CNS/Brain Cancer

Black and Hispanic patients under the age of 19 years are more likely to die from central nervous system (CNS) cancers than are non-Hispanic whites from the same age group, according to a study published in Scientific Reports.

While prior studies have shown the effects of racial/ethnic and socioeconomic risk factors on treatment outcomes in adult cancer populations, less is known about how these factors impact children with CNS cancers, explained study author Robert Fineberg, MD, of St. Anthony North Health Campus in Westminster, Colo., and colleagues.

The authors conducted their study to examine the effects of demographic and socioeconomic factors on survival in pediatric CNS cancers. Using data from the Surveillance, Epidemiology, and End Results database, the researchers identified 1,881 patients with CNS tumors, including both spinal and cranial neoplasms.

Data collection encompassed patient characteristics, socioeconomic parameters, tumor characteristics, treatment, and year of diagnosis. The primary outcomes were overall survival and disease stage at diagnosis.

Most patients were white (78.15%) and non-Hispanic (72.09%). The most common brain tumors were gliomas (n = 788), ependymomas (n = 418), and medulloblastomas (n = 393).

On multivariable analysis, the researchers found that black and Hispanic patients had worse survival, compared with white patients (hazard ratio, 1.39; P = .0014) and non-Hispanic patients (HR, 1.36; P = .0002).

After adjustment for socioeconomic parameters and treatment, the hazard ratios for both Hispanic (HR, 1.29; P = .0051) and black patients (HR, 1.29; P = .0206) slightly declined, but the differences remained significant.

On stratified analysis, poorer survival rates were observed for black and Hispanic patients with both metastatic and localized disease at diagnosis, compared with white non-Hispanic patients. However, after adjustment for mediating factors, the difference did not remain significant for black patients (P = .1026).

“Our findings on extent of disease at diagnosis demonstrated that neither black race nor Hispanic ethnicity increased the chance of metastatic disease at presentation when controlling for mediating variables,” the authors wrote. “These data suggest that racial and ethnic disparities appear to be partially explained by postdiagnosis mediating factors that may fall in the pathway between race/ethnicity and poorer survival.”

The researchers acknowledged that a key limitation of this study was the exclusion of insurance status because of incomplete access for some patients. As a result, potential associations between insurance and survival or extent of disease could not be determined.

“To better understand underlying causes that contribute to the disparity of outcomes in pediatric brain tumors, patient-level data should be utilized in future studies to investigate both biological factors and pre/postdiagnosis treatment gaps in the care of children diagnosed with CNS tumors in the hopes of improving outcomes,” the authors wrote.

In the meantime, collaboration among physicians could help improve outcomes for these patients, according to study author Adam Green, MD, of the University of Colorado at Denver in Aurora.

“[Clinicians] should establish good working relationships with pediatric oncology and neuro-oncology physicians in their community, and they should ask questions early of those teams when they have patients they’re concerned about,” Dr. Green said. “They can [ensure] that patients of minority race/ethnicity, nonprivate health insurance, and lower socioeconomic status have easy and timely access to appointments.”

This research was supported, in part, by grant funding from the National Institutes of Health. The authors reported having no conflicts of interest.

SOURCE: Fineberg R et al. Scientific Reports. 2020 Mar 12. doi: 10.1038/s41598-020-61237-2.

Black and Hispanic patients under the age of 19 years are more likely to die from central nervous system (CNS) cancers than are non-Hispanic whites from the same age group, according to a study published in Scientific Reports.

While prior studies have shown the effects of racial/ethnic and socioeconomic risk factors on treatment outcomes in adult cancer populations, less is known about how these factors impact children with CNS cancers, explained study author Robert Fineberg, MD, of St. Anthony North Health Campus in Westminster, Colo., and colleagues.

The authors conducted their study to examine the effects of demographic and socioeconomic factors on survival in pediatric CNS cancers. Using data from the Surveillance, Epidemiology, and End Results database, the researchers identified 1,881 patients with CNS tumors, including both spinal and cranial neoplasms.

Data collection encompassed patient characteristics, socioeconomic parameters, tumor characteristics, treatment, and year of diagnosis. The primary outcomes were overall survival and disease stage at diagnosis.

Most patients were white (78.15%) and non-Hispanic (72.09%). The most common brain tumors were gliomas (n = 788), ependymomas (n = 418), and medulloblastomas (n = 393).

On multivariable analysis, the researchers found that black and Hispanic patients had worse survival, compared with white patients (hazard ratio, 1.39; P = .0014) and non-Hispanic patients (HR, 1.36; P = .0002).

After adjustment for socioeconomic parameters and treatment, the hazard ratios for both Hispanic (HR, 1.29; P = .0051) and black patients (HR, 1.29; P = .0206) slightly declined, but the differences remained significant.

On stratified analysis, poorer survival rates were observed for black and Hispanic patients with both metastatic and localized disease at diagnosis, compared with white non-Hispanic patients. However, after adjustment for mediating factors, the difference did not remain significant for black patients (P = .1026).

“Our findings on extent of disease at diagnosis demonstrated that neither black race nor Hispanic ethnicity increased the chance of metastatic disease at presentation when controlling for mediating variables,” the authors wrote. “These data suggest that racial and ethnic disparities appear to be partially explained by postdiagnosis mediating factors that may fall in the pathway between race/ethnicity and poorer survival.”

The researchers acknowledged that a key limitation of this study was the exclusion of insurance status because of incomplete access for some patients. As a result, potential associations between insurance and survival or extent of disease could not be determined.

“To better understand underlying causes that contribute to the disparity of outcomes in pediatric brain tumors, patient-level data should be utilized in future studies to investigate both biological factors and pre/postdiagnosis treatment gaps in the care of children diagnosed with CNS tumors in the hopes of improving outcomes,” the authors wrote.

In the meantime, collaboration among physicians could help improve outcomes for these patients, according to study author Adam Green, MD, of the University of Colorado at Denver in Aurora.

“[Clinicians] should establish good working relationships with pediatric oncology and neuro-oncology physicians in their community, and they should ask questions early of those teams when they have patients they’re concerned about,” Dr. Green said. “They can [ensure] that patients of minority race/ethnicity, nonprivate health insurance, and lower socioeconomic status have easy and timely access to appointments.”

This research was supported, in part, by grant funding from the National Institutes of Health. The authors reported having no conflicts of interest.

SOURCE: Fineberg R et al. Scientific Reports. 2020 Mar 12. doi: 10.1038/s41598-020-61237-2.

Black and Hispanic patients under the age of 19 years are more likely to die from central nervous system (CNS) cancers than are non-Hispanic whites from the same age group, according to a study published in Scientific Reports.

While prior studies have shown the effects of racial/ethnic and socioeconomic risk factors on treatment outcomes in adult cancer populations, less is known about how these factors impact children with CNS cancers, explained study author Robert Fineberg, MD, of St. Anthony North Health Campus in Westminster, Colo., and colleagues.

The authors conducted their study to examine the effects of demographic and socioeconomic factors on survival in pediatric CNS cancers. Using data from the Surveillance, Epidemiology, and End Results database, the researchers identified 1,881 patients with CNS tumors, including both spinal and cranial neoplasms.

Data collection encompassed patient characteristics, socioeconomic parameters, tumor characteristics, treatment, and year of diagnosis. The primary outcomes were overall survival and disease stage at diagnosis.

Most patients were white (78.15%) and non-Hispanic (72.09%). The most common brain tumors were gliomas (n = 788), ependymomas (n = 418), and medulloblastomas (n = 393).

On multivariable analysis, the researchers found that black and Hispanic patients had worse survival, compared with white patients (hazard ratio, 1.39; P = .0014) and non-Hispanic patients (HR, 1.36; P = .0002).

After adjustment for socioeconomic parameters and treatment, the hazard ratios for both Hispanic (HR, 1.29; P = .0051) and black patients (HR, 1.29; P = .0206) slightly declined, but the differences remained significant.

On stratified analysis, poorer survival rates were observed for black and Hispanic patients with both metastatic and localized disease at diagnosis, compared with white non-Hispanic patients. However, after adjustment for mediating factors, the difference did not remain significant for black patients (P = .1026).

“Our findings on extent of disease at diagnosis demonstrated that neither black race nor Hispanic ethnicity increased the chance of metastatic disease at presentation when controlling for mediating variables,” the authors wrote. “These data suggest that racial and ethnic disparities appear to be partially explained by postdiagnosis mediating factors that may fall in the pathway between race/ethnicity and poorer survival.”

The researchers acknowledged that a key limitation of this study was the exclusion of insurance status because of incomplete access for some patients. As a result, potential associations between insurance and survival or extent of disease could not be determined.

“To better understand underlying causes that contribute to the disparity of outcomes in pediatric brain tumors, patient-level data should be utilized in future studies to investigate both biological factors and pre/postdiagnosis treatment gaps in the care of children diagnosed with CNS tumors in the hopes of improving outcomes,” the authors wrote.

In the meantime, collaboration among physicians could help improve outcomes for these patients, according to study author Adam Green, MD, of the University of Colorado at Denver in Aurora.

“[Clinicians] should establish good working relationships with pediatric oncology and neuro-oncology physicians in their community, and they should ask questions early of those teams when they have patients they’re concerned about,” Dr. Green said. “They can [ensure] that patients of minority race/ethnicity, nonprivate health insurance, and lower socioeconomic status have easy and timely access to appointments.”

This research was supported, in part, by grant funding from the National Institutes of Health. The authors reported having no conflicts of interest.

SOURCE: Fineberg R et al. Scientific Reports. 2020 Mar 12. doi: 10.1038/s41598-020-61237-2.

The biggest cancer research meeting of the year has been canceled as a reaction to the novel coronavirus (COVID-19) outbreak, which has also led to many other medical conferences being canceled or postponed.

The annual meeting of the American Association for Cancer Research (AACR) was due to take place April 24-29 in San Diego, California. More than 24,000 delegates from 80 countries and more than 500 exhibitors were expected to attend.

There are plans to reschedule it for later this year.

This has been a “difficult decision,” said the AACR board of directors, but “we believe that the decision to postpone the meeting is absolutely the correct one to safeguard our meeting participants from further potential exposure to the coronavirus.”

The board goes on to explain that “this evidence-based decision was made after a thorough review and discussion of all factors impacting the annual meeting, including the US government’s enforcement of restrictions on international travelers to enter the US; the imposition of travel restrictions issued by US government agencies, cancer centers, academic institutions, and pharmaceutical and biotech companies; and the counsel of infectious disease experts. It is clear that all of these elements significantly affect the ability of delegates, speakers, presenters of proffered papers, and exhibitors to participate fully in the annual meeting.”

Other cancer conferences that were planned for March and that have been canceled include the following:

• European Breast Cancer Conference (EBCC), Barcelona, Spain, which was to have taken place March 18-20. This conference has been postponed and will now take place September 30 to October 2 at the same venue. Abstracts that have been accepted for the initial conference will remain in the program, and organizers will reopen abstract submissions in May.
• National Comprehensive Cancer Network (NCCN), Orlando, Florida, was scheduled for March 19-22. This conference has been postponed. No new dates have been provided, but the society notes that “NCCN staff is working as quickly as possible to notify all conference registrants about the postponement and further information regarding the refund process.”
• European Association of Urology (EAU), Amsterdam, the Netherlands, at which there is always new research presented on prostate, kidney, and bladder cancer, was due to take place March 20-24. This conference has been postponed to July 2020.
• Society of Gynecologic Oncology (SGO), in Toronto, Canada, which was scheduled for March 28-31. SGO is “exploring alternatives for delivering the science and education.”

Overall, the move to cancel medical conferences over the next few months is a good idea, commented F. Perry Wilson, MD, MSCE, associate professor of medicine and director of Yale’s Program of Applied Translational Research, in a Medscape Medical News commentary.

“There’s a pretty straightforward case here,” he argued. “Medical professionals are at higher risk for exposure to coronavirus because we come into contact with lots and lots of patients. Gathering a large group of medical professionals in a single place increases the risk for exposure further. Factor in airplane flights to and from the conferences, and the chance that infection is spread is significant.”

This article first appeared on Medscape.com.

The biggest cancer research meeting of the year has been canceled as a reaction to the novel coronavirus (COVID-19) outbreak, which has also led to many other medical conferences being canceled or postponed.

The annual meeting of the American Association for Cancer Research (AACR) was due to take place April 24-29 in San Diego, California. More than 24,000 delegates from 80 countries and more than 500 exhibitors were expected to attend.

There are plans to reschedule it for later this year.

This has been a “difficult decision,” said the AACR board of directors, but “we believe that the decision to postpone the meeting is absolutely the correct one to safeguard our meeting participants from further potential exposure to the coronavirus.”

The board goes on to explain that “this evidence-based decision was made after a thorough review and discussion of all factors impacting the annual meeting, including the US government’s enforcement of restrictions on international travelers to enter the US; the imposition of travel restrictions issued by US government agencies, cancer centers, academic institutions, and pharmaceutical and biotech companies; and the counsel of infectious disease experts. It is clear that all of these elements significantly affect the ability of delegates, speakers, presenters of proffered papers, and exhibitors to participate fully in the annual meeting.”

Other cancer conferences that were planned for March and that have been canceled include the following:

• European Breast Cancer Conference (EBCC), Barcelona, Spain, which was to have taken place March 18-20. This conference has been postponed and will now take place September 30 to October 2 at the same venue. Abstracts that have been accepted for the initial conference will remain in the program, and organizers will reopen abstract submissions in May.
• National Comprehensive Cancer Network (NCCN), Orlando, Florida, was scheduled for March 19-22. This conference has been postponed. No new dates have been provided, but the society notes that “NCCN staff is working as quickly as possible to notify all conference registrants about the postponement and further information regarding the refund process.”
• European Association of Urology (EAU), Amsterdam, the Netherlands, at which there is always new research presented on prostate, kidney, and bladder cancer, was due to take place March 20-24. This conference has been postponed to July 2020.
• Society of Gynecologic Oncology (SGO), in Toronto, Canada, which was scheduled for March 28-31. SGO is “exploring alternatives for delivering the science and education.”

Overall, the move to cancel medical conferences over the next few months is a good idea, commented F. Perry Wilson, MD, MSCE, associate professor of medicine and director of Yale’s Program of Applied Translational Research, in a Medscape Medical News commentary.

“There’s a pretty straightforward case here,” he argued. “Medical professionals are at higher risk for exposure to coronavirus because we come into contact with lots and lots of patients. Gathering a large group of medical professionals in a single place increases the risk for exposure further. Factor in airplane flights to and from the conferences, and the chance that infection is spread is significant.”

This article first appeared on Medscape.com.

The biggest cancer research meeting of the year has been canceled as a reaction to the novel coronavirus (COVID-19) outbreak, which has also led to many other medical conferences being canceled or postponed.

The annual meeting of the American Association for Cancer Research (AACR) was due to take place April 24-29 in San Diego, California. More than 24,000 delegates from 80 countries and more than 500 exhibitors were expected to attend.

There are plans to reschedule it for later this year.

This has been a “difficult decision,” said the AACR board of directors, but “we believe that the decision to postpone the meeting is absolutely the correct one to safeguard our meeting participants from further potential exposure to the coronavirus.”

The board goes on to explain that “this evidence-based decision was made after a thorough review and discussion of all factors impacting the annual meeting, including the US government’s enforcement of restrictions on international travelers to enter the US; the imposition of travel restrictions issued by US government agencies, cancer centers, academic institutions, and pharmaceutical and biotech companies; and the counsel of infectious disease experts. It is clear that all of these elements significantly affect the ability of delegates, speakers, presenters of proffered papers, and exhibitors to participate fully in the annual meeting.”

Other cancer conferences that were planned for March and that have been canceled include the following:

• European Breast Cancer Conference (EBCC), Barcelona, Spain, which was to have taken place March 18-20. This conference has been postponed and will now take place September 30 to October 2 at the same venue. Abstracts that have been accepted for the initial conference will remain in the program, and organizers will reopen abstract submissions in May.
• National Comprehensive Cancer Network (NCCN), Orlando, Florida, was scheduled for March 19-22. This conference has been postponed. No new dates have been provided, but the society notes that “NCCN staff is working as quickly as possible to notify all conference registrants about the postponement and further information regarding the refund process.”
• European Association of Urology (EAU), Amsterdam, the Netherlands, at which there is always new research presented on prostate, kidney, and bladder cancer, was due to take place March 20-24. This conference has been postponed to July 2020.
• Society of Gynecologic Oncology (SGO), in Toronto, Canada, which was scheduled for March 28-31. SGO is “exploring alternatives for delivering the science and education.”

Overall, the move to cancel medical conferences over the next few months is a good idea, commented F. Perry Wilson, MD, MSCE, associate professor of medicine and director of Yale’s Program of Applied Translational Research, in a Medscape Medical News commentary.

“There’s a pretty straightforward case here,” he argued. “Medical professionals are at higher risk for exposure to coronavirus because we come into contact with lots and lots of patients. Gathering a large group of medical professionals in a single place increases the risk for exposure further. Factor in airplane flights to and from the conferences, and the chance that infection is spread is significant.”

This article first appeared on Medscape.com.

Intensive postoperative chemotherapy and focal radiation may improve event-free survival (EFS) among patients with atypical teratoid/rhabdoid tumors (AT/RT), results of the phase 3 ACNS0333 trial suggest.

Compared with historical therapies, the treatment protocol reduced the risk of EFS events by 57%, reported lead author Alyssa T. Reddy, MD, of the University of California San Francisco Benioff Children’s Hospital, and colleagues, who also noted that this is the first AT/RT-specific cooperative group trial.

“Case series and retrospective data suggested high-dose chemotherapy with peripheral blood stem cell (PBSC) rescue, early radiation therapy, and methotrexate had activity against AT/RT,” the investigators wrote in the Journal of Clinical Oncology.

Based on these findings, the investigators designed the ACNS0333 treatment protocol. Following surgery, all patients received two cycles of induction with methotrexate, vincristine, etoposide, cyclophosphamide, and cisplatin. They then underwent PBSC harvest.

Next, patients were divided into two groups based on age, disease location, and extent. Conformal radiotherapy was given between induction and consolidation to patients who were at least 6 months of age with tumor localized to the infratentorial brain or at least 12 months of age with tumor localized to the supratentorial brain. For younger patients or those with metastatic disease, radiotherapy was administered after consolidation was complete. Consolidation consisted of three cycles of thiotepa and carboplatin with PBSC support.

In addition to efficacy and safety analyses, molecular testing was performed on frozen tumor tissue and blood. This enabled a retrospective exploratory analysis of methylation profiles, which were used to subtype disease into three molecular classes: 2A/TYR, 2B/MYC, or 1/SHH-NOTCH.
 

Patient characteristics and results

The evaluable cohort included 65 patients, most of whom (83%) were younger than 36 months of age at baseline. About half of patients (51%) had infratentorial tumors, slightly fewer (40%) had supratentorial tumors, and 7.5% had a contiguous tumor in both locations. About one-third of patients (37%) had metastatic disease, and almost two-thirds (62%) had residual disease after surgery.

The median follow-up was 4.7 years. At 4 years, patients had an EFS rate of 35%. For patients aged 36 months or older, the 4-year EFS rate was higher still, at 48%.

These EFS rates compared favorably with the 6.4% EFS rate observed in a historical cohort of patients from the CCG-9921 trial (J Clin Oncol. 2005 Oct 20;23[30]:7621-31) and the POG-9233/4 trial (Neuro Oncol. 2014 Mar;16[3]:457-65). Overall, there was a 57% reduction in risk of EFS events in the ACNS0333 cohort compared with the historical controls (hazard ratio, 0.43; P less than .0005).

The 4-year overall survival rate was 43% for the entire ACNS0333 cohort and 57% for patients aged 36 months or older. Looking at molecular subtypes, patients with 1/SHH-NOTCH tumors had the best 4-year overall survival rate, at 56%, compared with 41% for 2A/TYR and 27% for 2B/MYC.

Adverse events were predominantly hematologic or infectious events reported during the induction and consolidation phases. Grade 4 or higher adverse events that occurred in at least 5% of patients were hypokalemia, hypotension, hypoxia, sepsis, ALT increase, and decreases in lymphocyte, neutrophil, platelet, and white blood cell counts.

Eight deaths were reported, four of which were associated with treatment. Causes of treatment-related death were sepsis after prolonged myelosuppression, respiratory failure from pulmonary fibrosis, and central nervous system necrosis (n = 2). One patient with central nervous system necrosis had viral encephalitis and sepsis at the time of death.

“ACNS0333 has shown that intensive multimodal therapy significantly improves survival for patients with AT/RT,” the investigators concluded. “However, further intensification using cytotoxic agents is likely not feasible. There are increasing data suggesting that AT/RT may be a good candidate for pathway-specific targeted therapies.”

The study was funded by the Children’s Oncology Group, the National Institutes of Health, the St. Baldrick’s Foundation, the Canadian Cancer Society, and the Children’s of Alabama Kaul Pediatric Research Institute. The investigators disclosed relationships with Novartis, AstraZeneca, and Merck Sharp & Dohme.

SOURCE: Reddy AT et al. J Clin Oncol. 2020 Feb 27. doi: 10.1200/JCO.19.01776.

Intensive postoperative chemotherapy and focal radiation may improve event-free survival (EFS) among patients with atypical teratoid/rhabdoid tumors (AT/RT), results of the phase 3 ACNS0333 trial suggest.

Compared with historical therapies, the treatment protocol reduced the risk of EFS events by 57%, reported lead author Alyssa T. Reddy, MD, of the University of California San Francisco Benioff Children’s Hospital, and colleagues, who also noted that this is the first AT/RT-specific cooperative group trial.

“Case series and retrospective data suggested high-dose chemotherapy with peripheral blood stem cell (PBSC) rescue, early radiation therapy, and methotrexate had activity against AT/RT,” the investigators wrote in the Journal of Clinical Oncology.

Based on these findings, the investigators designed the ACNS0333 treatment protocol. Following surgery, all patients received two cycles of induction with methotrexate, vincristine, etoposide, cyclophosphamide, and cisplatin. They then underwent PBSC harvest.

Next, patients were divided into two groups based on age, disease location, and extent. Conformal radiotherapy was given between induction and consolidation to patients who were at least 6 months of age with tumor localized to the infratentorial brain or at least 12 months of age with tumor localized to the supratentorial brain. For younger patients or those with metastatic disease, radiotherapy was administered after consolidation was complete. Consolidation consisted of three cycles of thiotepa and carboplatin with PBSC support.

In addition to efficacy and safety analyses, molecular testing was performed on frozen tumor tissue and blood. This enabled a retrospective exploratory analysis of methylation profiles, which were used to subtype disease into three molecular classes: 2A/TYR, 2B/MYC, or 1/SHH-NOTCH.
 

Patient characteristics and results

The evaluable cohort included 65 patients, most of whom (83%) were younger than 36 months of age at baseline. About half of patients (51%) had infratentorial tumors, slightly fewer (40%) had supratentorial tumors, and 7.5% had a contiguous tumor in both locations. About one-third of patients (37%) had metastatic disease, and almost two-thirds (62%) had residual disease after surgery.

The median follow-up was 4.7 years. At 4 years, patients had an EFS rate of 35%. For patients aged 36 months or older, the 4-year EFS rate was higher still, at 48%.

These EFS rates compared favorably with the 6.4% EFS rate observed in a historical cohort of patients from the CCG-9921 trial (J Clin Oncol. 2005 Oct 20;23[30]:7621-31) and the POG-9233/4 trial (Neuro Oncol. 2014 Mar;16[3]:457-65). Overall, there was a 57% reduction in risk of EFS events in the ACNS0333 cohort compared with the historical controls (hazard ratio, 0.43; P less than .0005).

The 4-year overall survival rate was 43% for the entire ACNS0333 cohort and 57% for patients aged 36 months or older. Looking at molecular subtypes, patients with 1/SHH-NOTCH tumors had the best 4-year overall survival rate, at 56%, compared with 41% for 2A/TYR and 27% for 2B/MYC.

Adverse events were predominantly hematologic or infectious events reported during the induction and consolidation phases. Grade 4 or higher adverse events that occurred in at least 5% of patients were hypokalemia, hypotension, hypoxia, sepsis, ALT increase, and decreases in lymphocyte, neutrophil, platelet, and white blood cell counts.

Eight deaths were reported, four of which were associated with treatment. Causes of treatment-related death were sepsis after prolonged myelosuppression, respiratory failure from pulmonary fibrosis, and central nervous system necrosis (n = 2). One patient with central nervous system necrosis had viral encephalitis and sepsis at the time of death.

“ACNS0333 has shown that intensive multimodal therapy significantly improves survival for patients with AT/RT,” the investigators concluded. “However, further intensification using cytotoxic agents is likely not feasible. There are increasing data suggesting that AT/RT may be a good candidate for pathway-specific targeted therapies.”

The study was funded by the Children’s Oncology Group, the National Institutes of Health, the St. Baldrick’s Foundation, the Canadian Cancer Society, and the Children’s of Alabama Kaul Pediatric Research Institute. The investigators disclosed relationships with Novartis, AstraZeneca, and Merck Sharp & Dohme.

SOURCE: Reddy AT et al. J Clin Oncol. 2020 Feb 27. doi: 10.1200/JCO.19.01776.

Intensive postoperative chemotherapy and focal radiation may improve event-free survival (EFS) among patients with atypical teratoid/rhabdoid tumors (AT/RT), results of the phase 3 ACNS0333 trial suggest.

Compared with historical therapies, the treatment protocol reduced the risk of EFS events by 57%, reported lead author Alyssa T. Reddy, MD, of the University of California San Francisco Benioff Children’s Hospital, and colleagues, who also noted that this is the first AT/RT-specific cooperative group trial.

“Case series and retrospective data suggested high-dose chemotherapy with peripheral blood stem cell (PBSC) rescue, early radiation therapy, and methotrexate had activity against AT/RT,” the investigators wrote in the Journal of Clinical Oncology.

Based on these findings, the investigators designed the ACNS0333 treatment protocol. Following surgery, all patients received two cycles of induction with methotrexate, vincristine, etoposide, cyclophosphamide, and cisplatin. They then underwent PBSC harvest.

Next, patients were divided into two groups based on age, disease location, and extent. Conformal radiotherapy was given between induction and consolidation to patients who were at least 6 months of age with tumor localized to the infratentorial brain or at least 12 months of age with tumor localized to the supratentorial brain. For younger patients or those with metastatic disease, radiotherapy was administered after consolidation was complete. Consolidation consisted of three cycles of thiotepa and carboplatin with PBSC support.

In addition to efficacy and safety analyses, molecular testing was performed on frozen tumor tissue and blood. This enabled a retrospective exploratory analysis of methylation profiles, which were used to subtype disease into three molecular classes: 2A/TYR, 2B/MYC, or 1/SHH-NOTCH.
 

Patient characteristics and results

The evaluable cohort included 65 patients, most of whom (83%) were younger than 36 months of age at baseline. About half of patients (51%) had infratentorial tumors, slightly fewer (40%) had supratentorial tumors, and 7.5% had a contiguous tumor in both locations. About one-third of patients (37%) had metastatic disease, and almost two-thirds (62%) had residual disease after surgery.

The median follow-up was 4.7 years. At 4 years, patients had an EFS rate of 35%. For patients aged 36 months or older, the 4-year EFS rate was higher still, at 48%.

These EFS rates compared favorably with the 6.4% EFS rate observed in a historical cohort of patients from the CCG-9921 trial (J Clin Oncol. 2005 Oct 20;23[30]:7621-31) and the POG-9233/4 trial (Neuro Oncol. 2014 Mar;16[3]:457-65). Overall, there was a 57% reduction in risk of EFS events in the ACNS0333 cohort compared with the historical controls (hazard ratio, 0.43; P less than .0005).

The 4-year overall survival rate was 43% for the entire ACNS0333 cohort and 57% for patients aged 36 months or older. Looking at molecular subtypes, patients with 1/SHH-NOTCH tumors had the best 4-year overall survival rate, at 56%, compared with 41% for 2A/TYR and 27% for 2B/MYC.

Adverse events were predominantly hematologic or infectious events reported during the induction and consolidation phases. Grade 4 or higher adverse events that occurred in at least 5% of patients were hypokalemia, hypotension, hypoxia, sepsis, ALT increase, and decreases in lymphocyte, neutrophil, platelet, and white blood cell counts.

Eight deaths were reported, four of which were associated with treatment. Causes of treatment-related death were sepsis after prolonged myelosuppression, respiratory failure from pulmonary fibrosis, and central nervous system necrosis (n = 2). One patient with central nervous system necrosis had viral encephalitis and sepsis at the time of death.

“ACNS0333 has shown that intensive multimodal therapy significantly improves survival for patients with AT/RT,” the investigators concluded. “However, further intensification using cytotoxic agents is likely not feasible. There are increasing data suggesting that AT/RT may be a good candidate for pathway-specific targeted therapies.”

The study was funded by the Children’s Oncology Group, the National Institutes of Health, the St. Baldrick’s Foundation, the Canadian Cancer Society, and the Children’s of Alabama Kaul Pediatric Research Institute. The investigators disclosed relationships with Novartis, AstraZeneca, and Merck Sharp & Dohme.

SOURCE: Reddy AT et al. J Clin Oncol. 2020 Feb 27. doi: 10.1200/JCO.19.01776.

Chlorotoxin (CLTX)-directed chimeric antigen receptor (CAR) T cells demonstrated activity against glioblastoma in a preclinical study and will soon be tested in a clinical trial.

“We sought to develop a CAR T cell using chlorotoxin peptide as the tumor-targeting domain,” wrote Dongrui Wang, a PhD candidate at City of Hope National Medical Center in Duarte, Calif., and colleagues. Their report is in Science Translational Medicine.

“CLTX has been established to bind broadly and specifically to glioblastoma and other neuroectodermal tumors while showing minimal cross-reactivity with nonmalignant cells,” the researchers noted.

The team evaluated CLTX binding capacity in 23 tumor samples from 15 glioblastoma patients, in patient-derived glioblastoma cell lines, and in orthotopic mouse xenograft models. These experiments showed that CLTX could bind to a high percentage of patient tumors as well as to most glioblastoma cells within a tumor.

In the design phase, the researchers engineered a peptide-bearing CAR, which overcame previous barriers of other glioblastoma-directed CARs, including antigen escape and tumor heterogeneity.

The team evaluated the antitumor activity of CLTX-CAR T cells in two orthotopic mouse xenograft models. Intracranial administration of CLTX-CAR T cells controlled tumor growth and extended survival in both models. All mice originally bearing PBT106-TS tumors became tumor-free and remained so for more than 170 days. However, only a subset of mice bearing PBT003-4-TS tumors experienced similar long-term tumor-free survival.

The researchers assessed potential off-target effects of CLTX-CAR T cells in normal human cells. The team observed limited binding of CLTX-CAR T cells to embryonic kidney cells, peripheral blood mononuclear cells, and neural progenitor cells, suggesting minimal off-target activity.

Further toxicity experiments demonstrated that, even at high doses, CLTX-CAR T cells were tolerated in mouse models, suggesting high potency for tumor cells and low risk of systemic toxicity.

Additional preclinical experiments elucidated mechanisms of CLTX-CAR T-cell function, namely the essential role of matrix metalloproteinase 2 expression for cell activation.

The researchers acknowledged that a key limitation of this study was the use of glioblastoma xenograft models, which may not fully represent tumor activity in glioblastoma patients.

Nevertheless, the researchers concluded that “CLTX-CAR T cells present a strategic combination of selective yet ubiquitous tumor targeting and are a candidate for clinical development as anti-glioblastoma immunotherapy.”

In fact, City of Hope is now screening patients for a clinical trial of CLTX-CAR T cells for the treatment of recurrent or progressive glioblastoma (NCT04214392).

The preclinical research was funded by the Ben and Catherine Ivy Foundation and the National Institutes of Health. Two authors disclosed financial affiliations with Mustang Bio.

SOURCE: Wang D et al. Sci Transl Med. 2020 Mar 4. doi: 10.1126/scitranslmed.aaw2672.

Chlorotoxin (CLTX)-directed chimeric antigen receptor (CAR) T cells demonstrated activity against glioblastoma in a preclinical study and will soon be tested in a clinical trial.

“We sought to develop a CAR T cell using chlorotoxin peptide as the tumor-targeting domain,” wrote Dongrui Wang, a PhD candidate at City of Hope National Medical Center in Duarte, Calif., and colleagues. Their report is in Science Translational Medicine.

“CLTX has been established to bind broadly and specifically to glioblastoma and other neuroectodermal tumors while showing minimal cross-reactivity with nonmalignant cells,” the researchers noted.

The team evaluated CLTX binding capacity in 23 tumor samples from 15 glioblastoma patients, in patient-derived glioblastoma cell lines, and in orthotopic mouse xenograft models. These experiments showed that CLTX could bind to a high percentage of patient tumors as well as to most glioblastoma cells within a tumor.

In the design phase, the researchers engineered a peptide-bearing CAR, which overcame previous barriers of other glioblastoma-directed CARs, including antigen escape and tumor heterogeneity.

The team evaluated the antitumor activity of CLTX-CAR T cells in two orthotopic mouse xenograft models. Intracranial administration of CLTX-CAR T cells controlled tumor growth and extended survival in both models. All mice originally bearing PBT106-TS tumors became tumor-free and remained so for more than 170 days. However, only a subset of mice bearing PBT003-4-TS tumors experienced similar long-term tumor-free survival.

The researchers assessed potential off-target effects of CLTX-CAR T cells in normal human cells. The team observed limited binding of CLTX-CAR T cells to embryonic kidney cells, peripheral blood mononuclear cells, and neural progenitor cells, suggesting minimal off-target activity.

Further toxicity experiments demonstrated that, even at high doses, CLTX-CAR T cells were tolerated in mouse models, suggesting high potency for tumor cells and low risk of systemic toxicity.

Additional preclinical experiments elucidated mechanisms of CLTX-CAR T-cell function, namely the essential role of matrix metalloproteinase 2 expression for cell activation.

The researchers acknowledged that a key limitation of this study was the use of glioblastoma xenograft models, which may not fully represent tumor activity in glioblastoma patients.

Nevertheless, the researchers concluded that “CLTX-CAR T cells present a strategic combination of selective yet ubiquitous tumor targeting and are a candidate for clinical development as anti-glioblastoma immunotherapy.”

In fact, City of Hope is now screening patients for a clinical trial of CLTX-CAR T cells for the treatment of recurrent or progressive glioblastoma (NCT04214392).

The preclinical research was funded by the Ben and Catherine Ivy Foundation and the National Institutes of Health. Two authors disclosed financial affiliations with Mustang Bio.

SOURCE: Wang D et al. Sci Transl Med. 2020 Mar 4. doi: 10.1126/scitranslmed.aaw2672.

Chlorotoxin (CLTX)-directed chimeric antigen receptor (CAR) T cells demonstrated activity against glioblastoma in a preclinical study and will soon be tested in a clinical trial.

“We sought to develop a CAR T cell using chlorotoxin peptide as the tumor-targeting domain,” wrote Dongrui Wang, a PhD candidate at City of Hope National Medical Center in Duarte, Calif., and colleagues. Their report is in Science Translational Medicine.

“CLTX has been established to bind broadly and specifically to glioblastoma and other neuroectodermal tumors while showing minimal cross-reactivity with nonmalignant cells,” the researchers noted.

The team evaluated CLTX binding capacity in 23 tumor samples from 15 glioblastoma patients, in patient-derived glioblastoma cell lines, and in orthotopic mouse xenograft models. These experiments showed that CLTX could bind to a high percentage of patient tumors as well as to most glioblastoma cells within a tumor.

In the design phase, the researchers engineered a peptide-bearing CAR, which overcame previous barriers of other glioblastoma-directed CARs, including antigen escape and tumor heterogeneity.

The team evaluated the antitumor activity of CLTX-CAR T cells in two orthotopic mouse xenograft models. Intracranial administration of CLTX-CAR T cells controlled tumor growth and extended survival in both models. All mice originally bearing PBT106-TS tumors became tumor-free and remained so for more than 170 days. However, only a subset of mice bearing PBT003-4-TS tumors experienced similar long-term tumor-free survival.

The researchers assessed potential off-target effects of CLTX-CAR T cells in normal human cells. The team observed limited binding of CLTX-CAR T cells to embryonic kidney cells, peripheral blood mononuclear cells, and neural progenitor cells, suggesting minimal off-target activity.

Further toxicity experiments demonstrated that, even at high doses, CLTX-CAR T cells were tolerated in mouse models, suggesting high potency for tumor cells and low risk of systemic toxicity.

Additional preclinical experiments elucidated mechanisms of CLTX-CAR T-cell function, namely the essential role of matrix metalloproteinase 2 expression for cell activation.

The researchers acknowledged that a key limitation of this study was the use of glioblastoma xenograft models, which may not fully represent tumor activity in glioblastoma patients.

Nevertheless, the researchers concluded that “CLTX-CAR T cells present a strategic combination of selective yet ubiquitous tumor targeting and are a candidate for clinical development as anti-glioblastoma immunotherapy.”

In fact, City of Hope is now screening patients for a clinical trial of CLTX-CAR T cells for the treatment of recurrent or progressive glioblastoma (NCT04214392).

The preclinical research was funded by the Ben and Catherine Ivy Foundation and the National Institutes of Health. Two authors disclosed financial affiliations with Mustang Bio.

SOURCE: Wang D et al. Sci Transl Med. 2020 Mar 4. doi: 10.1126/scitranslmed.aaw2672.

Adolescent and young adult cancer survivors have higher standardized mortality ratios (SMRs) than the general population but lower ratios than childhood cancer survivors, according to data from the Childhood Cancer Survivor Study.

Xavier_S/Thinkstock

At a median follow-up of 21 years, the SMR for all-cause mortality was 5.9 among survivors aged 15-20 years and 6.2 among diagnosis-matched children under 15 years, compared with expected rates at the same ages in the general population. For health-related causes – excluding primary cancer recurrence or progression but including late effects of cancer therapy – the SMRs were 4.8 in the older group and 6.8 in the younger group.

Eugene Suh, MD, of Loyola University Chicago Medical Center, Maywood, Ill., and colleagues reported these results in Lancet Oncology.

The difference between the older and younger survivors (n = 5,804 in each group) was most evident at least 20 years after cancer diagnosis, the authors noted.

For both groups, but more so for childhood cancer survivors, the risk of developing any chronic health condition and any grade 3-5 health condition was greater than for siblings of the same age who did not have cancer (hazard ratios, 4.2 for adolescents/young adults and 5.6 for childhood survivors). The same was true for grade 3-5 cardiac conditions (HRs, 4.3 and 5.6, respectively), endocrine conditions (HRs, 3.9 and 6.4, respectively), and musculoskeletal conditions (HRs, 6.5 and 8.0, respectively).

These findings, which confirm those of previous studies suggesting that younger children might be more vulnerable to the adverse effects of cancer treatment, “underscore that focused efforts are needed to ensure early-adolescent and young adult cancer survivors are receiving recommended risk-based care, with a focus on high-risk cancer screening, to reduce morbidity and premature mortality,” the researchers concluded, noting that “studies to date indicate that adherence to such high-risk screening is poor.”

In a related editorial, Päivi Lähteenmäki, MD, PhD, of University of Turku (Finland) and Turku University Hospital, wrote that these findings warrant long-term follow-up of adolescent and young adult cancer survivors. She also argued that the results “might not be fully generalizable to patients treated today who might be on different treatment regimens to those treated in previous decades” and that “[m]ore prospectively collected objective data focusing on survivors ... are needed.”

Accurate characterization of patients at high risk who would benefit from a tailored screening program is most important, and identifying underlying genetic or molecular factors that confer higher risk for late sequelae would be useful for “planning approaches to survivorship,” Dr. Lähteenmäki added.

This study was funded by the National Cancer Institute and American Lebanese-Syrian Associated Charities. Dr. Suh and Dr. Lähteenmäki reported having no competing interests.

[email protected]

SOURCES: Suh E et al. Lancet Oncology. 2020 Feb 14. doi: 10.1016/S1470-2045(19)30800-9;Lähteenmäki P. Lancet Oncol. 2020 Feb 14. doi: 10.106/S1470-2045(19)30858-7.

Adolescent and young adult cancer survivors have higher standardized mortality ratios (SMRs) than the general population but lower ratios than childhood cancer survivors, according to data from the Childhood Cancer Survivor Study.

Xavier_S/Thinkstock

At a median follow-up of 21 years, the SMR for all-cause mortality was 5.9 among survivors aged 15-20 years and 6.2 among diagnosis-matched children under 15 years, compared with expected rates at the same ages in the general population. For health-related causes – excluding primary cancer recurrence or progression but including late effects of cancer therapy – the SMRs were 4.8 in the older group and 6.8 in the younger group.

Eugene Suh, MD, of Loyola University Chicago Medical Center, Maywood, Ill., and colleagues reported these results in Lancet Oncology.

The difference between the older and younger survivors (n = 5,804 in each group) was most evident at least 20 years after cancer diagnosis, the authors noted.

For both groups, but more so for childhood cancer survivors, the risk of developing any chronic health condition and any grade 3-5 health condition was greater than for siblings of the same age who did not have cancer (hazard ratios, 4.2 for adolescents/young adults and 5.6 for childhood survivors). The same was true for grade 3-5 cardiac conditions (HRs, 4.3 and 5.6, respectively), endocrine conditions (HRs, 3.9 and 6.4, respectively), and musculoskeletal conditions (HRs, 6.5 and 8.0, respectively).

These findings, which confirm those of previous studies suggesting that younger children might be more vulnerable to the adverse effects of cancer treatment, “underscore that focused efforts are needed to ensure early-adolescent and young adult cancer survivors are receiving recommended risk-based care, with a focus on high-risk cancer screening, to reduce morbidity and premature mortality,” the researchers concluded, noting that “studies to date indicate that adherence to such high-risk screening is poor.”

In a related editorial, Päivi Lähteenmäki, MD, PhD, of University of Turku (Finland) and Turku University Hospital, wrote that these findings warrant long-term follow-up of adolescent and young adult cancer survivors. She also argued that the results “might not be fully generalizable to patients treated today who might be on different treatment regimens to those treated in previous decades” and that “[m]ore prospectively collected objective data focusing on survivors ... are needed.”

Accurate characterization of patients at high risk who would benefit from a tailored screening program is most important, and identifying underlying genetic or molecular factors that confer higher risk for late sequelae would be useful for “planning approaches to survivorship,” Dr. Lähteenmäki added.

This study was funded by the National Cancer Institute and American Lebanese-Syrian Associated Charities. Dr. Suh and Dr. Lähteenmäki reported having no competing interests.

[email protected]

SOURCES: Suh E et al. Lancet Oncology. 2020 Feb 14. doi: 10.1016/S1470-2045(19)30800-9;Lähteenmäki P. Lancet Oncol. 2020 Feb 14. doi: 10.106/S1470-2045(19)30858-7.

Adolescent and young adult cancer survivors have higher standardized mortality ratios (SMRs) than the general population but lower ratios than childhood cancer survivors, according to data from the Childhood Cancer Survivor Study.

Xavier_S/Thinkstock

At a median follow-up of 21 years, the SMR for all-cause mortality was 5.9 among survivors aged 15-20 years and 6.2 among diagnosis-matched children under 15 years, compared with expected rates at the same ages in the general population. For health-related causes – excluding primary cancer recurrence or progression but including late effects of cancer therapy – the SMRs were 4.8 in the older group and 6.8 in the younger group.

Eugene Suh, MD, of Loyola University Chicago Medical Center, Maywood, Ill., and colleagues reported these results in Lancet Oncology.

The difference between the older and younger survivors (n = 5,804 in each group) was most evident at least 20 years after cancer diagnosis, the authors noted.

For both groups, but more so for childhood cancer survivors, the risk of developing any chronic health condition and any grade 3-5 health condition was greater than for siblings of the same age who did not have cancer (hazard ratios, 4.2 for adolescents/young adults and 5.6 for childhood survivors). The same was true for grade 3-5 cardiac conditions (HRs, 4.3 and 5.6, respectively), endocrine conditions (HRs, 3.9 and 6.4, respectively), and musculoskeletal conditions (HRs, 6.5 and 8.0, respectively).

These findings, which confirm those of previous studies suggesting that younger children might be more vulnerable to the adverse effects of cancer treatment, “underscore that focused efforts are needed to ensure early-adolescent and young adult cancer survivors are receiving recommended risk-based care, with a focus on high-risk cancer screening, to reduce morbidity and premature mortality,” the researchers concluded, noting that “studies to date indicate that adherence to such high-risk screening is poor.”

In a related editorial, Päivi Lähteenmäki, MD, PhD, of University of Turku (Finland) and Turku University Hospital, wrote that these findings warrant long-term follow-up of adolescent and young adult cancer survivors. She also argued that the results “might not be fully generalizable to patients treated today who might be on different treatment regimens to those treated in previous decades” and that “[m]ore prospectively collected objective data focusing on survivors ... are needed.”

Accurate characterization of patients at high risk who would benefit from a tailored screening program is most important, and identifying underlying genetic or molecular factors that confer higher risk for late sequelae would be useful for “planning approaches to survivorship,” Dr. Lähteenmäki added.

This study was funded by the National Cancer Institute and American Lebanese-Syrian Associated Charities. Dr. Suh and Dr. Lähteenmäki reported having no competing interests.

[email protected]

SOURCES: Suh E et al. Lancet Oncology. 2020 Feb 14. doi: 10.1016/S1470-2045(19)30800-9;Lähteenmäki P. Lancet Oncol. 2020 Feb 14. doi: 10.106/S1470-2045(19)30858-7.

There is not enough evidence to suggest that radiofrequency radiation (RFR) associated with cell phone use causes cancer, according to a review by the Food and Drug Administration.

The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.

The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.

The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.

The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.

Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”

The full review is available on the FDA website.

[email protected]

There is not enough evidence to suggest that radiofrequency radiation (RFR) associated with cell phone use causes cancer, according to a review by the Food and Drug Administration.

The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.

The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.

The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.

The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.

Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”

The full review is available on the FDA website.

[email protected]

There is not enough evidence to suggest that radiofrequency radiation (RFR) associated with cell phone use causes cancer, according to a review by the Food and Drug Administration.

The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.

The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.

The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.

The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.

Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”

The full review is available on the FDA website.

[email protected]

Glioma treatment goals traditionally have focused on tumor shrinkage or prolonging survival, but it’s time for those endpoints to be supplemented by clinical outcomes that are meaningful to the patient, according to a recently published report from a neuro-oncology working group.

The group, which includes representatives of previous oncology working groups, the Food and Drug Administration, and observers from the European Medicines Agency, has established a core set of symptoms and functional points that they say could be used in clinical trials and clinical care for patients with high-grade gliomas.

“Patients want to live longer, but they also want to continue to function as well as possible for as long as possible,” said Terri S. Armstrong, PhD, of the National Cancer Institute (NCI), and coauthors in a report that sums up the work to date of the Fast Track COA Group.

That work, while specific to gliomas, echoes results from broader initiatives that seek to standardize patient-reported outcomes in oncology trials, Dr. Armstrong and coauthors wrote. The report was published in the Lancet Oncology.

The core set of symptom constructs and functional issues identified by the work group are represented already in patient-reported outcome measures, according to the authors.

The symptoms worth measuring fall into five categories, including pain, difficulty communicating, perceived cognition, seizures, and symptomatic adverse events. The functional issues were divided into two categories, physical functioning, including weakness or walking, and role functioning, which they defined as the ability to work or participate in social or leisure activities.

Some of those outcomes can be challenging or cumbersome to track, Dr. Armstrong and coauthors said.

Pain has “many dimensions“ and is important to track, the group wrote. Likewise, patients’ concerns related to language function also are important, but are very “noisy“ as a variable and can be specific to tumor location.

Collecting data on seizure frequency and severity is important yet complicated, because of the variability in seizures and considerable difference between focal and generalized seizures. Assessment of cognitive functioning can be lengthy and burdensome to patients.

Adverse events of relevance will vary, depending on the drug used, its mechanism of action, and available data, though some allowance needs to be made for the possibility of “overlap“ with disease-related symptoms, the report said.

Physical functioning, including walking and weakness, should be evaluated. It also would be useful to distinguish the duration of time that patients have deficits in physical functioning in the later stages of their disease progression, authors said.

Role and social functioning should be assessed in most patients with high-grade gliomas, who will have symptoms and deficits that prevent returning to a job. “Patients might spend a substantial portion of their lives feeling ill, unable to do usual activities, or meet occupational, social, financial, and family obligations,” said Dr. Armstrong and coauthors in the report.

The scales and tools used to measure symptoms and functional concerns need to be those that best fit a particular clinical trial or clinical practice scenario. Several instruments that would be appropriate are discussed in the report, including the NCI Patient-Reported Outcome of the Common Toxicity Criteria Adverse Events (NCI PRO-CTCAE) and symptom and function scales or items in the Patient-Reported Outcomes Measurement System (PROMIS).

The next steps, according to report authors, will be to figure out how the symptom and function constructs align with typical primary endpoints of glioma clinical trials, such as time to recurrence or survival.

“Strategies for introducing these constructs to clinical trial cooperative groups and sponsors will be necessary,” they concluded.

Dr. Armstrong reported employment as a senior investigator and deputy chief of the neuro-oncology branch of the Center for Cancer Research at the NCI. His coauthors reported disclosures related to several companies and interests, including AbbVie, AstraZeneca, Bristol-Myers Squibb, Genentech, Merck, Taiho, and Tocagen.

SOURCE: Armstrong TS et al. Lancet Oncol. 2020;21(2):e97-103.

Glioma treatment goals traditionally have focused on tumor shrinkage or prolonging survival, but it’s time for those endpoints to be supplemented by clinical outcomes that are meaningful to the patient, according to a recently published report from a neuro-oncology working group.

The group, which includes representatives of previous oncology working groups, the Food and Drug Administration, and observers from the European Medicines Agency, has established a core set of symptoms and functional points that they say could be used in clinical trials and clinical care for patients with high-grade gliomas.

“Patients want to live longer, but they also want to continue to function as well as possible for as long as possible,” said Terri S. Armstrong, PhD, of the National Cancer Institute (NCI), and coauthors in a report that sums up the work to date of the Fast Track COA Group.

That work, while specific to gliomas, echoes results from broader initiatives that seek to standardize patient-reported outcomes in oncology trials, Dr. Armstrong and coauthors wrote. The report was published in the Lancet Oncology.

The core set of symptom constructs and functional issues identified by the work group are represented already in patient-reported outcome measures, according to the authors.

The symptoms worth measuring fall into five categories, including pain, difficulty communicating, perceived cognition, seizures, and symptomatic adverse events. The functional issues were divided into two categories, physical functioning, including weakness or walking, and role functioning, which they defined as the ability to work or participate in social or leisure activities.

Some of those outcomes can be challenging or cumbersome to track, Dr. Armstrong and coauthors said.

Pain has “many dimensions“ and is important to track, the group wrote. Likewise, patients’ concerns related to language function also are important, but are very “noisy“ as a variable and can be specific to tumor location.

Collecting data on seizure frequency and severity is important yet complicated, because of the variability in seizures and considerable difference between focal and generalized seizures. Assessment of cognitive functioning can be lengthy and burdensome to patients.

Adverse events of relevance will vary, depending on the drug used, its mechanism of action, and available data, though some allowance needs to be made for the possibility of “overlap“ with disease-related symptoms, the report said.

Physical functioning, including walking and weakness, should be evaluated. It also would be useful to distinguish the duration of time that patients have deficits in physical functioning in the later stages of their disease progression, authors said.

Role and social functioning should be assessed in most patients with high-grade gliomas, who will have symptoms and deficits that prevent returning to a job. “Patients might spend a substantial portion of their lives feeling ill, unable to do usual activities, or meet occupational, social, financial, and family obligations,” said Dr. Armstrong and coauthors in the report.

The scales and tools used to measure symptoms and functional concerns need to be those that best fit a particular clinical trial or clinical practice scenario. Several instruments that would be appropriate are discussed in the report, including the NCI Patient-Reported Outcome of the Common Toxicity Criteria Adverse Events (NCI PRO-CTCAE) and symptom and function scales or items in the Patient-Reported Outcomes Measurement System (PROMIS).

The next steps, according to report authors, will be to figure out how the symptom and function constructs align with typical primary endpoints of glioma clinical trials, such as time to recurrence or survival.

“Strategies for introducing these constructs to clinical trial cooperative groups and sponsors will be necessary,” they concluded.

Dr. Armstrong reported employment as a senior investigator and deputy chief of the neuro-oncology branch of the Center for Cancer Research at the NCI. His coauthors reported disclosures related to several companies and interests, including AbbVie, AstraZeneca, Bristol-Myers Squibb, Genentech, Merck, Taiho, and Tocagen.

SOURCE: Armstrong TS et al. Lancet Oncol. 2020;21(2):e97-103.

Glioma treatment goals traditionally have focused on tumor shrinkage or prolonging survival, but it’s time for those endpoints to be supplemented by clinical outcomes that are meaningful to the patient, according to a recently published report from a neuro-oncology working group.

The group, which includes representatives of previous oncology working groups, the Food and Drug Administration, and observers from the European Medicines Agency, has established a core set of symptoms and functional points that they say could be used in clinical trials and clinical care for patients with high-grade gliomas.

“Patients want to live longer, but they also want to continue to function as well as possible for as long as possible,” said Terri S. Armstrong, PhD, of the National Cancer Institute (NCI), and coauthors in a report that sums up the work to date of the Fast Track COA Group.

That work, while specific to gliomas, echoes results from broader initiatives that seek to standardize patient-reported outcomes in oncology trials, Dr. Armstrong and coauthors wrote. The report was published in the Lancet Oncology.

The core set of symptom constructs and functional issues identified by the work group are represented already in patient-reported outcome measures, according to the authors.

The symptoms worth measuring fall into five categories, including pain, difficulty communicating, perceived cognition, seizures, and symptomatic adverse events. The functional issues were divided into two categories, physical functioning, including weakness or walking, and role functioning, which they defined as the ability to work or participate in social or leisure activities.

Some of those outcomes can be challenging or cumbersome to track, Dr. Armstrong and coauthors said.

Pain has “many dimensions“ and is important to track, the group wrote. Likewise, patients’ concerns related to language function also are important, but are very “noisy“ as a variable and can be specific to tumor location.

Collecting data on seizure frequency and severity is important yet complicated, because of the variability in seizures and considerable difference between focal and generalized seizures. Assessment of cognitive functioning can be lengthy and burdensome to patients.

Adverse events of relevance will vary, depending on the drug used, its mechanism of action, and available data, though some allowance needs to be made for the possibility of “overlap“ with disease-related symptoms, the report said.

Physical functioning, including walking and weakness, should be evaluated. It also would be useful to distinguish the duration of time that patients have deficits in physical functioning in the later stages of their disease progression, authors said.

Role and social functioning should be assessed in most patients with high-grade gliomas, who will have symptoms and deficits that prevent returning to a job. “Patients might spend a substantial portion of their lives feeling ill, unable to do usual activities, or meet occupational, social, financial, and family obligations,” said Dr. Armstrong and coauthors in the report.

The scales and tools used to measure symptoms and functional concerns need to be those that best fit a particular clinical trial or clinical practice scenario. Several instruments that would be appropriate are discussed in the report, including the NCI Patient-Reported Outcome of the Common Toxicity Criteria Adverse Events (NCI PRO-CTCAE) and symptom and function scales or items in the Patient-Reported Outcomes Measurement System (PROMIS).

The next steps, according to report authors, will be to figure out how the symptom and function constructs align with typical primary endpoints of glioma clinical trials, such as time to recurrence or survival.

“Strategies for introducing these constructs to clinical trial cooperative groups and sponsors will be necessary,” they concluded.

Dr. Armstrong reported employment as a senior investigator and deputy chief of the neuro-oncology branch of the Center for Cancer Research at the NCI. His coauthors reported disclosures related to several companies and interests, including AbbVie, AstraZeneca, Bristol-Myers Squibb, Genentech, Merck, Taiho, and Tocagen.

SOURCE: Armstrong TS et al. Lancet Oncol. 2020;21(2):e97-103.

SAN DIEGO – When Dawn Lemanne, MD, MPH, meets with cancer patients and their families, the question invariably comes up: “What should I eat?”

“The answer always is, ‘It depends,’” Dr. Lemanne, an oncologist who founded Oregon Integrative Oncology in Ashland, said at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine. “The answers are not the same for each of these patients.”

According to Dr. Lemanne, targeted nutrition is evolving as a key component of cancer care. One of the goals of this approach is to decrease mTOR signaling. Normally, mTOR signaling promotes cell proliferation and metabolism; aberrant mTOR signaling can contribute to cancer initiation and progression.

“When mTOR speaks it says, ‘grow,’” said Dr. Lemanne, who is also an assistant professor of clinical medicine at the Andrew Weil Center for Integrative Medicine at the University of Arizona in Tucson. This message is meant to be heard by normal tissues, to stimulate normal tissue proliferation, such as in growing children or when a wound needs to be healed.

“However, cancer cells can hear and respond to mTOR’s message,” she said. “Normal cells may listen to mTOR’s ‘grow’ message or not, depending on the task they perform. Once we reach adulthood, we all likely have some precancerous or cancerous cells around, but they’re usually dormant. That’s why once you’re an adult, however, you don’t want too much mTOR signaling, because that might stimulate growth of things you definitely don’t want to grow.”

Having excessive levels of the growth hormone insulin-like growth factor-1 (IGF-1) also appears to play a role in cancer risk. Researchers studying members of a South American clan with Laron dwarfism – an inherited IGF-1 deficiency – found that besides being very short, affected members of this family rarely develop cancer (Cells. 2019;8[6]:596). “They also don’t get diabetes,” Dr. Lemanne said. “What we see in those with Laron dwarfism is that mTOR signaling is missing.”

She went on to note that studying type 2 diabetes gives physicians “a clue as to what dietary measures we might offer our patients in terms of decreasing their risk of dying from cancer or getting cancer.” The most common types of cancer are indeed more common in patients with type 2 diabetes. In addition, once someone with type 2 diabetes is diagnosed with cancer, their prognosis is poorer, compared with a cancer patient without diabetes.

“Metformin is often prescribed to patients with type 2 diabetes because it helps keep blood sugar low,” she said. “What’s fascinating is that diabetics on metformin develop cancer less frequently than diabetics not taking this drug. And also interesting, those diabetics who do develop cancer seem to do better if they’re on metformin before and after diagnosis.”

On the other hand, exogenous insulin therapy given to people with type 2 diabetes doubles the risk of cancer. Consistent with this is the two-decades-old finding that an elevated fasting insulin level also is associated with a poor breast cancer prognosis (J Clin Oncol. 2002 Jan 1;20[1]:42-51). “It’s really important to understand that, in a person destined to become a type 2 diabetic, the level of fasting insulin rises long before fasting glucose becomes abnormally high,” Dr. Lemanne explained. “A normal fasting glucose doesn’t let you off the hook in terms of checking your patient for insulin resistance.

“We will miss diagnosing many patients with dangerous insulin resistance and prediabetes if we don’t check the fasting glucose and the fasting insulin levels together. If the fasting insulin level is high, it’s important to limit carbohydrate intake enough to bring it down permanently, even when the fasting glucose is normal, or the patient is likely at increased risk for developing cancer.”

Two large, prospective randomized trials have examined breast cancer and diet: the Women’s Intervention Study (WINS) and the Women’s Health Eating and Living Study (WHEL). Patients in both trials had early stage breast cancer and were put on low-fat diets. In the end, there was a weak to negligible connection between breast cancer survival and dietary fat restriction. “That kind of shook up the oncology world,” Dr. Lemanne said, “because before these two studies, everyone ‘knew’ that dietary fat was related to breast cancer risk. These studies showed that wasn’t the case at all.”

According to Dr. Lemanne, unexpectedly, moderate carbohydrate restriction has been associated with lower risk of breast cancer recurrence in patients with postmenopausal hormone-receptor expressing breast cancer. Researchers at the University of California, San Diego, conducted a subanalysis of 265 postmenopausal patients with estrogen receptor positive breast cancer from the WHEL cohort (Cancer Epidemiol Biomarkers Prev. 2014 23[7]:1273-9). The recurrence risk was halved in those who cut their carbohydrate intake after diagnosis. The amount of decrease was modest, only 27 grams per day – the equivalent of one banana. “That is on par with a lot of our drugs, and maybe a little bit better,” she said. The effect was strongest if the breast tumor expressed IGF-1 receptor. Dr. Lemanne pointed out that decreasing dietary carbohydrate load was not the only treatment. These patients also had appropriate conventional cancer treatments, including surgery, radiation, and chemotherapy. “If we cut just some of the daily carb load in these patients, they might have a better cancer prognosis,” she said.

Overweight or obese patients with colon cancer also may benefit from moderate carbohydrate restriction. The CALGB 89803 study assessed 1,011 subjects with stage III colon cancer. It found that the subjects in the highest quintile of daily glycemic load and total carbohydrate intake had an increased risk of cancer recurrence and mortality (hazard ratio, 2.26; J Nat Cancer Inst. 2012;104[22]:1702-11). “This is pretty strong evidence that glycemic load and total carbohydrate intake play a role in colon cancer recurrence, but there’s a caveat here,” she said. “The effect was seen only in patients who were overweight or obese.” There was no association between carbohydrate intake and colon cancer recurrence in the absence of overweight or obesity.

Based on existing evidence, she said, clinicians could recommend restricting carb intake to 100 grams per day for patients with postmenopausal hormone-receptor expressing breast cancer and for overweight or obese patients with colon cancer.

“That’s pretty modest; that’s 400 calories of carbohydrates per day,” Dr. Lemanne said. “I tell patients that they can have fruit, starchy vegetables, and even very small amounts of healthy whole grains, although I’m not a fan of grains due to the heavy carbohydrate load. All those things are OK. We’re not talking about jelly beans and white sugar.

“I also have them measure their fasting glucose each day, because different people have different blood glucose responses to the same food.” The goals she aims for with many of her patients are a fasting morning glucose between 79 and 83 mg/dL consistently, an HbA1c of 5.4 or less, and a BMI of 24.9 kg/m² or less. “This set of goals, however, has to be individualized,” she said.

The ketogenic diet is another form of carb restriction, “but it’s much more drastic,” Dr. Lemanne said. “Most people require a carbohydrate load below 30 grams a day to enter a state of ketosis. But ketosis lowers the blood sugar and dampens the mTOR signaling.”

Evidence is emerging to support the use of a ketogenic diet as an adjunct to radiation therapy and as part of a complete course of treatment for glioblastoma multiforme and cancer cachexia. As an adjunct to radiation, a ketogenic diet decreases insulin and IGF-1 signaling. “This causes normal cells to enter dormancy, decreasing oxidative damage in normal cells,” Dr. Lemanne said. “There is also suppression of tumor angiogenesis, and thus poor DNA repair of radiation damage in tumor cells (Cancer Metastasis Rev. 2014;33[1]:217-29). Being in ketosis widens the therapeutic window. There are many animal studies which show that the ketogenic diet is helpful in cancer, mainly when combined with other anticancer treatments, such as radiation. Unfortunately, the evidence in humans is very anecdotal.”

One study found that if you feed mice with cancer ketogenic chow versus standard chow, they have a modestly improved survival (a mean of 43 days vs. 33 days; PLoS ONE. 2012;7[5]:e36197). However, when radiation was added to the keto diet, there was a dramatic improvement in survival (P less than 0.001). In fact, 75% survived to 250 days. “That’s pretty spectacular,” Dr. Lemanne said.

A ketogenic diet is standard therapy for several nonmalignant conditions, including glucose transporter 1 deficiency syndrome, pyruvate dehydrogenase deficiency syndrome, and refractory infantile epilepsy. The three major ketone bodies involved in human nutrition are acetoacetate, beta hydroxybutyrate, and acetone. Dr. Lemanne said beta hydroxybutyrate decreases inflammation and inhibits hexadecynoic acids (which induces apoptosis in cancer cells). Beta hydroxybutyrate also increases sirtuins, innate immunity, and seizure threshold; modulates circadian rhythm; and decreases insulin levels, she said.

In one case report from the scientific literature, a 38-year-old male with glioblastoma multiforme was placed on a hypocaloric ketogenic diet (Front Nutr. 2018 Mar 29;5:20). The patient had surgery, radiation, chemotherapy, and hyperbaric oxygen, and was given high doses of green tea extract in an attempt to antagonize glutamine metabolism. Two years after the beginning of his treatment, he was alive and had maintained a good level of tumor regression.

“We’ll see how he does,” said Dr. Lemanne, who was not involved in the report. “In my experience, I have a patient right now with a diagnosis of glioblastoma multiforme. She’s getting a keto diet in combo with intensive chemo, radiation, and surgery. She’s also had some hyperbaric oxygen and IV ozone therapy and is taking repurposed drugs. She has exceeded her expected survival, but she continues to have disease and symptoms. We are by no means out of the woods with this patient. But the keto diet has been quite feasible for her, because she has a lot of family and outside support.”

A ketogenic diet also may benefit patients with cancer cachexia, which is a loss of lean tissue. “Cancer cachexia is not completely understood,” Dr. Lemanne said. “What we know is that it is caused by inflammation created by the tumor itself, and this, in turn results in severe insulin resistance. Therefore, giving more calories as carbohydrate makes the cancer cachexia situation worse. Animal models of cancer cachexia have shown that the ketogenic diet normalizes metabolism and prevents lean tissue loss. Human studies are underway; we’ll see how they turn out.”

She closed her presentation by noting that in copious amounts of animal studies, fasting has been linked to improvements in chemotherapy efficacy and decreased side effects. In one study carried out at the University of Southern California in Los Angeles, volunteers fasted up to 140 hours before chemotherapy and an additional 156 hours afterward (Aging. 2009;1[12]:988-1007). The researchers found that the fasting was well-tolerated.

“The patients had some mild light-headedness, but there were no adverse effects on tumor volume or serum tumor markers,” Dr. Lemanne said. A more recent study of patients on cisplatin found that acaloric fasting led to decreased DNA damage in white blood cells, decreased IFG-1, and better white blood cell counts (BMC Cancer. 2016 Jun 10;16:360). “The benefits are immediate, and the optimal fasting time appears to be 48 hours,” Dr. Lemanne said.

One of her patients is a 64-year-old man on adjuvant cisplatin-based chemotherapy for cholangiocarcinoma. He fasts 24 hours before and 24 hours after each infusion, and has experienced no emesis or nausea. “His immune suppression and anemia are much milder than we expected, and he has not required any treatment for chemotherapy-related side effects,” Dr. Lemanne said. “That’s a big monetary value.”

Fasting 13 hours overnight has been associated with fewer breast cancer-related problems in patients already diagnosed with the disease. Chronic caloric restriction, just cutting calories by 25%-40% daily, has been shown to delay all diseases of aging, including cancer, and is associated with increased longevity in many species. “Chronic caloric restriction is difficult, however, because it results in chronic hunger and weight loss,” she said. “Occasional fasting is superior to chronic caloric restriction because it maintains normal weight, preserves lean muscle mass, enhances tumor sensitivity to chemotherapy and radiotherapy, and diminishes the side effects of chemotherapy.”

Dr. Lemanne reported having no financial disclosures.

[email protected]

SAN DIEGO – When Dawn Lemanne, MD, MPH, meets with cancer patients and their families, the question invariably comes up: “What should I eat?”

“The answer always is, ‘It depends,’” Dr. Lemanne, an oncologist who founded Oregon Integrative Oncology in Ashland, said at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine. “The answers are not the same for each of these patients.”

According to Dr. Lemanne, targeted nutrition is evolving as a key component of cancer care. One of the goals of this approach is to decrease mTOR signaling. Normally, mTOR signaling promotes cell proliferation and metabolism; aberrant mTOR signaling can contribute to cancer initiation and progression.

“When mTOR speaks it says, ‘grow,’” said Dr. Lemanne, who is also an assistant professor of clinical medicine at the Andrew Weil Center for Integrative Medicine at the University of Arizona in Tucson. This message is meant to be heard by normal tissues, to stimulate normal tissue proliferation, such as in growing children or when a wound needs to be healed.

“However, cancer cells can hear and respond to mTOR’s message,” she said. “Normal cells may listen to mTOR’s ‘grow’ message or not, depending on the task they perform. Once we reach adulthood, we all likely have some precancerous or cancerous cells around, but they’re usually dormant. That’s why once you’re an adult, however, you don’t want too much mTOR signaling, because that might stimulate growth of things you definitely don’t want to grow.”

Having excessive levels of the growth hormone insulin-like growth factor-1 (IGF-1) also appears to play a role in cancer risk. Researchers studying members of a South American clan with Laron dwarfism – an inherited IGF-1 deficiency – found that besides being very short, affected members of this family rarely develop cancer (Cells. 2019;8[6]:596). “They also don’t get diabetes,” Dr. Lemanne said. “What we see in those with Laron dwarfism is that mTOR signaling is missing.”

She went on to note that studying type 2 diabetes gives physicians “a clue as to what dietary measures we might offer our patients in terms of decreasing their risk of dying from cancer or getting cancer.” The most common types of cancer are indeed more common in patients with type 2 diabetes. In addition, once someone with type 2 diabetes is diagnosed with cancer, their prognosis is poorer, compared with a cancer patient without diabetes.

“Metformin is often prescribed to patients with type 2 diabetes because it helps keep blood sugar low,” she said. “What’s fascinating is that diabetics on metformin develop cancer less frequently than diabetics not taking this drug. And also interesting, those diabetics who do develop cancer seem to do better if they’re on metformin before and after diagnosis.”

On the other hand, exogenous insulin therapy given to people with type 2 diabetes doubles the risk of cancer. Consistent with this is the two-decades-old finding that an elevated fasting insulin level also is associated with a poor breast cancer prognosis (J Clin Oncol. 2002 Jan 1;20[1]:42-51). “It’s really important to understand that, in a person destined to become a type 2 diabetic, the level of fasting insulin rises long before fasting glucose becomes abnormally high,” Dr. Lemanne explained. “A normal fasting glucose doesn’t let you off the hook in terms of checking your patient for insulin resistance.

“We will miss diagnosing many patients with dangerous insulin resistance and prediabetes if we don’t check the fasting glucose and the fasting insulin levels together. If the fasting insulin level is high, it’s important to limit carbohydrate intake enough to bring it down permanently, even when the fasting glucose is normal, or the patient is likely at increased risk for developing cancer.”

Two large, prospective randomized trials have examined breast cancer and diet: the Women’s Intervention Study (WINS) and the Women’s Health Eating and Living Study (WHEL). Patients in both trials had early stage breast cancer and were put on low-fat diets. In the end, there was a weak to negligible connection between breast cancer survival and dietary fat restriction. “That kind of shook up the oncology world,” Dr. Lemanne said, “because before these two studies, everyone ‘knew’ that dietary fat was related to breast cancer risk. These studies showed that wasn’t the case at all.”

According to Dr. Lemanne, unexpectedly, moderate carbohydrate restriction has been associated with lower risk of breast cancer recurrence in patients with postmenopausal hormone-receptor expressing breast cancer. Researchers at the University of California, San Diego, conducted a subanalysis of 265 postmenopausal patients with estrogen receptor positive breast cancer from the WHEL cohort (Cancer Epidemiol Biomarkers Prev. 2014 23[7]:1273-9). The recurrence risk was halved in those who cut their carbohydrate intake after diagnosis. The amount of decrease was modest, only 27 grams per day – the equivalent of one banana. “That is on par with a lot of our drugs, and maybe a little bit better,” she said. The effect was strongest if the breast tumor expressed IGF-1 receptor. Dr. Lemanne pointed out that decreasing dietary carbohydrate load was not the only treatment. These patients also had appropriate conventional cancer treatments, including surgery, radiation, and chemotherapy. “If we cut just some of the daily carb load in these patients, they might have a better cancer prognosis,” she said.

Overweight or obese patients with colon cancer also may benefit from moderate carbohydrate restriction. The CALGB 89803 study assessed 1,011 subjects with stage III colon cancer. It found that the subjects in the highest quintile of daily glycemic load and total carbohydrate intake had an increased risk of cancer recurrence and mortality (hazard ratio, 2.26; J Nat Cancer Inst. 2012;104[22]:1702-11). “This is pretty strong evidence that glycemic load and total carbohydrate intake play a role in colon cancer recurrence, but there’s a caveat here,” she said. “The effect was seen only in patients who were overweight or obese.” There was no association between carbohydrate intake and colon cancer recurrence in the absence of overweight or obesity.

Based on existing evidence, she said, clinicians could recommend restricting carb intake to 100 grams per day for patients with postmenopausal hormone-receptor expressing breast cancer and for overweight or obese patients with colon cancer.

“That’s pretty modest; that’s 400 calories of carbohydrates per day,” Dr. Lemanne said. “I tell patients that they can have fruit, starchy vegetables, and even very small amounts of healthy whole grains, although I’m not a fan of grains due to the heavy carbohydrate load. All those things are OK. We’re not talking about jelly beans and white sugar.

“I also have them measure their fasting glucose each day, because different people have different blood glucose responses to the same food.” The goals she aims for with many of her patients are a fasting morning glucose between 79 and 83 mg/dL consistently, an HbA1c of 5.4 or less, and a BMI of 24.9 kg/m² or less. “This set of goals, however, has to be individualized,” she said.

The ketogenic diet is another form of carb restriction, “but it’s much more drastic,” Dr. Lemanne said. “Most people require a carbohydrate load below 30 grams a day to enter a state of ketosis. But ketosis lowers the blood sugar and dampens the mTOR signaling.”

Evidence is emerging to support the use of a ketogenic diet as an adjunct to radiation therapy and as part of a complete course of treatment for glioblastoma multiforme and cancer cachexia. As an adjunct to radiation, a ketogenic diet decreases insulin and IGF-1 signaling. “This causes normal cells to enter dormancy, decreasing oxidative damage in normal cells,” Dr. Lemanne said. “There is also suppression of tumor angiogenesis, and thus poor DNA repair of radiation damage in tumor cells (Cancer Metastasis Rev. 2014;33[1]:217-29). Being in ketosis widens the therapeutic window. There are many animal studies which show that the ketogenic diet is helpful in cancer, mainly when combined with other anticancer treatments, such as radiation. Unfortunately, the evidence in humans is very anecdotal.”

One study found that if you feed mice with cancer ketogenic chow versus standard chow, they have a modestly improved survival (a mean of 43 days vs. 33 days; PLoS ONE. 2012;7[5]:e36197). However, when radiation was added to the keto diet, there was a dramatic improvement in survival (P less than 0.001). In fact, 75% survived to 250 days. “That’s pretty spectacular,” Dr. Lemanne said.

A ketogenic diet is standard therapy for several nonmalignant conditions, including glucose transporter 1 deficiency syndrome, pyruvate dehydrogenase deficiency syndrome, and refractory infantile epilepsy. The three major ketone bodies involved in human nutrition are acetoacetate, beta hydroxybutyrate, and acetone. Dr. Lemanne said beta hydroxybutyrate decreases inflammation and inhibits hexadecynoic acids (which induces apoptosis in cancer cells). Beta hydroxybutyrate also increases sirtuins, innate immunity, and seizure threshold; modulates circadian rhythm; and decreases insulin levels, she said.

In one case report from the scientific literature, a 38-year-old male with glioblastoma multiforme was placed on a hypocaloric ketogenic diet (Front Nutr. 2018 Mar 29;5:20). The patient had surgery, radiation, chemotherapy, and hyperbaric oxygen, and was given high doses of green tea extract in an attempt to antagonize glutamine metabolism. Two years after the beginning of his treatment, he was alive and had maintained a good level of tumor regression.

“We’ll see how he does,” said Dr. Lemanne, who was not involved in the report. “In my experience, I have a patient right now with a diagnosis of glioblastoma multiforme. She’s getting a keto diet in combo with intensive chemo, radiation, and surgery. She’s also had some hyperbaric oxygen and IV ozone therapy and is taking repurposed drugs. She has exceeded her expected survival, but she continues to have disease and symptoms. We are by no means out of the woods with this patient. But the keto diet has been quite feasible for her, because she has a lot of family and outside support.”

A ketogenic diet also may benefit patients with cancer cachexia, which is a loss of lean tissue. “Cancer cachexia is not completely understood,” Dr. Lemanne said. “What we know is that it is caused by inflammation created by the tumor itself, and this, in turn results in severe insulin resistance. Therefore, giving more calories as carbohydrate makes the cancer cachexia situation worse. Animal models of cancer cachexia have shown that the ketogenic diet normalizes metabolism and prevents lean tissue loss. Human studies are underway; we’ll see how they turn out.”

She closed her presentation by noting that in copious amounts of animal studies, fasting has been linked to improvements in chemotherapy efficacy and decreased side effects. In one study carried out at the University of Southern California in Los Angeles, volunteers fasted up to 140 hours before chemotherapy and an additional 156 hours afterward (Aging. 2009;1[12]:988-1007). The researchers found that the fasting was well-tolerated.

“The patients had some mild light-headedness, but there were no adverse effects on tumor volume or serum tumor markers,” Dr. Lemanne said. A more recent study of patients on cisplatin found that acaloric fasting led to decreased DNA damage in white blood cells, decreased IFG-1, and better white blood cell counts (BMC Cancer. 2016 Jun 10;16:360). “The benefits are immediate, and the optimal fasting time appears to be 48 hours,” Dr. Lemanne said.

One of her patients is a 64-year-old man on adjuvant cisplatin-based chemotherapy for cholangiocarcinoma. He fasts 24 hours before and 24 hours after each infusion, and has experienced no emesis or nausea. “His immune suppression and anemia are much milder than we expected, and he has not required any treatment for chemotherapy-related side effects,” Dr. Lemanne said. “That’s a big monetary value.”

Fasting 13 hours overnight has been associated with fewer breast cancer-related problems in patients already diagnosed with the disease. Chronic caloric restriction, just cutting calories by 25%-40% daily, has been shown to delay all diseases of aging, including cancer, and is associated with increased longevity in many species. “Chronic caloric restriction is difficult, however, because it results in chronic hunger and weight loss,” she said. “Occasional fasting is superior to chronic caloric restriction because it maintains normal weight, preserves lean muscle mass, enhances tumor sensitivity to chemotherapy and radiotherapy, and diminishes the side effects of chemotherapy.”

Dr. Lemanne reported having no financial disclosures.

[email protected]

SAN DIEGO – When Dawn Lemanne, MD, MPH, meets with cancer patients and their families, the question invariably comes up: “What should I eat?”

“The answer always is, ‘It depends,’” Dr. Lemanne, an oncologist who founded Oregon Integrative Oncology in Ashland, said at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine. “The answers are not the same for each of these patients.”

According to Dr. Lemanne, targeted nutrition is evolving as a key component of cancer care. One of the goals of this approach is to decrease mTOR signaling. Normally, mTOR signaling promotes cell proliferation and metabolism; aberrant mTOR signaling can contribute to cancer initiation and progression.

“When mTOR speaks it says, ‘grow,’” said Dr. Lemanne, who is also an assistant professor of clinical medicine at the Andrew Weil Center for Integrative Medicine at the University of Arizona in Tucson. This message is meant to be heard by normal tissues, to stimulate normal tissue proliferation, such as in growing children or when a wound needs to be healed.

“However, cancer cells can hear and respond to mTOR’s message,” she said. “Normal cells may listen to mTOR’s ‘grow’ message or not, depending on the task they perform. Once we reach adulthood, we all likely have some precancerous or cancerous cells around, but they’re usually dormant. That’s why once you’re an adult, however, you don’t want too much mTOR signaling, because that might stimulate growth of things you definitely don’t want to grow.”

Having excessive levels of the growth hormone insulin-like growth factor-1 (IGF-1) also appears to play a role in cancer risk. Researchers studying members of a South American clan with Laron dwarfism – an inherited IGF-1 deficiency – found that besides being very short, affected members of this family rarely develop cancer (Cells. 2019;8[6]:596). “They also don’t get diabetes,” Dr. Lemanne said. “What we see in those with Laron dwarfism is that mTOR signaling is missing.”

She went on to note that studying type 2 diabetes gives physicians “a clue as to what dietary measures we might offer our patients in terms of decreasing their risk of dying from cancer or getting cancer.” The most common types of cancer are indeed more common in patients with type 2 diabetes. In addition, once someone with type 2 diabetes is diagnosed with cancer, their prognosis is poorer, compared with a cancer patient without diabetes.

“Metformin is often prescribed to patients with type 2 diabetes because it helps keep blood sugar low,” she said. “What’s fascinating is that diabetics on metformin develop cancer less frequently than diabetics not taking this drug. And also interesting, those diabetics who do develop cancer seem to do better if they’re on metformin before and after diagnosis.”

On the other hand, exogenous insulin therapy given to people with type 2 diabetes doubles the risk of cancer. Consistent with this is the two-decades-old finding that an elevated fasting insulin level also is associated with a poor breast cancer prognosis (J Clin Oncol. 2002 Jan 1;20[1]:42-51). “It’s really important to understand that, in a person destined to become a type 2 diabetic, the level of fasting insulin rises long before fasting glucose becomes abnormally high,” Dr. Lemanne explained. “A normal fasting glucose doesn’t let you off the hook in terms of checking your patient for insulin resistance.

“We will miss diagnosing many patients with dangerous insulin resistance and prediabetes if we don’t check the fasting glucose and the fasting insulin levels together. If the fasting insulin level is high, it’s important to limit carbohydrate intake enough to bring it down permanently, even when the fasting glucose is normal, or the patient is likely at increased risk for developing cancer.”

Two large, prospective randomized trials have examined breast cancer and diet: the Women’s Intervention Study (WINS) and the Women’s Health Eating and Living Study (WHEL). Patients in both trials had early stage breast cancer and were put on low-fat diets. In the end, there was a weak to negligible connection between breast cancer survival and dietary fat restriction. “That kind of shook up the oncology world,” Dr. Lemanne said, “because before these two studies, everyone ‘knew’ that dietary fat was related to breast cancer risk. These studies showed that wasn’t the case at all.”

According to Dr. Lemanne, unexpectedly, moderate carbohydrate restriction has been associated with lower risk of breast cancer recurrence in patients with postmenopausal hormone-receptor expressing breast cancer. Researchers at the University of California, San Diego, conducted a subanalysis of 265 postmenopausal patients with estrogen receptor positive breast cancer from the WHEL cohort (Cancer Epidemiol Biomarkers Prev. 2014 23[7]:1273-9). The recurrence risk was halved in those who cut their carbohydrate intake after diagnosis. The amount of decrease was modest, only 27 grams per day – the equivalent of one banana. “That is on par with a lot of our drugs, and maybe a little bit better,” she said. The effect was strongest if the breast tumor expressed IGF-1 receptor. Dr. Lemanne pointed out that decreasing dietary carbohydrate load was not the only treatment. These patients also had appropriate conventional cancer treatments, including surgery, radiation, and chemotherapy. “If we cut just some of the daily carb load in these patients, they might have a better cancer prognosis,” she said.

Overweight or obese patients with colon cancer also may benefit from moderate carbohydrate restriction. The CALGB 89803 study assessed 1,011 subjects with stage III colon cancer. It found that the subjects in the highest quintile of daily glycemic load and total carbohydrate intake had an increased risk of cancer recurrence and mortality (hazard ratio, 2.26; J Nat Cancer Inst. 2012;104[22]:1702-11). “This is pretty strong evidence that glycemic load and total carbohydrate intake play a role in colon cancer recurrence, but there’s a caveat here,” she said. “The effect was seen only in patients who were overweight or obese.” There was no association between carbohydrate intake and colon cancer recurrence in the absence of overweight or obesity.

Based on existing evidence, she said, clinicians could recommend restricting carb intake to 100 grams per day for patients with postmenopausal hormone-receptor expressing breast cancer and for overweight or obese patients with colon cancer.

“That’s pretty modest; that’s 400 calories of carbohydrates per day,” Dr. Lemanne said. “I tell patients that they can have fruit, starchy vegetables, and even very small amounts of healthy whole grains, although I’m not a fan of grains due to the heavy carbohydrate load. All those things are OK. We’re not talking about jelly beans and white sugar.

“I also have them measure their fasting glucose each day, because different people have different blood glucose responses to the same food.” The goals she aims for with many of her patients are a fasting morning glucose between 79 and 83 mg/dL consistently, an HbA1c of 5.4 or less, and a BMI of 24.9 kg/m² or less. “This set of goals, however, has to be individualized,” she said.

The ketogenic diet is another form of carb restriction, “but it’s much more drastic,” Dr. Lemanne said. “Most people require a carbohydrate load below 30 grams a day to enter a state of ketosis. But ketosis lowers the blood sugar and dampens the mTOR signaling.”

Evidence is emerging to support the use of a ketogenic diet as an adjunct to radiation therapy and as part of a complete course of treatment for glioblastoma multiforme and cancer cachexia. As an adjunct to radiation, a ketogenic diet decreases insulin and IGF-1 signaling. “This causes normal cells to enter dormancy, decreasing oxidative damage in normal cells,” Dr. Lemanne said. “There is also suppression of tumor angiogenesis, and thus poor DNA repair of radiation damage in tumor cells (Cancer Metastasis Rev. 2014;33[1]:217-29). Being in ketosis widens the therapeutic window. There are many animal studies which show that the ketogenic diet is helpful in cancer, mainly when combined with other anticancer treatments, such as radiation. Unfortunately, the evidence in humans is very anecdotal.”

One study found that if you feed mice with cancer ketogenic chow versus standard chow, they have a modestly improved survival (a mean of 43 days vs. 33 days; PLoS ONE. 2012;7[5]:e36197). However, when radiation was added to the keto diet, there was a dramatic improvement in survival (P less than 0.001). In fact, 75% survived to 250 days. “That’s pretty spectacular,” Dr. Lemanne said.

A ketogenic diet is standard therapy for several nonmalignant conditions, including glucose transporter 1 deficiency syndrome, pyruvate dehydrogenase deficiency syndrome, and refractory infantile epilepsy. The three major ketone bodies involved in human nutrition are acetoacetate, beta hydroxybutyrate, and acetone. Dr. Lemanne said beta hydroxybutyrate decreases inflammation and inhibits hexadecynoic acids (which induces apoptosis in cancer cells). Beta hydroxybutyrate also increases sirtuins, innate immunity, and seizure threshold; modulates circadian rhythm; and decreases insulin levels, she said.

In one case report from the scientific literature, a 38-year-old male with glioblastoma multiforme was placed on a hypocaloric ketogenic diet (Front Nutr. 2018 Mar 29;5:20). The patient had surgery, radiation, chemotherapy, and hyperbaric oxygen, and was given high doses of green tea extract in an attempt to antagonize glutamine metabolism. Two years after the beginning of his treatment, he was alive and had maintained a good level of tumor regression.

“We’ll see how he does,” said Dr. Lemanne, who was not involved in the report. “In my experience, I have a patient right now with a diagnosis of glioblastoma multiforme. She’s getting a keto diet in combo with intensive chemo, radiation, and surgery. She’s also had some hyperbaric oxygen and IV ozone therapy and is taking repurposed drugs. She has exceeded her expected survival, but she continues to have disease and symptoms. We are by no means out of the woods with this patient. But the keto diet has been quite feasible for her, because she has a lot of family and outside support.”

A ketogenic diet also may benefit patients with cancer cachexia, which is a loss of lean tissue. “Cancer cachexia is not completely understood,” Dr. Lemanne said. “What we know is that it is caused by inflammation created by the tumor itself, and this, in turn results in severe insulin resistance. Therefore, giving more calories as carbohydrate makes the cancer cachexia situation worse. Animal models of cancer cachexia have shown that the ketogenic diet normalizes metabolism and prevents lean tissue loss. Human studies are underway; we’ll see how they turn out.”

She closed her presentation by noting that in copious amounts of animal studies, fasting has been linked to improvements in chemotherapy efficacy and decreased side effects. In one study carried out at the University of Southern California in Los Angeles, volunteers fasted up to 140 hours before chemotherapy and an additional 156 hours afterward (Aging. 2009;1[12]:988-1007). The researchers found that the fasting was well-tolerated.

“The patients had some mild light-headedness, but there were no adverse effects on tumor volume or serum tumor markers,” Dr. Lemanne said. A more recent study of patients on cisplatin found that acaloric fasting led to decreased DNA damage in white blood cells, decreased IFG-1, and better white blood cell counts (BMC Cancer. 2016 Jun 10;16:360). “The benefits are immediate, and the optimal fasting time appears to be 48 hours,” Dr. Lemanne said.

One of her patients is a 64-year-old man on adjuvant cisplatin-based chemotherapy for cholangiocarcinoma. He fasts 24 hours before and 24 hours after each infusion, and has experienced no emesis or nausea. “His immune suppression and anemia are much milder than we expected, and he has not required any treatment for chemotherapy-related side effects,” Dr. Lemanne said. “That’s a big monetary value.”

Fasting 13 hours overnight has been associated with fewer breast cancer-related problems in patients already diagnosed with the disease. Chronic caloric restriction, just cutting calories by 25%-40% daily, has been shown to delay all diseases of aging, including cancer, and is associated with increased longevity in many species. “Chronic caloric restriction is difficult, however, because it results in chronic hunger and weight loss,” she said. “Occasional fasting is superior to chronic caloric restriction because it maintains normal weight, preserves lean muscle mass, enhances tumor sensitivity to chemotherapy and radiotherapy, and diminishes the side effects of chemotherapy.”

Dr. Lemanne reported having no financial disclosures.

[email protected]

A massive collaborative project spanning four continents and 744 research centers has revealed driver mutations in both protein-coding and noncoding regions of 38 cancer types.

Pan-Cancer Analysis of Whole Genomes

The Pan-Cancer Analysis of Whole Genomes (PCAWG) is an integrative analysis of the whole-genome sequences from 2,658 donors across 38 common tumor types. The findings are expected to add exponentially to what’s currently known about the complex genetics of cancer, and they point to possible strategies for improving cancer prevention, diagnosis, and care.

Six articles summarizing the findings are presented in a series of papers in Nature, and 16 more appear in affiliated publications.

“It’s humbling that it was only 14 years ago that the genomics community sequenced its very first cancer exome, and it was able to identify mutations within the roughly 20,000 protein-coding genes in the human cell,” investigator Lincoln Stein, MD, PhD, of the Ontario Institute for Cancer Research in Toronto, said in a telephone briefing.

Exome sequencing, however, covers only protein-coding genomic regions, which constitute only about 1% of the entire genome, “so assembling an accurate portrait of the cancer genome using just the exome data is like trying to put together a 100,000-piece jigsaw puzzle when you’re missing 99% of the pieces and there’s no puzzle box with a completed picture to guide you,” Dr. Stein said.

Members of the PCAWG from centers in North America, Europe, Asia, and Australia screened 2,658 whole-cancer genomes and matched samples of noncancerous tissues from the same individuals, along with 1,188 transcriptomes cataloging the sequences and expression of RNA transcripts in a given tumor. The 6-year project netted more than 800 terabytes of genomic data, roughly equivalent to the digital holdings of the U.S. Library of Congress multiplied by 11.

The findings are summarized in papers focusing on cancer drivers, noncoding changes, mutational signatures, structural variants, cancer evolution over time, and RNA alterations.
 

Driver mutations

Investigators found that the average cancer genome contains four or five driver mutations located in both coding and noncoding regions. They also found, however, that in approximately 5% of cases no driver mutations could be identified.

A substantial proportion of tumors displayed “hallmarks of genomic catastrophes.” About 22% of tumors exhibited chromothripsis, a mutational process marked by hundreds or even thousands of clustered chromosomal rearrangements. About 18% showed chromoplexy, which is characterized by scattering and rearrangement of multiple strands of DNA from one or more chromosomes.

Analyzing driver point mutations and structural variants in noncoding regions, the investigators found the usual suspects – previously reported culprits – as well as novel candidates.

For example, they identified point mutations in the five prime region of the tumor suppressor gene TP53 and the three prime untranslated regions of NFKBIZ (a nuclear factor kappa B inhibitor) and TOB1 (an antiproliferative protein), focal deletion in BRD4 (a transcriptional and epigenetic regulator), and rearrangements in chromosomal loci in members of the AKR1C family of enzymes thought to play a role in disease progression.

In addition, investigators identified mutations in noncoding regions of TERT, a telomerase gene. These mutations result in ramped-up expression of telomerase, which in turn promotes uncontrollable division of tumor cells.
 

Mutational signatures

In a related line of research, PCAWG investigators identified new DNA mutational signatures ranging from single nucleotide polymorphisms to insertions and deletions, as well as to structural variants – rearrangements of large sections of the genome.

“The substantial size of our dataset, compared with previous analyses, enabled the discovery of new signatures, the separation of overlapping signatures, and the decomposition of signatures into components that may represent associated – but distinct – DNA damage, repair, and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogs of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA maintenance processes,” the investigators wrote.

They also acknowledged, however, that “many signatures are of unknown cause.”
 

Cancer evolution

One of the six main studies focused on the evolution of cancer over time. Instead of providing a “snapshot” of the genome as captured by sequencing tissue from a single biopsy, consortium investigators created full-length features of the “life history and evolution of mutational processes and driver mutation sequences.”

They found that early cancer development was marked by relatively few mutations in driver genes and by identifiable copy-number gains, including trisomy 7 in glioblastoma, and an abnormal mirroring of the arms (isochromosome) of chromosome 17 in medulloblastoma.

In 40% of the samples, however, there were significant changes in the mutational spectrum as the cancers grew, leading to a near quadrupling of driver genes and increased genomic instability in later-stage tumors.

“Copy-number alterations often occur in mitotic crises and lead to simultaneous gains of chromosomal segments,” the investigators wrote. “Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer and highlight opportunities for early cancer detection.”
 

Implications for cancer care

“When I used to treat patients with cancer, I was always completely amazed and puzzled by how two patients could have what looked like the same tumor. It would look the same under the microscope, have the same size, and the two patients would receive exactly the same treatment, but the two patients would have completely opposite outcomes; one would survive, and one would die. What this analysis … has done is really laid bare the reasons for that unpredictability in clinical outcomes,” Peter Campbell, MD, PhD, of the Wellcome Sanger Institute in Hinxton, England, said during the telebriefing.

“The most striking finding out of all of the suite of papers is just how different one person’s cancer genome is from another person’s. We see thousands of different combinations of mutations that can cause the cancer, and more than 80 different underlying processes generating the mutations in a cancer, and that leads to very different shapes and patterns in the genome that result,” he added.

On a positive note, the research shows that one or more driver mutations can be identified in about 95% of all cancer patients, and it elucidates the sequence of events leading to oncogenesis and tumor evolution, providing opportunities for earlier identification and potential interventions to prevent cancer, Dr. Campbell said.

The PCAWG was a collaborative multinational effort with multiple funding sources and many investigators.

SOURCE: Nature. 2020 Feb 5. https://www.nature.com/collections/pcawg/

A massive collaborative project spanning four continents and 744 research centers has revealed driver mutations in both protein-coding and noncoding regions of 38 cancer types.

Pan-Cancer Analysis of Whole Genomes

The Pan-Cancer Analysis of Whole Genomes (PCAWG) is an integrative analysis of the whole-genome sequences from 2,658 donors across 38 common tumor types. The findings are expected to add exponentially to what’s currently known about the complex genetics of cancer, and they point to possible strategies for improving cancer prevention, diagnosis, and care.

Six articles summarizing the findings are presented in a series of papers in Nature, and 16 more appear in affiliated publications.

“It’s humbling that it was only 14 years ago that the genomics community sequenced its very first cancer exome, and it was able to identify mutations within the roughly 20,000 protein-coding genes in the human cell,” investigator Lincoln Stein, MD, PhD, of the Ontario Institute for Cancer Research in Toronto, said in a telephone briefing.

Exome sequencing, however, covers only protein-coding genomic regions, which constitute only about 1% of the entire genome, “so assembling an accurate portrait of the cancer genome using just the exome data is like trying to put together a 100,000-piece jigsaw puzzle when you’re missing 99% of the pieces and there’s no puzzle box with a completed picture to guide you,” Dr. Stein said.

Members of the PCAWG from centers in North America, Europe, Asia, and Australia screened 2,658 whole-cancer genomes and matched samples of noncancerous tissues from the same individuals, along with 1,188 transcriptomes cataloging the sequences and expression of RNA transcripts in a given tumor. The 6-year project netted more than 800 terabytes of genomic data, roughly equivalent to the digital holdings of the U.S. Library of Congress multiplied by 11.

The findings are summarized in papers focusing on cancer drivers, noncoding changes, mutational signatures, structural variants, cancer evolution over time, and RNA alterations.
 

Driver mutations

Investigators found that the average cancer genome contains four or five driver mutations located in both coding and noncoding regions. They also found, however, that in approximately 5% of cases no driver mutations could be identified.

A substantial proportion of tumors displayed “hallmarks of genomic catastrophes.” About 22% of tumors exhibited chromothripsis, a mutational process marked by hundreds or even thousands of clustered chromosomal rearrangements. About 18% showed chromoplexy, which is characterized by scattering and rearrangement of multiple strands of DNA from one or more chromosomes.

Analyzing driver point mutations and structural variants in noncoding regions, the investigators found the usual suspects – previously reported culprits – as well as novel candidates.

For example, they identified point mutations in the five prime region of the tumor suppressor gene TP53 and the three prime untranslated regions of NFKBIZ (a nuclear factor kappa B inhibitor) and TOB1 (an antiproliferative protein), focal deletion in BRD4 (a transcriptional and epigenetic regulator), and rearrangements in chromosomal loci in members of the AKR1C family of enzymes thought to play a role in disease progression.

In addition, investigators identified mutations in noncoding regions of TERT, a telomerase gene. These mutations result in ramped-up expression of telomerase, which in turn promotes uncontrollable division of tumor cells.
 

Mutational signatures

In a related line of research, PCAWG investigators identified new DNA mutational signatures ranging from single nucleotide polymorphisms to insertions and deletions, as well as to structural variants – rearrangements of large sections of the genome.

“The substantial size of our dataset, compared with previous analyses, enabled the discovery of new signatures, the separation of overlapping signatures, and the decomposition of signatures into components that may represent associated – but distinct – DNA damage, repair, and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogs of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA maintenance processes,” the investigators wrote.

They also acknowledged, however, that “many signatures are of unknown cause.”
 

Cancer evolution

One of the six main studies focused on the evolution of cancer over time. Instead of providing a “snapshot” of the genome as captured by sequencing tissue from a single biopsy, consortium investigators created full-length features of the “life history and evolution of mutational processes and driver mutation sequences.”

They found that early cancer development was marked by relatively few mutations in driver genes and by identifiable copy-number gains, including trisomy 7 in glioblastoma, and an abnormal mirroring of the arms (isochromosome) of chromosome 17 in medulloblastoma.

In 40% of the samples, however, there were significant changes in the mutational spectrum as the cancers grew, leading to a near quadrupling of driver genes and increased genomic instability in later-stage tumors.

“Copy-number alterations often occur in mitotic crises and lead to simultaneous gains of chromosomal segments,” the investigators wrote. “Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer and highlight opportunities for early cancer detection.”
 

Implications for cancer care

“When I used to treat patients with cancer, I was always completely amazed and puzzled by how two patients could have what looked like the same tumor. It would look the same under the microscope, have the same size, and the two patients would receive exactly the same treatment, but the two patients would have completely opposite outcomes; one would survive, and one would die. What this analysis … has done is really laid bare the reasons for that unpredictability in clinical outcomes,” Peter Campbell, MD, PhD, of the Wellcome Sanger Institute in Hinxton, England, said during the telebriefing.

“The most striking finding out of all of the suite of papers is just how different one person’s cancer genome is from another person’s. We see thousands of different combinations of mutations that can cause the cancer, and more than 80 different underlying processes generating the mutations in a cancer, and that leads to very different shapes and patterns in the genome that result,” he added.

On a positive note, the research shows that one or more driver mutations can be identified in about 95% of all cancer patients, and it elucidates the sequence of events leading to oncogenesis and tumor evolution, providing opportunities for earlier identification and potential interventions to prevent cancer, Dr. Campbell said.

The PCAWG was a collaborative multinational effort with multiple funding sources and many investigators.

SOURCE: Nature. 2020 Feb 5. https://www.nature.com/collections/pcawg/

A massive collaborative project spanning four continents and 744 research centers has revealed driver mutations in both protein-coding and noncoding regions of 38 cancer types.

Pan-Cancer Analysis of Whole Genomes

The Pan-Cancer Analysis of Whole Genomes (PCAWG) is an integrative analysis of the whole-genome sequences from 2,658 donors across 38 common tumor types. The findings are expected to add exponentially to what’s currently known about the complex genetics of cancer, and they point to possible strategies for improving cancer prevention, diagnosis, and care.

Six articles summarizing the findings are presented in a series of papers in Nature, and 16 more appear in affiliated publications.

“It’s humbling that it was only 14 years ago that the genomics community sequenced its very first cancer exome, and it was able to identify mutations within the roughly 20,000 protein-coding genes in the human cell,” investigator Lincoln Stein, MD, PhD, of the Ontario Institute for Cancer Research in Toronto, said in a telephone briefing.

Exome sequencing, however, covers only protein-coding genomic regions, which constitute only about 1% of the entire genome, “so assembling an accurate portrait of the cancer genome using just the exome data is like trying to put together a 100,000-piece jigsaw puzzle when you’re missing 99% of the pieces and there’s no puzzle box with a completed picture to guide you,” Dr. Stein said.

Members of the PCAWG from centers in North America, Europe, Asia, and Australia screened 2,658 whole-cancer genomes and matched samples of noncancerous tissues from the same individuals, along with 1,188 transcriptomes cataloging the sequences and expression of RNA transcripts in a given tumor. The 6-year project netted more than 800 terabytes of genomic data, roughly equivalent to the digital holdings of the U.S. Library of Congress multiplied by 11.

The findings are summarized in papers focusing on cancer drivers, noncoding changes, mutational signatures, structural variants, cancer evolution over time, and RNA alterations.
 

Driver mutations

Investigators found that the average cancer genome contains four or five driver mutations located in both coding and noncoding regions. They also found, however, that in approximately 5% of cases no driver mutations could be identified.

A substantial proportion of tumors displayed “hallmarks of genomic catastrophes.” About 22% of tumors exhibited chromothripsis, a mutational process marked by hundreds or even thousands of clustered chromosomal rearrangements. About 18% showed chromoplexy, which is characterized by scattering and rearrangement of multiple strands of DNA from one or more chromosomes.

Analyzing driver point mutations and structural variants in noncoding regions, the investigators found the usual suspects – previously reported culprits – as well as novel candidates.

For example, they identified point mutations in the five prime region of the tumor suppressor gene TP53 and the three prime untranslated regions of NFKBIZ (a nuclear factor kappa B inhibitor) and TOB1 (an antiproliferative protein), focal deletion in BRD4 (a transcriptional and epigenetic regulator), and rearrangements in chromosomal loci in members of the AKR1C family of enzymes thought to play a role in disease progression.

In addition, investigators identified mutations in noncoding regions of TERT, a telomerase gene. These mutations result in ramped-up expression of telomerase, which in turn promotes uncontrollable division of tumor cells.
 

Mutational signatures

In a related line of research, PCAWG investigators identified new DNA mutational signatures ranging from single nucleotide polymorphisms to insertions and deletions, as well as to structural variants – rearrangements of large sections of the genome.

“The substantial size of our dataset, compared with previous analyses, enabled the discovery of new signatures, the separation of overlapping signatures, and the decomposition of signatures into components that may represent associated – but distinct – DNA damage, repair, and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogs of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA maintenance processes,” the investigators wrote.

They also acknowledged, however, that “many signatures are of unknown cause.”
 

Cancer evolution

One of the six main studies focused on the evolution of cancer over time. Instead of providing a “snapshot” of the genome as captured by sequencing tissue from a single biopsy, consortium investigators created full-length features of the “life history and evolution of mutational processes and driver mutation sequences.”

They found that early cancer development was marked by relatively few mutations in driver genes and by identifiable copy-number gains, including trisomy 7 in glioblastoma, and an abnormal mirroring of the arms (isochromosome) of chromosome 17 in medulloblastoma.

In 40% of the samples, however, there were significant changes in the mutational spectrum as the cancers grew, leading to a near quadrupling of driver genes and increased genomic instability in later-stage tumors.

“Copy-number alterations often occur in mitotic crises and lead to simultaneous gains of chromosomal segments,” the investigators wrote. “Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer and highlight opportunities for early cancer detection.”
 

Implications for cancer care

“When I used to treat patients with cancer, I was always completely amazed and puzzled by how two patients could have what looked like the same tumor. It would look the same under the microscope, have the same size, and the two patients would receive exactly the same treatment, but the two patients would have completely opposite outcomes; one would survive, and one would die. What this analysis … has done is really laid bare the reasons for that unpredictability in clinical outcomes,” Peter Campbell, MD, PhD, of the Wellcome Sanger Institute in Hinxton, England, said during the telebriefing.

“The most striking finding out of all of the suite of papers is just how different one person’s cancer genome is from another person’s. We see thousands of different combinations of mutations that can cause the cancer, and more than 80 different underlying processes generating the mutations in a cancer, and that leads to very different shapes and patterns in the genome that result,” he added.

On a positive note, the research shows that one or more driver mutations can be identified in about 95% of all cancer patients, and it elucidates the sequence of events leading to oncogenesis and tumor evolution, providing opportunities for earlier identification and potential interventions to prevent cancer, Dr. Campbell said.

The PCAWG was a collaborative multinational effort with multiple funding sources and many investigators.

SOURCE: Nature. 2020 Feb 5. https://www.nature.com/collections/pcawg/

In addition to offering an overall survival benefit for patients with MGMT-methylated glioblastoma, the combination of lomustine and temozolomide did not impair health-related quality of life (HRQOL) compared with temozolomide alone, investigators report.

Among 129 patients with newly-diagnosed glioblastoma with methylation of the MGMT promoter, there were no significant differences in any items on the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 and the EORTC brain cancer module (BN20) between patients who received oral combined lomustine and temozolomide or temozolomide alone, reported Johannes Weller, MD, of University Hospital Bonn, Germany, and colleagues.

Although the combination was associated with slightly lower scores on the Mini-Mental State Exam (MMSE), the differences were not clinically significant, the investigators asserted.

“The absence of systematic and clinically relevant changes in HRQOL and neurocognitive function combined with the survival benefit of lomustine-temozolomide versus temozolomide alone suggests that a long-term net clinical benefit exists for patients with newly diagnosed glioblastoma with methylation of the MGMT promoter and supports the use of lomustine-temozolomide as a treatment option for these patients,” they wrote. The report is in The Lancet Oncology.

The investigators previously reported that median overall survival was improved from 31.4 months with temozolomide to 48.1 months with lomustine-temozolomide, translating into a hazard ratio (HR) for death with the combination of 0.60 (P = .0492).

In the current report, Dr. Weller and associates looked at the secondary endpoints of HRQOL as measured by the EORTC scales, and at neurocognitive function as assessed by the MMSE and a neurocognitive test battery (NOA-07) that include Trail Making Test A and B (TMT-A and B), working memory tests, and tests for word and semantic verbal fluency.

The modified intention-to-treat analysis included all patients who received at least one dose of study chemotherapy. The analysis included data on 63 patients randomly assigned to receive standard oral temozolomide, consisting of 75 mg/m² daily during radiotherapy plus six 4-week courses of temozolomide at doses ranging from 150 to 200 mg/m² on days 1-5, every 4 weeks; and 66 patients assigned to receive oral combined lomustine consisting of a 100 mg/m² dose on day 1, plus temozolomide 100 to 200 mg/m² on days 2-6 for six cycles of 6 weeks each.

After a median follow-up of 19.4 months for the HRQOL endpoint, there were no significant differences between the groups in decline from baselines in Karnofsky Performance Score, global health, physical functioning, cognitive functioning, social functioning, or communication deficit.

As noted before, however, there were small but significant differences between the groups favoring temozolomide on the MMSE, after a median follow-up for this measure of 15.3 months. The authors noted that the differences “were not significant when adjusted for multiple testing and were also not clinically relevant, because even over the time course of 4 years the differences between the groups would only add up to 1.76/30 points and clinically significant results would require a difference of more than 3/30 points.”

There were also no significant differences between the groups in any item of the neurocognitive test, they added.

The investigators acknowledged that the trial was limited by its relatively small size, and that after 3.5 years of follow-up about half of all the expected HRQOL forms were missing, which might lead to reporting bias.

“Overall, we conclude that the addition of lomustine to temozolomide in patients with newly diagnosed MGMT-methylated glioblastoma is associated with a clear long-term net clinical benefit and our data provide a good rationale for the trial regimen as a treatment option for these patients. Nevertheless, changes in HRQOL during the first year after beginning treatment needs further exploration in future studies,” Dr. Weller and colleagues wrote.

The German Federal Ministry of Education and Research funded the study. Dr. Weller reported having no conflict of interest. Several coauthors reported relationships with industry outside the submitted work.

SOURCE: Weller J et al. Lancet Oncol. Sept 2. doi: 10.1016/S1470-2045(19)30502-9.

In addition to offering an overall survival benefit for patients with MGMT-methylated glioblastoma, the combination of lomustine and temozolomide did not impair health-related quality of life (HRQOL) compared with temozolomide alone, investigators report.

Among 129 patients with newly-diagnosed glioblastoma with methylation of the MGMT promoter, there were no significant differences in any items on the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 and the EORTC brain cancer module (BN20) between patients who received oral combined lomustine and temozolomide or temozolomide alone, reported Johannes Weller, MD, of University Hospital Bonn, Germany, and colleagues.

Although the combination was associated with slightly lower scores on the Mini-Mental State Exam (MMSE), the differences were not clinically significant, the investigators asserted.

“The absence of systematic and clinically relevant changes in HRQOL and neurocognitive function combined with the survival benefit of lomustine-temozolomide versus temozolomide alone suggests that a long-term net clinical benefit exists for patients with newly diagnosed glioblastoma with methylation of the MGMT promoter and supports the use of lomustine-temozolomide as a treatment option for these patients,” they wrote. The report is in The Lancet Oncology.

The investigators previously reported that median overall survival was improved from 31.4 months with temozolomide to 48.1 months with lomustine-temozolomide, translating into a hazard ratio (HR) for death with the combination of 0.60 (P = .0492).

In the current report, Dr. Weller and associates looked at the secondary endpoints of HRQOL as measured by the EORTC scales, and at neurocognitive function as assessed by the MMSE and a neurocognitive test battery (NOA-07) that include Trail Making Test A and B (TMT-A and B), working memory tests, and tests for word and semantic verbal fluency.

The modified intention-to-treat analysis included all patients who received at least one dose of study chemotherapy. The analysis included data on 63 patients randomly assigned to receive standard oral temozolomide, consisting of 75 mg/m² daily during radiotherapy plus six 4-week courses of temozolomide at doses ranging from 150 to 200 mg/m² on days 1-5, every 4 weeks; and 66 patients assigned to receive oral combined lomustine consisting of a 100 mg/m² dose on day 1, plus temozolomide 100 to 200 mg/m² on days 2-6 for six cycles of 6 weeks each.

After a median follow-up of 19.4 months for the HRQOL endpoint, there were no significant differences between the groups in decline from baselines in Karnofsky Performance Score, global health, physical functioning, cognitive functioning, social functioning, or communication deficit.

As noted before, however, there were small but significant differences between the groups favoring temozolomide on the MMSE, after a median follow-up for this measure of 15.3 months. The authors noted that the differences “were not significant when adjusted for multiple testing and were also not clinically relevant, because even over the time course of 4 years the differences between the groups would only add up to 1.76/30 points and clinically significant results would require a difference of more than 3/30 points.”

There were also no significant differences between the groups in any item of the neurocognitive test, they added.

The investigators acknowledged that the trial was limited by its relatively small size, and that after 3.5 years of follow-up about half of all the expected HRQOL forms were missing, which might lead to reporting bias.

“Overall, we conclude that the addition of lomustine to temozolomide in patients with newly diagnosed MGMT-methylated glioblastoma is associated with a clear long-term net clinical benefit and our data provide a good rationale for the trial regimen as a treatment option for these patients. Nevertheless, changes in HRQOL during the first year after beginning treatment needs further exploration in future studies,” Dr. Weller and colleagues wrote.

The German Federal Ministry of Education and Research funded the study. Dr. Weller reported having no conflict of interest. Several coauthors reported relationships with industry outside the submitted work.

SOURCE: Weller J et al. Lancet Oncol. Sept 2. doi: 10.1016/S1470-2045(19)30502-9.

In addition to offering an overall survival benefit for patients with MGMT-methylated glioblastoma, the combination of lomustine and temozolomide did not impair health-related quality of life (HRQOL) compared with temozolomide alone, investigators report.

Among 129 patients with newly-diagnosed glioblastoma with methylation of the MGMT promoter, there were no significant differences in any items on the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 and the EORTC brain cancer module (BN20) between patients who received oral combined lomustine and temozolomide or temozolomide alone, reported Johannes Weller, MD, of University Hospital Bonn, Germany, and colleagues.

Although the combination was associated with slightly lower scores on the Mini-Mental State Exam (MMSE), the differences were not clinically significant, the investigators asserted.

“The absence of systematic and clinically relevant changes in HRQOL and neurocognitive function combined with the survival benefit of lomustine-temozolomide versus temozolomide alone suggests that a long-term net clinical benefit exists for patients with newly diagnosed glioblastoma with methylation of the MGMT promoter and supports the use of lomustine-temozolomide as a treatment option for these patients,” they wrote. The report is in The Lancet Oncology.

The investigators previously reported that median overall survival was improved from 31.4 months with temozolomide to 48.1 months with lomustine-temozolomide, translating into a hazard ratio (HR) for death with the combination of 0.60 (P = .0492).

In the current report, Dr. Weller and associates looked at the secondary endpoints of HRQOL as measured by the EORTC scales, and at neurocognitive function as assessed by the MMSE and a neurocognitive test battery (NOA-07) that include Trail Making Test A and B (TMT-A and B), working memory tests, and tests for word and semantic verbal fluency.

The modified intention-to-treat analysis included all patients who received at least one dose of study chemotherapy. The analysis included data on 63 patients randomly assigned to receive standard oral temozolomide, consisting of 75 mg/m² daily during radiotherapy plus six 4-week courses of temozolomide at doses ranging from 150 to 200 mg/m² on days 1-5, every 4 weeks; and 66 patients assigned to receive oral combined lomustine consisting of a 100 mg/m² dose on day 1, plus temozolomide 100 to 200 mg/m² on days 2-6 for six cycles of 6 weeks each.

After a median follow-up of 19.4 months for the HRQOL endpoint, there were no significant differences between the groups in decline from baselines in Karnofsky Performance Score, global health, physical functioning, cognitive functioning, social functioning, or communication deficit.

As noted before, however, there were small but significant differences between the groups favoring temozolomide on the MMSE, after a median follow-up for this measure of 15.3 months. The authors noted that the differences “were not significant when adjusted for multiple testing and were also not clinically relevant, because even over the time course of 4 years the differences between the groups would only add up to 1.76/30 points and clinically significant results would require a difference of more than 3/30 points.”

There were also no significant differences between the groups in any item of the neurocognitive test, they added.

The investigators acknowledged that the trial was limited by its relatively small size, and that after 3.5 years of follow-up about half of all the expected HRQOL forms were missing, which might lead to reporting bias.

“Overall, we conclude that the addition of lomustine to temozolomide in patients with newly diagnosed MGMT-methylated glioblastoma is associated with a clear long-term net clinical benefit and our data provide a good rationale for the trial regimen as a treatment option for these patients. Nevertheless, changes in HRQOL during the first year after beginning treatment needs further exploration in future studies,” Dr. Weller and colleagues wrote.

The German Federal Ministry of Education and Research funded the study. Dr. Weller reported having no conflict of interest. Several coauthors reported relationships with industry outside the submitted work.

SOURCE: Weller J et al. Lancet Oncol. Sept 2. doi: 10.1016/S1470-2045(19)30502-9.