AVAHO

TOPLINE:

For patients with gastric cancer, extending regular follow-up beyond the typical 5 years after gastrectomy was associated with improved overall and post-recurrence survival rates, new data from a retrospective analysis showed.

METHODOLOGY:

• Currently, postgastrectomy cancer surveillance typically lasts 5 years, although some centers now monitor patients beyond this point.
• To investigate the potential benefit of extended surveillance, researchers used Korean National Health Insurance claims data to identify 40,468 patients with gastric cancer who were disease free 5 years after gastrectomy — 14,294 received extended regular follow-up visits and 26,174 did not.
• The extended regular follow-up group was defined as having endoscopy or abdominopelvic CT between 2 months and 2 years before diagnosis of late recurrence or gastric remnant cancer and having two or more examinations between 5.5 and 8.5 years after gastrectomy. Late recurrence was a recurrence diagnosed 5 years after gastrectomy.
• Researchers used Cox proportional hazards regression to evaluate the independent association between follow-up and overall and postrecurrence survival rates.

TAKEAWAY:

• Overall, 5 years postgastrectomy, the incidence of late recurrence or gastric remnant cancer was 7.8% — 4.0% between 5 and 10 years (1610 of 40,468 patients) and 9.4% after 10 years (1528 of 16,287 patients).
• Regular follow-up beyond 5 years was associated with a significant reduction in overall mortality — from 49.4% to 36.9% at 15 years (P < .001). Overall survival after late recurrence or gastric remnant cancer also improved significantly with extended regular follow-up, with the 5-year postrecurrence survival rate increasing from 32.7% to 71.1% (P < .001).
• The combination of endoscopy and abdominopelvic CT provided the highest 5-year postrecurrence survival rate (74.5%), compared with endoscopy alone (54.5%) or CT alone (47.1%).
• A time interval of more than 2 years between a previous endoscopy or abdominopelvic CT and diagnosis of late recurrence or gastric remnant cancer significantly decreased postrecurrence survival (hazard ratio [HR], 1.72 for endoscopy and HR, 1.48 for abdominopelvic CT).

IN PRACTICE:

“These findings suggest that extended regular follow-up after 5 years post gastrectomy should be implemented clinically and that current practice and value of follow-up protocols in postoperative care of patients with gastric cancer be reconsidered,” the authors concluded.

The authors of an accompanying commentary cautioned that, while the study “successfully establishes groundwork for extending surveillance of gastric cancer in high-risk populations, more work is needed to strategically identify those who would benefit most from extended surveillance.”
 

SOURCE:

The study, with first author Ju-Hee Lee, MD, PhD, Department of Surgery, Hanyang University College of Medicine, Seoul, South Korea, and accompanying commentary were published online on June 18 in JAMA Surgery.

LIMITATIONS:

Recurrent cancer and gastric remnant cancer could not be distinguished from each other because clinical records were not analyzed. The claims database lacked detailed clinical information on individual patients, including cancer stages, and a separate analysis of tumor markers could not be performed.

DISCLOSURES:

The study was funded by a grant from the Korean Gastric Cancer Association. The study authors and commentary authors reported no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

For patients with gastric cancer, extending regular follow-up beyond the typical 5 years after gastrectomy was associated with improved overall and post-recurrence survival rates, new data from a retrospective analysis showed.

METHODOLOGY:

• Currently, postgastrectomy cancer surveillance typically lasts 5 years, although some centers now monitor patients beyond this point.
• To investigate the potential benefit of extended surveillance, researchers used Korean National Health Insurance claims data to identify 40,468 patients with gastric cancer who were disease free 5 years after gastrectomy — 14,294 received extended regular follow-up visits and 26,174 did not.
• The extended regular follow-up group was defined as having endoscopy or abdominopelvic CT between 2 months and 2 years before diagnosis of late recurrence or gastric remnant cancer and having two or more examinations between 5.5 and 8.5 years after gastrectomy. Late recurrence was a recurrence diagnosed 5 years after gastrectomy.
• Researchers used Cox proportional hazards regression to evaluate the independent association between follow-up and overall and postrecurrence survival rates.

TAKEAWAY:

• Overall, 5 years postgastrectomy, the incidence of late recurrence or gastric remnant cancer was 7.8% — 4.0% between 5 and 10 years (1610 of 40,468 patients) and 9.4% after 10 years (1528 of 16,287 patients).
• Regular follow-up beyond 5 years was associated with a significant reduction in overall mortality — from 49.4% to 36.9% at 15 years (P < .001). Overall survival after late recurrence or gastric remnant cancer also improved significantly with extended regular follow-up, with the 5-year postrecurrence survival rate increasing from 32.7% to 71.1% (P < .001).
• The combination of endoscopy and abdominopelvic CT provided the highest 5-year postrecurrence survival rate (74.5%), compared with endoscopy alone (54.5%) or CT alone (47.1%).
• A time interval of more than 2 years between a previous endoscopy or abdominopelvic CT and diagnosis of late recurrence or gastric remnant cancer significantly decreased postrecurrence survival (hazard ratio [HR], 1.72 for endoscopy and HR, 1.48 for abdominopelvic CT).

IN PRACTICE:

“These findings suggest that extended regular follow-up after 5 years post gastrectomy should be implemented clinically and that current practice and value of follow-up protocols in postoperative care of patients with gastric cancer be reconsidered,” the authors concluded.

The authors of an accompanying commentary cautioned that, while the study “successfully establishes groundwork for extending surveillance of gastric cancer in high-risk populations, more work is needed to strategically identify those who would benefit most from extended surveillance.”
 

SOURCE:

The study, with first author Ju-Hee Lee, MD, PhD, Department of Surgery, Hanyang University College of Medicine, Seoul, South Korea, and accompanying commentary were published online on June 18 in JAMA Surgery.

LIMITATIONS:

Recurrent cancer and gastric remnant cancer could not be distinguished from each other because clinical records were not analyzed. The claims database lacked detailed clinical information on individual patients, including cancer stages, and a separate analysis of tumor markers could not be performed.

DISCLOSURES:

The study was funded by a grant from the Korean Gastric Cancer Association. The study authors and commentary authors reported no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

For patients with gastric cancer, extending regular follow-up beyond the typical 5 years after gastrectomy was associated with improved overall and post-recurrence survival rates, new data from a retrospective analysis showed.

METHODOLOGY:

• Currently, postgastrectomy cancer surveillance typically lasts 5 years, although some centers now monitor patients beyond this point.
• To investigate the potential benefit of extended surveillance, researchers used Korean National Health Insurance claims data to identify 40,468 patients with gastric cancer who were disease free 5 years after gastrectomy — 14,294 received extended regular follow-up visits and 26,174 did not.
• The extended regular follow-up group was defined as having endoscopy or abdominopelvic CT between 2 months and 2 years before diagnosis of late recurrence or gastric remnant cancer and having two or more examinations between 5.5 and 8.5 years after gastrectomy. Late recurrence was a recurrence diagnosed 5 years after gastrectomy.
• Researchers used Cox proportional hazards regression to evaluate the independent association between follow-up and overall and postrecurrence survival rates.

TAKEAWAY:

• Overall, 5 years postgastrectomy, the incidence of late recurrence or gastric remnant cancer was 7.8% — 4.0% between 5 and 10 years (1610 of 40,468 patients) and 9.4% after 10 years (1528 of 16,287 patients).
• Regular follow-up beyond 5 years was associated with a significant reduction in overall mortality — from 49.4% to 36.9% at 15 years (P < .001). Overall survival after late recurrence or gastric remnant cancer also improved significantly with extended regular follow-up, with the 5-year postrecurrence survival rate increasing from 32.7% to 71.1% (P < .001).
• The combination of endoscopy and abdominopelvic CT provided the highest 5-year postrecurrence survival rate (74.5%), compared with endoscopy alone (54.5%) or CT alone (47.1%).
• A time interval of more than 2 years between a previous endoscopy or abdominopelvic CT and diagnosis of late recurrence or gastric remnant cancer significantly decreased postrecurrence survival (hazard ratio [HR], 1.72 for endoscopy and HR, 1.48 for abdominopelvic CT).

IN PRACTICE:

“These findings suggest that extended regular follow-up after 5 years post gastrectomy should be implemented clinically and that current practice and value of follow-up protocols in postoperative care of patients with gastric cancer be reconsidered,” the authors concluded.

The authors of an accompanying commentary cautioned that, while the study “successfully establishes groundwork for extending surveillance of gastric cancer in high-risk populations, more work is needed to strategically identify those who would benefit most from extended surveillance.”
 

SOURCE:

The study, with first author Ju-Hee Lee, MD, PhD, Department of Surgery, Hanyang University College of Medicine, Seoul, South Korea, and accompanying commentary were published online on June 18 in JAMA Surgery.

LIMITATIONS:

Recurrent cancer and gastric remnant cancer could not be distinguished from each other because clinical records were not analyzed. The claims database lacked detailed clinical information on individual patients, including cancer stages, and a separate analysis of tumor markers could not be performed.

DISCLOSURES:

The study was funded by a grant from the Korean Gastric Cancer Association. The study authors and commentary authors reported no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Achieving a pathologic complete response was associated with a twofold higher 5-year overall survival rate among patients with localized pancreatic adenocarcinoma who underwent preoperative chemo(radio)therapy and resection, a multicenter cohort study found. Several factors, including treatment type and tumor features, influenced the outcomes.

METHODOLOGY:

• Preoperative chemo(radio)therapy is increasingly used in patients with localized pancreatic adenocarcinoma and may improve the chance of a pathologic complete response. Achieving a pathologic complete response is associated with improved overall survival.
• However, the evidence on pathologic complete response is based on large national databases or small single-center series. Multicenter studies with in-depth data about complete response are lacking.
• In the current analysis, researchers investigated the incidence and factors associated with pathologic complete response after preoperative chemo(radio)therapy among 1758 patients (mean age, 64 years; 50% men) with localized pancreatic adenocarcinoma who underwent resection after two or more cycles of chemotherapy (with or without radiotherapy).
• Patients were treated at 19 centers in eight countries. The median follow-up was 19 months. Pathologic complete response was defined as the absence of vital tumor cells in the patient’s sampled pancreas specimen after resection.
• Factors associated with overall survival and pathologic complete response were investigated with Cox proportional hazards and logistic regression models, respectively.

TAKEAWAY:

• Researchers found that the rate of pathologic complete response was 4.8% in patients who received chemo(radio)therapy before pancreatic cancer resection.
• Having a pathologic complete response was associated with a 54% lower risk for death (hazard ratio, 0.46). At 5 years, the overall survival rate was 63% in patients with a pathologic complete response vs 30% in patients without one.
• More patients who received preoperative modified FOLFIRINOX achieved a pathologic complete response (58.8% vs 44.7%). Other factors associated with pathologic complete response included tumors located in the pancreatic head (odds ratio [OR], 2.51), tumors > 40 mm at diagnosis (OR, 2.58), partial or complete radiologic response (OR, 13.0), and normal(ized) serum carbohydrate antigen 19-9 after preoperative therapy (OR, 3.76).
• Preoperative radiotherapy (OR, 2.03) and preoperative stereotactic body radiotherapy (OR, 8.91) were also associated with a pathologic complete response; however, preoperative radiotherapy did not improve overall survival, and preoperative stereotactic body radiotherapy was independently associated with worse overall survival. These findings suggest that a pathologic complete response might not always reflect an optimal disease response.

IN PRACTICE:

Although pathologic complete response does not reflect cure, it is associated with better overall survival, the authors wrote. Factors associated with a pathologic complete response may inform treatment decisions.

SOURCE:

The study, with first author Thomas F. Stoop, MD, University of Amsterdam, the Netherlands, was published online on June 18 in JAMA Network Open.

LIMITATIONS:

The study had several limitations. The sample size and the limited number of events precluded comparative subanalyses, as well as a more detailed stratification for preoperative chemotherapy regimens. Information about patients’ race and the presence of BRCA germline mutations, both of which seem to be relevant to the chance of achieving a major pathologic response, was not collected or available.

DISCLOSURES:

No specific funding was noted. Several coauthors have industry relationships outside of the submitted work.

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

TOPLINE:

Achieving a pathologic complete response was associated with a twofold higher 5-year overall survival rate among patients with localized pancreatic adenocarcinoma who underwent preoperative chemo(radio)therapy and resection, a multicenter cohort study found. Several factors, including treatment type and tumor features, influenced the outcomes.

METHODOLOGY:

• Preoperative chemo(radio)therapy is increasingly used in patients with localized pancreatic adenocarcinoma and may improve the chance of a pathologic complete response. Achieving a pathologic complete response is associated with improved overall survival.
• However, the evidence on pathologic complete response is based on large national databases or small single-center series. Multicenter studies with in-depth data about complete response are lacking.
• In the current analysis, researchers investigated the incidence and factors associated with pathologic complete response after preoperative chemo(radio)therapy among 1758 patients (mean age, 64 years; 50% men) with localized pancreatic adenocarcinoma who underwent resection after two or more cycles of chemotherapy (with or without radiotherapy).
• Patients were treated at 19 centers in eight countries. The median follow-up was 19 months. Pathologic complete response was defined as the absence of vital tumor cells in the patient’s sampled pancreas specimen after resection.
• Factors associated with overall survival and pathologic complete response were investigated with Cox proportional hazards and logistic regression models, respectively.

TAKEAWAY:

• Researchers found that the rate of pathologic complete response was 4.8% in patients who received chemo(radio)therapy before pancreatic cancer resection.
• Having a pathologic complete response was associated with a 54% lower risk for death (hazard ratio, 0.46). At 5 years, the overall survival rate was 63% in patients with a pathologic complete response vs 30% in patients without one.
• More patients who received preoperative modified FOLFIRINOX achieved a pathologic complete response (58.8% vs 44.7%). Other factors associated with pathologic complete response included tumors located in the pancreatic head (odds ratio [OR], 2.51), tumors > 40 mm at diagnosis (OR, 2.58), partial or complete radiologic response (OR, 13.0), and normal(ized) serum carbohydrate antigen 19-9 after preoperative therapy (OR, 3.76).
• Preoperative radiotherapy (OR, 2.03) and preoperative stereotactic body radiotherapy (OR, 8.91) were also associated with a pathologic complete response; however, preoperative radiotherapy did not improve overall survival, and preoperative stereotactic body radiotherapy was independently associated with worse overall survival. These findings suggest that a pathologic complete response might not always reflect an optimal disease response.

IN PRACTICE:

Although pathologic complete response does not reflect cure, it is associated with better overall survival, the authors wrote. Factors associated with a pathologic complete response may inform treatment decisions.

SOURCE:

The study, with first author Thomas F. Stoop, MD, University of Amsterdam, the Netherlands, was published online on June 18 in JAMA Network Open.

LIMITATIONS:

The study had several limitations. The sample size and the limited number of events precluded comparative subanalyses, as well as a more detailed stratification for preoperative chemotherapy regimens. Information about patients’ race and the presence of BRCA germline mutations, both of which seem to be relevant to the chance of achieving a major pathologic response, was not collected or available.

DISCLOSURES:

No specific funding was noted. Several coauthors have industry relationships outside of the submitted work.

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

TOPLINE:

Achieving a pathologic complete response was associated with a twofold higher 5-year overall survival rate among patients with localized pancreatic adenocarcinoma who underwent preoperative chemo(radio)therapy and resection, a multicenter cohort study found. Several factors, including treatment type and tumor features, influenced the outcomes.

METHODOLOGY:

• Preoperative chemo(radio)therapy is increasingly used in patients with localized pancreatic adenocarcinoma and may improve the chance of a pathologic complete response. Achieving a pathologic complete response is associated with improved overall survival.
• However, the evidence on pathologic complete response is based on large national databases or small single-center series. Multicenter studies with in-depth data about complete response are lacking.
• In the current analysis, researchers investigated the incidence and factors associated with pathologic complete response after preoperative chemo(radio)therapy among 1758 patients (mean age, 64 years; 50% men) with localized pancreatic adenocarcinoma who underwent resection after two or more cycles of chemotherapy (with or without radiotherapy).
• Patients were treated at 19 centers in eight countries. The median follow-up was 19 months. Pathologic complete response was defined as the absence of vital tumor cells in the patient’s sampled pancreas specimen after resection.
• Factors associated with overall survival and pathologic complete response were investigated with Cox proportional hazards and logistic regression models, respectively.

TAKEAWAY:

• Researchers found that the rate of pathologic complete response was 4.8% in patients who received chemo(radio)therapy before pancreatic cancer resection.
• Having a pathologic complete response was associated with a 54% lower risk for death (hazard ratio, 0.46). At 5 years, the overall survival rate was 63% in patients with a pathologic complete response vs 30% in patients without one.
• More patients who received preoperative modified FOLFIRINOX achieved a pathologic complete response (58.8% vs 44.7%). Other factors associated with pathologic complete response included tumors located in the pancreatic head (odds ratio [OR], 2.51), tumors > 40 mm at diagnosis (OR, 2.58), partial or complete radiologic response (OR, 13.0), and normal(ized) serum carbohydrate antigen 19-9 after preoperative therapy (OR, 3.76).
• Preoperative radiotherapy (OR, 2.03) and preoperative stereotactic body radiotherapy (OR, 8.91) were also associated with a pathologic complete response; however, preoperative radiotherapy did not improve overall survival, and preoperative stereotactic body radiotherapy was independently associated with worse overall survival. These findings suggest that a pathologic complete response might not always reflect an optimal disease response.

IN PRACTICE:

Although pathologic complete response does not reflect cure, it is associated with better overall survival, the authors wrote. Factors associated with a pathologic complete response may inform treatment decisions.

SOURCE:

The study, with first author Thomas F. Stoop, MD, University of Amsterdam, the Netherlands, was published online on June 18 in JAMA Network Open.

LIMITATIONS:

The study had several limitations. The sample size and the limited number of events precluded comparative subanalyses, as well as a more detailed stratification for preoperative chemotherapy regimens. Information about patients’ race and the presence of BRCA germline mutations, both of which seem to be relevant to the chance of achieving a major pathologic response, was not collected or available.

DISCLOSURES:

No specific funding was noted. Several coauthors have industry relationships outside of the submitted work.

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

A growing body of evidence has shown that people who regularly take aspirin have a lower risk for colorectal cancer (CRC) and are less likely to die if they do develop the disease.

A 2020 meta-analysis, for instance, found that 325 mg of daily aspirin — the typical dose in a single tablet — conferred a 35% reduced risk of developing CRC, and a highly cited The Lancet study from 2010 found that a low dose of daily aspirin reduced the incidence of colon cancer by 24% and colon cancer deaths by 35% over 20 years.

The evidence surrounding aspirin and CRC is so intriguing that more than 70,000 people are currently participating in more than two dozen clinical studies worldwide, putting aspirin through its paces as an intervention in CRC.

But what, exactly, is aspirin doing?

We know that aspirin inhibits cyclooxygenase (COX) enzymes — COX-1 and COX-2, specifically — and that the COX-2 pathway is implicated in the development and progression of CRC, explained Marco Scarpa, MD, PhD, staff surgeon at the University of Padova in Padova, Italy.

“However, the new thing we’ve found is that aspirin may have a direct role in enhancing immunosurveillance,” Dr. Scarpa said in an interview.

In April, Dr. Scarpa’s team published a paper in Cancer describing a mechanism that provides deeper insight into the aspirin-CRC connection.

Dr. Scarpa heads up the IMMUNOREACT study group, a collaboration of dozens of researchers across Italy running studies on immunosurveillance in rectal cancer. In the baseline study, IMMUNOREACT 1, the team created and analyzed a database of records from 238 patients who underwent surgery for CRC at the Azienda Ospedale Università di Padova, Padova, Italy, from 2015 to 2019.

Using the same database, the latest findings from IMMUNOREACT 7 focused on the fate of the 31 patients (13%) who used aspirin regularly.

The researchers found that regular aspirin use did not appear to affect colorectal tumor stage at diagnosis, but tumor grading was significantly lower overall, especially in patients with BRAF mutations. Regular aspirin users were also less likely to have nodal metastases and metastatic lymph nodes, and this effect was more pronounced in patients with proximal (right-sided) colon cancer vs distal (left-sided).

Most notably, IMMUNOREACT 7 revealed that aspirin has beneficial effects on the CRC immune microenvironment.

The team found that aspirin directly boosts the presence of antigens on gastrointestinal epithelial tumor cells, which can direct the body’s immune response to combat the cancer.

At a macro level, the aspirin users in the study were more likely to have high levels of tumor-infiltrating lymphocytes (TILs). Dr. Scarpa’s team had previously shown that high levels of CD8+ and CD3+ TILs were predictive of successful neoadjuvant therapy in rectal cancer.

Cytotoxic CD8+ T cells are central to the anticancer immune response, and in the latest study, a high ratio of CD8+/CD3+ T cells was more common in aspirin users, suggesting a stronger presence of cancer-killing CD8+ cells. Expression of CD8 beta+, an activation marker of CD8+ cells, was also enhanced in aspirin users.

The most significant discovery, according to Dr. Scarpa, was that aspirin users were more likely to show high expression of CD80 on the surface of their rectal epithelial cells.

CD80 is a molecule that allows T cells to identify the tumor cell as foreign and kill it. Although cancer cells can downregulate their CD80 to avoid detection by T cells, the study suggests that aspirin appears to help foil this strategy by boosting the production of CD80 on the surface of the tumor cells.

The researchers confirmed the clinical findings by showing that aspirin increased CD80 gene expression in lab-cultivated CRC cells.

“We didn’t expect the activation through CD80,” said Dr. Scarpa. “This means that aspirin can act on this very first interaction between the epithelial cell and the CD8+ lymphocyte.”

Overall, these new data suggest that aspirin helps activate the immune system, which helps explain its potential chemopreventive effect in CRC.

However, one puzzling result was that aspirin boosted expression of PD-L1 genes in the CRC cells, said Joanna Davies, DPhil, an immunologist who heads up the San Diego Biomedical Research Institute, San Diego, California, and was not involved in the study.

PD-L1 serves as an “off” switch for patrolling T cells, which protects the tumor cell from being recognized.

“If aspirin is inducing PD-L1 on cancer cells, that is a potential problem,” said Dr. Davies. “An ideal therapy might be the combination of aspirin to enhance the CD8 T cells in the tumor and immune checkpoint blockade to block PD-L1.”

David Kerr, CBE, MD, DSc, agreed that high-dose aspirin plus immunotherapy might be “a wee bit more effective.” However, the combination would be blocked by the economics of drug development: “Will anybody ever do a trial of 10,000 patients to prove that? Not on your nelly,” said Dr. Kerr, professor of cancer medicine at the University of Oxford, Oxford, England.

Despite the small patient numbers in the study, Dr. Kerr felt encouraged by the IMMUNOREACT analysis. “It’s a plausible piece of science and some quite promising work on the tumor immune microenvironment and the effects of aspirin on it,” Dr. Kerr said in a recent commentary for this news organization.

Dr. Scarpa and Dr. Davies had no conflicts of interest to declare.

A version of this article appeared on Medscape.com .

A growing body of evidence has shown that people who regularly take aspirin have a lower risk for colorectal cancer (CRC) and are less likely to die if they do develop the disease.

A 2020 meta-analysis, for instance, found that 325 mg of daily aspirin — the typical dose in a single tablet — conferred a 35% reduced risk of developing CRC, and a highly cited The Lancet study from 2010 found that a low dose of daily aspirin reduced the incidence of colon cancer by 24% and colon cancer deaths by 35% over 20 years.

The evidence surrounding aspirin and CRC is so intriguing that more than 70,000 people are currently participating in more than two dozen clinical studies worldwide, putting aspirin through its paces as an intervention in CRC.

But what, exactly, is aspirin doing?

We know that aspirin inhibits cyclooxygenase (COX) enzymes — COX-1 and COX-2, specifically — and that the COX-2 pathway is implicated in the development and progression of CRC, explained Marco Scarpa, MD, PhD, staff surgeon at the University of Padova in Padova, Italy.

“However, the new thing we’ve found is that aspirin may have a direct role in enhancing immunosurveillance,” Dr. Scarpa said in an interview.

In April, Dr. Scarpa’s team published a paper in Cancer describing a mechanism that provides deeper insight into the aspirin-CRC connection.

Dr. Scarpa heads up the IMMUNOREACT study group, a collaboration of dozens of researchers across Italy running studies on immunosurveillance in rectal cancer. In the baseline study, IMMUNOREACT 1, the team created and analyzed a database of records from 238 patients who underwent surgery for CRC at the Azienda Ospedale Università di Padova, Padova, Italy, from 2015 to 2019.

Using the same database, the latest findings from IMMUNOREACT 7 focused on the fate of the 31 patients (13%) who used aspirin regularly.

The researchers found that regular aspirin use did not appear to affect colorectal tumor stage at diagnosis, but tumor grading was significantly lower overall, especially in patients with BRAF mutations. Regular aspirin users were also less likely to have nodal metastases and metastatic lymph nodes, and this effect was more pronounced in patients with proximal (right-sided) colon cancer vs distal (left-sided).

Most notably, IMMUNOREACT 7 revealed that aspirin has beneficial effects on the CRC immune microenvironment.

The team found that aspirin directly boosts the presence of antigens on gastrointestinal epithelial tumor cells, which can direct the body’s immune response to combat the cancer.

At a macro level, the aspirin users in the study were more likely to have high levels of tumor-infiltrating lymphocytes (TILs). Dr. Scarpa’s team had previously shown that high levels of CD8+ and CD3+ TILs were predictive of successful neoadjuvant therapy in rectal cancer.

Cytotoxic CD8+ T cells are central to the anticancer immune response, and in the latest study, a high ratio of CD8+/CD3+ T cells was more common in aspirin users, suggesting a stronger presence of cancer-killing CD8+ cells. Expression of CD8 beta+, an activation marker of CD8+ cells, was also enhanced in aspirin users.

The most significant discovery, according to Dr. Scarpa, was that aspirin users were more likely to show high expression of CD80 on the surface of their rectal epithelial cells.

CD80 is a molecule that allows T cells to identify the tumor cell as foreign and kill it. Although cancer cells can downregulate their CD80 to avoid detection by T cells, the study suggests that aspirin appears to help foil this strategy by boosting the production of CD80 on the surface of the tumor cells.

The researchers confirmed the clinical findings by showing that aspirin increased CD80 gene expression in lab-cultivated CRC cells.

“We didn’t expect the activation through CD80,” said Dr. Scarpa. “This means that aspirin can act on this very first interaction between the epithelial cell and the CD8+ lymphocyte.”

Overall, these new data suggest that aspirin helps activate the immune system, which helps explain its potential chemopreventive effect in CRC.

However, one puzzling result was that aspirin boosted expression of PD-L1 genes in the CRC cells, said Joanna Davies, DPhil, an immunologist who heads up the San Diego Biomedical Research Institute, San Diego, California, and was not involved in the study.

PD-L1 serves as an “off” switch for patrolling T cells, which protects the tumor cell from being recognized.

“If aspirin is inducing PD-L1 on cancer cells, that is a potential problem,” said Dr. Davies. “An ideal therapy might be the combination of aspirin to enhance the CD8 T cells in the tumor and immune checkpoint blockade to block PD-L1.”

David Kerr, CBE, MD, DSc, agreed that high-dose aspirin plus immunotherapy might be “a wee bit more effective.” However, the combination would be blocked by the economics of drug development: “Will anybody ever do a trial of 10,000 patients to prove that? Not on your nelly,” said Dr. Kerr, professor of cancer medicine at the University of Oxford, Oxford, England.

Despite the small patient numbers in the study, Dr. Kerr felt encouraged by the IMMUNOREACT analysis. “It’s a plausible piece of science and some quite promising work on the tumor immune microenvironment and the effects of aspirin on it,” Dr. Kerr said in a recent commentary for this news organization.

Dr. Scarpa and Dr. Davies had no conflicts of interest to declare.

A version of this article appeared on Medscape.com .

A growing body of evidence has shown that people who regularly take aspirin have a lower risk for colorectal cancer (CRC) and are less likely to die if they do develop the disease.

A 2020 meta-analysis, for instance, found that 325 mg of daily aspirin — the typical dose in a single tablet — conferred a 35% reduced risk of developing CRC, and a highly cited The Lancet study from 2010 found that a low dose of daily aspirin reduced the incidence of colon cancer by 24% and colon cancer deaths by 35% over 20 years.

The evidence surrounding aspirin and CRC is so intriguing that more than 70,000 people are currently participating in more than two dozen clinical studies worldwide, putting aspirin through its paces as an intervention in CRC.

But what, exactly, is aspirin doing?

We know that aspirin inhibits cyclooxygenase (COX) enzymes — COX-1 and COX-2, specifically — and that the COX-2 pathway is implicated in the development and progression of CRC, explained Marco Scarpa, MD, PhD, staff surgeon at the University of Padova in Padova, Italy.

“However, the new thing we’ve found is that aspirin may have a direct role in enhancing immunosurveillance,” Dr. Scarpa said in an interview.

In April, Dr. Scarpa’s team published a paper in Cancer describing a mechanism that provides deeper insight into the aspirin-CRC connection.

Dr. Scarpa heads up the IMMUNOREACT study group, a collaboration of dozens of researchers across Italy running studies on immunosurveillance in rectal cancer. In the baseline study, IMMUNOREACT 1, the team created and analyzed a database of records from 238 patients who underwent surgery for CRC at the Azienda Ospedale Università di Padova, Padova, Italy, from 2015 to 2019.

Using the same database, the latest findings from IMMUNOREACT 7 focused on the fate of the 31 patients (13%) who used aspirin regularly.

The researchers found that regular aspirin use did not appear to affect colorectal tumor stage at diagnosis, but tumor grading was significantly lower overall, especially in patients with BRAF mutations. Regular aspirin users were also less likely to have nodal metastases and metastatic lymph nodes, and this effect was more pronounced in patients with proximal (right-sided) colon cancer vs distal (left-sided).

Most notably, IMMUNOREACT 7 revealed that aspirin has beneficial effects on the CRC immune microenvironment.

The team found that aspirin directly boosts the presence of antigens on gastrointestinal epithelial tumor cells, which can direct the body’s immune response to combat the cancer.

At a macro level, the aspirin users in the study were more likely to have high levels of tumor-infiltrating lymphocytes (TILs). Dr. Scarpa’s team had previously shown that high levels of CD8+ and CD3+ TILs were predictive of successful neoadjuvant therapy in rectal cancer.

Cytotoxic CD8+ T cells are central to the anticancer immune response, and in the latest study, a high ratio of CD8+/CD3+ T cells was more common in aspirin users, suggesting a stronger presence of cancer-killing CD8+ cells. Expression of CD8 beta+, an activation marker of CD8+ cells, was also enhanced in aspirin users.

The most significant discovery, according to Dr. Scarpa, was that aspirin users were more likely to show high expression of CD80 on the surface of their rectal epithelial cells.

CD80 is a molecule that allows T cells to identify the tumor cell as foreign and kill it. Although cancer cells can downregulate their CD80 to avoid detection by T cells, the study suggests that aspirin appears to help foil this strategy by boosting the production of CD80 on the surface of the tumor cells.

The researchers confirmed the clinical findings by showing that aspirin increased CD80 gene expression in lab-cultivated CRC cells.

“We didn’t expect the activation through CD80,” said Dr. Scarpa. “This means that aspirin can act on this very first interaction between the epithelial cell and the CD8+ lymphocyte.”

Overall, these new data suggest that aspirin helps activate the immune system, which helps explain its potential chemopreventive effect in CRC.

However, one puzzling result was that aspirin boosted expression of PD-L1 genes in the CRC cells, said Joanna Davies, DPhil, an immunologist who heads up the San Diego Biomedical Research Institute, San Diego, California, and was not involved in the study.

PD-L1 serves as an “off” switch for patrolling T cells, which protects the tumor cell from being recognized.

“If aspirin is inducing PD-L1 on cancer cells, that is a potential problem,” said Dr. Davies. “An ideal therapy might be the combination of aspirin to enhance the CD8 T cells in the tumor and immune checkpoint blockade to block PD-L1.”

David Kerr, CBE, MD, DSc, agreed that high-dose aspirin plus immunotherapy might be “a wee bit more effective.” However, the combination would be blocked by the economics of drug development: “Will anybody ever do a trial of 10,000 patients to prove that? Not on your nelly,” said Dr. Kerr, professor of cancer medicine at the University of Oxford, Oxford, England.

Despite the small patient numbers in the study, Dr. Kerr felt encouraged by the IMMUNOREACT analysis. “It’s a plausible piece of science and some quite promising work on the tumor immune microenvironment and the effects of aspirin on it,” Dr. Kerr said in a recent commentary for this news organization.

Dr. Scarpa and Dr. Davies had no conflicts of interest to declare.

A version of this article appeared on Medscape.com .

TOPLINE:

Men at higher genetic risk for prostate cancer had more than a threefold increased risk for early death from the disease, and about one third of these deaths may have been preventable through healthy lifestyle choices, a new analysis found.

METHODOLOGY:

• About one third of men die from prostate cancer before age 75, highlighting the need for prevention strategies that target high-risk populations.
• In the current study, researchers analyzed data from two prospective cohort studies — the Malmö Diet and Cancer Study (MDCS) and the Health Professionals Follow-Up Study (HPFS) — which included 19,607 men with a median age at inclusion of 59 years (MDCS) and 65.1 years (HPFS) followed from 1991 to 2019.
• Participants were categorized by genetic risk and lifestyle score. Genetic risk was defined using a multiancestry polygenic risk score (PRS) for overall prostate cancer that included 400 genetic risk variants.
• A healthy lifestyle score was defined as 3-6, while an unhealthy lifestyle score was 0-2. Lifestyle factors included smoking, weight, physical activity, and diet.
• The researchers calculated hazard ratios (HRs) for the association between genetic and lifestyle factors and prostate cancer death.

TAKEAWAY:

• Combining the PRS and family history of cancer, 67% of men overall (13,186 of 19,607) were considered to have higher genetic risk, and about 30% overall had an unhealthy lifestyle score of 0-2.
• Men at higher genetic risk accounted for 88% (94 of 107) of early prostate cancer deaths.
• Compared with men at lower genetic risk, those at higher genetic risk had more than a threefold higher rate of early prostate cancer death (HR, 3.26) and more than a twofold increased rate of late prostate cancer death (HR, 2.26) as well as a higher lifetime risk for prostate cancer death.
• Among men at higher genetic risk, an unhealthy lifestyle was associated with a higher risk of early prostate cancer death, with smoking and a BMI of ≥ 30 being significant factors. Depending on the definition of a healthy lifestyle, the researchers estimated that 22%-36% of early prostate cancer deaths among men at higher genetic risk might be preventable.

IN PRACTICE:

“Based on data from two prospective cohort studies, this analysis provides evidence for targeting men at increased genetic risk with prevention strategies aimed at reducing premature deaths from prostate cancer,” the researchers concluded.

SOURCE:

The study, with first author Anna Plym, PhD, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet in Stockholm, Sweden, was published online on July 3 in JAMA Network Open.

LIMITATIONS:

Differences in prostate cancer testing and treatment may account for some of the observed association between a healthy lifestyle and prostate cancer death. This analysis provides an estimate of what is achievable in terms of prevention had everyone adopted a healthy lifestyle. The authors only considered factors at study entry, which would not include changes that happen later.

DISCLOSURES:

The study authors reported several disclosures. Fredrik Wiklund, PhD, received grants from GE Healthcare, personal fees from Janssen, Varian Medical Systems, and WebMD, and stock options and personal fees from Cortechs Labs outside the submitted work. Adam S. Kibel, MD, received personal fees from Janssen, Pfizer, Bristol Myers Squibb, Cellvax, Merck, and Roche and served as a consultant for Bristol Myers Squibb and Candel outside the submitted work. Additional disclosures are noted in the original article.
 

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:

Men at higher genetic risk for prostate cancer had more than a threefold increased risk for early death from the disease, and about one third of these deaths may have been preventable through healthy lifestyle choices, a new analysis found.

METHODOLOGY:

• About one third of men die from prostate cancer before age 75, highlighting the need for prevention strategies that target high-risk populations.
• In the current study, researchers analyzed data from two prospective cohort studies — the Malmö Diet and Cancer Study (MDCS) and the Health Professionals Follow-Up Study (HPFS) — which included 19,607 men with a median age at inclusion of 59 years (MDCS) and 65.1 years (HPFS) followed from 1991 to 2019.
• Participants were categorized by genetic risk and lifestyle score. Genetic risk was defined using a multiancestry polygenic risk score (PRS) for overall prostate cancer that included 400 genetic risk variants.
• A healthy lifestyle score was defined as 3-6, while an unhealthy lifestyle score was 0-2. Lifestyle factors included smoking, weight, physical activity, and diet.
• The researchers calculated hazard ratios (HRs) for the association between genetic and lifestyle factors and prostate cancer death.

TAKEAWAY:

• Combining the PRS and family history of cancer, 67% of men overall (13,186 of 19,607) were considered to have higher genetic risk, and about 30% overall had an unhealthy lifestyle score of 0-2.
• Men at higher genetic risk accounted for 88% (94 of 107) of early prostate cancer deaths.
• Compared with men at lower genetic risk, those at higher genetic risk had more than a threefold higher rate of early prostate cancer death (HR, 3.26) and more than a twofold increased rate of late prostate cancer death (HR, 2.26) as well as a higher lifetime risk for prostate cancer death.
• Among men at higher genetic risk, an unhealthy lifestyle was associated with a higher risk of early prostate cancer death, with smoking and a BMI of ≥ 30 being significant factors. Depending on the definition of a healthy lifestyle, the researchers estimated that 22%-36% of early prostate cancer deaths among men at higher genetic risk might be preventable.

IN PRACTICE:

“Based on data from two prospective cohort studies, this analysis provides evidence for targeting men at increased genetic risk with prevention strategies aimed at reducing premature deaths from prostate cancer,” the researchers concluded.

SOURCE:

The study, with first author Anna Plym, PhD, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet in Stockholm, Sweden, was published online on July 3 in JAMA Network Open.

LIMITATIONS:

Differences in prostate cancer testing and treatment may account for some of the observed association between a healthy lifestyle and prostate cancer death. This analysis provides an estimate of what is achievable in terms of prevention had everyone adopted a healthy lifestyle. The authors only considered factors at study entry, which would not include changes that happen later.

DISCLOSURES:

The study authors reported several disclosures. Fredrik Wiklund, PhD, received grants from GE Healthcare, personal fees from Janssen, Varian Medical Systems, and WebMD, and stock options and personal fees from Cortechs Labs outside the submitted work. Adam S. Kibel, MD, received personal fees from Janssen, Pfizer, Bristol Myers Squibb, Cellvax, Merck, and Roche and served as a consultant for Bristol Myers Squibb and Candel outside the submitted work. Additional disclosures are noted in the original article.
 

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:

Men at higher genetic risk for prostate cancer had more than a threefold increased risk for early death from the disease, and about one third of these deaths may have been preventable through healthy lifestyle choices, a new analysis found.

METHODOLOGY:

• About one third of men die from prostate cancer before age 75, highlighting the need for prevention strategies that target high-risk populations.
• In the current study, researchers analyzed data from two prospective cohort studies — the Malmö Diet and Cancer Study (MDCS) and the Health Professionals Follow-Up Study (HPFS) — which included 19,607 men with a median age at inclusion of 59 years (MDCS) and 65.1 years (HPFS) followed from 1991 to 2019.
• Participants were categorized by genetic risk and lifestyle score. Genetic risk was defined using a multiancestry polygenic risk score (PRS) for overall prostate cancer that included 400 genetic risk variants.
• A healthy lifestyle score was defined as 3-6, while an unhealthy lifestyle score was 0-2. Lifestyle factors included smoking, weight, physical activity, and diet.
• The researchers calculated hazard ratios (HRs) for the association between genetic and lifestyle factors and prostate cancer death.

TAKEAWAY:

• Combining the PRS and family history of cancer, 67% of men overall (13,186 of 19,607) were considered to have higher genetic risk, and about 30% overall had an unhealthy lifestyle score of 0-2.
• Men at higher genetic risk accounted for 88% (94 of 107) of early prostate cancer deaths.
• Compared with men at lower genetic risk, those at higher genetic risk had more than a threefold higher rate of early prostate cancer death (HR, 3.26) and more than a twofold increased rate of late prostate cancer death (HR, 2.26) as well as a higher lifetime risk for prostate cancer death.
• Among men at higher genetic risk, an unhealthy lifestyle was associated with a higher risk of early prostate cancer death, with smoking and a BMI of ≥ 30 being significant factors. Depending on the definition of a healthy lifestyle, the researchers estimated that 22%-36% of early prostate cancer deaths among men at higher genetic risk might be preventable.

IN PRACTICE:

“Based on data from two prospective cohort studies, this analysis provides evidence for targeting men at increased genetic risk with prevention strategies aimed at reducing premature deaths from prostate cancer,” the researchers concluded.

SOURCE:

The study, with first author Anna Plym, PhD, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet in Stockholm, Sweden, was published online on July 3 in JAMA Network Open.

LIMITATIONS:

Differences in prostate cancer testing and treatment may account for some of the observed association between a healthy lifestyle and prostate cancer death. This analysis provides an estimate of what is achievable in terms of prevention had everyone adopted a healthy lifestyle. The authors only considered factors at study entry, which would not include changes that happen later.

DISCLOSURES:

The study authors reported several disclosures. Fredrik Wiklund, PhD, received grants from GE Healthcare, personal fees from Janssen, Varian Medical Systems, and WebMD, and stock options and personal fees from Cortechs Labs outside the submitted work. Adam S. Kibel, MD, received personal fees from Janssen, Pfizer, Bristol Myers Squibb, Cellvax, Merck, and Roche and served as a consultant for Bristol Myers Squibb and Candel outside the submitted work. Additional disclosures are noted in the original article.
 

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.

Eribulin seems to be an equally effective chemotherapy to pair with a dual HER2 blockade as taxane as first-line treatment for women with HER2-positive, locally advanced or metastatic breast cancer.

The results of this multicenter, randomized, open-label, parallel-group, phase 3 Japanese trial suggest that patients who cannot tolerate the standard taxane-based regimen have a new option for treatment.

“Our study is the first to show the non-inferiority of eribulin to a taxane, when used in combination with dual HER2 blockade as first-line treatment for this population,” lead author Toshinari Yamashita, MD, PhD, from the Kanagawa Cancer Center, in Kanagawa, Japan, said at the annual meeting of the American Society of Clinical Oncology.

“To our knowledge, noninferiority of eribulin to a taxane when used in combination with dual HER2 blockade has not been investigated,” Dr. Yamashita said.

“The combination of trastuzumab, pertuzumab, and taxane is a current standard first-line therapy for recurrent or metastatic HER2-positive breast cancer,” explained Dr. Yamashita. “However, because of taxane-induced toxicity, the development of less toxic but equally effective alternatives are needed.

“Because its efficacy is comparable to that of the current standard regimen, the combination of eribulin, trastuzumab, and pertuzumab is one of the options for first-line treatment of how to fight locally advanced or metastatic breast cancer,” he continued.
 

Study Results and Methods

The trial enrolled 446 patients, mean age 56 years, all of whom had locally advanced or metastatic breast cancer and no prior use of chemotherapy, excluding T-DM1. Patients who had received hormonal or HER2 therapy alone or the combination, as treatment for recurrence, were also eligible.

They were randomized 1:1 to receive a 21-day chemotherapy cycle of either (i) eribulin (1.4 mg/m² on days 1 and 8), or (ii) a taxane (docetaxel 75 mg/m² on day 1 or paclitaxel 80 mg/m² on days 1, 8 and 15), each being administered in combination with a dual HER2 blockade of trastuzumab plus pertuzumab.

Baseline characteristics of both groups were well balanced, with 257 (57.6%) having ER-positive disease, 292 (65.5%) visceral metastasis, and 263 (59%) with de novo stage 4 disease, explained Dr. Yamashita.

For the primary endpoint, the median progression-free survival (PFS) was 14 versus 12.9 months in the eribulin and taxane group, respectively (hazard ratio [HR] 0.95, P = .6817), confirming non-inferiority of the study regimen, he reported.

The clinical benefit rate was similar between the two groups, with an objective response rate of 76.8% in the eribulin group and 75.2% in the taxane group.

Median OS was 65.3 months in the taxane group, but has not been reached in the study group (HR 1.09).

In terms of side-effects, the incidence of treatment-emergent adverse events was similar between the eribulin and taxane groups (58.9% vs 59.2%, respectively, for grade 3 or higher).

“Skin-related adverse events (62.4% vs 40.6%), diarrhea (54.1% vs 36.6%), and edema (42.2% vs 8.5%) tend to be more common with taxane, whereas neutropenia (61.6% vs 30.7%) and peripheral neuropathy (61.2% vs 52.8%) tend to be more common with eribulin use,” he said.

Overall, “these results suggest that eribulin is less toxic chemotherapeutic partner for dual HER2 blockade and can be used for a longer,” he said.
 

Findings Are a ‘Clinical Pearl’

Harold Burstein, MD, PhD, a breast cancer expert at Dana-Farber Cancer Institute and professor at Harvard Medical School in Boston, described the findings as “a nice clinical pearl,” because some patients do not tolerate taxane therapy. “In such cases, you can substitute eribulin, which is usually tolerated without allergic hypersensitivity issues,” he said in an interview.

Eribulin has specific properties that “could make it a perfect candidate” as an adjunct to standard treatment regimens across different breast cancer subtypes, observed Wynne Wijaya, MD an oncology researcher at the University of Oxford, England, and Universitas Gadjah Mada, in Yogyakarta, Indonesia, in a recent review (World J Exp Med. 2024;14[2]:92558).

Dr. Wijaya, who was not involved in this study, said in an interview that the findings have important implications.

“This encouraging result adds eribulin as another option in the first line treatment regimen for patients with HER2-positive, locally advanced or metastatic breast cancer, especially in terms of side effects/toxicities,” she said. “As clinicians, we can offer to tailor the choice of therapy between eribulin versus taxane in the regimen based on [which side effects patients are better able to tolerate]. It would also be interesting and worthwhile to conduct similar trials in different types of populations to provide more robust evidence.”

Eisai Co. funded the research. Dr. Yamashita disclosed ties with AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eisai, Kyowa Hakko Kiri, Lilly, MSD, Pfizer, Taiho, Gilead Sciences, Nihonkayaku, Ono Yakuhin, and Seagen. Dr. Burstein disclosed a research grant from National Cancer Institute. Dr. Wijaya had no relevant disclosures.

Eribulin seems to be an equally effective chemotherapy to pair with a dual HER2 blockade as taxane as first-line treatment for women with HER2-positive, locally advanced or metastatic breast cancer.

The results of this multicenter, randomized, open-label, parallel-group, phase 3 Japanese trial suggest that patients who cannot tolerate the standard taxane-based regimen have a new option for treatment.

“Our study is the first to show the non-inferiority of eribulin to a taxane, when used in combination with dual HER2 blockade as first-line treatment for this population,” lead author Toshinari Yamashita, MD, PhD, from the Kanagawa Cancer Center, in Kanagawa, Japan, said at the annual meeting of the American Society of Clinical Oncology.

“To our knowledge, noninferiority of eribulin to a taxane when used in combination with dual HER2 blockade has not been investigated,” Dr. Yamashita said.

“The combination of trastuzumab, pertuzumab, and taxane is a current standard first-line therapy for recurrent or metastatic HER2-positive breast cancer,” explained Dr. Yamashita. “However, because of taxane-induced toxicity, the development of less toxic but equally effective alternatives are needed.

“Because its efficacy is comparable to that of the current standard regimen, the combination of eribulin, trastuzumab, and pertuzumab is one of the options for first-line treatment of how to fight locally advanced or metastatic breast cancer,” he continued.
 

Study Results and Methods

The trial enrolled 446 patients, mean age 56 years, all of whom had locally advanced or metastatic breast cancer and no prior use of chemotherapy, excluding T-DM1. Patients who had received hormonal or HER2 therapy alone or the combination, as treatment for recurrence, were also eligible.

They were randomized 1:1 to receive a 21-day chemotherapy cycle of either (i) eribulin (1.4 mg/m² on days 1 and 8), or (ii) a taxane (docetaxel 75 mg/m² on day 1 or paclitaxel 80 mg/m² on days 1, 8 and 15), each being administered in combination with a dual HER2 blockade of trastuzumab plus pertuzumab.

Baseline characteristics of both groups were well balanced, with 257 (57.6%) having ER-positive disease, 292 (65.5%) visceral metastasis, and 263 (59%) with de novo stage 4 disease, explained Dr. Yamashita.

For the primary endpoint, the median progression-free survival (PFS) was 14 versus 12.9 months in the eribulin and taxane group, respectively (hazard ratio [HR] 0.95, P = .6817), confirming non-inferiority of the study regimen, he reported.

The clinical benefit rate was similar between the two groups, with an objective response rate of 76.8% in the eribulin group and 75.2% in the taxane group.

Median OS was 65.3 months in the taxane group, but has not been reached in the study group (HR 1.09).

In terms of side-effects, the incidence of treatment-emergent adverse events was similar between the eribulin and taxane groups (58.9% vs 59.2%, respectively, for grade 3 or higher).

“Skin-related adverse events (62.4% vs 40.6%), diarrhea (54.1% vs 36.6%), and edema (42.2% vs 8.5%) tend to be more common with taxane, whereas neutropenia (61.6% vs 30.7%) and peripheral neuropathy (61.2% vs 52.8%) tend to be more common with eribulin use,” he said.

Overall, “these results suggest that eribulin is less toxic chemotherapeutic partner for dual HER2 blockade and can be used for a longer,” he said.
 

Findings Are a ‘Clinical Pearl’

Harold Burstein, MD, PhD, a breast cancer expert at Dana-Farber Cancer Institute and professor at Harvard Medical School in Boston, described the findings as “a nice clinical pearl,” because some patients do not tolerate taxane therapy. “In such cases, you can substitute eribulin, which is usually tolerated without allergic hypersensitivity issues,” he said in an interview.

Eribulin has specific properties that “could make it a perfect candidate” as an adjunct to standard treatment regimens across different breast cancer subtypes, observed Wynne Wijaya, MD an oncology researcher at the University of Oxford, England, and Universitas Gadjah Mada, in Yogyakarta, Indonesia, in a recent review (World J Exp Med. 2024;14[2]:92558).

Dr. Wijaya, who was not involved in this study, said in an interview that the findings have important implications.

“This encouraging result adds eribulin as another option in the first line treatment regimen for patients with HER2-positive, locally advanced or metastatic breast cancer, especially in terms of side effects/toxicities,” she said. “As clinicians, we can offer to tailor the choice of therapy between eribulin versus taxane in the regimen based on [which side effects patients are better able to tolerate]. It would also be interesting and worthwhile to conduct similar trials in different types of populations to provide more robust evidence.”

Eisai Co. funded the research. Dr. Yamashita disclosed ties with AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eisai, Kyowa Hakko Kiri, Lilly, MSD, Pfizer, Taiho, Gilead Sciences, Nihonkayaku, Ono Yakuhin, and Seagen. Dr. Burstein disclosed a research grant from National Cancer Institute. Dr. Wijaya had no relevant disclosures.

Eribulin seems to be an equally effective chemotherapy to pair with a dual HER2 blockade as taxane as first-line treatment for women with HER2-positive, locally advanced or metastatic breast cancer.

The results of this multicenter, randomized, open-label, parallel-group, phase 3 Japanese trial suggest that patients who cannot tolerate the standard taxane-based regimen have a new option for treatment.

“Our study is the first to show the non-inferiority of eribulin to a taxane, when used in combination with dual HER2 blockade as first-line treatment for this population,” lead author Toshinari Yamashita, MD, PhD, from the Kanagawa Cancer Center, in Kanagawa, Japan, said at the annual meeting of the American Society of Clinical Oncology.

“To our knowledge, noninferiority of eribulin to a taxane when used in combination with dual HER2 blockade has not been investigated,” Dr. Yamashita said.

“The combination of trastuzumab, pertuzumab, and taxane is a current standard first-line therapy for recurrent or metastatic HER2-positive breast cancer,” explained Dr. Yamashita. “However, because of taxane-induced toxicity, the development of less toxic but equally effective alternatives are needed.

“Because its efficacy is comparable to that of the current standard regimen, the combination of eribulin, trastuzumab, and pertuzumab is one of the options for first-line treatment of how to fight locally advanced or metastatic breast cancer,” he continued.
 

Study Results and Methods

The trial enrolled 446 patients, mean age 56 years, all of whom had locally advanced or metastatic breast cancer and no prior use of chemotherapy, excluding T-DM1. Patients who had received hormonal or HER2 therapy alone or the combination, as treatment for recurrence, were also eligible.

They were randomized 1:1 to receive a 21-day chemotherapy cycle of either (i) eribulin (1.4 mg/m² on days 1 and 8), or (ii) a taxane (docetaxel 75 mg/m² on day 1 or paclitaxel 80 mg/m² on days 1, 8 and 15), each being administered in combination with a dual HER2 blockade of trastuzumab plus pertuzumab.

Baseline characteristics of both groups were well balanced, with 257 (57.6%) having ER-positive disease, 292 (65.5%) visceral metastasis, and 263 (59%) with de novo stage 4 disease, explained Dr. Yamashita.

For the primary endpoint, the median progression-free survival (PFS) was 14 versus 12.9 months in the eribulin and taxane group, respectively (hazard ratio [HR] 0.95, P = .6817), confirming non-inferiority of the study regimen, he reported.

The clinical benefit rate was similar between the two groups, with an objective response rate of 76.8% in the eribulin group and 75.2% in the taxane group.

Median OS was 65.3 months in the taxane group, but has not been reached in the study group (HR 1.09).

In terms of side-effects, the incidence of treatment-emergent adverse events was similar between the eribulin and taxane groups (58.9% vs 59.2%, respectively, for grade 3 or higher).

“Skin-related adverse events (62.4% vs 40.6%), diarrhea (54.1% vs 36.6%), and edema (42.2% vs 8.5%) tend to be more common with taxane, whereas neutropenia (61.6% vs 30.7%) and peripheral neuropathy (61.2% vs 52.8%) tend to be more common with eribulin use,” he said.

Overall, “these results suggest that eribulin is less toxic chemotherapeutic partner for dual HER2 blockade and can be used for a longer,” he said.
 

Findings Are a ‘Clinical Pearl’

Harold Burstein, MD, PhD, a breast cancer expert at Dana-Farber Cancer Institute and professor at Harvard Medical School in Boston, described the findings as “a nice clinical pearl,” because some patients do not tolerate taxane therapy. “In such cases, you can substitute eribulin, which is usually tolerated without allergic hypersensitivity issues,” he said in an interview.

Eribulin has specific properties that “could make it a perfect candidate” as an adjunct to standard treatment regimens across different breast cancer subtypes, observed Wynne Wijaya, MD an oncology researcher at the University of Oxford, England, and Universitas Gadjah Mada, in Yogyakarta, Indonesia, in a recent review (World J Exp Med. 2024;14[2]:92558).

Dr. Wijaya, who was not involved in this study, said in an interview that the findings have important implications.

“This encouraging result adds eribulin as another option in the first line treatment regimen for patients with HER2-positive, locally advanced or metastatic breast cancer, especially in terms of side effects/toxicities,” she said. “As clinicians, we can offer to tailor the choice of therapy between eribulin versus taxane in the regimen based on [which side effects patients are better able to tolerate]. It would also be interesting and worthwhile to conduct similar trials in different types of populations to provide more robust evidence.”

Eisai Co. funded the research. Dr. Yamashita disclosed ties with AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eisai, Kyowa Hakko Kiri, Lilly, MSD, Pfizer, Taiho, Gilead Sciences, Nihonkayaku, Ono Yakuhin, and Seagen. Dr. Burstein disclosed a research grant from National Cancer Institute. Dr. Wijaya had no relevant disclosures.

Patients with treatment-refractory cancers who did not meet eligibility criteria for a pan-cancer clinical trial but received waivers allowing them to participate had similar outcomes to patients who participated without waivers, a new analysis revealed.

The study, published online in Clinical Cancer Research, highlighted the potential benefits of broadening eligibility criteria for clinical trials.

“It is well known that results in an ‘ideal’ population do not always translate to the real-world population,” senior author Hans Gelderblom, MD, chair of the Department of Medical Oncology at the Leiden University Medical Center, Leiden, the Netherlands, said in a press release. “Eligibility criteria are often too strict, and educated exemptions by experienced investigators can help individual patients, especially in a last-resort trial.”

Although experts have expressed interest in improving trial inclusivity, it’s unclear how doing so might impact treatment safety and efficacy.

In the Drug Rediscovery Protocol (DRUP), Dr. Gelderblom and colleagues examined the impact of broadening trial eligibility on patient outcomes. DRUP is an ongoing Dutch national, multicenter, pan-cancer, nonrandomized clinical trial in which patients are treated off-label with approved molecularly targeted or immunotherapies.

In the trial, 1019 patients with treatment-refractory disease were matched to one of the available study drugs based on their tumor molecular profile and enrolled in parallel cohorts. Cohorts were defined by tumor type, molecular profile, and study drug.

Among these patients, 82 patients — 8% of the cohort — were granted waivers to participate. Most waivers (45%) were granted as exceptions to general- or drug-related eligibility criteria, often because of out-of-range lab results. Other categories included treatment and testing exceptions, as well as out-of-window testing. 

The researchers then compared safety and efficacy outcomes between the 82 participants granted waivers and the 937 who did not receive waivers. 

Overall, Dr. Gelderblom’s team found that the rate of serious adverse events was similar between patients who received a waiver and those who did not: 39% vs 41%, respectively.

A relationship between waivers and serious adverse events was deemed “unlikely” for 86% of patients and “possible” for 14%. In two cases concerning a direct relationship, for instance, patients who received waivers for decreased hemoglobin levels developed anemia.

The rate of clinical benefit — defined as an objective response or stable disease for at least 16 weeks — was similar between the groups. Overall, 40% of patients who received a waiver (33 of 82) had a clinical benefit vs 33% of patients without a waiver (P = .43). Median overall survival for patients that received a waiver was also similar — 11 months in the waiver group and 8 months in the nonwaiver group (hazard ratio, 0.87; P = .33).

“Safety and clinical benefit were preserved in patients for whom a waiver was granted,” the authors concluded.

The study had several limitations. The diversity of cancer types, treatments, and reasons for protocol exemptions precluded subgroup analyses. In addition, because the decision to grant waivers depended in large part on the likelihood of clinical benefit, “it is possible that patients who received waivers were positively selected for clinical benefit compared with the general study population,” the authors wrote.

So, “although the clinical benefit rate of the patient group for whom a waiver was granted appears to be slightly higher, this difference might be explained by the selection process of the central study team, in which each waiver request was carefully considered, weighing the risks and potential benefits for the patient in question,” the authors explained.

Overall, “these findings advocate for a broader and more inclusive design when establishing novel trials, paving the way for a more effective and tailored application of cancer therapies in patients with advanced or refractory disease,” Dr. Gelderblom said.

Commenting on the study, Bishal Gyawali, MD, PhD, said that “relaxing eligibility criteria is important, and I support this. Trials should include patients that are more representative of the real-world, so that results are generalizable.”

However, “the paper overemphasized efficacy,” said Dr. Gyawali, from Queen’s University, Kingston, Ontario, Canada. The sample size of waiver-granted patients was small, plus “the clinical benefit rate is not a marker of efficacy.

“The response rate is somewhat better, but for a heterogeneous study with multiple targets and drugs, it is difficult to say much about treatment effects here,” Dr. Gyawali added. Overall, “we shouldn’t read too much into treatment benefits based on these numbers.”

Funding for the study was provided by the Stelvio for Life Foundation, the Dutch Cancer Society, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, pharma&, Eisai Co., Ipsen, Merck Sharp & Dohme, Novartis, Pfizer, and Roche. Dr. Gelderblom declared no conflicts of interest, and Dr. Gyawali declared no conflicts of interest related to his comment.
 

A version of this article appeared on Medscape.com.

Patients with treatment-refractory cancers who did not meet eligibility criteria for a pan-cancer clinical trial but received waivers allowing them to participate had similar outcomes to patients who participated without waivers, a new analysis revealed.

The study, published online in Clinical Cancer Research, highlighted the potential benefits of broadening eligibility criteria for clinical trials.

“It is well known that results in an ‘ideal’ population do not always translate to the real-world population,” senior author Hans Gelderblom, MD, chair of the Department of Medical Oncology at the Leiden University Medical Center, Leiden, the Netherlands, said in a press release. “Eligibility criteria are often too strict, and educated exemptions by experienced investigators can help individual patients, especially in a last-resort trial.”

Although experts have expressed interest in improving trial inclusivity, it’s unclear how doing so might impact treatment safety and efficacy.

In the Drug Rediscovery Protocol (DRUP), Dr. Gelderblom and colleagues examined the impact of broadening trial eligibility on patient outcomes. DRUP is an ongoing Dutch national, multicenter, pan-cancer, nonrandomized clinical trial in which patients are treated off-label with approved molecularly targeted or immunotherapies.

In the trial, 1019 patients with treatment-refractory disease were matched to one of the available study drugs based on their tumor molecular profile and enrolled in parallel cohorts. Cohorts were defined by tumor type, molecular profile, and study drug.

Among these patients, 82 patients — 8% of the cohort — were granted waivers to participate. Most waivers (45%) were granted as exceptions to general- or drug-related eligibility criteria, often because of out-of-range lab results. Other categories included treatment and testing exceptions, as well as out-of-window testing. 

The researchers then compared safety and efficacy outcomes between the 82 participants granted waivers and the 937 who did not receive waivers. 

Overall, Dr. Gelderblom’s team found that the rate of serious adverse events was similar between patients who received a waiver and those who did not: 39% vs 41%, respectively.

A relationship between waivers and serious adverse events was deemed “unlikely” for 86% of patients and “possible” for 14%. In two cases concerning a direct relationship, for instance, patients who received waivers for decreased hemoglobin levels developed anemia.

The rate of clinical benefit — defined as an objective response or stable disease for at least 16 weeks — was similar between the groups. Overall, 40% of patients who received a waiver (33 of 82) had a clinical benefit vs 33% of patients without a waiver (P = .43). Median overall survival for patients that received a waiver was also similar — 11 months in the waiver group and 8 months in the nonwaiver group (hazard ratio, 0.87; P = .33).

“Safety and clinical benefit were preserved in patients for whom a waiver was granted,” the authors concluded.

The study had several limitations. The diversity of cancer types, treatments, and reasons for protocol exemptions precluded subgroup analyses. In addition, because the decision to grant waivers depended in large part on the likelihood of clinical benefit, “it is possible that patients who received waivers were positively selected for clinical benefit compared with the general study population,” the authors wrote.

So, “although the clinical benefit rate of the patient group for whom a waiver was granted appears to be slightly higher, this difference might be explained by the selection process of the central study team, in which each waiver request was carefully considered, weighing the risks and potential benefits for the patient in question,” the authors explained.

Overall, “these findings advocate for a broader and more inclusive design when establishing novel trials, paving the way for a more effective and tailored application of cancer therapies in patients with advanced or refractory disease,” Dr. Gelderblom said.

Commenting on the study, Bishal Gyawali, MD, PhD, said that “relaxing eligibility criteria is important, and I support this. Trials should include patients that are more representative of the real-world, so that results are generalizable.”

However, “the paper overemphasized efficacy,” said Dr. Gyawali, from Queen’s University, Kingston, Ontario, Canada. The sample size of waiver-granted patients was small, plus “the clinical benefit rate is not a marker of efficacy.

“The response rate is somewhat better, but for a heterogeneous study with multiple targets and drugs, it is difficult to say much about treatment effects here,” Dr. Gyawali added. Overall, “we shouldn’t read too much into treatment benefits based on these numbers.”

Funding for the study was provided by the Stelvio for Life Foundation, the Dutch Cancer Society, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, pharma&, Eisai Co., Ipsen, Merck Sharp & Dohme, Novartis, Pfizer, and Roche. Dr. Gelderblom declared no conflicts of interest, and Dr. Gyawali declared no conflicts of interest related to his comment.
 

A version of this article appeared on Medscape.com.

Patients with treatment-refractory cancers who did not meet eligibility criteria for a pan-cancer clinical trial but received waivers allowing them to participate had similar outcomes to patients who participated without waivers, a new analysis revealed.

The study, published online in Clinical Cancer Research, highlighted the potential benefits of broadening eligibility criteria for clinical trials.

“It is well known that results in an ‘ideal’ population do not always translate to the real-world population,” senior author Hans Gelderblom, MD, chair of the Department of Medical Oncology at the Leiden University Medical Center, Leiden, the Netherlands, said in a press release. “Eligibility criteria are often too strict, and educated exemptions by experienced investigators can help individual patients, especially in a last-resort trial.”

Although experts have expressed interest in improving trial inclusivity, it’s unclear how doing so might impact treatment safety and efficacy.

In the Drug Rediscovery Protocol (DRUP), Dr. Gelderblom and colleagues examined the impact of broadening trial eligibility on patient outcomes. DRUP is an ongoing Dutch national, multicenter, pan-cancer, nonrandomized clinical trial in which patients are treated off-label with approved molecularly targeted or immunotherapies.

In the trial, 1019 patients with treatment-refractory disease were matched to one of the available study drugs based on their tumor molecular profile and enrolled in parallel cohorts. Cohorts were defined by tumor type, molecular profile, and study drug.

Among these patients, 82 patients — 8% of the cohort — were granted waivers to participate. Most waivers (45%) were granted as exceptions to general- or drug-related eligibility criteria, often because of out-of-range lab results. Other categories included treatment and testing exceptions, as well as out-of-window testing. 

The researchers then compared safety and efficacy outcomes between the 82 participants granted waivers and the 937 who did not receive waivers. 

Overall, Dr. Gelderblom’s team found that the rate of serious adverse events was similar between patients who received a waiver and those who did not: 39% vs 41%, respectively.

A relationship between waivers and serious adverse events was deemed “unlikely” for 86% of patients and “possible” for 14%. In two cases concerning a direct relationship, for instance, patients who received waivers for decreased hemoglobin levels developed anemia.

The rate of clinical benefit — defined as an objective response or stable disease for at least 16 weeks — was similar between the groups. Overall, 40% of patients who received a waiver (33 of 82) had a clinical benefit vs 33% of patients without a waiver (P = .43). Median overall survival for patients that received a waiver was also similar — 11 months in the waiver group and 8 months in the nonwaiver group (hazard ratio, 0.87; P = .33).

“Safety and clinical benefit were preserved in patients for whom a waiver was granted,” the authors concluded.

The study had several limitations. The diversity of cancer types, treatments, and reasons for protocol exemptions precluded subgroup analyses. In addition, because the decision to grant waivers depended in large part on the likelihood of clinical benefit, “it is possible that patients who received waivers were positively selected for clinical benefit compared with the general study population,” the authors wrote.

So, “although the clinical benefit rate of the patient group for whom a waiver was granted appears to be slightly higher, this difference might be explained by the selection process of the central study team, in which each waiver request was carefully considered, weighing the risks and potential benefits for the patient in question,” the authors explained.

Overall, “these findings advocate for a broader and more inclusive design when establishing novel trials, paving the way for a more effective and tailored application of cancer therapies in patients with advanced or refractory disease,” Dr. Gelderblom said.

Commenting on the study, Bishal Gyawali, MD, PhD, said that “relaxing eligibility criteria is important, and I support this. Trials should include patients that are more representative of the real-world, so that results are generalizable.”

However, “the paper overemphasized efficacy,” said Dr. Gyawali, from Queen’s University, Kingston, Ontario, Canada. The sample size of waiver-granted patients was small, plus “the clinical benefit rate is not a marker of efficacy.

“The response rate is somewhat better, but for a heterogeneous study with multiple targets and drugs, it is difficult to say much about treatment effects here,” Dr. Gyawali added. Overall, “we shouldn’t read too much into treatment benefits based on these numbers.”

Funding for the study was provided by the Stelvio for Life Foundation, the Dutch Cancer Society, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, pharma&, Eisai Co., Ipsen, Merck Sharp & Dohme, Novartis, Pfizer, and Roche. Dr. Gelderblom declared no conflicts of interest, and Dr. Gyawali declared no conflicts of interest related to his comment.
 

A version of this article appeared on Medscape.com.

The newly updated US Department of Veterans Affairs (VA) prostate cancer clinical pathway looks like a set of guidelines, but it’s really something unique. As attendees learned at an Association of VA Hematology/Oncology (AVAHO) regional meeting in Detroit in June, the clinical pathways are designed to point the way toward a standard ideal treatment for the majority of cases, not just to suggest a number of possible options.

“Pathways will always offer one scenario. They try to get oncologists to practice in a similar fashion so things can be managed more uniformly,” Michael M. Goodman, MD, told Federal Practitioner prior to the AVAHO meeting that was focused on prostate cancer care. Goodman is an associate professor of medicine with Atrium Health Wake Forest Baptist Medical Center and helped develop the VA genitourinary oncology pathways.

“The overall goal is not just to standardize care as much as possible but also to synthesize the best and most cost-effective practices,” Goodman said. For example, “If you have 5 different therapies, and they all have about the same efficacy and safety, and 1 is less costly than the other 4, then it would make sense to choose that.”

The VA has offered pathways for multiple types of cancer since 2021, and the pathway for prostate cancer is among the most comprehensive. The VA system updated the pathway in March 2024, is available online both via SharePoint and externally.

“It goes through the entire gamut from screening, diagnosis, and management to end of life,” Goodman explained. Multiple disciplines, from primary care and surgery to genetics and imaging, can rely on the pathway to assist decision-making.

In terms of screening, the pathway offers a flow map guiding the screening choices. In patients aged ≤ 54 years, only certain high-risk groups, such as African Americans and those with a family history of prostate cancer, should be screened. From ages 54 to 69 years, patients should be consulted as part of a shared decision making process, while screening is not recommended for patients aged ≥ 70 years.

Pathway flow maps also provide information about diagnostic standards, evaluation of the newly diagnosed, risk stratification, molecular testing, and end-of-life care.

Goodman says the pathway is now integrated into the VA electronic health record system via a template so clinicians can easily document pathway use. This allows the VA to track the use of the pathways locally, regionally, and nationally track the use of the pathways.

Clinicians are not mandated to follow every step in the pathway, but Goodman said the goal is > 80% adherence. If clinicians follow the standards, he said, “you’re considering efficacy, safety, and cost for that veteran.”

Prospective data suggests that adherence to the pathway eliminates certain disparities. African American veterans, for example, are as well-represented or even better represented than White veterans in prostate cancer care when pathways are followed.

Why might clinicians veer from the pathway? “If you’re seeing a patient who was treated in the community with drug X, but drug Y is chosen by the pathway, you can carry on with the previous care.” Alternatively, in some cases, patients may not tolerate the pathway standard, Goodman noted.

Goodman reports that he consults the pathway every day. “It’s helped standardize the care I provide to ensure there’s no gaps in how I’m treating patients.”

The newly updated US Department of Veterans Affairs (VA) prostate cancer clinical pathway looks like a set of guidelines, but it’s really something unique. As attendees learned at an Association of VA Hematology/Oncology (AVAHO) regional meeting in Detroit in June, the clinical pathways are designed to point the way toward a standard ideal treatment for the majority of cases, not just to suggest a number of possible options.

“Pathways will always offer one scenario. They try to get oncologists to practice in a similar fashion so things can be managed more uniformly,” Michael M. Goodman, MD, told Federal Practitioner prior to the AVAHO meeting that was focused on prostate cancer care. Goodman is an associate professor of medicine with Atrium Health Wake Forest Baptist Medical Center and helped develop the VA genitourinary oncology pathways.

“The overall goal is not just to standardize care as much as possible but also to synthesize the best and most cost-effective practices,” Goodman said. For example, “If you have 5 different therapies, and they all have about the same efficacy and safety, and 1 is less costly than the other 4, then it would make sense to choose that.”

The VA has offered pathways for multiple types of cancer since 2021, and the pathway for prostate cancer is among the most comprehensive. The VA system updated the pathway in March 2024, is available online both via SharePoint and externally.

“It goes through the entire gamut from screening, diagnosis, and management to end of life,” Goodman explained. Multiple disciplines, from primary care and surgery to genetics and imaging, can rely on the pathway to assist decision-making.

In terms of screening, the pathway offers a flow map guiding the screening choices. In patients aged ≤ 54 years, only certain high-risk groups, such as African Americans and those with a family history of prostate cancer, should be screened. From ages 54 to 69 years, patients should be consulted as part of a shared decision making process, while screening is not recommended for patients aged ≥ 70 years.

Pathway flow maps also provide information about diagnostic standards, evaluation of the newly diagnosed, risk stratification, molecular testing, and end-of-life care.

Goodman says the pathway is now integrated into the VA electronic health record system via a template so clinicians can easily document pathway use. This allows the VA to track the use of the pathways locally, regionally, and nationally track the use of the pathways.

Clinicians are not mandated to follow every step in the pathway, but Goodman said the goal is > 80% adherence. If clinicians follow the standards, he said, “you’re considering efficacy, safety, and cost for that veteran.”

Prospective data suggests that adherence to the pathway eliminates certain disparities. African American veterans, for example, are as well-represented or even better represented than White veterans in prostate cancer care when pathways are followed.

Why might clinicians veer from the pathway? “If you’re seeing a patient who was treated in the community with drug X, but drug Y is chosen by the pathway, you can carry on with the previous care.” Alternatively, in some cases, patients may not tolerate the pathway standard, Goodman noted.

Goodman reports that he consults the pathway every day. “It’s helped standardize the care I provide to ensure there’s no gaps in how I’m treating patients.”

The newly updated US Department of Veterans Affairs (VA) prostate cancer clinical pathway looks like a set of guidelines, but it’s really something unique. As attendees learned at an Association of VA Hematology/Oncology (AVAHO) regional meeting in Detroit in June, the clinical pathways are designed to point the way toward a standard ideal treatment for the majority of cases, not just to suggest a number of possible options.

“Pathways will always offer one scenario. They try to get oncologists to practice in a similar fashion so things can be managed more uniformly,” Michael M. Goodman, MD, told Federal Practitioner prior to the AVAHO meeting that was focused on prostate cancer care. Goodman is an associate professor of medicine with Atrium Health Wake Forest Baptist Medical Center and helped develop the VA genitourinary oncology pathways.

“The overall goal is not just to standardize care as much as possible but also to synthesize the best and most cost-effective practices,” Goodman said. For example, “If you have 5 different therapies, and they all have about the same efficacy and safety, and 1 is less costly than the other 4, then it would make sense to choose that.”

The VA has offered pathways for multiple types of cancer since 2021, and the pathway for prostate cancer is among the most comprehensive. The VA system updated the pathway in March 2024, is available online both via SharePoint and externally.

“It goes through the entire gamut from screening, diagnosis, and management to end of life,” Goodman explained. Multiple disciplines, from primary care and surgery to genetics and imaging, can rely on the pathway to assist decision-making.

In terms of screening, the pathway offers a flow map guiding the screening choices. In patients aged ≤ 54 years, only certain high-risk groups, such as African Americans and those with a family history of prostate cancer, should be screened. From ages 54 to 69 years, patients should be consulted as part of a shared decision making process, while screening is not recommended for patients aged ≥ 70 years.

Pathway flow maps also provide information about diagnostic standards, evaluation of the newly diagnosed, risk stratification, molecular testing, and end-of-life care.

Goodman says the pathway is now integrated into the VA electronic health record system via a template so clinicians can easily document pathway use. This allows the VA to track the use of the pathways locally, regionally, and nationally track the use of the pathways.

Clinicians are not mandated to follow every step in the pathway, but Goodman said the goal is > 80% adherence. If clinicians follow the standards, he said, “you’re considering efficacy, safety, and cost for that veteran.”

Prospective data suggests that adherence to the pathway eliminates certain disparities. African American veterans, for example, are as well-represented or even better represented than White veterans in prostate cancer care when pathways are followed.

Why might clinicians veer from the pathway? “If you’re seeing a patient who was treated in the community with drug X, but drug Y is chosen by the pathway, you can carry on with the previous care.” Alternatively, in some cases, patients may not tolerate the pathway standard, Goodman noted.

Goodman reports that he consults the pathway every day. “It’s helped standardize the care I provide to ensure there’s no gaps in how I’m treating patients.”

This transcript has been edited for clarity. 

Hello. I’m Mark Lewis, director of gastrointestinal (GI) oncology at Intermountain Health in Utah. I’m speaking from the 2024 ASCO Annual Meeting in Chicago, where we’ve seen some interesting, new data in GI cancers.

If you allow me, I’d like to go in a craniocaudal fashion. It’s my anatomic mnemonic. I think that’s appropriate because our plenary session yesterday kicked off with some exciting data in esophageal cancer, specifically esophageal adenocarcinoma. 

This was the long-awaited ESOPEC trial. It’s a phase 3 study looking at perioperative FLOT (5-FU/leucovorin/oxaliplatin/docetaxel), a chemo triplet, vs the CROSS protocol, which is neoadjuvant chemoradiation with carboplatin and paclitaxel. The primary endpoint was overall survival, and at first blush, FLOT looked to be the true winner. There were some really remarkable milestones in this study, and I have some reservations about the FLOT arm that I’ll raise in just a second. 

The investigators are to be commended because in a truly deadly disease, they reported a 5-year overall survival in half of the patients who were receiving FLOT. That is truly commendable and really a milestone in our field. The reason I take a little bit of issue with the trial is that I still have some questions about methodology.

It wasn’t that long ago at ASCO GI that there was a really heated debate called “FLOT or Not” — not in this precise setting, but asking the question, do we think that patients with upper GI malignancy are even fit enough to handle a chemo triplet like FLOT? 

The reason I bring that up now in 2024 is that, to my surprise, and I think to many others’, there was a lower-than-expected completion rate of the patients in this trial who were receiving the CROSS regimen. The number of people who were able to complete that in full was about two-thirds, which compared with a historical control from a trial scheme that first emerged over a decade ago that used to be over 90% completion. I found that quite strange. 

I also think this trial suffers a little bit, and unavoidably, from the evolution of care that’s happened since it was first enrolling. Of course, I refer to adjuvant immunotherapy. Now, the real question is whether there is synergy between patients who receive radiation upfront and then adjuvant nivolumab, as per CheckMate 577. 

In her plenary discussion, I thought Dr. Karyn Goodman did a masterful job — I would encourage you to watch it on ASCO’s website —discussing how we can take all these data and reconcile them for optimal patient outcome. She ultimately suggested that we might deploy all four modalities in the management of these people. 

She proposed a paradigm with a PET-adapted, upfront induction chemotherapy, then moving to chemoradiation, then moving to surgery, and finally moving to immunotherapy. That is all four of the traditional arms of oncology. I find that really rather remarkable. Watch that space. This is a great trial with really remarkable survival data, but I’m not entirely convinced that the CROSS arm was given its due. 

Next up, I want to talk about pancreas cancer, which is something near and dear to my heart. It affects about one in four of my patients and it remains, unfortunately, a highly lethal disease. I think the top-line news from this meeting is that the KRAS mutation is druggable. I’m probably showing my age, but when I did my fellowship in 2009 through 2012, I was taught that KRAS was sort of the undruggable mutation par excellence. At this meeting, we’ve seen maturing data in regard to targeting KRAS G12C with both sotorasib and adagrasib. The disease control rates are astounding, at 80% and more, which is really remarkable. I wouldn’t have believed that even a few years ago. 

I’m even more excited about how we bring a rising tide that can lift all boats and apply this to other KRAS mutations, and not just KRAS G12C but all KRAS mutations. I think that’s coming, hopefully, with the pan-RAS inhibitors, because once that happens — if that happens; I’ll try not to be irrationally exuberant — that would take the traditional mutation found in almost all pancreas cancers and really make it its own Achilles heel. I think that could be such a huge leap forward. 

Another matter, however, that remains unresolved at this meeting is in the neoadjuvant setting with pancreatic ductal adenocarcinoma. There’s still equipoise, actually, between neoadjuvant gemcitabine, paclitaxel, and FOLFIRINOX. I thought that that was very well spelled out by some of our Dutch colleagues, who continue to do great work in a variety of cancers, including colorectal. 

Where I’d like to move next is colorectal cancer. Of course, immunotherapy remains a hot topic at all of these conferences. There were three different aspects of immunotherapy I’d like to highlight at this conference in regard to colon and rectal cancer. 

First, Dr. Heinz-Josef Lenz presented updated data from CheckMate 8HW, which looked at nivolumab and ipilimumab (nivo/ipi) vs chemotherapy in the first line for MSI-high or mismatch repair–deficient colon cancer. Once again, the data we’ve had now for several years at the 2-year mark are incredibly impressive. The 2-year progression-free survival (PFS) rates for nivo/ipi are above 70% and down at around 14% for chemo. 

What was impressive about this meeting is that Dr. Lenz presented PFS2, trying to determine the impact, if any, of subsequent therapy. What was going on here, which I think was ethically responsible by the investigators, was crossover. About two-thirds of the chemo arm crossed over to any form of immuno-oncology (IO), and just under a half crossed over to nivo and ipi. The PFS benefits continued with up-front IO. The way that Dr. Lenz phrased it is that you really never get the chance to win back the benefit that you would derive by giving immunotherapy first line to someone who has MSI-high or mismatch repair–deficient metastatic colon cancer. 

One thing that’s still not settled in my mind, though, is, does this really dethrone single-agent immunotherapy, such as pembrolizumab in KEYNOTE-177? What I’m really driving at is the ipilimumab. Is the juice worth the squeeze? Is the addition of an anti-CTLA4 agent worth the toxicity that we know comes along with that mechanism of action? Watch this space. 

I was also really interested in NEOPRISM-CRC, which looked at the role of immunotherapy in neoadjuvant down-staging of radiographically high-risk stage II or stage III colon cancer. Here, the investigators really make a strong case that, up front in these potentially respectable cases, not only should we know about mismatch repair deficiency but we should actually be interrogating further for tumor mutational burden (TMB). 

They had TMB-high patients. In fact, the median TMB was 42 mutations per megabase, with really impressive down-staging using three cycles of every-3-week pembrolizumab before surgery. Again, I really think we’re at an exciting time where, even for colon cancer that looks operable up front, we might actually have the opportunity to improve pathologic and clinical complete responses before and after surgery. 

Finally, I want to bring up what continues to amaze me. Two years ago, at ASCO 2022, we heard from Dr. Andrea Cercek and the Memorial Sloan Kettering group about the incredible experience they were having with neoadjuvant, or frankly, definitive dostarlimab in mismatch repair–deficient locally advanced rectal cancer. 

I remember being at the conference and there was simultaneous publication of that abstract in The New York Times because it was so remarkable. There was a 100% clinical complete response. The patients didn’t require radiation, they didn’t require chemotherapy, and they didn’t require surgery for locally advanced rectal cancer, provided there was this vulnerability of mismatch-repair deficiency. 

Now, 2 years later, Dr. Cercek and her group have updated those data with more than 40 patients, and again, a 100% clinical complete response, including mature, complete responses at over a year in about 20 patients. Again, we are really doing our rectal cancer patients a disservice if we’re not checking for mismatch-repair deficiency upfront, and especially if we’re not talking about them in multidisciplinary conferences. 

One of the things that absolutely blows my mind about rectal cancer is just how complicated it’s becoming. I think it is the standard of care to discuss these cases upfront with radiation oncology, surgical oncology, medical oncology, and pathology. 

Maybe the overarching message I would take from everything I’ve said today is that the oncologist without the pathologist is blind. It’s really a dyad, a partnership that guides optimal medical oncology care. As much as I love ASCO, I often wish we had more of our pathology colleagues here. I look forward to taking all the findings from this meeting back to the tumor board and really having a dynamic dialogue.

Dr. Lewis is director, Department of Gastrointestinal Oncology, Intermountain Health, Salt Lake City, Utah. He has disclosed no relevant financial relationships. 

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity. 

Hello. I’m Mark Lewis, director of gastrointestinal (GI) oncology at Intermountain Health in Utah. I’m speaking from the 2024 ASCO Annual Meeting in Chicago, where we’ve seen some interesting, new data in GI cancers.

If you allow me, I’d like to go in a craniocaudal fashion. It’s my anatomic mnemonic. I think that’s appropriate because our plenary session yesterday kicked off with some exciting data in esophageal cancer, specifically esophageal adenocarcinoma. 

This was the long-awaited ESOPEC trial. It’s a phase 3 study looking at perioperative FLOT (5-FU/leucovorin/oxaliplatin/docetaxel), a chemo triplet, vs the CROSS protocol, which is neoadjuvant chemoradiation with carboplatin and paclitaxel. The primary endpoint was overall survival, and at first blush, FLOT looked to be the true winner. There were some really remarkable milestones in this study, and I have some reservations about the FLOT arm that I’ll raise in just a second. 

The investigators are to be commended because in a truly deadly disease, they reported a 5-year overall survival in half of the patients who were receiving FLOT. That is truly commendable and really a milestone in our field. The reason I take a little bit of issue with the trial is that I still have some questions about methodology.

It wasn’t that long ago at ASCO GI that there was a really heated debate called “FLOT or Not” — not in this precise setting, but asking the question, do we think that patients with upper GI malignancy are even fit enough to handle a chemo triplet like FLOT? 

The reason I bring that up now in 2024 is that, to my surprise, and I think to many others’, there was a lower-than-expected completion rate of the patients in this trial who were receiving the CROSS regimen. The number of people who were able to complete that in full was about two-thirds, which compared with a historical control from a trial scheme that first emerged over a decade ago that used to be over 90% completion. I found that quite strange. 

I also think this trial suffers a little bit, and unavoidably, from the evolution of care that’s happened since it was first enrolling. Of course, I refer to adjuvant immunotherapy. Now, the real question is whether there is synergy between patients who receive radiation upfront and then adjuvant nivolumab, as per CheckMate 577. 

In her plenary discussion, I thought Dr. Karyn Goodman did a masterful job — I would encourage you to watch it on ASCO’s website —discussing how we can take all these data and reconcile them for optimal patient outcome. She ultimately suggested that we might deploy all four modalities in the management of these people. 

She proposed a paradigm with a PET-adapted, upfront induction chemotherapy, then moving to chemoradiation, then moving to surgery, and finally moving to immunotherapy. That is all four of the traditional arms of oncology. I find that really rather remarkable. Watch that space. This is a great trial with really remarkable survival data, but I’m not entirely convinced that the CROSS arm was given its due. 

Next up, I want to talk about pancreas cancer, which is something near and dear to my heart. It affects about one in four of my patients and it remains, unfortunately, a highly lethal disease. I think the top-line news from this meeting is that the KRAS mutation is druggable. I’m probably showing my age, but when I did my fellowship in 2009 through 2012, I was taught that KRAS was sort of the undruggable mutation par excellence. At this meeting, we’ve seen maturing data in regard to targeting KRAS G12C with both sotorasib and adagrasib. The disease control rates are astounding, at 80% and more, which is really remarkable. I wouldn’t have believed that even a few years ago. 

I’m even more excited about how we bring a rising tide that can lift all boats and apply this to other KRAS mutations, and not just KRAS G12C but all KRAS mutations. I think that’s coming, hopefully, with the pan-RAS inhibitors, because once that happens — if that happens; I’ll try not to be irrationally exuberant — that would take the traditional mutation found in almost all pancreas cancers and really make it its own Achilles heel. I think that could be such a huge leap forward. 

Another matter, however, that remains unresolved at this meeting is in the neoadjuvant setting with pancreatic ductal adenocarcinoma. There’s still equipoise, actually, between neoadjuvant gemcitabine, paclitaxel, and FOLFIRINOX. I thought that that was very well spelled out by some of our Dutch colleagues, who continue to do great work in a variety of cancers, including colorectal. 

Where I’d like to move next is colorectal cancer. Of course, immunotherapy remains a hot topic at all of these conferences. There were three different aspects of immunotherapy I’d like to highlight at this conference in regard to colon and rectal cancer. 

First, Dr. Heinz-Josef Lenz presented updated data from CheckMate 8HW, which looked at nivolumab and ipilimumab (nivo/ipi) vs chemotherapy in the first line for MSI-high or mismatch repair–deficient colon cancer. Once again, the data we’ve had now for several years at the 2-year mark are incredibly impressive. The 2-year progression-free survival (PFS) rates for nivo/ipi are above 70% and down at around 14% for chemo. 

What was impressive about this meeting is that Dr. Lenz presented PFS2, trying to determine the impact, if any, of subsequent therapy. What was going on here, which I think was ethically responsible by the investigators, was crossover. About two-thirds of the chemo arm crossed over to any form of immuno-oncology (IO), and just under a half crossed over to nivo and ipi. The PFS benefits continued with up-front IO. The way that Dr. Lenz phrased it is that you really never get the chance to win back the benefit that you would derive by giving immunotherapy first line to someone who has MSI-high or mismatch repair–deficient metastatic colon cancer. 

One thing that’s still not settled in my mind, though, is, does this really dethrone single-agent immunotherapy, such as pembrolizumab in KEYNOTE-177? What I’m really driving at is the ipilimumab. Is the juice worth the squeeze? Is the addition of an anti-CTLA4 agent worth the toxicity that we know comes along with that mechanism of action? Watch this space. 

I was also really interested in NEOPRISM-CRC, which looked at the role of immunotherapy in neoadjuvant down-staging of radiographically high-risk stage II or stage III colon cancer. Here, the investigators really make a strong case that, up front in these potentially respectable cases, not only should we know about mismatch repair deficiency but we should actually be interrogating further for tumor mutational burden (TMB). 

They had TMB-high patients. In fact, the median TMB was 42 mutations per megabase, with really impressive down-staging using three cycles of every-3-week pembrolizumab before surgery. Again, I really think we’re at an exciting time where, even for colon cancer that looks operable up front, we might actually have the opportunity to improve pathologic and clinical complete responses before and after surgery. 

Finally, I want to bring up what continues to amaze me. Two years ago, at ASCO 2022, we heard from Dr. Andrea Cercek and the Memorial Sloan Kettering group about the incredible experience they were having with neoadjuvant, or frankly, definitive dostarlimab in mismatch repair–deficient locally advanced rectal cancer. 

I remember being at the conference and there was simultaneous publication of that abstract in The New York Times because it was so remarkable. There was a 100% clinical complete response. The patients didn’t require radiation, they didn’t require chemotherapy, and they didn’t require surgery for locally advanced rectal cancer, provided there was this vulnerability of mismatch-repair deficiency. 

Now, 2 years later, Dr. Cercek and her group have updated those data with more than 40 patients, and again, a 100% clinical complete response, including mature, complete responses at over a year in about 20 patients. Again, we are really doing our rectal cancer patients a disservice if we’re not checking for mismatch-repair deficiency upfront, and especially if we’re not talking about them in multidisciplinary conferences. 

One of the things that absolutely blows my mind about rectal cancer is just how complicated it’s becoming. I think it is the standard of care to discuss these cases upfront with radiation oncology, surgical oncology, medical oncology, and pathology. 

Maybe the overarching message I would take from everything I’ve said today is that the oncologist without the pathologist is blind. It’s really a dyad, a partnership that guides optimal medical oncology care. As much as I love ASCO, I often wish we had more of our pathology colleagues here. I look forward to taking all the findings from this meeting back to the tumor board and really having a dynamic dialogue.

Dr. Lewis is director, Department of Gastrointestinal Oncology, Intermountain Health, Salt Lake City, Utah. He has disclosed no relevant financial relationships. 

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity. 

Hello. I’m Mark Lewis, director of gastrointestinal (GI) oncology at Intermountain Health in Utah. I’m speaking from the 2024 ASCO Annual Meeting in Chicago, where we’ve seen some interesting, new data in GI cancers.

If you allow me, I’d like to go in a craniocaudal fashion. It’s my anatomic mnemonic. I think that’s appropriate because our plenary session yesterday kicked off with some exciting data in esophageal cancer, specifically esophageal adenocarcinoma. 

This was the long-awaited ESOPEC trial. It’s a phase 3 study looking at perioperative FLOT (5-FU/leucovorin/oxaliplatin/docetaxel), a chemo triplet, vs the CROSS protocol, which is neoadjuvant chemoradiation with carboplatin and paclitaxel. The primary endpoint was overall survival, and at first blush, FLOT looked to be the true winner. There were some really remarkable milestones in this study, and I have some reservations about the FLOT arm that I’ll raise in just a second. 

The investigators are to be commended because in a truly deadly disease, they reported a 5-year overall survival in half of the patients who were receiving FLOT. That is truly commendable and really a milestone in our field. The reason I take a little bit of issue with the trial is that I still have some questions about methodology.

It wasn’t that long ago at ASCO GI that there was a really heated debate called “FLOT or Not” — not in this precise setting, but asking the question, do we think that patients with upper GI malignancy are even fit enough to handle a chemo triplet like FLOT? 

The reason I bring that up now in 2024 is that, to my surprise, and I think to many others’, there was a lower-than-expected completion rate of the patients in this trial who were receiving the CROSS regimen. The number of people who were able to complete that in full was about two-thirds, which compared with a historical control from a trial scheme that first emerged over a decade ago that used to be over 90% completion. I found that quite strange. 

I also think this trial suffers a little bit, and unavoidably, from the evolution of care that’s happened since it was first enrolling. Of course, I refer to adjuvant immunotherapy. Now, the real question is whether there is synergy between patients who receive radiation upfront and then adjuvant nivolumab, as per CheckMate 577. 

In her plenary discussion, I thought Dr. Karyn Goodman did a masterful job — I would encourage you to watch it on ASCO’s website —discussing how we can take all these data and reconcile them for optimal patient outcome. She ultimately suggested that we might deploy all four modalities in the management of these people. 

She proposed a paradigm with a PET-adapted, upfront induction chemotherapy, then moving to chemoradiation, then moving to surgery, and finally moving to immunotherapy. That is all four of the traditional arms of oncology. I find that really rather remarkable. Watch that space. This is a great trial with really remarkable survival data, but I’m not entirely convinced that the CROSS arm was given its due. 

Next up, I want to talk about pancreas cancer, which is something near and dear to my heart. It affects about one in four of my patients and it remains, unfortunately, a highly lethal disease. I think the top-line news from this meeting is that the KRAS mutation is druggable. I’m probably showing my age, but when I did my fellowship in 2009 through 2012, I was taught that KRAS was sort of the undruggable mutation par excellence. At this meeting, we’ve seen maturing data in regard to targeting KRAS G12C with both sotorasib and adagrasib. The disease control rates are astounding, at 80% and more, which is really remarkable. I wouldn’t have believed that even a few years ago. 

I’m even more excited about how we bring a rising tide that can lift all boats and apply this to other KRAS mutations, and not just KRAS G12C but all KRAS mutations. I think that’s coming, hopefully, with the pan-RAS inhibitors, because once that happens — if that happens; I’ll try not to be irrationally exuberant — that would take the traditional mutation found in almost all pancreas cancers and really make it its own Achilles heel. I think that could be such a huge leap forward. 

Another matter, however, that remains unresolved at this meeting is in the neoadjuvant setting with pancreatic ductal adenocarcinoma. There’s still equipoise, actually, between neoadjuvant gemcitabine, paclitaxel, and FOLFIRINOX. I thought that that was very well spelled out by some of our Dutch colleagues, who continue to do great work in a variety of cancers, including colorectal. 

Where I’d like to move next is colorectal cancer. Of course, immunotherapy remains a hot topic at all of these conferences. There were three different aspects of immunotherapy I’d like to highlight at this conference in regard to colon and rectal cancer. 

First, Dr. Heinz-Josef Lenz presented updated data from CheckMate 8HW, which looked at nivolumab and ipilimumab (nivo/ipi) vs chemotherapy in the first line for MSI-high or mismatch repair–deficient colon cancer. Once again, the data we’ve had now for several years at the 2-year mark are incredibly impressive. The 2-year progression-free survival (PFS) rates for nivo/ipi are above 70% and down at around 14% for chemo. 

What was impressive about this meeting is that Dr. Lenz presented PFS2, trying to determine the impact, if any, of subsequent therapy. What was going on here, which I think was ethically responsible by the investigators, was crossover. About two-thirds of the chemo arm crossed over to any form of immuno-oncology (IO), and just under a half crossed over to nivo and ipi. The PFS benefits continued with up-front IO. The way that Dr. Lenz phrased it is that you really never get the chance to win back the benefit that you would derive by giving immunotherapy first line to someone who has MSI-high or mismatch repair–deficient metastatic colon cancer. 

One thing that’s still not settled in my mind, though, is, does this really dethrone single-agent immunotherapy, such as pembrolizumab in KEYNOTE-177? What I’m really driving at is the ipilimumab. Is the juice worth the squeeze? Is the addition of an anti-CTLA4 agent worth the toxicity that we know comes along with that mechanism of action? Watch this space. 

I was also really interested in NEOPRISM-CRC, which looked at the role of immunotherapy in neoadjuvant down-staging of radiographically high-risk stage II or stage III colon cancer. Here, the investigators really make a strong case that, up front in these potentially respectable cases, not only should we know about mismatch repair deficiency but we should actually be interrogating further for tumor mutational burden (TMB). 

They had TMB-high patients. In fact, the median TMB was 42 mutations per megabase, with really impressive down-staging using three cycles of every-3-week pembrolizumab before surgery. Again, I really think we’re at an exciting time where, even for colon cancer that looks operable up front, we might actually have the opportunity to improve pathologic and clinical complete responses before and after surgery. 

Finally, I want to bring up what continues to amaze me. Two years ago, at ASCO 2022, we heard from Dr. Andrea Cercek and the Memorial Sloan Kettering group about the incredible experience they were having with neoadjuvant, or frankly, definitive dostarlimab in mismatch repair–deficient locally advanced rectal cancer. 

I remember being at the conference and there was simultaneous publication of that abstract in The New York Times because it was so remarkable. There was a 100% clinical complete response. The patients didn’t require radiation, they didn’t require chemotherapy, and they didn’t require surgery for locally advanced rectal cancer, provided there was this vulnerability of mismatch-repair deficiency. 

Now, 2 years later, Dr. Cercek and her group have updated those data with more than 40 patients, and again, a 100% clinical complete response, including mature, complete responses at over a year in about 20 patients. Again, we are really doing our rectal cancer patients a disservice if we’re not checking for mismatch-repair deficiency upfront, and especially if we’re not talking about them in multidisciplinary conferences. 

One of the things that absolutely blows my mind about rectal cancer is just how complicated it’s becoming. I think it is the standard of care to discuss these cases upfront with radiation oncology, surgical oncology, medical oncology, and pathology. 

Maybe the overarching message I would take from everything I’ve said today is that the oncologist without the pathologist is blind. It’s really a dyad, a partnership that guides optimal medical oncology care. As much as I love ASCO, I often wish we had more of our pathology colleagues here. I look forward to taking all the findings from this meeting back to the tumor board and really having a dynamic dialogue.

Dr. Lewis is director, Department of Gastrointestinal Oncology, Intermountain Health, Salt Lake City, Utah. He has disclosed no relevant financial relationships. 

A version of this article appeared on Medscape.com.

Should 5 mg of tamoxifen — known as “baby TAM” — or the usual 20 mg dose be standard of care for breast cancer prevention in high-risk women?

Research to date clearly shows that tamoxifen can reduce the risk for breast cancer in high-risk individuals by 30%-50%. Recent evidence also indicates that this chemoprevention approach can reduce the risk of dying from breast cancer by as much as 57%.

In 2019, the US Preventive Services Task Force issued updated recommendations that clinicians offer risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women at an increased risk for breast cancer and a low risk for adverse medication effects.

However, this prophylactic strategy remains underused.

A major roadblock: The drugs’ side effects, which include venous thromboembolic events and endometrial cancer as well as symptoms of menopause, such as hot flashes and sexual issues, have made uptake and adherence a challenge.

Offering women a lower dose of tamoxifen could allay fears about toxicities and improve uptake as well as reduce side effects and boost long-term adherence among those receiving baby TAM.

However, experts remain uncertain about whether patients need the standard dose to experience the full prevention benefit.
 

The Debate

Years ago, Andrea De Censi, MD, a breast cancer researcher at the Galliera Hospital in Genova, Italy, and his colleagues reasoned that, because tamoxifen is a competitive estrogen receptor inhibitor, it may indeed have a minimal effective dose below 20 mg/d.

The fruits of that line of thought were presented to the world in the TAM-01 trial, first published in 2019, which pitted tamoxifen 5 mg/d for 3 years against placebo in 500 women with high-risk lesions, including lobular and ductal carcinoma in situ.

Dr. De Censi and colleagues found that baby TAM reduced the risk for invasive breast cancer by 52% and the risk for contralateral breast cancer by 75%.

Treatment adherence was slightly higher in the baby TAM group at 65% vs 61% in the placebo group.

A recent 10-year follow-up showed ongoing benefits associated with baby TAM vs placebo — a 42% reduction in breast cancer and a 64% drop in contralateral lesions.

The baby TAM group vs placebo experienced a slight increase in hot flashes but no significant increase in other common side effects.

Regarding serious adverse events, the baby TAM arm had one case of stage 1 endometrial cancer (0.4% of patients) and 20 cases of endometrial polyps (5%) vs 13 cases of endometrial polyps in the placebo arm. But there were no significant differences in thrombosis, cataracts, bone fractures, and other serious events.

Dr. De Censi said he’s surprised the baby TAM vs tamoxifen topic is still being debated. “Baby TAM, in my opinion, is a new standard of care for endocrine prevention of breast cancer in high-risk [women],” and baby TAM over 3 years is enough, said Dr. De Censi during a debate on the topic at the 2024 European Society for Medical Oncology Breast Cancer Congress in Berlin.

Gareth Evans, MD, a cancer genetics and prevention specialist at the University of Manchester, Manchester, England, however, isn’t convinced.

During the debate, Dr. Evans explained that  his main concern was that the baby TAM trial was limited to women with high-risk lesions, not other common reasons for tamoxifen prophylaxis, such as a positive family history or BRCA mutations.

“In Manchester, we have put over a thousand women on tamoxifen who have a family history or other risk factors, not high-risk lesions,” and there simply isn’t definitive evidence for baby TAM in these women, Dr. Evans said.

The vast weight of evidence for tamoxifen prophylaxis, he added, is in trials involving tens of thousands of women, followed in some cases for 20 years, who received the 20 mg dose for 5 years.

As a result, women in Manchester are started on 20 mg and dropped down to 5 mg only for side effects. That way, Evans explained, we are not taking away the benefit among women who can tolerate 20 mg.

Meanwhile, there’s no evidence that baby TAM improves medication adherence, he noted. Trials have reported similar adherence rates to baby TAM and standard dose tamoxifen as well as no definitive evidence that the risk for cancer and thrombosis is less with baby TAM, he said.

In fact, Dr. Evans noted, “many women take tamoxifen 20 mg for 5 years with no side effects.”

Overall, “I don’t think we’ve got the evidence yet to drop” dosages, particularly in women without high-risk lesions, Dr. Evans said. A real concern, he added, is poor metabolizers for whom 5 mg won’t be enough to have a preventive effect.

Dr. De Censi noted, however, that there will likely never be a definitive answer to the question of baby TAM vs standard dosing because industry has no financial incentive to do a head-to-head trial; tamoxifen went off patent over 30 years ago.

Still, a poll of the audience favored Evans’ approach — 80% said they would start high-risk women on 20 mg for breast cancer prophylaxis and reduce for side effects as needed.

Dr. De Censi didn’t have any disclosures. Dr. Evans is a consultant/advisor for AstraZeneca, SpringWorks, Recursion, Everything Genetic, and Syantra.

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

Should 5 mg of tamoxifen — known as “baby TAM” — or the usual 20 mg dose be standard of care for breast cancer prevention in high-risk women?

Research to date clearly shows that tamoxifen can reduce the risk for breast cancer in high-risk individuals by 30%-50%. Recent evidence also indicates that this chemoprevention approach can reduce the risk of dying from breast cancer by as much as 57%.

In 2019, the US Preventive Services Task Force issued updated recommendations that clinicians offer risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women at an increased risk for breast cancer and a low risk for adverse medication effects.

However, this prophylactic strategy remains underused.

A major roadblock: The drugs’ side effects, which include venous thromboembolic events and endometrial cancer as well as symptoms of menopause, such as hot flashes and sexual issues, have made uptake and adherence a challenge.

Offering women a lower dose of tamoxifen could allay fears about toxicities and improve uptake as well as reduce side effects and boost long-term adherence among those receiving baby TAM.

However, experts remain uncertain about whether patients need the standard dose to experience the full prevention benefit.
 

The Debate

Years ago, Andrea De Censi, MD, a breast cancer researcher at the Galliera Hospital in Genova, Italy, and his colleagues reasoned that, because tamoxifen is a competitive estrogen receptor inhibitor, it may indeed have a minimal effective dose below 20 mg/d.

The fruits of that line of thought were presented to the world in the TAM-01 trial, first published in 2019, which pitted tamoxifen 5 mg/d for 3 years against placebo in 500 women with high-risk lesions, including lobular and ductal carcinoma in situ.

Dr. De Censi and colleagues found that baby TAM reduced the risk for invasive breast cancer by 52% and the risk for contralateral breast cancer by 75%.

Treatment adherence was slightly higher in the baby TAM group at 65% vs 61% in the placebo group.

A recent 10-year follow-up showed ongoing benefits associated with baby TAM vs placebo — a 42% reduction in breast cancer and a 64% drop in contralateral lesions.

The baby TAM group vs placebo experienced a slight increase in hot flashes but no significant increase in other common side effects.

Regarding serious adverse events, the baby TAM arm had one case of stage 1 endometrial cancer (0.4% of patients) and 20 cases of endometrial polyps (5%) vs 13 cases of endometrial polyps in the placebo arm. But there were no significant differences in thrombosis, cataracts, bone fractures, and other serious events.

Dr. De Censi said he’s surprised the baby TAM vs tamoxifen topic is still being debated. “Baby TAM, in my opinion, is a new standard of care for endocrine prevention of breast cancer in high-risk [women],” and baby TAM over 3 years is enough, said Dr. De Censi during a debate on the topic at the 2024 European Society for Medical Oncology Breast Cancer Congress in Berlin.

Gareth Evans, MD, a cancer genetics and prevention specialist at the University of Manchester, Manchester, England, however, isn’t convinced.

During the debate, Dr. Evans explained that  his main concern was that the baby TAM trial was limited to women with high-risk lesions, not other common reasons for tamoxifen prophylaxis, such as a positive family history or BRCA mutations.

“In Manchester, we have put over a thousand women on tamoxifen who have a family history or other risk factors, not high-risk lesions,” and there simply isn’t definitive evidence for baby TAM in these women, Dr. Evans said.

The vast weight of evidence for tamoxifen prophylaxis, he added, is in trials involving tens of thousands of women, followed in some cases for 20 years, who received the 20 mg dose for 5 years.

As a result, women in Manchester are started on 20 mg and dropped down to 5 mg only for side effects. That way, Evans explained, we are not taking away the benefit among women who can tolerate 20 mg.

Meanwhile, there’s no evidence that baby TAM improves medication adherence, he noted. Trials have reported similar adherence rates to baby TAM and standard dose tamoxifen as well as no definitive evidence that the risk for cancer and thrombosis is less with baby TAM, he said.

In fact, Dr. Evans noted, “many women take tamoxifen 20 mg for 5 years with no side effects.”

Overall, “I don’t think we’ve got the evidence yet to drop” dosages, particularly in women without high-risk lesions, Dr. Evans said. A real concern, he added, is poor metabolizers for whom 5 mg won’t be enough to have a preventive effect.

Dr. De Censi noted, however, that there will likely never be a definitive answer to the question of baby TAM vs standard dosing because industry has no financial incentive to do a head-to-head trial; tamoxifen went off patent over 30 years ago.

Still, a poll of the audience favored Evans’ approach — 80% said they would start high-risk women on 20 mg for breast cancer prophylaxis and reduce for side effects as needed.

Dr. De Censi didn’t have any disclosures. Dr. Evans is a consultant/advisor for AstraZeneca, SpringWorks, Recursion, Everything Genetic, and Syantra.

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

Should 5 mg of tamoxifen — known as “baby TAM” — or the usual 20 mg dose be standard of care for breast cancer prevention in high-risk women?

Research to date clearly shows that tamoxifen can reduce the risk for breast cancer in high-risk individuals by 30%-50%. Recent evidence also indicates that this chemoprevention approach can reduce the risk of dying from breast cancer by as much as 57%.

In 2019, the US Preventive Services Task Force issued updated recommendations that clinicians offer risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women at an increased risk for breast cancer and a low risk for adverse medication effects.

However, this prophylactic strategy remains underused.

A major roadblock: The drugs’ side effects, which include venous thromboembolic events and endometrial cancer as well as symptoms of menopause, such as hot flashes and sexual issues, have made uptake and adherence a challenge.

Offering women a lower dose of tamoxifen could allay fears about toxicities and improve uptake as well as reduce side effects and boost long-term adherence among those receiving baby TAM.

However, experts remain uncertain about whether patients need the standard dose to experience the full prevention benefit.
 

The Debate

Years ago, Andrea De Censi, MD, a breast cancer researcher at the Galliera Hospital in Genova, Italy, and his colleagues reasoned that, because tamoxifen is a competitive estrogen receptor inhibitor, it may indeed have a minimal effective dose below 20 mg/d.

The fruits of that line of thought were presented to the world in the TAM-01 trial, first published in 2019, which pitted tamoxifen 5 mg/d for 3 years against placebo in 500 women with high-risk lesions, including lobular and ductal carcinoma in situ.

Dr. De Censi and colleagues found that baby TAM reduced the risk for invasive breast cancer by 52% and the risk for contralateral breast cancer by 75%.

Treatment adherence was slightly higher in the baby TAM group at 65% vs 61% in the placebo group.

A recent 10-year follow-up showed ongoing benefits associated with baby TAM vs placebo — a 42% reduction in breast cancer and a 64% drop in contralateral lesions.

The baby TAM group vs placebo experienced a slight increase in hot flashes but no significant increase in other common side effects.

Regarding serious adverse events, the baby TAM arm had one case of stage 1 endometrial cancer (0.4% of patients) and 20 cases of endometrial polyps (5%) vs 13 cases of endometrial polyps in the placebo arm. But there were no significant differences in thrombosis, cataracts, bone fractures, and other serious events.

Dr. De Censi said he’s surprised the baby TAM vs tamoxifen topic is still being debated. “Baby TAM, in my opinion, is a new standard of care for endocrine prevention of breast cancer in high-risk [women],” and baby TAM over 3 years is enough, said Dr. De Censi during a debate on the topic at the 2024 European Society for Medical Oncology Breast Cancer Congress in Berlin.

Gareth Evans, MD, a cancer genetics and prevention specialist at the University of Manchester, Manchester, England, however, isn’t convinced.

During the debate, Dr. Evans explained that  his main concern was that the baby TAM trial was limited to women with high-risk lesions, not other common reasons for tamoxifen prophylaxis, such as a positive family history or BRCA mutations.

“In Manchester, we have put over a thousand women on tamoxifen who have a family history or other risk factors, not high-risk lesions,” and there simply isn’t definitive evidence for baby TAM in these women, Dr. Evans said.

The vast weight of evidence for tamoxifen prophylaxis, he added, is in trials involving tens of thousands of women, followed in some cases for 20 years, who received the 20 mg dose for 5 years.

As a result, women in Manchester are started on 20 mg and dropped down to 5 mg only for side effects. That way, Evans explained, we are not taking away the benefit among women who can tolerate 20 mg.

Meanwhile, there’s no evidence that baby TAM improves medication adherence, he noted. Trials have reported similar adherence rates to baby TAM and standard dose tamoxifen as well as no definitive evidence that the risk for cancer and thrombosis is less with baby TAM, he said.

In fact, Dr. Evans noted, “many women take tamoxifen 20 mg for 5 years with no side effects.”

Overall, “I don’t think we’ve got the evidence yet to drop” dosages, particularly in women without high-risk lesions, Dr. Evans said. A real concern, he added, is poor metabolizers for whom 5 mg won’t be enough to have a preventive effect.

Dr. De Censi noted, however, that there will likely never be a definitive answer to the question of baby TAM vs standard dosing because industry has no financial incentive to do a head-to-head trial; tamoxifen went off patent over 30 years ago.

Still, a poll of the audience favored Evans’ approach — 80% said they would start high-risk women on 20 mg for breast cancer prophylaxis and reduce for side effects as needed.

Dr. De Censi didn’t have any disclosures. Dr. Evans is a consultant/advisor for AstraZeneca, SpringWorks, Recursion, Everything Genetic, and Syantra.

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

An elderly gentleman was truly suffering, so his doctor decided to try something new.

“He’d had a number of cumulative side effects after almost two years of IV chemotherapy for his metastatic colon cancer,” said Anuj Patel, MD, a senior physician at Dana-Farber Cancer Institute in Boston, recalling his patient. “When we switched him to combination treatment with trifluridine/tipiracil and bevacizumab, he constantly remarked on how well he now felt. He described no side effects from this new regimen.”

Nearly a year after the US Food and Drug Administration (FDA) approved trifluridine/tipiracil combined with bevacizumab for refractory mCRC, the tremendous value of its results in practice are clear.

Trifluridine/tipiracil (Lonsurf) had been used to treat advanced gastric cancer, while bevacizumab had been therapeutic for a wider range of diseases, including cervical, brain, liver, kidney, gynecological and lung cancers. Used together for treating refractory mCRC, well-known initial findings about their effectiveness have been proven true over time.

“Patients taking both drugs can experience, on average, a life extension of three months,” said Richard M. Goldberg, MD, professor emeritus of the West Virginia University Cancer Institute and director of Fight Colorectal Cancer.
 

The History of the Combined Therapy’s Approval

The FDA originally approved trifluridine/tipiracil in September 2015 for use in patients with metastatic colorectal cancer. Patients eligible to take it had to have been treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor (VEGF) biological therapy, and—if RAS wild-type—an anti-epidermal growth factor receptor (EGFR) therapy, according to data published by the National Center for Biotechnology Information. The FDA’s August 2023 approval of the trifluridine/tipiracil and bevacizumab combination regimen is for patients meeting the same eligibility requirements.

Another drug, regorafenib, had already been approved by the FDA in September 2012 to treat mCRC. The drug has a wide range of potential side effects, however, including complications relating to the limbs.

“One of my patients tried regorafenib as his initial third- line treatment,” Dr. Goldberg said. “I checked in on him at his farm, and he was sitting in the barn near his tractor.

He had such severe hand-foot syndrome that he could barely walk.”

Trifluridine/tipiracil alone proved to be very helpful in this case. “We switched him to it, and he tolerated it well,” Dr. Goldberg continued. “He got his fields plowed and was on it for months before he passed away. We both felt it kept him going longer.”

A new research review confirms the regimen’s success, determining that trifluridine/tipiracil plus bevacizumab was associated with improved outcomes compared to therapy solely with trifluridine/tipiracil.
 

A True Practice Changer

Now that the regimen has been on the market for more than half a year, there are longer-term data available.

Patients on average live within the same timeframe as the patients in the SUNLIGHT study, and many feel physically better on the therapy. “The combination has very quickly shifted the standard of care,” Dr. Goldberg said.

The regimen can also provide significant psychological benefits to patients.

“As patients can maintain good performance status for longer with the combination, it increases the perception of quality of life,” said Jacobo Hincapie-Echeverri, MD, a GI and geriatric oncologist at Orlando Health Cancer Institute in Orlando, Florida.

The regimen is unique too, in that it can help doctors plan additional treatment strategies.

“This current approval, for the combination of trifluridine/tipiracil and bevacizumab, is practice-changing in that it helps clarify the sequence for later treatments for patients with mCRC,” said Dr. Patel, who is also clinical director of the Center for Esophageal and Gastric Cancer and assistant professor of medicine at Harvard Medical School, Boston. “Previously, it had been difficult to decide between trifluridine/tipiracil and regorafenib in this setting.”

The fact that the regimen has been shown to give time and improved quality of life to patients in ways regorafenib does not is clarifying. “Now, with the improved outcomes seen, I do think that trifluridine/tipiracil plus bevacizumab is the better option for most mCRC patients after IV chemotherapies,” Dr. Patel added.

When it comes to his specific experience with prescribing the regimen for his patients, Dr. Patel reported that it’s easier on his patients than other therapies.

“I find that it is generally well tolerated,” he elaborated. “As an oral agent, it is also usually somewhat easier to take (than other delivery methods of medication). These factors are critical for patients who have likely already had at least 2 or 3 prior lines of chemotherapy. I have had many patients with mCRC who, after disease progression on prior IV chemotherapy regimens, have had periods of meaningful disease control – often with fewer and manageable side effects.”

Dr. Goldberg mentioned another benefit.

“The nice thing about the combination of trifluridine/tipiracil and bevacizumab is that in terms of toxicity, there’s very little difference compared to the toxicity of trifluridine/tipiracil used alone.”
 

Are There Downsides to the Regimen?

The pros are obvious, but the regimen has some cons as well. Medically, patients should have a platelet count over 75,000/mm³ and absolute neutrophil count (ANC) over 1,500/mm³ prior to the start of each cycle, and their liver and renal function should be monitored.

Patients with metastatic colorectal cancer must be also carefully monitored for hematologic adverse events (AEs) , including chemotherapy-associated neutropenia. Biweekly treatments may reduce the risk of AEs as a whole, however, according to research.

The regimen is also expensive – an approximate cost of $8,191 for a 28-day supply. According to a new study, patients managing both AE expenses along with the cost of trifluridine/tipiracil-bevacizumab face a monthly bill of about $17,179.

Some very good news, though: 100% of Medicare drug plans cover trifluridine/tipiracil, with an average copay of $57-$292. Bevacizumab is also covered by Medicare, with a copay as low as $0-$25.

Private insurers do cover the drugs, depending on a patient’s specific plan. However, if a patient’s claim is denied, financial assistance for trifluridine/tipiracil through the drug’s manufacturers may be available for some patients, reducing prescriptions to a zero cost in some cases. Bevacizumab can be made available to patients who may not have health insurance at all, too. Patients can use a financial assistance tool through the drug’s manufacturer to receive up to $25,000 in yearly copay assistance.
 

What Does the Latest Research on the Regimen Indicate?

In May 2024, two abstracts were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) that explored expanded possible use of trifluridine/tipiracil plus bevacizumab as a treatment for metastatic colorectal cancer.

The first abstract studied trifluridine/tipiracil plus bevacizumab as upfront treatment for mCRC, adding capecitabine to the regimen.

“It’s a phase 1 study looking at dose findings for the three-drug combination, where the active drug is a chemotherapy agent classified as a fluoropyrimidine ... I would characterize this as a study combining two [fluoropyrimidines] with a single targeted therapy,” Dr. Goldberg said.

“Combining two fluoropyrimidines is an unusual approach, because they tend to have overlapping side effects, and the potential is there for either innate drug resistance to the class of drugs or that the combination of two agents that work by a similar mechanism of action could hasten the development of acquired drug resistance. There is apparently a signal that combining the two chemotherapy agents enhances each other’s activity in cell culture and animal models,” he added.

Ultimately, Dr. Goldberg said he thinks more evidence is needed to prove the regimen’s effectiveness.

“This is a very early study and really provides no information about its potential given that no response data was presented,” he added. “While this is an interesting idea, it is unclear if it will pan out until we see the data on the Phase II study in progress.”

The other abstract looked at the impact of colorectal liver metastases in patients with mCRC who in phase 3 of the SUNLIGHT trial received trifluridine/tipiracil with or without bevacizumab.

“There is not much that is novel here,” Dr. Goldberg said. “The retrospective analysis shows that trifluridine/tipiracil plus bevacizumab is better than trifluridine/tipiracil alone in the subset of patients with liver metastases, as it was shown to be in the entire patient population. While this is reassuring, it’s not unexpected, especially since the vast majority of people enrolled in the SUNLIGHT trial had liver metastases.”

The Bottom Line

In the future, the potential exists for trifluridine/tipiracil combined with bevacizumab to work in first-line and second-line patients.

“Seventy percent of colorectal cancer patients reach second line treatment right now, but only 30% reach third line treatment — either they become too sick to continue, or choose not to,” Dr. Goldberg said. “The hope is that using these drugs earlier can help more patients reach and prolong treatment.”

It’s also possible that the regimen can be applied in new ways.

“Further research combining trifluridine/tipiracil and bevacizumab with other targeted therapies could yield additional advances for refractory mCRC patients,” Dr. Hincapie-Echeverri said. “The survival benefit of this therapy reinforces the importance of continuing to develop new therapies to improve outcomes in the refractory mCRC setting.”

Dr. Patel’s patient felt lucky to simply live a longer life.

Because of the regimen, “his cancer remained stable for approximately 8 months. Upon its progression, he chose not to pursue any further chemotherapy. He instead expressed his gratitude at having been able to feel more like himself for nearly a year.”

Dr. Patel received research funding in 2017 from Taiho, which manufactures trifluridine/tipiracil. He receives no current funding from Taiho and has no additional conflicts of interest. Dr. Goldberg helped represent Taiho in a patent law dispute regarding Lonsurf for which he was paid, but he is no longer paid by the company. Dr. Hincapie-Echeverri is a speaker for Astellas Pharma, which does not manufacture trifluridine/tipiracil or bevacizumab, and he has no additional conflicts of interest.

An elderly gentleman was truly suffering, so his doctor decided to try something new.

“He’d had a number of cumulative side effects after almost two years of IV chemotherapy for his metastatic colon cancer,” said Anuj Patel, MD, a senior physician at Dana-Farber Cancer Institute in Boston, recalling his patient. “When we switched him to combination treatment with trifluridine/tipiracil and bevacizumab, he constantly remarked on how well he now felt. He described no side effects from this new regimen.”

Nearly a year after the US Food and Drug Administration (FDA) approved trifluridine/tipiracil combined with bevacizumab for refractory mCRC, the tremendous value of its results in practice are clear.

Trifluridine/tipiracil (Lonsurf) had been used to treat advanced gastric cancer, while bevacizumab had been therapeutic for a wider range of diseases, including cervical, brain, liver, kidney, gynecological and lung cancers. Used together for treating refractory mCRC, well-known initial findings about their effectiveness have been proven true over time.

“Patients taking both drugs can experience, on average, a life extension of three months,” said Richard M. Goldberg, MD, professor emeritus of the West Virginia University Cancer Institute and director of Fight Colorectal Cancer.
 

The History of the Combined Therapy’s Approval

The FDA originally approved trifluridine/tipiracil in September 2015 for use in patients with metastatic colorectal cancer. Patients eligible to take it had to have been treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor (VEGF) biological therapy, and—if RAS wild-type—an anti-epidermal growth factor receptor (EGFR) therapy, according to data published by the National Center for Biotechnology Information. The FDA’s August 2023 approval of the trifluridine/tipiracil and bevacizumab combination regimen is for patients meeting the same eligibility requirements.

Another drug, regorafenib, had already been approved by the FDA in September 2012 to treat mCRC. The drug has a wide range of potential side effects, however, including complications relating to the limbs.

“One of my patients tried regorafenib as his initial third- line treatment,” Dr. Goldberg said. “I checked in on him at his farm, and he was sitting in the barn near his tractor.

He had such severe hand-foot syndrome that he could barely walk.”

Trifluridine/tipiracil alone proved to be very helpful in this case. “We switched him to it, and he tolerated it well,” Dr. Goldberg continued. “He got his fields plowed and was on it for months before he passed away. We both felt it kept him going longer.”

A new research review confirms the regimen’s success, determining that trifluridine/tipiracil plus bevacizumab was associated with improved outcomes compared to therapy solely with trifluridine/tipiracil.
 

A True Practice Changer

Now that the regimen has been on the market for more than half a year, there are longer-term data available.

Patients on average live within the same timeframe as the patients in the SUNLIGHT study, and many feel physically better on the therapy. “The combination has very quickly shifted the standard of care,” Dr. Goldberg said.

The regimen can also provide significant psychological benefits to patients.

“As patients can maintain good performance status for longer with the combination, it increases the perception of quality of life,” said Jacobo Hincapie-Echeverri, MD, a GI and geriatric oncologist at Orlando Health Cancer Institute in Orlando, Florida.

The regimen is unique too, in that it can help doctors plan additional treatment strategies.

“This current approval, for the combination of trifluridine/tipiracil and bevacizumab, is practice-changing in that it helps clarify the sequence for later treatments for patients with mCRC,” said Dr. Patel, who is also clinical director of the Center for Esophageal and Gastric Cancer and assistant professor of medicine at Harvard Medical School, Boston. “Previously, it had been difficult to decide between trifluridine/tipiracil and regorafenib in this setting.”

The fact that the regimen has been shown to give time and improved quality of life to patients in ways regorafenib does not is clarifying. “Now, with the improved outcomes seen, I do think that trifluridine/tipiracil plus bevacizumab is the better option for most mCRC patients after IV chemotherapies,” Dr. Patel added.

When it comes to his specific experience with prescribing the regimen for his patients, Dr. Patel reported that it’s easier on his patients than other therapies.

“I find that it is generally well tolerated,” he elaborated. “As an oral agent, it is also usually somewhat easier to take (than other delivery methods of medication). These factors are critical for patients who have likely already had at least 2 or 3 prior lines of chemotherapy. I have had many patients with mCRC who, after disease progression on prior IV chemotherapy regimens, have had periods of meaningful disease control – often with fewer and manageable side effects.”

Dr. Goldberg mentioned another benefit.

“The nice thing about the combination of trifluridine/tipiracil and bevacizumab is that in terms of toxicity, there’s very little difference compared to the toxicity of trifluridine/tipiracil used alone.”
 

Are There Downsides to the Regimen?

The pros are obvious, but the regimen has some cons as well. Medically, patients should have a platelet count over 75,000/mm³ and absolute neutrophil count (ANC) over 1,500/mm³ prior to the start of each cycle, and their liver and renal function should be monitored.

Patients with metastatic colorectal cancer must be also carefully monitored for hematologic adverse events (AEs) , including chemotherapy-associated neutropenia. Biweekly treatments may reduce the risk of AEs as a whole, however, according to research.

The regimen is also expensive – an approximate cost of $8,191 for a 28-day supply. According to a new study, patients managing both AE expenses along with the cost of trifluridine/tipiracil-bevacizumab face a monthly bill of about $17,179.

Some very good news, though: 100% of Medicare drug plans cover trifluridine/tipiracil, with an average copay of $57-$292. Bevacizumab is also covered by Medicare, with a copay as low as $0-$25.

Private insurers do cover the drugs, depending on a patient’s specific plan. However, if a patient’s claim is denied, financial assistance for trifluridine/tipiracil through the drug’s manufacturers may be available for some patients, reducing prescriptions to a zero cost in some cases. Bevacizumab can be made available to patients who may not have health insurance at all, too. Patients can use a financial assistance tool through the drug’s manufacturer to receive up to $25,000 in yearly copay assistance.
 

What Does the Latest Research on the Regimen Indicate?

In May 2024, two abstracts were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) that explored expanded possible use of trifluridine/tipiracil plus bevacizumab as a treatment for metastatic colorectal cancer.

The first abstract studied trifluridine/tipiracil plus bevacizumab as upfront treatment for mCRC, adding capecitabine to the regimen.

“It’s a phase 1 study looking at dose findings for the three-drug combination, where the active drug is a chemotherapy agent classified as a fluoropyrimidine ... I would characterize this as a study combining two [fluoropyrimidines] with a single targeted therapy,” Dr. Goldberg said.

“Combining two fluoropyrimidines is an unusual approach, because they tend to have overlapping side effects, and the potential is there for either innate drug resistance to the class of drugs or that the combination of two agents that work by a similar mechanism of action could hasten the development of acquired drug resistance. There is apparently a signal that combining the two chemotherapy agents enhances each other’s activity in cell culture and animal models,” he added.

Ultimately, Dr. Goldberg said he thinks more evidence is needed to prove the regimen’s effectiveness.

“This is a very early study and really provides no information about its potential given that no response data was presented,” he added. “While this is an interesting idea, it is unclear if it will pan out until we see the data on the Phase II study in progress.”

The other abstract looked at the impact of colorectal liver metastases in patients with mCRC who in phase 3 of the SUNLIGHT trial received trifluridine/tipiracil with or without bevacizumab.

“There is not much that is novel here,” Dr. Goldberg said. “The retrospective analysis shows that trifluridine/tipiracil plus bevacizumab is better than trifluridine/tipiracil alone in the subset of patients with liver metastases, as it was shown to be in the entire patient population. While this is reassuring, it’s not unexpected, especially since the vast majority of people enrolled in the SUNLIGHT trial had liver metastases.”

The Bottom Line

In the future, the potential exists for trifluridine/tipiracil combined with bevacizumab to work in first-line and second-line patients.

“Seventy percent of colorectal cancer patients reach second line treatment right now, but only 30% reach third line treatment — either they become too sick to continue, or choose not to,” Dr. Goldberg said. “The hope is that using these drugs earlier can help more patients reach and prolong treatment.”

It’s also possible that the regimen can be applied in new ways.

“Further research combining trifluridine/tipiracil and bevacizumab with other targeted therapies could yield additional advances for refractory mCRC patients,” Dr. Hincapie-Echeverri said. “The survival benefit of this therapy reinforces the importance of continuing to develop new therapies to improve outcomes in the refractory mCRC setting.”

Dr. Patel’s patient felt lucky to simply live a longer life.

Because of the regimen, “his cancer remained stable for approximately 8 months. Upon its progression, he chose not to pursue any further chemotherapy. He instead expressed his gratitude at having been able to feel more like himself for nearly a year.”

Dr. Patel received research funding in 2017 from Taiho, which manufactures trifluridine/tipiracil. He receives no current funding from Taiho and has no additional conflicts of interest. Dr. Goldberg helped represent Taiho in a patent law dispute regarding Lonsurf for which he was paid, but he is no longer paid by the company. Dr. Hincapie-Echeverri is a speaker for Astellas Pharma, which does not manufacture trifluridine/tipiracil or bevacizumab, and he has no additional conflicts of interest.

An elderly gentleman was truly suffering, so his doctor decided to try something new.

“He’d had a number of cumulative side effects after almost two years of IV chemotherapy for his metastatic colon cancer,” said Anuj Patel, MD, a senior physician at Dana-Farber Cancer Institute in Boston, recalling his patient. “When we switched him to combination treatment with trifluridine/tipiracil and bevacizumab, he constantly remarked on how well he now felt. He described no side effects from this new regimen.”

Nearly a year after the US Food and Drug Administration (FDA) approved trifluridine/tipiracil combined with bevacizumab for refractory mCRC, the tremendous value of its results in practice are clear.

Trifluridine/tipiracil (Lonsurf) had been used to treat advanced gastric cancer, while bevacizumab had been therapeutic for a wider range of diseases, including cervical, brain, liver, kidney, gynecological and lung cancers. Used together for treating refractory mCRC, well-known initial findings about their effectiveness have been proven true over time.

“Patients taking both drugs can experience, on average, a life extension of three months,” said Richard M. Goldberg, MD, professor emeritus of the West Virginia University Cancer Institute and director of Fight Colorectal Cancer.
 

The History of the Combined Therapy’s Approval

The FDA originally approved trifluridine/tipiracil in September 2015 for use in patients with metastatic colorectal cancer. Patients eligible to take it had to have been treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor (VEGF) biological therapy, and—if RAS wild-type—an anti-epidermal growth factor receptor (EGFR) therapy, according to data published by the National Center for Biotechnology Information. The FDA’s August 2023 approval of the trifluridine/tipiracil and bevacizumab combination regimen is for patients meeting the same eligibility requirements.

Another drug, regorafenib, had already been approved by the FDA in September 2012 to treat mCRC. The drug has a wide range of potential side effects, however, including complications relating to the limbs.

“One of my patients tried regorafenib as his initial third- line treatment,” Dr. Goldberg said. “I checked in on him at his farm, and he was sitting in the barn near his tractor.

He had such severe hand-foot syndrome that he could barely walk.”

Trifluridine/tipiracil alone proved to be very helpful in this case. “We switched him to it, and he tolerated it well,” Dr. Goldberg continued. “He got his fields plowed and was on it for months before he passed away. We both felt it kept him going longer.”

A new research review confirms the regimen’s success, determining that trifluridine/tipiracil plus bevacizumab was associated with improved outcomes compared to therapy solely with trifluridine/tipiracil.
 

A True Practice Changer

Now that the regimen has been on the market for more than half a year, there are longer-term data available.

Patients on average live within the same timeframe as the patients in the SUNLIGHT study, and many feel physically better on the therapy. “The combination has very quickly shifted the standard of care,” Dr. Goldberg said.

The regimen can also provide significant psychological benefits to patients.

“As patients can maintain good performance status for longer with the combination, it increases the perception of quality of life,” said Jacobo Hincapie-Echeverri, MD, a GI and geriatric oncologist at Orlando Health Cancer Institute in Orlando, Florida.

The regimen is unique too, in that it can help doctors plan additional treatment strategies.

“This current approval, for the combination of trifluridine/tipiracil and bevacizumab, is practice-changing in that it helps clarify the sequence for later treatments for patients with mCRC,” said Dr. Patel, who is also clinical director of the Center for Esophageal and Gastric Cancer and assistant professor of medicine at Harvard Medical School, Boston. “Previously, it had been difficult to decide between trifluridine/tipiracil and regorafenib in this setting.”

The fact that the regimen has been shown to give time and improved quality of life to patients in ways regorafenib does not is clarifying. “Now, with the improved outcomes seen, I do think that trifluridine/tipiracil plus bevacizumab is the better option for most mCRC patients after IV chemotherapies,” Dr. Patel added.

When it comes to his specific experience with prescribing the regimen for his patients, Dr. Patel reported that it’s easier on his patients than other therapies.

“I find that it is generally well tolerated,” he elaborated. “As an oral agent, it is also usually somewhat easier to take (than other delivery methods of medication). These factors are critical for patients who have likely already had at least 2 or 3 prior lines of chemotherapy. I have had many patients with mCRC who, after disease progression on prior IV chemotherapy regimens, have had periods of meaningful disease control – often with fewer and manageable side effects.”

Dr. Goldberg mentioned another benefit.

“The nice thing about the combination of trifluridine/tipiracil and bevacizumab is that in terms of toxicity, there’s very little difference compared to the toxicity of trifluridine/tipiracil used alone.”
 

Are There Downsides to the Regimen?

The pros are obvious, but the regimen has some cons as well. Medically, patients should have a platelet count over 75,000/mm³ and absolute neutrophil count (ANC) over 1,500/mm³ prior to the start of each cycle, and their liver and renal function should be monitored.

Patients with metastatic colorectal cancer must be also carefully monitored for hematologic adverse events (AEs) , including chemotherapy-associated neutropenia. Biweekly treatments may reduce the risk of AEs as a whole, however, according to research.

The regimen is also expensive – an approximate cost of $8,191 for a 28-day supply. According to a new study, patients managing both AE expenses along with the cost of trifluridine/tipiracil-bevacizumab face a monthly bill of about $17,179.

Some very good news, though: 100% of Medicare drug plans cover trifluridine/tipiracil, with an average copay of $57-$292. Bevacizumab is also covered by Medicare, with a copay as low as $0-$25.

Private insurers do cover the drugs, depending on a patient’s specific plan. However, if a patient’s claim is denied, financial assistance for trifluridine/tipiracil through the drug’s manufacturers may be available for some patients, reducing prescriptions to a zero cost in some cases. Bevacizumab can be made available to patients who may not have health insurance at all, too. Patients can use a financial assistance tool through the drug’s manufacturer to receive up to $25,000 in yearly copay assistance.
 

What Does the Latest Research on the Regimen Indicate?

In May 2024, two abstracts were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) that explored expanded possible use of trifluridine/tipiracil plus bevacizumab as a treatment for metastatic colorectal cancer.

The first abstract studied trifluridine/tipiracil plus bevacizumab as upfront treatment for mCRC, adding capecitabine to the regimen.

“It’s a phase 1 study looking at dose findings for the three-drug combination, where the active drug is a chemotherapy agent classified as a fluoropyrimidine ... I would characterize this as a study combining two [fluoropyrimidines] with a single targeted therapy,” Dr. Goldberg said.

“Combining two fluoropyrimidines is an unusual approach, because they tend to have overlapping side effects, and the potential is there for either innate drug resistance to the class of drugs or that the combination of two agents that work by a similar mechanism of action could hasten the development of acquired drug resistance. There is apparently a signal that combining the two chemotherapy agents enhances each other’s activity in cell culture and animal models,” he added.

Ultimately, Dr. Goldberg said he thinks more evidence is needed to prove the regimen’s effectiveness.

“This is a very early study and really provides no information about its potential given that no response data was presented,” he added. “While this is an interesting idea, it is unclear if it will pan out until we see the data on the Phase II study in progress.”

The other abstract looked at the impact of colorectal liver metastases in patients with mCRC who in phase 3 of the SUNLIGHT trial received trifluridine/tipiracil with or without bevacizumab.

“There is not much that is novel here,” Dr. Goldberg said. “The retrospective analysis shows that trifluridine/tipiracil plus bevacizumab is better than trifluridine/tipiracil alone in the subset of patients with liver metastases, as it was shown to be in the entire patient population. While this is reassuring, it’s not unexpected, especially since the vast majority of people enrolled in the SUNLIGHT trial had liver metastases.”

The Bottom Line

In the future, the potential exists for trifluridine/tipiracil combined with bevacizumab to work in first-line and second-line patients.

“Seventy percent of colorectal cancer patients reach second line treatment right now, but only 30% reach third line treatment — either they become too sick to continue, or choose not to,” Dr. Goldberg said. “The hope is that using these drugs earlier can help more patients reach and prolong treatment.”

It’s also possible that the regimen can be applied in new ways.

“Further research combining trifluridine/tipiracil and bevacizumab with other targeted therapies could yield additional advances for refractory mCRC patients,” Dr. Hincapie-Echeverri said. “The survival benefit of this therapy reinforces the importance of continuing to develop new therapies to improve outcomes in the refractory mCRC setting.”

Dr. Patel’s patient felt lucky to simply live a longer life.

Because of the regimen, “his cancer remained stable for approximately 8 months. Upon its progression, he chose not to pursue any further chemotherapy. He instead expressed his gratitude at having been able to feel more like himself for nearly a year.”

Dr. Patel received research funding in 2017 from Taiho, which manufactures trifluridine/tipiracil. He receives no current funding from Taiho and has no additional conflicts of interest. Dr. Goldberg helped represent Taiho in a patent law dispute regarding Lonsurf for which he was paid, but he is no longer paid by the company. Dr. Hincapie-Echeverri is a speaker for Astellas Pharma, which does not manufacture trifluridine/tipiracil or bevacizumab, and he has no additional conflicts of interest.