• Overall, there were 1098 cases of LP (median age, 66 years; 74% women); the crude prevalence of LP was 0.19% and the age- and sex-standardized overall prevalence was 0.15%. Prevalence in women was 1.77 times higher than in men.
• Asian patients showed the highest standardized prevalence (0.2%), followed by Black patients (0.16). Prevalence increased with age, ranging from 0.04% among those aged 18-29 years to 0.26% among those aged 60-69 years and 0.33% among those aged 70-79 years.

IN PRACTICE:

“LP is a fairly common disease, which disproportionately affects women and individuals older than 60 years of age,” the authors wrote. “Future research to help identify patients who may need systemic treatment and determine appropriate treatments for patients with LP to limit sequelae is important as no medication is currently FDA approved for LP.”

SOURCE:

The study was led by Natalia Pelet Del Toro, MD, Department of Dermatology, Northwell Health, New Hyde Park, New York, and was published online in The Journal of the American Academy of Dermatology.

LIMITATIONS:

The absence of a precise diagnosis code for non-oral LP introduces potential misclassification risks. Additionally, the study design did not allow for the establishment of disease severity levels, limiting the ability to correlate treatment choices with disease severity.

DISCLOSURES:

The study did not receive any funding. Two authors reported to have received advisory fees, grants, and/or honoraria from several pharmaceutical companies. Pelet Del Toro and another author did not declare any conflict of interests.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Lichen planus (LP) affects an estimated 0.15% of US adults, and more than half of patients do not receive treatment within a year of diagnosis by a dermatologist.

METHODOLOGY:

• To evaluate the prevalence of LP, researchers analyzed 566,851 eligible patients from the Explorys database, comprising electronic medical records from over 40 healthcare networks and 53 million patients across the United States.
• They also assessed treatment plans separately among 1998 newly diagnosed patients with LP between October 2015 and January 2020, who required at least one dermatology encounter within the first year following diagnosis.
• The primary outcome was overall prevalence of LP in the United States, including prevalence across specific age, sex, and racial subgroups. Additionally, dermatologist-prescribed treatments for non-oral LP were also reported.

TAKEAWAY:

• Overall, there were 1098 cases of LP (median age, 66 years; 74% women); the crude prevalence of LP was 0.19% and the age- and sex-standardized overall prevalence was 0.15%. Prevalence in women was 1.77 times higher than in men.
• Asian patients showed the highest standardized prevalence (0.2%), followed by Black patients (0.16). Prevalence increased with age, ranging from 0.04% among those aged 18-29 years to 0.26% among those aged 60-69 years and 0.33% among those aged 70-79 years.

IN PRACTICE:

“LP is a fairly common disease, which disproportionately affects women and individuals older than 60 years of age,” the authors wrote. “Future research to help identify patients who may need systemic treatment and determine appropriate treatments for patients with LP to limit sequelae is important as no medication is currently FDA approved for LP.”

SOURCE:

The study was led by Natalia Pelet Del Toro, MD, Department of Dermatology, Northwell Health, New Hyde Park, New York, and was published online in The Journal of the American Academy of Dermatology.

LIMITATIONS:

The absence of a precise diagnosis code for non-oral LP introduces potential misclassification risks. Additionally, the study design did not allow for the establishment of disease severity levels, limiting the ability to correlate treatment choices with disease severity.

DISCLOSURES:

The study did not receive any funding. Two authors reported to have received advisory fees, grants, and/or honoraria from several pharmaceutical companies. Pelet Del Toro and another author did not declare any conflict of interests.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Diet is increasingly seen as a modifiable risk factor in prostate cancer.

Recent studies have shown that ultralow-carbohydrate diets, weight loss diets, supplementation with omega-3 fatty acids, pro- and anti-inflammatory diets, fasting, and even tea drinking may affect prostate cancer risk or risk for progression.

In October, a cohort study involving about 900 men under active surveillance for early stage prostate cancers found that those who reported eating a diet that adhered closely to the US government’s recommendations as indicated by the Healthy Eating Index (HEI) saw a lower risk for progression at a median 6.5 months follow-up.

These findings follow results from an observational study, published in May, that followed about 2000 men with locally advanced prostate tumors. Men consuming a primarily plant-based diet (one closely adhering to the plant-based diet index) had less likelihood of progression over a median 6.5 years than those consuming diets low in plant-based foods.

“There is an increasing body of literature that says your diet matters,” said urologist Stephen J. Freedland, MD, of Cedars-Sinai Medical Center in Los Angeles, California, and director of its Center for Integrated Research in Cancer and Lifestyle. “At the same time, there are a lot of things that could explain these associations. People who can afford lots of plant-based foods tend to have higher socioeconomic status, for example.”

What’s needed, Freedland said, are more randomized trials to test the hypotheses emerging from the longitudinal cohort studies. “That’s where I’m going with my own research,” he said. “I’d like to look at a study like [one of these] and design a trial. Let’s say we get half of patients to eat according to the healthy eating index, while half eat whatever they want. Can dietary modification change which genes are turned on and off in a tumor, as a start?”

 

Oncologist and Nutritionist Collaborate on Multiple Studies

Nutritionist Pao-Hwa Lin, PhD, of Duke University in Durham, North Carolina, has been working for several years with Freedland on trials of nutrition interventions. A longtime researcher of chronic disease and diet, she first collaborated with Freedland on a study, published in 2019, that looked at whether insulin could be driven down with diet and exercise in men treated with androgen deprivation therapy.

Not only are high levels of insulin a known contributor to prostate cancer growth, Lin said, but “insulin resistance is a very common side effect of hormone therapy. And we saw that the low carb diet was very helpful for that.” The finding led Freedland and Lin to design further trials investigating carbohydrate restriction in people with prostate cancer.

Lin said randomized trials tend to be smaller and shorter in duration than the observational cohort studies because “interventions like these can be hard to maintain, and recruitment can be hard to sustain. A very well controlled and intensive nutrition intervention is not going to be super long.” Short trial durations also mean that prostate cancer progression can be difficult to capture. Risk for progression has to be measured using surrogate markers, such as the doubling time for prostate-specific antigen (PSA).

In 2020, Freedland and Lin published results from a pilot study of 57 men who had been treated with surgery or radiation for localized prostate cancer but had a PSA recurrence and were randomized to an ultralow-carbohydrate diet or no restrictions for 6 months. The investigators saw that PSA doubling times, an intermediate measure of tumor growth rate, were slower among those consuming the low-carb diet.

Currently they are wrapping up a trial that randomizes men who have been scheduled for radical prostatectomy to daily supplementation with walnuts, a natural source of polyphenols and omega-3 acids. This time, the aim is to determine whether gene expression in tumors changes in response to supplementation.

The researchers are also recruiting for a study in men being treated for metastatic prostate cancer. This study randomizes patients to a fasting-mimicking diet, which is a type of intermittent fasting, or no dietary restrictions for 6 months.

Developed by biologist Valter Longo, PhD, of the University of Southern California, Los Angeles, the fasting-mimicking diet has been shown to boost treatment effects in women with hormone receptor–positive breast cancer. In 2023, Longo and his colleagues published results from a small pilot study of the same diet in men with prostate cancer, reporting some positive metabolic findings.

Longo, who is consulting on Lin and Freedland’s trial, “has proven that the diet is helpful in treatment outcomes for breast cancer. So we connected and decided to test it and see if it’s helpful in prostate cancer as well.”

 

More Than One Approach Likely to Work

Though Lin and Freedland have focused most of their investigations on carbohydrate restriction, neither dismisses the potential for other dietary approaches to show benefit.

“There are two main schools of thought in terms of the relationship between diet and prostate cancer,” Lin said. “One is the insulin angle, and that’s what we hypothesized when we first tested the low-carb diet. The other is the inflammation angle.”

Studies have shown greater adherence to the HEI — a diet quality indicator that favors grains, fruits, dairy, vegetables, beans, and seafood — or the plant-based diet index to be associated with lower biomarkers of inflammation, she noted.

Insulin resistance, Lin explained, “is also highly related to inflammation.” (Several of the diets being investigated in prostate cancer were originally studied in diabetes.)

Moreover, weight loss caused by low-carb diets — or other healthy diets — can have a positive effect on insulin resistance independent of diet composition. “So it is a very complicated picture — and that doesn’t exclude other pathways that could also be contributing,” she said.

On the surface, a low-carb diet that is heavy in eggs, cheeses, and meats would seem to have little in common with the HEI or a plant-based diet. But Freedland noted that there are commonalities among the approaches being studied. “No one’s promoting eating a lot of simple sugars. No one’s saying eat a lot of processed foods. All of these diets emphasize whole, natural foods,” he said.

Lin hopes that she and Freedland will one day be able to test a diet that is both lower carb and anti-inflammatory in men with prostate cancer. “Why not combine the approaches, have all the good features together?” she asked.

But Freeland pointed out and explained why most clinicians don’t make dietary recommendations to their newly diagnosed patients.

“A new prostate cancer patient already gets easily an hour discussion of treatment options, of pros and cons. Patients often become overwhelmed. And then to extend it further to talk about diet, they’ll end up even more overwhelmed.” Moreover, he said, current evidence offers doctors few take-home messages to deliver besides avoiding sugar and processed foods.

Multiple dietary approaches are likely to prove helpful in prostate cancer, and when the evidence for them is better established, patients and their doctors will want to consider lifestyle factors in choosing one. The best diet will depend on a patient’s philosophy, tastes, and willingness to follow it, he concluded.

“At the end of the day I’m not rooting for one diet or another. I just want to get the answers.”

Lin disclosed no financial conflicts of interest. Freedland disclosed serving as a speaker for AstraZeneca, Astellas, and Pfizer and as a consultant for Astellas, AstraZeneca, Bayer, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Sanofi-Aventis, and Sumitomo.

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

Diet is increasingly seen as a modifiable risk factor in prostate cancer.

Recent studies have shown that ultralow-carbohydrate diets, weight loss diets, supplementation with omega-3 fatty acids, pro- and anti-inflammatory diets, fasting, and even tea drinking may affect prostate cancer risk or risk for progression.

In October, a cohort study involving about 900 men under active surveillance for early stage prostate cancers found that those who reported eating a diet that adhered closely to the US government’s recommendations as indicated by the Healthy Eating Index (HEI) saw a lower risk for progression at a median 6.5 months follow-up.

These findings follow results from an observational study, published in May, that followed about 2000 men with locally advanced prostate tumors. Men consuming a primarily plant-based diet (one closely adhering to the plant-based diet index) had less likelihood of progression over a median 6.5 years than those consuming diets low in plant-based foods.

“There is an increasing body of literature that says your diet matters,” said urologist Stephen J. Freedland, MD, of Cedars-Sinai Medical Center in Los Angeles, California, and director of its Center for Integrated Research in Cancer and Lifestyle. “At the same time, there are a lot of things that could explain these associations. People who can afford lots of plant-based foods tend to have higher socioeconomic status, for example.”

What’s needed, Freedland said, are more randomized trials to test the hypotheses emerging from the longitudinal cohort studies. “That’s where I’m going with my own research,” he said. “I’d like to look at a study like [one of these] and design a trial. Let’s say we get half of patients to eat according to the healthy eating index, while half eat whatever they want. Can dietary modification change which genes are turned on and off in a tumor, as a start?”

 

Oncologist and Nutritionist Collaborate on Multiple Studies

Nutritionist Pao-Hwa Lin, PhD, of Duke University in Durham, North Carolina, has been working for several years with Freedland on trials of nutrition interventions. A longtime researcher of chronic disease and diet, she first collaborated with Freedland on a study, published in 2019, that looked at whether insulin could be driven down with diet and exercise in men treated with androgen deprivation therapy.

Not only are high levels of insulin a known contributor to prostate cancer growth, Lin said, but “insulin resistance is a very common side effect of hormone therapy. And we saw that the low carb diet was very helpful for that.” The finding led Freedland and Lin to design further trials investigating carbohydrate restriction in people with prostate cancer.

Lin said randomized trials tend to be smaller and shorter in duration than the observational cohort studies because “interventions like these can be hard to maintain, and recruitment can be hard to sustain. A very well controlled and intensive nutrition intervention is not going to be super long.” Short trial durations also mean that prostate cancer progression can be difficult to capture. Risk for progression has to be measured using surrogate markers, such as the doubling time for prostate-specific antigen (PSA).

In 2020, Freedland and Lin published results from a pilot study of 57 men who had been treated with surgery or radiation for localized prostate cancer but had a PSA recurrence and were randomized to an ultralow-carbohydrate diet or no restrictions for 6 months. The investigators saw that PSA doubling times, an intermediate measure of tumor growth rate, were slower among those consuming the low-carb diet.

Currently they are wrapping up a trial that randomizes men who have been scheduled for radical prostatectomy to daily supplementation with walnuts, a natural source of polyphenols and omega-3 acids. This time, the aim is to determine whether gene expression in tumors changes in response to supplementation.

The researchers are also recruiting for a study in men being treated for metastatic prostate cancer. This study randomizes patients to a fasting-mimicking diet, which is a type of intermittent fasting, or no dietary restrictions for 6 months.

Developed by biologist Valter Longo, PhD, of the University of Southern California, Los Angeles, the fasting-mimicking diet has been shown to boost treatment effects in women with hormone receptor–positive breast cancer. In 2023, Longo and his colleagues published results from a small pilot study of the same diet in men with prostate cancer, reporting some positive metabolic findings.

Longo, who is consulting on Lin and Freedland’s trial, “has proven that the diet is helpful in treatment outcomes for breast cancer. So we connected and decided to test it and see if it’s helpful in prostate cancer as well.”

 

More Than One Approach Likely to Work

Though Lin and Freedland have focused most of their investigations on carbohydrate restriction, neither dismisses the potential for other dietary approaches to show benefit.

“There are two main schools of thought in terms of the relationship between diet and prostate cancer,” Lin said. “One is the insulin angle, and that’s what we hypothesized when we first tested the low-carb diet. The other is the inflammation angle.”

Studies have shown greater adherence to the HEI — a diet quality indicator that favors grains, fruits, dairy, vegetables, beans, and seafood — or the plant-based diet index to be associated with lower biomarkers of inflammation, she noted.

Insulin resistance, Lin explained, “is also highly related to inflammation.” (Several of the diets being investigated in prostate cancer were originally studied in diabetes.)

Moreover, weight loss caused by low-carb diets — or other healthy diets — can have a positive effect on insulin resistance independent of diet composition. “So it is a very complicated picture — and that doesn’t exclude other pathways that could also be contributing,” she said.

On the surface, a low-carb diet that is heavy in eggs, cheeses, and meats would seem to have little in common with the HEI or a plant-based diet. But Freedland noted that there are commonalities among the approaches being studied. “No one’s promoting eating a lot of simple sugars. No one’s saying eat a lot of processed foods. All of these diets emphasize whole, natural foods,” he said.

Lin hopes that she and Freedland will one day be able to test a diet that is both lower carb and anti-inflammatory in men with prostate cancer. “Why not combine the approaches, have all the good features together?” she asked.

But Freeland pointed out and explained why most clinicians don’t make dietary recommendations to their newly diagnosed patients.

“A new prostate cancer patient already gets easily an hour discussion of treatment options, of pros and cons. Patients often become overwhelmed. And then to extend it further to talk about diet, they’ll end up even more overwhelmed.” Moreover, he said, current evidence offers doctors few take-home messages to deliver besides avoiding sugar and processed foods.

Multiple dietary approaches are likely to prove helpful in prostate cancer, and when the evidence for them is better established, patients and their doctors will want to consider lifestyle factors in choosing one. The best diet will depend on a patient’s philosophy, tastes, and willingness to follow it, he concluded.

“At the end of the day I’m not rooting for one diet or another. I just want to get the answers.”

Lin disclosed no financial conflicts of interest. Freedland disclosed serving as a speaker for AstraZeneca, Astellas, and Pfizer and as a consultant for Astellas, AstraZeneca, Bayer, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Sanofi-Aventis, and Sumitomo.

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

Diet is increasingly seen as a modifiable risk factor in prostate cancer.

Recent studies have shown that ultralow-carbohydrate diets, weight loss diets, supplementation with omega-3 fatty acids, pro- and anti-inflammatory diets, fasting, and even tea drinking may affect prostate cancer risk or risk for progression.

In October, a cohort study involving about 900 men under active surveillance for early stage prostate cancers found that those who reported eating a diet that adhered closely to the US government’s recommendations as indicated by the Healthy Eating Index (HEI) saw a lower risk for progression at a median 6.5 months follow-up.

These findings follow results from an observational study, published in May, that followed about 2000 men with locally advanced prostate tumors. Men consuming a primarily plant-based diet (one closely adhering to the plant-based diet index) had less likelihood of progression over a median 6.5 years than those consuming diets low in plant-based foods.

“There is an increasing body of literature that says your diet matters,” said urologist Stephen J. Freedland, MD, of Cedars-Sinai Medical Center in Los Angeles, California, and director of its Center for Integrated Research in Cancer and Lifestyle. “At the same time, there are a lot of things that could explain these associations. People who can afford lots of plant-based foods tend to have higher socioeconomic status, for example.”

What’s needed, Freedland said, are more randomized trials to test the hypotheses emerging from the longitudinal cohort studies. “That’s where I’m going with my own research,” he said. “I’d like to look at a study like [one of these] and design a trial. Let’s say we get half of patients to eat according to the healthy eating index, while half eat whatever they want. Can dietary modification change which genes are turned on and off in a tumor, as a start?”

 

Oncologist and Nutritionist Collaborate on Multiple Studies

Nutritionist Pao-Hwa Lin, PhD, of Duke University in Durham, North Carolina, has been working for several years with Freedland on trials of nutrition interventions. A longtime researcher of chronic disease and diet, she first collaborated with Freedland on a study, published in 2019, that looked at whether insulin could be driven down with diet and exercise in men treated with androgen deprivation therapy.

Not only are high levels of insulin a known contributor to prostate cancer growth, Lin said, but “insulin resistance is a very common side effect of hormone therapy. And we saw that the low carb diet was very helpful for that.” The finding led Freedland and Lin to design further trials investigating carbohydrate restriction in people with prostate cancer.

Lin said randomized trials tend to be smaller and shorter in duration than the observational cohort studies because “interventions like these can be hard to maintain, and recruitment can be hard to sustain. A very well controlled and intensive nutrition intervention is not going to be super long.” Short trial durations also mean that prostate cancer progression can be difficult to capture. Risk for progression has to be measured using surrogate markers, such as the doubling time for prostate-specific antigen (PSA).

In 2020, Freedland and Lin published results from a pilot study of 57 men who had been treated with surgery or radiation for localized prostate cancer but had a PSA recurrence and were randomized to an ultralow-carbohydrate diet or no restrictions for 6 months. The investigators saw that PSA doubling times, an intermediate measure of tumor growth rate, were slower among those consuming the low-carb diet.

Currently they are wrapping up a trial that randomizes men who have been scheduled for radical prostatectomy to daily supplementation with walnuts, a natural source of polyphenols and omega-3 acids. This time, the aim is to determine whether gene expression in tumors changes in response to supplementation.

The researchers are also recruiting for a study in men being treated for metastatic prostate cancer. This study randomizes patients to a fasting-mimicking diet, which is a type of intermittent fasting, or no dietary restrictions for 6 months.

Developed by biologist Valter Longo, PhD, of the University of Southern California, Los Angeles, the fasting-mimicking diet has been shown to boost treatment effects in women with hormone receptor–positive breast cancer. In 2023, Longo and his colleagues published results from a small pilot study of the same diet in men with prostate cancer, reporting some positive metabolic findings.

Longo, who is consulting on Lin and Freedland’s trial, “has proven that the diet is helpful in treatment outcomes for breast cancer. So we connected and decided to test it and see if it’s helpful in prostate cancer as well.”

 

More Than One Approach Likely to Work

Though Lin and Freedland have focused most of their investigations on carbohydrate restriction, neither dismisses the potential for other dietary approaches to show benefit.

“There are two main schools of thought in terms of the relationship between diet and prostate cancer,” Lin said. “One is the insulin angle, and that’s what we hypothesized when we first tested the low-carb diet. The other is the inflammation angle.”

Studies have shown greater adherence to the HEI — a diet quality indicator that favors grains, fruits, dairy, vegetables, beans, and seafood — or the plant-based diet index to be associated with lower biomarkers of inflammation, she noted.

Insulin resistance, Lin explained, “is also highly related to inflammation.” (Several of the diets being investigated in prostate cancer were originally studied in diabetes.)

Moreover, weight loss caused by low-carb diets — or other healthy diets — can have a positive effect on insulin resistance independent of diet composition. “So it is a very complicated picture — and that doesn’t exclude other pathways that could also be contributing,” she said.

On the surface, a low-carb diet that is heavy in eggs, cheeses, and meats would seem to have little in common with the HEI or a plant-based diet. But Freedland noted that there are commonalities among the approaches being studied. “No one’s promoting eating a lot of simple sugars. No one’s saying eat a lot of processed foods. All of these diets emphasize whole, natural foods,” he said.

Lin hopes that she and Freedland will one day be able to test a diet that is both lower carb and anti-inflammatory in men with prostate cancer. “Why not combine the approaches, have all the good features together?” she asked.

But Freeland pointed out and explained why most clinicians don’t make dietary recommendations to their newly diagnosed patients.

“A new prostate cancer patient already gets easily an hour discussion of treatment options, of pros and cons. Patients often become overwhelmed. And then to extend it further to talk about diet, they’ll end up even more overwhelmed.” Moreover, he said, current evidence offers doctors few take-home messages to deliver besides avoiding sugar and processed foods.

Multiple dietary approaches are likely to prove helpful in prostate cancer, and when the evidence for them is better established, patients and their doctors will want to consider lifestyle factors in choosing one. The best diet will depend on a patient’s philosophy, tastes, and willingness to follow it, he concluded.

“At the end of the day I’m not rooting for one diet or another. I just want to get the answers.”

Lin disclosed no financial conflicts of interest. Freedland disclosed serving as a speaker for AstraZeneca, Astellas, and Pfizer and as a consultant for Astellas, AstraZeneca, Bayer, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Sanofi-Aventis, and Sumitomo.

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

This video transcript has been edited for clarity. 

Robert D. Glatter, MD: Hi and welcome. I’m Dr. Robert Glatter, medical adviser for Medscape Emergency Medicine. Joining me today to discuss a novel, plant-based approach to stopping moderate to severe bleeding is Joe Landolina, CEO and cofounder of Cresilon. Welcome, Joe. 

Joe Landolina, MS: Thank you so much for taking the time. It’s great to be here.

Educational Background and Inception of Cresilon

Glatter: It’s a pleasure to have you join me, and I want to congratulate you on your recent 510(k) FDA clearance for your novel product to save lives and stop bleeding. To begin with, can you explain how the idea for launching your company came about? 

Landolina: The way that Cresilon came about was a little bit unorthodox, because I was 17 years old when I invented the technology behind the product that eventually became Traumagel®. 

My grandfather was an ex-pharmaceutical executive, who later in life started a vineyard. I grew up on a vineyard with a winery chemistry lab across the street from my house and a grandfather who learned lab safety in the 60s. So, that meant that the day I learned how to walk, I was tossed into a lab and I fell head over heels in love with lab research.

That started experimentation and my academic pursuits. That led to discovering a blend of two plant-based polymers derived from algae that stop bleeding on contact, effectively creating a mechanical barrier and allowing anything from a gunshot wound to anything quite a bit more minor to stop in a matter of seconds.

Glatter: Your background is in biomedical engineering. How is it that you started tinkering and doing all this type of work? 

Landolina: That’s correct. I did my undergrad in chemical engineering, and my graduate studies were in biomedical engineering. For me, that was supposed to be a pathway into medical school. I always wanted to be a surgeon myself, and I love the field of medicine. 

As a freshman in college at NYU Engineering, I had this idea. I entered it into NYU’s business plan competition, and we won at the engineering school. That gave us just enough capital to start developing and researching Traumagel more, and Cresilon was born out of that research.

 

Techniques for Stopping Hemorrhage

Glatter: In terms of stopping hemorrhage, which takes so many lives in the United States and globally — certainly, uncontrolled hemorrhage — what are the techniques that you see, prior to the arrival of your product, as being effective? Can you elucidate some of these techniques? 

Landolina: In emergency medicine, the primary mode of controlling hemorrhage is passive. It’s what, in Brooklyn, we like to call “pressure and a prayer”, where you have a material that’s either gauze or an impregnated gauze in most cases, where the mode of action is absorbing blood, with the adjunct of pressure by the first responder or by the clinician who’s providing aid.

The idea is to stop the flow of blood to concentrate blood factors at the surface of the gauze product, and to promote either platelet activation or the production of fibrin to create a clot. 

These types of technologies are widespread. There are many versions of this technology carried by EMS agencies, trauma bays, US military soldiers, and soldiers across NATO countries. But these types of technologies tend to be relatively inefficient, meaning that they’re very difficult to get into wounds because of the gauze or the powder form of the devices, and it’s very hard to get them in contact with the form of bleeding.

On top of that, if the patient is clotting compromised or immunocompromised in some way, the ability to create a durable clot that will not be ripped off when you remove the product at the next level of care is also of concern. And so, this type of technology or the type of treatment of massive hemorrhage hasn’t changed in decades.

 

Current Applications and Potential Use

Glatter: I envision this product will be carried by paramedics, used on the battlefield at some point after your FDA clearance, and recently it went through.

Do you see any possibility that this could be an AED equivalent to Stop the Bleed? In other words, could the average lay person be trained to use your product if kits are available? 

Landolina: To be very clear, Traumagel today is only approved or cleared under a “prescription-only” indication, which means that it will not initially be available OTC. However, that is our goal. Our goal is to make this product available and usable by someone with no medical training whatsoever. 

The form factor of being a gel in a syringe lends itself well to that, meaning that we try to make it as easy as point and shoot to control hemorrhage, where there’s not as much technique to be learned in the application of a product like Traumagel as there is in current hemorrhage control techniques. 

 

Mechanism of Action and Physiology

Glatter: Once you apply Traumagel, can you explain what happens to the product after it’s applied and the bleeding has stopped? Does it get reabsorbed by the body? What’s the process here? 

Landolina: Under Traumagel’s indication, because it’s used in traumatic injury, it must be removed within 24 hours.

One of the big benefits of Traumagel is that when the patient produces a blood clot underneath Traumagel, it doesn’t become incorporated within the gel itself. To contrast that with the use of gauze, gauze is porous. The clot ends up wrapped around the fibers of the gauze, so if you peel the gauze away, it’s very likely that clot is coming off with it. The surgeon or the clinician at the next level of care is going to have to deal with the re-bleed. 

You can remove Traumagel cleanly and entirely without disturbing the underlying clot. That’s a major benefit, not only to the patient but also to the next level of care, to the next clinician or physician that is required to remove the product.

Glatter: How is it possible to remove the substance without disturbing the clot? Can you explain in more detail? 

Landolina: That’s one of the hallmarks of these plant-based polymers and the way that we design Traumagel itself. Traumagel is completely nonporous, and it has no fibrous nature to it. What that means is when the patient produces a blood clot or fibrin next to or on top of Traumagel, that fibrin ends up not incorporated within the polymers of Traumagel itself. 

Over time, because Traumagel is a hydrogel, meaning that by weight it’s mostly water, you end up having less adhesion to the clot over time. When it’s time to remove Traumagel from the injury, it has lost almost all of its adhesive capabilities, meaning that when you peel it away, that clot is going to stick better to tissue than it will to the gel itself. 

Glatter: Can you explain a little bit about the matrix that’s formed, the physiology, and how the polymers work to form this matrix? 

Landolina: Sure. Traumagel is made of two polysaccharides that are plant derived. One polysaccharide is polyanionic, and the other is polycationic, meaning one has negative charges and the other has positive charges, which together create almost a Lego block effect, where when the material comes in contact with tissue, it adheres strongly and allows for itself to effectively create a mechanical barrier against bleeding.

Courtesy of Cresilon

Landolina: Even in the face of major arterial blood flow, Traumagel will stay where it needs to stay, and it’s not going to get washed away. This means that it is much more easily appliable to these types of surfaces and will allow the patient to produce their own endogenous fibrin clot at that location.

Like I mentioned before, when that fibrin clot is formed, because the gel itself has no pores or fibers, it doesn’t become incorporated within the fibrin clot. You can take the gel away, leaving that clot behind without the chance of a rebleed.

 

Testing With Major Bleeds

Glatter: In terms of bleeding itself, have you tested your product with major aortic bleeds or carotid bleeds in preclinical work?

Landolina: We have used the US military’s model for lethal hemorrhage, and the idea there is to create a model that is just that — lethal. These are the worst types of bleeds that you can possibly imagine, where the patients are clotting compromised, and where you have, in most cases, a very strong arterial component, so something like a femoral artery bleed.

We’ve also tested in carotid artery, aortic applications, as well as combinations of venous and arterial bleeds. The idea here is to show the use of the product in the absolute worst-case scenario so that when this translates into the clinic, the models that we’ve used for evaluation, hopefully, are worse than what actually rolls into the trauma bay.

Glatter: Excellent. What’s the mean time to stop an arterial vs a venous bleed? Are we talking a matter of seconds?

Landolina: In the case of a healthy patient, meaning a patient without clotting compromise, you’re in a matter of seconds. It’s less than 10 seconds. 

In the case where you have clotting compromise, a deep, complicated wound geometry, we recommend holding a pressure bandage on for 3 minutes just because it increases the chance of Traumagel coming into contact with the bleed, especially when you can’t visualize the bleed in the bleed source. Because of that pressure time, that becomes the mean. But again, it’s highly dependent on the type of bleed and the style of application.

 

Failure Rates and Effectiveness

Glatter: As a segue to that, what is the failure rate based on your studies and internal research using Traumagel? Have there been cases where bleeding has not been able to be stopped? 

Landolina: It depends on the study, but the failure rates are incredibly low with Traumagel, assuming that it’s correctly used. That’s one of the benefits to this product, where with proper technique, with overwrap with gauze, you nearly always get control of hemorrhage with a product like this. 

Glatter: Is manual pressure required in that sense? From what you described earlier, manual pressure would not be required. 

Landolina: It depends on the injury. What we recommend is that, if you have a very deep wound where you cannot visualize the source of bleed, you use pressure to seat Traumagel into the source of bleeding, meaning that you’re following Committee on Tactical Combat Casualty Care (Co-TCCC) regulations or requirements, where you’re over wrapping with gauze, and you’re providing a pressure wrapping to ensure that the Traumagel is in contact with the bleed while it’s doing what it’s doing. 

In most cases, it doesn’t hurt to apply pressure on top of Traumagel as well. In more surface level bleeds, you don’t need pressure at all. 

 

Applications Beyond Trauma

Glatter: Interesting. In terms of further applications (eg, nose bleeds or GYN bleeding, which are life-threatening), do you see this coming as an application for the future? 

Landolina: That’s where we’re working. Traumagel is the successor to an animal health product called Vetigel. The formulations of the gel behind Vetigel and Traumagel are identical. Vetigel has a full surgical indication, and that’s everything from epistaxis to neuro and spine procedures, into cardiovascular and soft tissue surgeries, orthopedic medicine, and so on.

Cresilon’s goal is to eventually expand the indication of our technology to include surgical indications and other indications where we can help any patient that’s bleeding. 

Glatter: That’s important, because we use prehospital whole blood, low titer, specifically, when patients have life-threatening hemorrhage. With your product, that would reduce the amount of blood products that would need to be administered. This could be a real game changer. 

Landolina: Definitely, that’s the goal we’re working on. 

Infection Risks and Biocompatibility

Glatter: In terms of any risk for infection, has that been studied as well? Does Traumagel in any way lead to increased rates of infection?

Landolina: Traumagel is biocompatible. It’s a sterile product. We’ve done the full suite of biocompatibility testing as required by FDA. On top of that, remember that Vetigel, which is the same formulation, is an implantable product. As a result, that has even extended biocompatibility testing beyond what would be necessary for an external product.

In Vetigel’s use case, which has been used now in over 60,000 patients, primarily companion animals, dogs and cats, we haven’t seen instances of infection. There’s no reason to believe that we would see that clinically with Traumagel.

 

Research Collaborations and Future Applications

Glatter: In terms of other research that your company’s embarked on preclinically, I understand there were some studies done at Walter Reed Army Institute of Research. I was wondering if you could expand on these, specifically, in terms of traumatic brain injury (TBI) and hemorrhage related to that. For example, with shrapnel or even a gunshot wound. 

Landolina: The Walter Reed collaboration with Cresilon is something that I’m particularly excited about, because it marks Cresilon’s first project that’s outside the scope of just hemostasis. Walter Reed came to us with this proposal where there’s a big challenge in a subset of TBI called penetrating ballistic-like brain injury, where the brain has been penetrated by a bullet, shrapnel, or some other projectile, and there’s an injury that exposes the brain to the outside. 

Today, there is no standard of care to treat patients with those types of injuries. In many cases, mortality is caused through swelling of the brain, or collapse of the brain. What they came to us with was the potential of using our technology, not primarily as a hemostatic agent, but to be able to stabilize that patient enough to get to the next level of care to be treated by a neurosurgeon.

That study Walter Reed did was just a pilot that was done in small animals. In that pilot, they showed that over the period of treatment, there was no negative change in vital signs, no increase in edema or in swelling, or in any of the biomarkers that were being monitored at that time. 

At the very least, this is not full indication that this indication will work for Cresilon, but it shows that there’s promise. It’s something that we’re working on and hopefully we’ll be able to bring to market soon.

Glatter: Certainly, maintaining intracranial pressure and cerebral perfusion pressures are very critical. In the future, do you think this product would be able to be deployed endovascularly? Imagine this in terms of stopping bleeding from some source, whether it’s from a stroke or another intracranial source. 

Landolina: That’s been an area of interest for us. We have no evidence to prove that indication works at this point, but there’s also nothing to say that it wouldn’t be possible for our technology. At this point, we’ve only looked at a cursory level at those indications. 

Glatter: Does the use of Traumagel obviate the need for a more definitive repair (eg, with sutures) or something that’s more permanent?

Landolina: I always say that Traumagel — and Vetigel, for that matter — is not a replacement for good surgical technique. The surgeon always needs to make his or her best judgment when reviewing the patient. That doesn’t mean that there won’t need to be sutures or vascular repair in most of these cases, especially in major trauma.

Final Takeaways

Glatter: Do you have some bullet points or pearls you could give our audience as a takeaway? 

Landolina: When Cresilon looks at Traumagel — and for us, Traumagel is the next generation of hemostatic agent, especially in trauma care and in emergency medicine — it allows for a far-simplified application of the product and much faster control of hemorrhage with better patient outcomes.

As we roll this out through EMS agencies, trauma hospitals, military agencies, and eventually to the general public through a future indication, it’s something we’re very excited about. Personally, I started this business 14 years ago, and so it’s great to see our mission of saving lives transitioning to saving human lives.

Glatter: I look forward to seeing this product in the emergency department, but also in other settings, such as in the operating room where we can really help patients who are dying from hemorrhage, certainly on the battlefield, and the lay public. If someone were to come upon a patient who’s bleeding out, this could be certainly a game changer and a lifesaver. 

I want to thank you for your time. This is a really important product that’s transformed the lives of so many animals, but also people in the future.

Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He reported no relevant conflicts of interest. Mr. Landolina is the CEO and co-founder of Cresilon, a biotechnology company specializing in plant-based solutions for emergency bleeding control.

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

This video transcript has been edited for clarity. 

Robert D. Glatter, MD: Hi and welcome. I’m Dr. Robert Glatter, medical adviser for Medscape Emergency Medicine. Joining me today to discuss a novel, plant-based approach to stopping moderate to severe bleeding is Joe Landolina, CEO and cofounder of Cresilon. Welcome, Joe. 

Joe Landolina, MS: Thank you so much for taking the time. It’s great to be here.

Educational Background and Inception of Cresilon

Glatter: It’s a pleasure to have you join me, and I want to congratulate you on your recent 510(k) FDA clearance for your novel product to save lives and stop bleeding. To begin with, can you explain how the idea for launching your company came about? 

Landolina: The way that Cresilon came about was a little bit unorthodox, because I was 17 years old when I invented the technology behind the product that eventually became Traumagel®. 

My grandfather was an ex-pharmaceutical executive, who later in life started a vineyard. I grew up on a vineyard with a winery chemistry lab across the street from my house and a grandfather who learned lab safety in the 60s. So, that meant that the day I learned how to walk, I was tossed into a lab and I fell head over heels in love with lab research.

That started experimentation and my academic pursuits. That led to discovering a blend of two plant-based polymers derived from algae that stop bleeding on contact, effectively creating a mechanical barrier and allowing anything from a gunshot wound to anything quite a bit more minor to stop in a matter of seconds.

Glatter: Your background is in biomedical engineering. How is it that you started tinkering and doing all this type of work? 

Landolina: That’s correct. I did my undergrad in chemical engineering, and my graduate studies were in biomedical engineering. For me, that was supposed to be a pathway into medical school. I always wanted to be a surgeon myself, and I love the field of medicine. 

As a freshman in college at NYU Engineering, I had this idea. I entered it into NYU’s business plan competition, and we won at the engineering school. That gave us just enough capital to start developing and researching Traumagel more, and Cresilon was born out of that research.

 

Techniques for Stopping Hemorrhage

Glatter: In terms of stopping hemorrhage, which takes so many lives in the United States and globally — certainly, uncontrolled hemorrhage — what are the techniques that you see, prior to the arrival of your product, as being effective? Can you elucidate some of these techniques? 

Landolina: In emergency medicine, the primary mode of controlling hemorrhage is passive. It’s what, in Brooklyn, we like to call “pressure and a prayer”, where you have a material that’s either gauze or an impregnated gauze in most cases, where the mode of action is absorbing blood, with the adjunct of pressure by the first responder or by the clinician who’s providing aid.

The idea is to stop the flow of blood to concentrate blood factors at the surface of the gauze product, and to promote either platelet activation or the production of fibrin to create a clot. 

These types of technologies are widespread. There are many versions of this technology carried by EMS agencies, trauma bays, US military soldiers, and soldiers across NATO countries. But these types of technologies tend to be relatively inefficient, meaning that they’re very difficult to get into wounds because of the gauze or the powder form of the devices, and it’s very hard to get them in contact with the form of bleeding.

On top of that, if the patient is clotting compromised or immunocompromised in some way, the ability to create a durable clot that will not be ripped off when you remove the product at the next level of care is also of concern. And so, this type of technology or the type of treatment of massive hemorrhage hasn’t changed in decades.

 

Current Applications and Potential Use

Glatter: I envision this product will be carried by paramedics, used on the battlefield at some point after your FDA clearance, and recently it went through.

Do you see any possibility that this could be an AED equivalent to Stop the Bleed? In other words, could the average lay person be trained to use your product if kits are available? 

Landolina: To be very clear, Traumagel today is only approved or cleared under a “prescription-only” indication, which means that it will not initially be available OTC. However, that is our goal. Our goal is to make this product available and usable by someone with no medical training whatsoever. 

The form factor of being a gel in a syringe lends itself well to that, meaning that we try to make it as easy as point and shoot to control hemorrhage, where there’s not as much technique to be learned in the application of a product like Traumagel as there is in current hemorrhage control techniques. 

 

Mechanism of Action and Physiology

Glatter: Once you apply Traumagel, can you explain what happens to the product after it’s applied and the bleeding has stopped? Does it get reabsorbed by the body? What’s the process here? 

Landolina: Under Traumagel’s indication, because it’s used in traumatic injury, it must be removed within 24 hours.

One of the big benefits of Traumagel is that when the patient produces a blood clot underneath Traumagel, it doesn’t become incorporated within the gel itself. To contrast that with the use of gauze, gauze is porous. The clot ends up wrapped around the fibers of the gauze, so if you peel the gauze away, it’s very likely that clot is coming off with it. The surgeon or the clinician at the next level of care is going to have to deal with the re-bleed. 

You can remove Traumagel cleanly and entirely without disturbing the underlying clot. That’s a major benefit, not only to the patient but also to the next level of care, to the next clinician or physician that is required to remove the product.

Glatter: How is it possible to remove the substance without disturbing the clot? Can you explain in more detail? 

Landolina: That’s one of the hallmarks of these plant-based polymers and the way that we design Traumagel itself. Traumagel is completely nonporous, and it has no fibrous nature to it. What that means is when the patient produces a blood clot or fibrin next to or on top of Traumagel, that fibrin ends up not incorporated within the polymers of Traumagel itself. 

Over time, because Traumagel is a hydrogel, meaning that by weight it’s mostly water, you end up having less adhesion to the clot over time. When it’s time to remove Traumagel from the injury, it has lost almost all of its adhesive capabilities, meaning that when you peel it away, that clot is going to stick better to tissue than it will to the gel itself. 

Glatter: Can you explain a little bit about the matrix that’s formed, the physiology, and how the polymers work to form this matrix? 

Landolina: Sure. Traumagel is made of two polysaccharides that are plant derived. One polysaccharide is polyanionic, and the other is polycationic, meaning one has negative charges and the other has positive charges, which together create almost a Lego block effect, where when the material comes in contact with tissue, it adheres strongly and allows for itself to effectively create a mechanical barrier against bleeding.

Courtesy of Cresilon

Landolina: Even in the face of major arterial blood flow, Traumagel will stay where it needs to stay, and it’s not going to get washed away. This means that it is much more easily appliable to these types of surfaces and will allow the patient to produce their own endogenous fibrin clot at that location.

Like I mentioned before, when that fibrin clot is formed, because the gel itself has no pores or fibers, it doesn’t become incorporated within the fibrin clot. You can take the gel away, leaving that clot behind without the chance of a rebleed.

 

Testing With Major Bleeds

Glatter: In terms of bleeding itself, have you tested your product with major aortic bleeds or carotid bleeds in preclinical work?

Landolina: We have used the US military’s model for lethal hemorrhage, and the idea there is to create a model that is just that — lethal. These are the worst types of bleeds that you can possibly imagine, where the patients are clotting compromised, and where you have, in most cases, a very strong arterial component, so something like a femoral artery bleed.

We’ve also tested in carotid artery, aortic applications, as well as combinations of venous and arterial bleeds. The idea here is to show the use of the product in the absolute worst-case scenario so that when this translates into the clinic, the models that we’ve used for evaluation, hopefully, are worse than what actually rolls into the trauma bay.

Glatter: Excellent. What’s the mean time to stop an arterial vs a venous bleed? Are we talking a matter of seconds?

Landolina: In the case of a healthy patient, meaning a patient without clotting compromise, you’re in a matter of seconds. It’s less than 10 seconds. 

In the case where you have clotting compromise, a deep, complicated wound geometry, we recommend holding a pressure bandage on for 3 minutes just because it increases the chance of Traumagel coming into contact with the bleed, especially when you can’t visualize the bleed in the bleed source. Because of that pressure time, that becomes the mean. But again, it’s highly dependent on the type of bleed and the style of application.

 

Failure Rates and Effectiveness

Glatter: As a segue to that, what is the failure rate based on your studies and internal research using Traumagel? Have there been cases where bleeding has not been able to be stopped? 

Landolina: It depends on the study, but the failure rates are incredibly low with Traumagel, assuming that it’s correctly used. That’s one of the benefits to this product, where with proper technique, with overwrap with gauze, you nearly always get control of hemorrhage with a product like this. 

Glatter: Is manual pressure required in that sense? From what you described earlier, manual pressure would not be required. 

Landolina: It depends on the injury. What we recommend is that, if you have a very deep wound where you cannot visualize the source of bleed, you use pressure to seat Traumagel into the source of bleeding, meaning that you’re following Committee on Tactical Combat Casualty Care (Co-TCCC) regulations or requirements, where you’re over wrapping with gauze, and you’re providing a pressure wrapping to ensure that the Traumagel is in contact with the bleed while it’s doing what it’s doing. 

In most cases, it doesn’t hurt to apply pressure on top of Traumagel as well. In more surface level bleeds, you don’t need pressure at all. 

 

Applications Beyond Trauma

Glatter: Interesting. In terms of further applications (eg, nose bleeds or GYN bleeding, which are life-threatening), do you see this coming as an application for the future? 

Landolina: That’s where we’re working. Traumagel is the successor to an animal health product called Vetigel. The formulations of the gel behind Vetigel and Traumagel are identical. Vetigel has a full surgical indication, and that’s everything from epistaxis to neuro and spine procedures, into cardiovascular and soft tissue surgeries, orthopedic medicine, and so on.

Cresilon’s goal is to eventually expand the indication of our technology to include surgical indications and other indications where we can help any patient that’s bleeding. 

Glatter: That’s important, because we use prehospital whole blood, low titer, specifically, when patients have life-threatening hemorrhage. With your product, that would reduce the amount of blood products that would need to be administered. This could be a real game changer. 

Landolina: Definitely, that’s the goal we’re working on. 

Infection Risks and Biocompatibility

Glatter: In terms of any risk for infection, has that been studied as well? Does Traumagel in any way lead to increased rates of infection?

Landolina: Traumagel is biocompatible. It’s a sterile product. We’ve done the full suite of biocompatibility testing as required by FDA. On top of that, remember that Vetigel, which is the same formulation, is an implantable product. As a result, that has even extended biocompatibility testing beyond what would be necessary for an external product.

In Vetigel’s use case, which has been used now in over 60,000 patients, primarily companion animals, dogs and cats, we haven’t seen instances of infection. There’s no reason to believe that we would see that clinically with Traumagel.

 

Research Collaborations and Future Applications

Glatter: In terms of other research that your company’s embarked on preclinically, I understand there were some studies done at Walter Reed Army Institute of Research. I was wondering if you could expand on these, specifically, in terms of traumatic brain injury (TBI) and hemorrhage related to that. For example, with shrapnel or even a gunshot wound. 

Landolina: The Walter Reed collaboration with Cresilon is something that I’m particularly excited about, because it marks Cresilon’s first project that’s outside the scope of just hemostasis. Walter Reed came to us with this proposal where there’s a big challenge in a subset of TBI called penetrating ballistic-like brain injury, where the brain has been penetrated by a bullet, shrapnel, or some other projectile, and there’s an injury that exposes the brain to the outside. 

Today, there is no standard of care to treat patients with those types of injuries. In many cases, mortality is caused through swelling of the brain, or collapse of the brain. What they came to us with was the potential of using our technology, not primarily as a hemostatic agent, but to be able to stabilize that patient enough to get to the next level of care to be treated by a neurosurgeon.

That study Walter Reed did was just a pilot that was done in small animals. In that pilot, they showed that over the period of treatment, there was no negative change in vital signs, no increase in edema or in swelling, or in any of the biomarkers that were being monitored at that time. 

At the very least, this is not full indication that this indication will work for Cresilon, but it shows that there’s promise. It’s something that we’re working on and hopefully we’ll be able to bring to market soon.

Glatter: Certainly, maintaining intracranial pressure and cerebral perfusion pressures are very critical. In the future, do you think this product would be able to be deployed endovascularly? Imagine this in terms of stopping bleeding from some source, whether it’s from a stroke or another intracranial source. 

Landolina: That’s been an area of interest for us. We have no evidence to prove that indication works at this point, but there’s also nothing to say that it wouldn’t be possible for our technology. At this point, we’ve only looked at a cursory level at those indications. 

Glatter: Does the use of Traumagel obviate the need for a more definitive repair (eg, with sutures) or something that’s more permanent?

Landolina: I always say that Traumagel — and Vetigel, for that matter — is not a replacement for good surgical technique. The surgeon always needs to make his or her best judgment when reviewing the patient. That doesn’t mean that there won’t need to be sutures or vascular repair in most of these cases, especially in major trauma.

Final Takeaways

Glatter: Do you have some bullet points or pearls you could give our audience as a takeaway? 

Landolina: When Cresilon looks at Traumagel — and for us, Traumagel is the next generation of hemostatic agent, especially in trauma care and in emergency medicine — it allows for a far-simplified application of the product and much faster control of hemorrhage with better patient outcomes.

As we roll this out through EMS agencies, trauma hospitals, military agencies, and eventually to the general public through a future indication, it’s something we’re very excited about. Personally, I started this business 14 years ago, and so it’s great to see our mission of saving lives transitioning to saving human lives.

Glatter: I look forward to seeing this product in the emergency department, but also in other settings, such as in the operating room where we can really help patients who are dying from hemorrhage, certainly on the battlefield, and the lay public. If someone were to come upon a patient who’s bleeding out, this could be certainly a game changer and a lifesaver. 

I want to thank you for your time. This is a really important product that’s transformed the lives of so many animals, but also people in the future.

Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He reported no relevant conflicts of interest. Mr. Landolina is the CEO and co-founder of Cresilon, a biotechnology company specializing in plant-based solutions for emergency bleeding control.

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

This video transcript has been edited for clarity. 

Robert D. Glatter, MD: Hi and welcome. I’m Dr. Robert Glatter, medical adviser for Medscape Emergency Medicine. Joining me today to discuss a novel, plant-based approach to stopping moderate to severe bleeding is Joe Landolina, CEO and cofounder of Cresilon. Welcome, Joe. 

Joe Landolina, MS: Thank you so much for taking the time. It’s great to be here.

Educational Background and Inception of Cresilon

Glatter: It’s a pleasure to have you join me, and I want to congratulate you on your recent 510(k) FDA clearance for your novel product to save lives and stop bleeding. To begin with, can you explain how the idea for launching your company came about? 

Landolina: The way that Cresilon came about was a little bit unorthodox, because I was 17 years old when I invented the technology behind the product that eventually became Traumagel®. 

My grandfather was an ex-pharmaceutical executive, who later in life started a vineyard. I grew up on a vineyard with a winery chemistry lab across the street from my house and a grandfather who learned lab safety in the 60s. So, that meant that the day I learned how to walk, I was tossed into a lab and I fell head over heels in love with lab research.

That started experimentation and my academic pursuits. That led to discovering a blend of two plant-based polymers derived from algae that stop bleeding on contact, effectively creating a mechanical barrier and allowing anything from a gunshot wound to anything quite a bit more minor to stop in a matter of seconds.

Glatter: Your background is in biomedical engineering. How is it that you started tinkering and doing all this type of work? 

Landolina: That’s correct. I did my undergrad in chemical engineering, and my graduate studies were in biomedical engineering. For me, that was supposed to be a pathway into medical school. I always wanted to be a surgeon myself, and I love the field of medicine. 

As a freshman in college at NYU Engineering, I had this idea. I entered it into NYU’s business plan competition, and we won at the engineering school. That gave us just enough capital to start developing and researching Traumagel more, and Cresilon was born out of that research.

 

Techniques for Stopping Hemorrhage

Glatter: In terms of stopping hemorrhage, which takes so many lives in the United States and globally — certainly, uncontrolled hemorrhage — what are the techniques that you see, prior to the arrival of your product, as being effective? Can you elucidate some of these techniques? 

Landolina: In emergency medicine, the primary mode of controlling hemorrhage is passive. It’s what, in Brooklyn, we like to call “pressure and a prayer”, where you have a material that’s either gauze or an impregnated gauze in most cases, where the mode of action is absorbing blood, with the adjunct of pressure by the first responder or by the clinician who’s providing aid.

The idea is to stop the flow of blood to concentrate blood factors at the surface of the gauze product, and to promote either platelet activation or the production of fibrin to create a clot. 

These types of technologies are widespread. There are many versions of this technology carried by EMS agencies, trauma bays, US military soldiers, and soldiers across NATO countries. But these types of technologies tend to be relatively inefficient, meaning that they’re very difficult to get into wounds because of the gauze or the powder form of the devices, and it’s very hard to get them in contact with the form of bleeding.

On top of that, if the patient is clotting compromised or immunocompromised in some way, the ability to create a durable clot that will not be ripped off when you remove the product at the next level of care is also of concern. And so, this type of technology or the type of treatment of massive hemorrhage hasn’t changed in decades.

 

Current Applications and Potential Use

Glatter: I envision this product will be carried by paramedics, used on the battlefield at some point after your FDA clearance, and recently it went through.

Do you see any possibility that this could be an AED equivalent to Stop the Bleed? In other words, could the average lay person be trained to use your product if kits are available? 

Landolina: To be very clear, Traumagel today is only approved or cleared under a “prescription-only” indication, which means that it will not initially be available OTC. However, that is our goal. Our goal is to make this product available and usable by someone with no medical training whatsoever. 

The form factor of being a gel in a syringe lends itself well to that, meaning that we try to make it as easy as point and shoot to control hemorrhage, where there’s not as much technique to be learned in the application of a product like Traumagel as there is in current hemorrhage control techniques. 

 

Mechanism of Action and Physiology

Glatter: Once you apply Traumagel, can you explain what happens to the product after it’s applied and the bleeding has stopped? Does it get reabsorbed by the body? What’s the process here? 

Landolina: Under Traumagel’s indication, because it’s used in traumatic injury, it must be removed within 24 hours.

One of the big benefits of Traumagel is that when the patient produces a blood clot underneath Traumagel, it doesn’t become incorporated within the gel itself. To contrast that with the use of gauze, gauze is porous. The clot ends up wrapped around the fibers of the gauze, so if you peel the gauze away, it’s very likely that clot is coming off with it. The surgeon or the clinician at the next level of care is going to have to deal with the re-bleed. 

You can remove Traumagel cleanly and entirely without disturbing the underlying clot. That’s a major benefit, not only to the patient but also to the next level of care, to the next clinician or physician that is required to remove the product.

Glatter: How is it possible to remove the substance without disturbing the clot? Can you explain in more detail? 

Landolina: That’s one of the hallmarks of these plant-based polymers and the way that we design Traumagel itself. Traumagel is completely nonporous, and it has no fibrous nature to it. What that means is when the patient produces a blood clot or fibrin next to or on top of Traumagel, that fibrin ends up not incorporated within the polymers of Traumagel itself. 

Over time, because Traumagel is a hydrogel, meaning that by weight it’s mostly water, you end up having less adhesion to the clot over time. When it’s time to remove Traumagel from the injury, it has lost almost all of its adhesive capabilities, meaning that when you peel it away, that clot is going to stick better to tissue than it will to the gel itself. 

Glatter: Can you explain a little bit about the matrix that’s formed, the physiology, and how the polymers work to form this matrix? 

Landolina: Sure. Traumagel is made of two polysaccharides that are plant derived. One polysaccharide is polyanionic, and the other is polycationic, meaning one has negative charges and the other has positive charges, which together create almost a Lego block effect, where when the material comes in contact with tissue, it adheres strongly and allows for itself to effectively create a mechanical barrier against bleeding.

Courtesy of Cresilon

Landolina: Even in the face of major arterial blood flow, Traumagel will stay where it needs to stay, and it’s not going to get washed away. This means that it is much more easily appliable to these types of surfaces and will allow the patient to produce their own endogenous fibrin clot at that location.

Like I mentioned before, when that fibrin clot is formed, because the gel itself has no pores or fibers, it doesn’t become incorporated within the fibrin clot. You can take the gel away, leaving that clot behind without the chance of a rebleed.

 

Testing With Major Bleeds

Glatter: In terms of bleeding itself, have you tested your product with major aortic bleeds or carotid bleeds in preclinical work?

Landolina: We have used the US military’s model for lethal hemorrhage, and the idea there is to create a model that is just that — lethal. These are the worst types of bleeds that you can possibly imagine, where the patients are clotting compromised, and where you have, in most cases, a very strong arterial component, so something like a femoral artery bleed.

We’ve also tested in carotid artery, aortic applications, as well as combinations of venous and arterial bleeds. The idea here is to show the use of the product in the absolute worst-case scenario so that when this translates into the clinic, the models that we’ve used for evaluation, hopefully, are worse than what actually rolls into the trauma bay.

Glatter: Excellent. What’s the mean time to stop an arterial vs a venous bleed? Are we talking a matter of seconds?

Landolina: In the case of a healthy patient, meaning a patient without clotting compromise, you’re in a matter of seconds. It’s less than 10 seconds. 

In the case where you have clotting compromise, a deep, complicated wound geometry, we recommend holding a pressure bandage on for 3 minutes just because it increases the chance of Traumagel coming into contact with the bleed, especially when you can’t visualize the bleed in the bleed source. Because of that pressure time, that becomes the mean. But again, it’s highly dependent on the type of bleed and the style of application.

 

Failure Rates and Effectiveness

Glatter: As a segue to that, what is the failure rate based on your studies and internal research using Traumagel? Have there been cases where bleeding has not been able to be stopped? 

Landolina: It depends on the study, but the failure rates are incredibly low with Traumagel, assuming that it’s correctly used. That’s one of the benefits to this product, where with proper technique, with overwrap with gauze, you nearly always get control of hemorrhage with a product like this. 

Glatter: Is manual pressure required in that sense? From what you described earlier, manual pressure would not be required. 

Landolina: It depends on the injury. What we recommend is that, if you have a very deep wound where you cannot visualize the source of bleed, you use pressure to seat Traumagel into the source of bleeding, meaning that you’re following Committee on Tactical Combat Casualty Care (Co-TCCC) regulations or requirements, where you’re over wrapping with gauze, and you’re providing a pressure wrapping to ensure that the Traumagel is in contact with the bleed while it’s doing what it’s doing. 

In most cases, it doesn’t hurt to apply pressure on top of Traumagel as well. In more surface level bleeds, you don’t need pressure at all. 

 

Applications Beyond Trauma

Glatter: Interesting. In terms of further applications (eg, nose bleeds or GYN bleeding, which are life-threatening), do you see this coming as an application for the future? 

Landolina: That’s where we’re working. Traumagel is the successor to an animal health product called Vetigel. The formulations of the gel behind Vetigel and Traumagel are identical. Vetigel has a full surgical indication, and that’s everything from epistaxis to neuro and spine procedures, into cardiovascular and soft tissue surgeries, orthopedic medicine, and so on.

Cresilon’s goal is to eventually expand the indication of our technology to include surgical indications and other indications where we can help any patient that’s bleeding. 

Glatter: That’s important, because we use prehospital whole blood, low titer, specifically, when patients have life-threatening hemorrhage. With your product, that would reduce the amount of blood products that would need to be administered. This could be a real game changer. 

Landolina: Definitely, that’s the goal we’re working on. 

Infection Risks and Biocompatibility

Glatter: In terms of any risk for infection, has that been studied as well? Does Traumagel in any way lead to increased rates of infection?

Landolina: Traumagel is biocompatible. It’s a sterile product. We’ve done the full suite of biocompatibility testing as required by FDA. On top of that, remember that Vetigel, which is the same formulation, is an implantable product. As a result, that has even extended biocompatibility testing beyond what would be necessary for an external product.

In Vetigel’s use case, which has been used now in over 60,000 patients, primarily companion animals, dogs and cats, we haven’t seen instances of infection. There’s no reason to believe that we would see that clinically with Traumagel.

 

Research Collaborations and Future Applications

Glatter: In terms of other research that your company’s embarked on preclinically, I understand there were some studies done at Walter Reed Army Institute of Research. I was wondering if you could expand on these, specifically, in terms of traumatic brain injury (TBI) and hemorrhage related to that. For example, with shrapnel or even a gunshot wound. 

Landolina: The Walter Reed collaboration with Cresilon is something that I’m particularly excited about, because it marks Cresilon’s first project that’s outside the scope of just hemostasis. Walter Reed came to us with this proposal where there’s a big challenge in a subset of TBI called penetrating ballistic-like brain injury, where the brain has been penetrated by a bullet, shrapnel, or some other projectile, and there’s an injury that exposes the brain to the outside. 

Today, there is no standard of care to treat patients with those types of injuries. In many cases, mortality is caused through swelling of the brain, or collapse of the brain. What they came to us with was the potential of using our technology, not primarily as a hemostatic agent, but to be able to stabilize that patient enough to get to the next level of care to be treated by a neurosurgeon.

That study Walter Reed did was just a pilot that was done in small animals. In that pilot, they showed that over the period of treatment, there was no negative change in vital signs, no increase in edema or in swelling, or in any of the biomarkers that were being monitored at that time. 

At the very least, this is not full indication that this indication will work for Cresilon, but it shows that there’s promise. It’s something that we’re working on and hopefully we’ll be able to bring to market soon.

Glatter: Certainly, maintaining intracranial pressure and cerebral perfusion pressures are very critical. In the future, do you think this product would be able to be deployed endovascularly? Imagine this in terms of stopping bleeding from some source, whether it’s from a stroke or another intracranial source. 

Landolina: That’s been an area of interest for us. We have no evidence to prove that indication works at this point, but there’s also nothing to say that it wouldn’t be possible for our technology. At this point, we’ve only looked at a cursory level at those indications. 

Glatter: Does the use of Traumagel obviate the need for a more definitive repair (eg, with sutures) or something that’s more permanent?

Landolina: I always say that Traumagel — and Vetigel, for that matter — is not a replacement for good surgical technique. The surgeon always needs to make his or her best judgment when reviewing the patient. That doesn’t mean that there won’t need to be sutures or vascular repair in most of these cases, especially in major trauma.

Final Takeaways

Glatter: Do you have some bullet points or pearls you could give our audience as a takeaway? 

Landolina: When Cresilon looks at Traumagel — and for us, Traumagel is the next generation of hemostatic agent, especially in trauma care and in emergency medicine — it allows for a far-simplified application of the product and much faster control of hemorrhage with better patient outcomes.

As we roll this out through EMS agencies, trauma hospitals, military agencies, and eventually to the general public through a future indication, it’s something we’re very excited about. Personally, I started this business 14 years ago, and so it’s great to see our mission of saving lives transitioning to saving human lives.

Glatter: I look forward to seeing this product in the emergency department, but also in other settings, such as in the operating room where we can really help patients who are dying from hemorrhage, certainly on the battlefield, and the lay public. If someone were to come upon a patient who’s bleeding out, this could be certainly a game changer and a lifesaver. 

I want to thank you for your time. This is a really important product that’s transformed the lives of so many animals, but also people in the future.

Dr. Glatter is an assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He reported no relevant conflicts of interest. Mr. Landolina is the CEO and co-founder of Cresilon, a biotechnology company specializing in plant-based solutions for emergency bleeding control.

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