Hodgkin Lymphoma

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

New research suggests that people living in the Appalachian region of the US are more likely to develop cancer than people in the rest of the country.

The study showed that Appalachians had a significantly higher incidence of cancer overall and higher rates of many solid tumor malignancies.

However, lymphoma rates were similar between Appalachians and non-Appalachians, and Appalachians had a significantly lower rate of myeloma.

This research was published in Cancer Epidemiology, Biomarkers & Prevention.

“The Appalachian region, which extends from parts of New York to Mississippi, spans 420 counties in 13 US states, and about 25 million people reside in this area,” said study author Reda Wilson, MPH, of the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia.

“This region is primarily made up of rural areas, with persistent poverty levels that are at least 20%, which is higher than the national average.”

In 2007, the CDC’s National Program of Cancer Registries (NPCR) published a comprehensive evaluation of cancer incidence rates in Appalachia between 2001 and 2003.

The data showed higher cancer rates in Appalachia than in the rest of the US. However, this publication had some shortcomings, including data that were not available for analysis.

“The current analyses reported here were performed to update the earlier evaluation by expanding the diagnosis years from 2004 to 2011 and including data on 100% of the Appalachian and non-Appalachian populations,” Wilson said.

For this study, Wilson and her colleagues used data from the NPCR and the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program. Together, NPCR and SEER cover 100% of the US population.

The researchers analyzed the Appalachian population by region (north, central, and south Appalachia), gender, race (black and white only), and Appalachian Regional Commission-designated economic status (distressed, at-risk, transitional, competitive, and attainment). And the team compared these data with data on the non-Appalachian population.

The results showed that cancer incidence rates (IRs) were elevated among Appalachians regardless of how they were categorized. The IRs were per 100,000 people, age-adjusted to the 2000 US standard population.

The IR for all cancers was 565.8 for males in Appalachia and 543.0 for non-Appalachian males (P<0.05). And the cancer IRs for females were 428.7 in Appalachia and 418.2 outside the region (P<0.05).

There was no significant difference between the regions in IRs for lymphomas. The Hodgkin lymphoma IRs were 3.1 in Appalachian males, 3.2 in non-Appalachian males, and 2.5 for females in both regions.

The non-Hodgkin lymphoma IRs were 23.3 in Appalachian males, 23.4 in non-Appalachian males, 16.4 in Appalachian females, and 16.3 in non-Appalachian females.

Myeloma IRs were significantly lower in Appalachia (P<0.05). The myeloma IRs were 7.3 in Appalachian males, 7.5 in non-Appalachian males, 4.7 in Appalachian females, and 4.9 in non-Appalachian females.

There was no significant difference in leukemia IRs among males, but females in Appalachia had a significantly higher leukemia IR (P<0.05). The leukemia IRs were 16.9 in Appalachian males, 16.7 in non-Appalachian males, 10.4 in Appalachian females, and 10.2 in non-Appalachian females.

“Appalachia continues to have higher cancer incidence rates than the rest of the country,” Wilson said. “But a promising finding is that we’re seeing the gap narrow in the incidence rates between Appalachia and non-Appalachia since the 2007 analysis, with the exception of cancers of the oral cavity and pharynx, larynx, lung and bronchus, and thyroid.”

“This study helps identify types of cancer in the Appalachian region that could be reduced through more evidence-based screening and detection. Our study also emphasizes the importance of lifestyle changes needed to prevent and reduce cancer burden.”

The researchers noted that this study did not differentiate urban versus rural areas within each county, and data on screening and risk factors were based on self-reported responses.

Furthermore, cancer IRs were calculated for all ages combined and were not evaluated by age groups. Future analyses will be targeted toward capturing these finer details, Wilson said.

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

New research suggests that people living in the Appalachian region of the US are more likely to develop cancer than people in the rest of the country.

The study showed that Appalachians had a significantly higher incidence of cancer overall and higher rates of many solid tumor malignancies.

However, lymphoma rates were similar between Appalachians and non-Appalachians, and Appalachians had a significantly lower rate of myeloma.

This research was published in Cancer Epidemiology, Biomarkers & Prevention.

“The Appalachian region, which extends from parts of New York to Mississippi, spans 420 counties in 13 US states, and about 25 million people reside in this area,” said study author Reda Wilson, MPH, of the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia.

“This region is primarily made up of rural areas, with persistent poverty levels that are at least 20%, which is higher than the national average.”

In 2007, the CDC’s National Program of Cancer Registries (NPCR) published a comprehensive evaluation of cancer incidence rates in Appalachia between 2001 and 2003.

The data showed higher cancer rates in Appalachia than in the rest of the US. However, this publication had some shortcomings, including data that were not available for analysis.

“The current analyses reported here were performed to update the earlier evaluation by expanding the diagnosis years from 2004 to 2011 and including data on 100% of the Appalachian and non-Appalachian populations,” Wilson said.

For this study, Wilson and her colleagues used data from the NPCR and the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program. Together, NPCR and SEER cover 100% of the US population.

The researchers analyzed the Appalachian population by region (north, central, and south Appalachia), gender, race (black and white only), and Appalachian Regional Commission-designated economic status (distressed, at-risk, transitional, competitive, and attainment). And the team compared these data with data on the non-Appalachian population.

The results showed that cancer incidence rates (IRs) were elevated among Appalachians regardless of how they were categorized. The IRs were per 100,000 people, age-adjusted to the 2000 US standard population.

The IR for all cancers was 565.8 for males in Appalachia and 543.0 for non-Appalachian males (P<0.05). And the cancer IRs for females were 428.7 in Appalachia and 418.2 outside the region (P<0.05).

There was no significant difference between the regions in IRs for lymphomas. The Hodgkin lymphoma IRs were 3.1 in Appalachian males, 3.2 in non-Appalachian males, and 2.5 for females in both regions.

The non-Hodgkin lymphoma IRs were 23.3 in Appalachian males, 23.4 in non-Appalachian males, 16.4 in Appalachian females, and 16.3 in non-Appalachian females.

Myeloma IRs were significantly lower in Appalachia (P<0.05). The myeloma IRs were 7.3 in Appalachian males, 7.5 in non-Appalachian males, 4.7 in Appalachian females, and 4.9 in non-Appalachian females.

There was no significant difference in leukemia IRs among males, but females in Appalachia had a significantly higher leukemia IR (P<0.05). The leukemia IRs were 16.9 in Appalachian males, 16.7 in non-Appalachian males, 10.4 in Appalachian females, and 10.2 in non-Appalachian females.

“Appalachia continues to have higher cancer incidence rates than the rest of the country,” Wilson said. “But a promising finding is that we’re seeing the gap narrow in the incidence rates between Appalachia and non-Appalachia since the 2007 analysis, with the exception of cancers of the oral cavity and pharynx, larynx, lung and bronchus, and thyroid.”

“This study helps identify types of cancer in the Appalachian region that could be reduced through more evidence-based screening and detection. Our study also emphasizes the importance of lifestyle changes needed to prevent and reduce cancer burden.”

The researchers noted that this study did not differentiate urban versus rural areas within each county, and data on screening and risk factors were based on self-reported responses.

Furthermore, cancer IRs were calculated for all ages combined and were not evaluated by age groups. Future analyses will be targeted toward capturing these finer details, Wilson said.

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

New research suggests that people living in the Appalachian region of the US are more likely to develop cancer than people in the rest of the country.

The study showed that Appalachians had a significantly higher incidence of cancer overall and higher rates of many solid tumor malignancies.

However, lymphoma rates were similar between Appalachians and non-Appalachians, and Appalachians had a significantly lower rate of myeloma.

This research was published in Cancer Epidemiology, Biomarkers & Prevention.

“The Appalachian region, which extends from parts of New York to Mississippi, spans 420 counties in 13 US states, and about 25 million people reside in this area,” said study author Reda Wilson, MPH, of the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia.

“This region is primarily made up of rural areas, with persistent poverty levels that are at least 20%, which is higher than the national average.”

In 2007, the CDC’s National Program of Cancer Registries (NPCR) published a comprehensive evaluation of cancer incidence rates in Appalachia between 2001 and 2003.

The data showed higher cancer rates in Appalachia than in the rest of the US. However, this publication had some shortcomings, including data that were not available for analysis.

“The current analyses reported here were performed to update the earlier evaluation by expanding the diagnosis years from 2004 to 2011 and including data on 100% of the Appalachian and non-Appalachian populations,” Wilson said.

For this study, Wilson and her colleagues used data from the NPCR and the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program. Together, NPCR and SEER cover 100% of the US population.

The researchers analyzed the Appalachian population by region (north, central, and south Appalachia), gender, race (black and white only), and Appalachian Regional Commission-designated economic status (distressed, at-risk, transitional, competitive, and attainment). And the team compared these data with data on the non-Appalachian population.

The results showed that cancer incidence rates (IRs) were elevated among Appalachians regardless of how they were categorized. The IRs were per 100,000 people, age-adjusted to the 2000 US standard population.

The IR for all cancers was 565.8 for males in Appalachia and 543.0 for non-Appalachian males (P<0.05). And the cancer IRs for females were 428.7 in Appalachia and 418.2 outside the region (P<0.05).

There was no significant difference between the regions in IRs for lymphomas. The Hodgkin lymphoma IRs were 3.1 in Appalachian males, 3.2 in non-Appalachian males, and 2.5 for females in both regions.

The non-Hodgkin lymphoma IRs were 23.3 in Appalachian males, 23.4 in non-Appalachian males, 16.4 in Appalachian females, and 16.3 in non-Appalachian females.

Myeloma IRs were significantly lower in Appalachia (P<0.05). The myeloma IRs were 7.3 in Appalachian males, 7.5 in non-Appalachian males, 4.7 in Appalachian females, and 4.9 in non-Appalachian females.

There was no significant difference in leukemia IRs among males, but females in Appalachia had a significantly higher leukemia IR (P<0.05). The leukemia IRs were 16.9 in Appalachian males, 16.7 in non-Appalachian males, 10.4 in Appalachian females, and 10.2 in non-Appalachian females.

“Appalachia continues to have higher cancer incidence rates than the rest of the country,” Wilson said. “But a promising finding is that we’re seeing the gap narrow in the incidence rates between Appalachia and non-Appalachia since the 2007 analysis, with the exception of cancers of the oral cavity and pharynx, larynx, lung and bronchus, and thyroid.”

“This study helps identify types of cancer in the Appalachian region that could be reduced through more evidence-based screening and detection. Our study also emphasizes the importance of lifestyle changes needed to prevent and reduce cancer burden.”

The researchers noted that this study did not differentiate urban versus rural areas within each county, and data on screening and risk factors were based on self-reported responses.

Furthermore, cancer IRs were calculated for all ages combined and were not evaluated by age groups. Future analyses will be targeted toward capturing these finer details, Wilson said.

Joseph Panoff, MD

Photo courtesy of Sylvester

Comprehensive Cancer Center

In a retrospective study, young African American patients with Hodgkin lymphoma (HL) had inferior long-term overall survival when compared to their Hispanic and white peers.

Hispanic and white patients had similar rates of overall survival, but Hispanic males had inferior disease-specific survival compared to white males.

The study, published in Pediatric Blood & Cancer, is the largest yet on racial and ethnic disparity in the pediatric HL population in the US.

“Little was known about the association between race, ethnicity, and survival in the pediatric Hodgkin lymphoma population,” said Joseph Panoff, MD, of Sylvester Comprehensive Cancer Center at the University of Miami in Florida.

“Our study showed that African American children and teenagers had worse overall survival than whites and Hispanics at 25 years after diagnosis. We also found that Hispanic males had inferior disease-specific survival compared to white males.”

Dr Panoff and his colleagues analyzed data from more than 7800 patients listed in the Florida Cancer Data System (FCDS) and the National Institutes of Health’s Surveillance, Epidemiology, and End Results Program (SEER).

The patients were 0.1 to 21 years of age (average, 17 years) and were diagnosed with HL from 1981 to 2010.

In the FCDS cohort, which was significantly smaller than the SEER cohort (1778 vs 6027), African Americans had a 33% overall survival rate at 25 years, compared to 44.7% for Hispanics and 49.2% for whites (P=0.0005).

In a multivariate analysis, African American race was associated with inferior overall survival. The hazard ratio was 1.81 (P=0.0003).

Patients in the FCDS cohort had worse overall survival than patients in the SEER cohort, indicating that patients treated in Florida have worse outcomes when compared to the rest of the nation.

In the SEER cohort, the overall survival rate at 25 years was 74.2% for African Americans and 82% for both Hispanic and white patients (P=0.0005). Disease-specific survival rates at 25 years were 85.7% for African Americans, 88.1% for Hispanics, and 90.8% for whites (P=0.0002).

The researchers noted that Hispanic males had inferior disease-specific survival when compared to white males—84.8% and 90.6%, respectively (P=0.0478).

And Hispanic race was a predictor of inferior disease-specific survival in multivariate analysis. The hazard ratio was 1.238 (P<0.0001).

“Clearly, racial and ethnic disparities persist in the pediatric Hodgkin lymphoma population, despite modern treatment, particularly in Florida,” Dr Panoff noted. “The underlying causes of these disparities are complex and need further explanation.”

As a next step, Dr Panoff suggests identifying flaws in the diagnostic and treatment process with regard to African American and Hispanic patients.

“It is important to identify sociocultural factors and health behaviors that negatively affect overall survival in African American patients and disease-free survival in Hispanic males,” he said. “The fact that the entire Florida cohort seems to have worse overall survival than patients in the rest of the country is a new finding that requires further research.”

Joseph Panoff, MD

Photo courtesy of Sylvester

Comprehensive Cancer Center

In a retrospective study, young African American patients with Hodgkin lymphoma (HL) had inferior long-term overall survival when compared to their Hispanic and white peers.

Hispanic and white patients had similar rates of overall survival, but Hispanic males had inferior disease-specific survival compared to white males.

The study, published in Pediatric Blood & Cancer, is the largest yet on racial and ethnic disparity in the pediatric HL population in the US.

“Little was known about the association between race, ethnicity, and survival in the pediatric Hodgkin lymphoma population,” said Joseph Panoff, MD, of Sylvester Comprehensive Cancer Center at the University of Miami in Florida.

“Our study showed that African American children and teenagers had worse overall survival than whites and Hispanics at 25 years after diagnosis. We also found that Hispanic males had inferior disease-specific survival compared to white males.”

Dr Panoff and his colleagues analyzed data from more than 7800 patients listed in the Florida Cancer Data System (FCDS) and the National Institutes of Health’s Surveillance, Epidemiology, and End Results Program (SEER).

The patients were 0.1 to 21 years of age (average, 17 years) and were diagnosed with HL from 1981 to 2010.

In the FCDS cohort, which was significantly smaller than the SEER cohort (1778 vs 6027), African Americans had a 33% overall survival rate at 25 years, compared to 44.7% for Hispanics and 49.2% for whites (P=0.0005).

In a multivariate analysis, African American race was associated with inferior overall survival. The hazard ratio was 1.81 (P=0.0003).

Patients in the FCDS cohort had worse overall survival than patients in the SEER cohort, indicating that patients treated in Florida have worse outcomes when compared to the rest of the nation.

In the SEER cohort, the overall survival rate at 25 years was 74.2% for African Americans and 82% for both Hispanic and white patients (P=0.0005). Disease-specific survival rates at 25 years were 85.7% for African Americans, 88.1% for Hispanics, and 90.8% for whites (P=0.0002).

The researchers noted that Hispanic males had inferior disease-specific survival when compared to white males—84.8% and 90.6%, respectively (P=0.0478).

And Hispanic race was a predictor of inferior disease-specific survival in multivariate analysis. The hazard ratio was 1.238 (P<0.0001).

“Clearly, racial and ethnic disparities persist in the pediatric Hodgkin lymphoma population, despite modern treatment, particularly in Florida,” Dr Panoff noted. “The underlying causes of these disparities are complex and need further explanation.”

As a next step, Dr Panoff suggests identifying flaws in the diagnostic and treatment process with regard to African American and Hispanic patients.

“It is important to identify sociocultural factors and health behaviors that negatively affect overall survival in African American patients and disease-free survival in Hispanic males,” he said. “The fact that the entire Florida cohort seems to have worse overall survival than patients in the rest of the country is a new finding that requires further research.”

Joseph Panoff, MD

Photo courtesy of Sylvester

Comprehensive Cancer Center

In a retrospective study, young African American patients with Hodgkin lymphoma (HL) had inferior long-term overall survival when compared to their Hispanic and white peers.

Hispanic and white patients had similar rates of overall survival, but Hispanic males had inferior disease-specific survival compared to white males.

The study, published in Pediatric Blood & Cancer, is the largest yet on racial and ethnic disparity in the pediatric HL population in the US.

“Little was known about the association between race, ethnicity, and survival in the pediatric Hodgkin lymphoma population,” said Joseph Panoff, MD, of Sylvester Comprehensive Cancer Center at the University of Miami in Florida.

“Our study showed that African American children and teenagers had worse overall survival than whites and Hispanics at 25 years after diagnosis. We also found that Hispanic males had inferior disease-specific survival compared to white males.”

Dr Panoff and his colleagues analyzed data from more than 7800 patients listed in the Florida Cancer Data System (FCDS) and the National Institutes of Health’s Surveillance, Epidemiology, and End Results Program (SEER).

The patients were 0.1 to 21 years of age (average, 17 years) and were diagnosed with HL from 1981 to 2010.

In the FCDS cohort, which was significantly smaller than the SEER cohort (1778 vs 6027), African Americans had a 33% overall survival rate at 25 years, compared to 44.7% for Hispanics and 49.2% for whites (P=0.0005).

In a multivariate analysis, African American race was associated with inferior overall survival. The hazard ratio was 1.81 (P=0.0003).

Patients in the FCDS cohort had worse overall survival than patients in the SEER cohort, indicating that patients treated in Florida have worse outcomes when compared to the rest of the nation.

In the SEER cohort, the overall survival rate at 25 years was 74.2% for African Americans and 82% for both Hispanic and white patients (P=0.0005). Disease-specific survival rates at 25 years were 85.7% for African Americans, 88.1% for Hispanics, and 90.8% for whites (P=0.0002).

The researchers noted that Hispanic males had inferior disease-specific survival when compared to white males—84.8% and 90.6%, respectively (P=0.0478).

And Hispanic race was a predictor of inferior disease-specific survival in multivariate analysis. The hazard ratio was 1.238 (P<0.0001).

“Clearly, racial and ethnic disparities persist in the pediatric Hodgkin lymphoma population, despite modern treatment, particularly in Florida,” Dr Panoff noted. “The underlying causes of these disparities are complex and need further explanation.”

As a next step, Dr Panoff suggests identifying flaws in the diagnostic and treatment process with regard to African American and Hispanic patients.

“It is important to identify sociocultural factors and health behaviors that negatively affect overall survival in African American patients and disease-free survival in Hispanic males,” he said. “The fact that the entire Florida cohort seems to have worse overall survival than patients in the rest of the country is a new finding that requires further research.”

Child with cancer

Photo by Bill Branson

Results of a large study suggest that long-term survivors of childhood cancer are living longer, partly due to a reduction in the use of certain treatments.

The 15-year death rate among the more than 34,000 childhood cancer survivors studied decreased steadily from 1970 onward.

And this decline coincided with changes in pediatric cancer therapy, including reductions in the use and dose of radiation therapy and anthracyclines.

These therapies are known to put cancer survivors at increased risk for developing second malignancies, heart failure, and other serious health problems.

“This study is the first to show that younger survivors from more recent treatment eras are less likely to die from the late effects of cancer treatment and more likely to enjoy longer lives,” said study author Greg Armstrong, MD, of St. Jude Children's Research Hospital in Memphis, Tennessee.

He and his colleagues reported these results in NEJM.

The study included 34,033 subjects who had been diagnosed with cancer and received treatment between 1970 and 1999 when they were age 20 or younger. All patients lived at least 5 years after their cancers were discovered and were considered long-term survivors.

Changes in mortality

At a median follow-up of 21 years (range, 5 to 38), there were 3958 deaths. Forty-one percent of deaths (n=1618) were considered health-related. This included 746 deaths from subsequent neoplasms, 241 from cardiac causes, 137 from pulmonary causes, and 494 from other causes.

The 15-year death rate (death from any cause) fell from 12.4% in the early 1970s to 6% in the 1990s (P<0.001). During the same period, the rate of death from health-related causes fell from 3.5% to 2.1% (P<0.001).

The researchers said there were significant reductions across treatment eras in the rates of death from any health-related cause among patients with acute lymphoblastic leukemia (ALL), Hodgkin lymphoma (HL), Wilms’ tumor, and astrocytoma, but not among patients with other cancers.

The rate of health-related death among ALL patients fell from 3.2% in the early 1970s to 2.1% in the 1990s (P<0.001). The rate fell from 5.3% to 2.6% (P=0.006) for HL patients, from 2.6% to 0.4% (P=0.005) for Wilms’ tumor patients, and from 4.7% to 1.8% (P=0.02) for astrocytoma patients.

The researchers said these reductions in mortality were attributable to decreases in the rates of death from subsequent neoplasm (P<0.001), cardiac causes (P<0.001), and pulmonary causes (P=0.04).

Treatment changes

The overall use of anthracyclines fell from 73% in the 1970s to 42% in the 1990s. And the use of any radiation decreased from 77% to 41%.

The use of cranial radiotherapy for ALL fell from 85% to 19%. The use of abdominal radiotherapy for Wilms’ tumor decreased from 78% to 43%. And the use of chest radiotherapy for HL fell from 87% to 61%.

The researchers noted that temporal reductions in 15-year rates of death from health-related causes followed temporal reductions in therapeutic exposure for patients with ALL, HL, Wilms’ tumor, and astrocytoma.

However, when the team adjusted their analysis for therapy (eg, anthracycline dose), the effect of the treatment era on the relative rate of death from health-related causes was attenuated in ALL (unadjusted relative rate=0.88, adjusted relative rate=1.02) and Wilms’ tumor (0.68 and 0.80, respectively) but not in HL (0.79 in both models) and astrocytoma (0.81 and 0.82, respectively).

Still, the researchers said the results of this study suggest the strategy of lowering therapeutic exposure has contributed to the decline in late mortality among 5-year survivors of childhood cancer.

Child with cancer

Photo by Bill Branson

Results of a large study suggest that long-term survivors of childhood cancer are living longer, partly due to a reduction in the use of certain treatments.

The 15-year death rate among the more than 34,000 childhood cancer survivors studied decreased steadily from 1970 onward.

And this decline coincided with changes in pediatric cancer therapy, including reductions in the use and dose of radiation therapy and anthracyclines.

These therapies are known to put cancer survivors at increased risk for developing second malignancies, heart failure, and other serious health problems.

“This study is the first to show that younger survivors from more recent treatment eras are less likely to die from the late effects of cancer treatment and more likely to enjoy longer lives,” said study author Greg Armstrong, MD, of St. Jude Children's Research Hospital in Memphis, Tennessee.

He and his colleagues reported these results in NEJM.

The study included 34,033 subjects who had been diagnosed with cancer and received treatment between 1970 and 1999 when they were age 20 or younger. All patients lived at least 5 years after their cancers were discovered and were considered long-term survivors.

Changes in mortality

At a median follow-up of 21 years (range, 5 to 38), there were 3958 deaths. Forty-one percent of deaths (n=1618) were considered health-related. This included 746 deaths from subsequent neoplasms, 241 from cardiac causes, 137 from pulmonary causes, and 494 from other causes.

The 15-year death rate (death from any cause) fell from 12.4% in the early 1970s to 6% in the 1990s (P<0.001). During the same period, the rate of death from health-related causes fell from 3.5% to 2.1% (P<0.001).

The researchers said there were significant reductions across treatment eras in the rates of death from any health-related cause among patients with acute lymphoblastic leukemia (ALL), Hodgkin lymphoma (HL), Wilms’ tumor, and astrocytoma, but not among patients with other cancers.

The rate of health-related death among ALL patients fell from 3.2% in the early 1970s to 2.1% in the 1990s (P<0.001). The rate fell from 5.3% to 2.6% (P=0.006) for HL patients, from 2.6% to 0.4% (P=0.005) for Wilms’ tumor patients, and from 4.7% to 1.8% (P=0.02) for astrocytoma patients.

The researchers said these reductions in mortality were attributable to decreases in the rates of death from subsequent neoplasm (P<0.001), cardiac causes (P<0.001), and pulmonary causes (P=0.04).

Treatment changes

The overall use of anthracyclines fell from 73% in the 1970s to 42% in the 1990s. And the use of any radiation decreased from 77% to 41%.

The use of cranial radiotherapy for ALL fell from 85% to 19%. The use of abdominal radiotherapy for Wilms’ tumor decreased from 78% to 43%. And the use of chest radiotherapy for HL fell from 87% to 61%.

The researchers noted that temporal reductions in 15-year rates of death from health-related causes followed temporal reductions in therapeutic exposure for patients with ALL, HL, Wilms’ tumor, and astrocytoma.

However, when the team adjusted their analysis for therapy (eg, anthracycline dose), the effect of the treatment era on the relative rate of death from health-related causes was attenuated in ALL (unadjusted relative rate=0.88, adjusted relative rate=1.02) and Wilms’ tumor (0.68 and 0.80, respectively) but not in HL (0.79 in both models) and astrocytoma (0.81 and 0.82, respectively).

Still, the researchers said the results of this study suggest the strategy of lowering therapeutic exposure has contributed to the decline in late mortality among 5-year survivors of childhood cancer.

Child with cancer

Photo by Bill Branson

Results of a large study suggest that long-term survivors of childhood cancer are living longer, partly due to a reduction in the use of certain treatments.

The 15-year death rate among the more than 34,000 childhood cancer survivors studied decreased steadily from 1970 onward.

And this decline coincided with changes in pediatric cancer therapy, including reductions in the use and dose of radiation therapy and anthracyclines.

These therapies are known to put cancer survivors at increased risk for developing second malignancies, heart failure, and other serious health problems.

“This study is the first to show that younger survivors from more recent treatment eras are less likely to die from the late effects of cancer treatment and more likely to enjoy longer lives,” said study author Greg Armstrong, MD, of St. Jude Children's Research Hospital in Memphis, Tennessee.

He and his colleagues reported these results in NEJM.

The study included 34,033 subjects who had been diagnosed with cancer and received treatment between 1970 and 1999 when they were age 20 or younger. All patients lived at least 5 years after their cancers were discovered and were considered long-term survivors.

Changes in mortality

At a median follow-up of 21 years (range, 5 to 38), there were 3958 deaths. Forty-one percent of deaths (n=1618) were considered health-related. This included 746 deaths from subsequent neoplasms, 241 from cardiac causes, 137 from pulmonary causes, and 494 from other causes.

The 15-year death rate (death from any cause) fell from 12.4% in the early 1970s to 6% in the 1990s (P<0.001). During the same period, the rate of death from health-related causes fell from 3.5% to 2.1% (P<0.001).

The researchers said there were significant reductions across treatment eras in the rates of death from any health-related cause among patients with acute lymphoblastic leukemia (ALL), Hodgkin lymphoma (HL), Wilms’ tumor, and astrocytoma, but not among patients with other cancers.

The rate of health-related death among ALL patients fell from 3.2% in the early 1970s to 2.1% in the 1990s (P<0.001). The rate fell from 5.3% to 2.6% (P=0.006) for HL patients, from 2.6% to 0.4% (P=0.005) for Wilms’ tumor patients, and from 4.7% to 1.8% (P=0.02) for astrocytoma patients.

The researchers said these reductions in mortality were attributable to decreases in the rates of death from subsequent neoplasm (P<0.001), cardiac causes (P<0.001), and pulmonary causes (P=0.04).

Treatment changes

The overall use of anthracyclines fell from 73% in the 1970s to 42% in the 1990s. And the use of any radiation decreased from 77% to 41%.

The use of cranial radiotherapy for ALL fell from 85% to 19%. The use of abdominal radiotherapy for Wilms’ tumor decreased from 78% to 43%. And the use of chest radiotherapy for HL fell from 87% to 61%.

The researchers noted that temporal reductions in 15-year rates of death from health-related causes followed temporal reductions in therapeutic exposure for patients with ALL, HL, Wilms’ tumor, and astrocytoma.

However, when the team adjusted their analysis for therapy (eg, anthracycline dose), the effect of the treatment era on the relative rate of death from health-related causes was attenuated in ALL (unadjusted relative rate=0.88, adjusted relative rate=1.02) and Wilms’ tumor (0.68 and 0.80, respectively) but not in HL (0.79 in both models) and astrocytoma (0.81 and 0.82, respectively).

Still, the researchers said the results of this study suggest the strategy of lowering therapeutic exposure has contributed to the decline in late mortality among 5-year survivors of childhood cancer.

HIV budding from a

cultured lymphocyte

Image courtesy of the CDC

Patients with HIV-associated Hodgkin lymphoma may not be getting potentially curative treatment, according to a study published in the journal AIDS.

The study showed that 16% of HIV-positive patients did not receive treatment for their lymphoma, compared to 9% of Hodgkin lymphoma patients who were HIV-negative.

“Hodgkin lymphoma is generally believed to be highly curable,” said study author Adam Olszewski, MD, of Brown University in Providence, Rhode Island.

“We have an expectation to cure over 90% of early stage patients and even 70% to 80% of quite advanced cases.”

It hasn’t been clear whether HIV-positive patients with Hodgkin lymphoma survive the cancer as well as people who are HIV-negative. While some small studies, particularly in Europe, have shown that HIV status makes no difference to survival, observations in the US population suggest that being HIV-positive makes survival less likely.

The new study, which is the largest of its kind to date, may reconcile that conflict. It suggests that, in the US, the reason people with HIV seem to fare worse with the cancer is because they are less likely to be treated for it.

The study included 2090 cases of HIV-associated Hodgkin lymphoma recorded in the National Cancer Data Base between 2004 and 2012, as well as 41,846 cases of Hodgkin lymphoma in patients who were HIV-negative.

The unadjusted 5-year overall survival was 66% for HIV-positive patients and 80% for the HIV-negative population.

Among the HIV-positive patients, 81% received chemotherapy (12% in combination with radiation), 13% received any radiation therapy, and 16% received no treatment for their lymphoma. The corresponding numbers for HIV-negative patients were 87%, 31%, and 9%, respectively (P<0.00001 for all comparisons).

The researchers assessed patient- and disease-related factors associated with the risk of not receiving chemotherapy in the HIV-positive population.

And they found the risk was significantly higher for patients who were older than 40, male, “nonwhite” (black, Hispanic, or Asian/”other”), did not have health insurance, lived in areas with the lowest median income, and had early stage Hodgkin lymphoma or an undetermined histology.

Dr Olszewski said the lack of treatment among HIV-positive patients could be due to a lingering assumption that they won’t tolerate the treatment well. Or some patients may be declining treatment, either for HIV (thereby making them seem more vulnerable) or for the lymphoma itself.

He noted, however, that lymphoma treatment can be effective for and tolerated by HIV-positive patients, especially when the lymphoma subtype is known.

Among the patients who received chemotherapy in this study, there was no significant difference in the hazard of death between HIV-positive and HIV-negative patients who had one of the defined classical histologic subtypes: nodular sclerosis, mixed cellularity, lymphocyte-rich, or lymphocyte-depleted Hodgkin lymphoma. However, mortality was significantly higher for HIV-positive patients with an undetermined histologic subtype.

HIV budding from a

cultured lymphocyte

Image courtesy of the CDC

Patients with HIV-associated Hodgkin lymphoma may not be getting potentially curative treatment, according to a study published in the journal AIDS.

The study showed that 16% of HIV-positive patients did not receive treatment for their lymphoma, compared to 9% of Hodgkin lymphoma patients who were HIV-negative.

“Hodgkin lymphoma is generally believed to be highly curable,” said study author Adam Olszewski, MD, of Brown University in Providence, Rhode Island.

“We have an expectation to cure over 90% of early stage patients and even 70% to 80% of quite advanced cases.”

It hasn’t been clear whether HIV-positive patients with Hodgkin lymphoma survive the cancer as well as people who are HIV-negative. While some small studies, particularly in Europe, have shown that HIV status makes no difference to survival, observations in the US population suggest that being HIV-positive makes survival less likely.

The new study, which is the largest of its kind to date, may reconcile that conflict. It suggests that, in the US, the reason people with HIV seem to fare worse with the cancer is because they are less likely to be treated for it.

The study included 2090 cases of HIV-associated Hodgkin lymphoma recorded in the National Cancer Data Base between 2004 and 2012, as well as 41,846 cases of Hodgkin lymphoma in patients who were HIV-negative.

The unadjusted 5-year overall survival was 66% for HIV-positive patients and 80% for the HIV-negative population.

Among the HIV-positive patients, 81% received chemotherapy (12% in combination with radiation), 13% received any radiation therapy, and 16% received no treatment for their lymphoma. The corresponding numbers for HIV-negative patients were 87%, 31%, and 9%, respectively (P<0.00001 for all comparisons).

The researchers assessed patient- and disease-related factors associated with the risk of not receiving chemotherapy in the HIV-positive population.

And they found the risk was significantly higher for patients who were older than 40, male, “nonwhite” (black, Hispanic, or Asian/”other”), did not have health insurance, lived in areas with the lowest median income, and had early stage Hodgkin lymphoma or an undetermined histology.

Dr Olszewski said the lack of treatment among HIV-positive patients could be due to a lingering assumption that they won’t tolerate the treatment well. Or some patients may be declining treatment, either for HIV (thereby making them seem more vulnerable) or for the lymphoma itself.

He noted, however, that lymphoma treatment can be effective for and tolerated by HIV-positive patients, especially when the lymphoma subtype is known.

Among the patients who received chemotherapy in this study, there was no significant difference in the hazard of death between HIV-positive and HIV-negative patients who had one of the defined classical histologic subtypes: nodular sclerosis, mixed cellularity, lymphocyte-rich, or lymphocyte-depleted Hodgkin lymphoma. However, mortality was significantly higher for HIV-positive patients with an undetermined histologic subtype.

HIV budding from a

cultured lymphocyte

Image courtesy of the CDC

Patients with HIV-associated Hodgkin lymphoma may not be getting potentially curative treatment, according to a study published in the journal AIDS.

The study showed that 16% of HIV-positive patients did not receive treatment for their lymphoma, compared to 9% of Hodgkin lymphoma patients who were HIV-negative.

“Hodgkin lymphoma is generally believed to be highly curable,” said study author Adam Olszewski, MD, of Brown University in Providence, Rhode Island.

“We have an expectation to cure over 90% of early stage patients and even 70% to 80% of quite advanced cases.”

It hasn’t been clear whether HIV-positive patients with Hodgkin lymphoma survive the cancer as well as people who are HIV-negative. While some small studies, particularly in Europe, have shown that HIV status makes no difference to survival, observations in the US population suggest that being HIV-positive makes survival less likely.

The new study, which is the largest of its kind to date, may reconcile that conflict. It suggests that, in the US, the reason people with HIV seem to fare worse with the cancer is because they are less likely to be treated for it.

The study included 2090 cases of HIV-associated Hodgkin lymphoma recorded in the National Cancer Data Base between 2004 and 2012, as well as 41,846 cases of Hodgkin lymphoma in patients who were HIV-negative.

The unadjusted 5-year overall survival was 66% for HIV-positive patients and 80% for the HIV-negative population.

Among the HIV-positive patients, 81% received chemotherapy (12% in combination with radiation), 13% received any radiation therapy, and 16% received no treatment for their lymphoma. The corresponding numbers for HIV-negative patients were 87%, 31%, and 9%, respectively (P<0.00001 for all comparisons).

The researchers assessed patient- and disease-related factors associated with the risk of not receiving chemotherapy in the HIV-positive population.

And they found the risk was significantly higher for patients who were older than 40, male, “nonwhite” (black, Hispanic, or Asian/”other”), did not have health insurance, lived in areas with the lowest median income, and had early stage Hodgkin lymphoma or an undetermined histology.

Dr Olszewski said the lack of treatment among HIV-positive patients could be due to a lingering assumption that they won’t tolerate the treatment well. Or some patients may be declining treatment, either for HIV (thereby making them seem more vulnerable) or for the lymphoma itself.

He noted, however, that lymphoma treatment can be effective for and tolerated by HIV-positive patients, especially when the lymphoma subtype is known.

Among the patients who received chemotherapy in this study, there was no significant difference in the hazard of death between HIV-positive and HIV-negative patients who had one of the defined classical histologic subtypes: nodular sclerosis, mixed cellularity, lymphocyte-rich, or lymphocyte-depleted Hodgkin lymphoma. However, mortality was significantly higher for HIV-positive patients with an undetermined histologic subtype.

Women who become pregnant while in remission from Hodgkin lymphoma were not at increased risk for cancer relapse, according to an analysis of data from Swedish health care registries combined with medical records.

Of 449 women who were diagnosed with Hodgkin lymphoma between 1992 and 2009, 144 (32%) became pregnant during follow-up, which started 6 months after diagnosis, when the disease was assumed to be in remission. Only one of these women experienced a pregnancy-associated relapse, which was defined as a relapse occurring during pregnancy or within 5 years of delivery. Of the women who did not become pregnant, 46 had a relapse.

©Jupiterimages/thinkstockphotos.com

The effect of pregnancy on relapse has been a concern of patients and clinicians, but “our findings suggest that the risk of pregnancy-associated relapse does not need to be taken into account in family planning for women whose Hodgkin lymphoma is in remission,” said Caroline E. Weibull of Karolinska Institutet in Stockholm, and her associates.

The researchers used the nationwide “Swedish Cancer Register” to identify all cases of Hodgkin lymphoma (reporting is mandatory) and merged this data with clinical information from other registries and medical records.

The pregnancy rates were similar among women who had limited- and advanced-stage disease and among women with and without B symptoms at diagnosis – a finding that negates consideration of a so-called “healthy mother effect” in protecting against relapse, they wrote (J Clin Onc. 2015 Dec. 14 [doi:10.1200/JCO.2015.63.3446]).

The researchers also found that the absolute risk for relapse was highest in the first 2-3 years after diagnosis, which suggests that women should be advised, “if possible, to wait 2 years after cessation of treatment before becoming pregnant.” Additionally, the relapse rate more than doubled in women aged 30 years or older at diagnosis, compared with women aged 18-24 years at diagnosis – a finding consistent with previous research, they noted.

Women in the study were aged 18-40 at diagnosis. Follow-up ended on the date of relapse, the date of death, or at the end of 2010, whichever came first.

Women who become pregnant while in remission from Hodgkin lymphoma were not at increased risk for cancer relapse, according to an analysis of data from Swedish health care registries combined with medical records.

Of 449 women who were diagnosed with Hodgkin lymphoma between 1992 and 2009, 144 (32%) became pregnant during follow-up, which started 6 months after diagnosis, when the disease was assumed to be in remission. Only one of these women experienced a pregnancy-associated relapse, which was defined as a relapse occurring during pregnancy or within 5 years of delivery. Of the women who did not become pregnant, 46 had a relapse.

©Jupiterimages/thinkstockphotos.com

The effect of pregnancy on relapse has been a concern of patients and clinicians, but “our findings suggest that the risk of pregnancy-associated relapse does not need to be taken into account in family planning for women whose Hodgkin lymphoma is in remission,” said Caroline E. Weibull of Karolinska Institutet in Stockholm, and her associates.

The researchers used the nationwide “Swedish Cancer Register” to identify all cases of Hodgkin lymphoma (reporting is mandatory) and merged this data with clinical information from other registries and medical records.

The pregnancy rates were similar among women who had limited- and advanced-stage disease and among women with and without B symptoms at diagnosis – a finding that negates consideration of a so-called “healthy mother effect” in protecting against relapse, they wrote (J Clin Onc. 2015 Dec. 14 [doi:10.1200/JCO.2015.63.3446]).

The researchers also found that the absolute risk for relapse was highest in the first 2-3 years after diagnosis, which suggests that women should be advised, “if possible, to wait 2 years after cessation of treatment before becoming pregnant.” Additionally, the relapse rate more than doubled in women aged 30 years or older at diagnosis, compared with women aged 18-24 years at diagnosis – a finding consistent with previous research, they noted.

Women in the study were aged 18-40 at diagnosis. Follow-up ended on the date of relapse, the date of death, or at the end of 2010, whichever came first.

Women who become pregnant while in remission from Hodgkin lymphoma were not at increased risk for cancer relapse, according to an analysis of data from Swedish health care registries combined with medical records.

Of 449 women who were diagnosed with Hodgkin lymphoma between 1992 and 2009, 144 (32%) became pregnant during follow-up, which started 6 months after diagnosis, when the disease was assumed to be in remission. Only one of these women experienced a pregnancy-associated relapse, which was defined as a relapse occurring during pregnancy or within 5 years of delivery. Of the women who did not become pregnant, 46 had a relapse.

©Jupiterimages/thinkstockphotos.com

The effect of pregnancy on relapse has been a concern of patients and clinicians, but “our findings suggest that the risk of pregnancy-associated relapse does not need to be taken into account in family planning for women whose Hodgkin lymphoma is in remission,” said Caroline E. Weibull of Karolinska Institutet in Stockholm, and her associates.

The researchers used the nationwide “Swedish Cancer Register” to identify all cases of Hodgkin lymphoma (reporting is mandatory) and merged this data with clinical information from other registries and medical records.

The pregnancy rates were similar among women who had limited- and advanced-stage disease and among women with and without B symptoms at diagnosis – a finding that negates consideration of a so-called “healthy mother effect” in protecting against relapse, they wrote (J Clin Onc. 2015 Dec. 14 [doi:10.1200/JCO.2015.63.3446]).

The researchers also found that the absolute risk for relapse was highest in the first 2-3 years after diagnosis, which suggests that women should be advised, “if possible, to wait 2 years after cessation of treatment before becoming pregnant.” Additionally, the relapse rate more than doubled in women aged 30 years or older at diagnosis, compared with women aged 18-24 years at diagnosis – a finding consistent with previous research, they noted.

Women in the study were aged 18-40 at diagnosis. Follow-up ended on the date of relapse, the date of death, or at the end of 2010, whichever came first.

Moderator: Catherine Bollard, MD, FRACP, FRCPA¹

Discussants: Mitchell S. Cairo, MD²; Eric J. Lowe, MD³; Thomas G. Gross, MD, PhD⁴

Address for correspondence: Catherine Bollard, MD, FRACP, FRCPA, 111 Michigan Avenue, NW, 5th Floor Main, Suite 5225, Washington, DC 20010

E-mail: [email protected] 

Biographical sketch: From The George Washington University, School of Medicine and Health Sciences, Washington, DC1; Westchester Medical Center, New York Medical College, Valhalla, NY2; Children’s Hospital of the King’s Daughters, Norfolk, VA3; Center for Global Health at the National Cancer Institute, Rockville, MD

DR. BOLLARD: My name is Dr. Catherine Bollard. I'm Chief of the Division of Allergy and Immunology at Children's National Health System and the Chair of the NHL Committee of the Children's Oncology Group. I hope that today we can provide some clarity and give you some of our first-hand expertise and experience regarding some of the challenges and controversies of treating pediatric patients with non-Hodgkin lymphoma (NHL). Here with me are Drs. Mitchell Cairo, Chief of Pediatric Hematology/Oncology and Stem Cell Transplantation at New York Medical College in the Maria Fareri Children's Hospital, Westchester Medical Center; Eric Lowe, Division Director for Pediatric Hematology/Oncology at the Children's Hospital of the King's Daughters; and Thomas Gross, Deputy Director for Science at the Center for Global Health at the National Cancer Institute.

I'd like to start the questioning, firstly to Dr. Cairo, who recently published with a group of leaders in the pediatric lymphoma field, new staging and response classifications. Dr. Cairo, I’d like you to highlight how these are different from the current classifications, and what you see are the strengths and the limitations at this time.

DR. CAIRO: Thank you, Cath. The original staging classification was developed in the late 1970s by Dr. Murphy while she was at St. Jude's hospital, and either goes by the name the Murphy Staging Classification or the St. Jude's Classification. That classification I think was quite useful at that time when we recognized really only a couple subtypes of NHL, as well as the capabilities we had in those days both imaging as well as further molecular identification as well as trying to identify sites of spread. As some 35 years have evolved, new pathological entities have been identified, much more precise imaging techniques, new methods of detecting more evidence of minimal disease, and also identifying new organ sites of involvement, allowed the creation of a multidisciplinary international task force to look at how we could enhance the original observations by the St. Jude's group.

As Dr. Bollard pointed out, we eventually, over 9 years of evidence-based review, came up with an enhanced staging classification called the International Pediatric NHL Staging System (IPNHLSS).¹ In this new system we account for new histological subtypes, allow for different organ distributions, improve on the new imaging techniques to identify areas of involvement, and also to more molecularly identify extent of disease. I think the advantages are stated above. The disadvantage is that like all staging systems it's a breathing document. It will require international collaboration. As time evolves, this staging system will of course need to be updated as we gain new experience.

Briefly, in terms of the response classification that also came out of the same international multidisciplinary task force that was led by Dr. Sandlund at St. Jude's²; there had never been a response criteria that had been focused entirely in childhood and adolescent NHL. The previous response criteria had been developed by adult NHL investigators, and there was a need to develop the first response criteria for pediatric NHL because of different histologies, different sites of sanctuary disease, and now obviously enhanced imaging capabilities. That also now has been named the International Pediatric Non-Hodgkin Lymphoma Response Criteria (IPNHLRC)—hopefully for harmonizing a response across new studies, but also a breathing document that is going to be limited as we gain new knowledge into how we can better assess response as new techniques are developed.

DR. BOLLARD: I thank you very much for your detailed response. My next question is actually to Dr. Gross, who is currently chairing the international study for upfront diffuse large B-cell lymphoma and Burkitt lymphoma in pediatric young adults. I would like you to speak to a couple of issues, and you can put it in the context of the current randomized trial, looking at rituximab vs no rituximab for this disease. I think firstly it would be useful for you to speak to the implications of this new classification system as we go forward with choosing new therapeutic strategies for these patients, and in particular I'd like to focus on the newly diagnosed diffuse large B-cell lymphoma patients who are in that adolescent/young adult range.

I would also be interested in your opinion regarding how you would manage a patient who is 17 years old but is going to turn 18 tomorrow, and he comes to you with newly diagnosed diffuse large B-cell lymphoma. As you know, the adult oncologists treat diffuse large B-cell lymphoma different to Burkitt lymphoma, and in pediatrics we generally treat these diseases the same. Do you tell this patient that you will treat him today on a pediatric regimen, or do you tell him to go tomorrow, when he's 18, to be treated by an adult oncologist? I would like you to justify your answer please.

DR. GROSS: First to discuss the implications of the new staging as it applies to the current international trial. As Dr. Cairo pointed out, this was developed through a literature review and evidence based analyses, but like any new staging system, the value of staging is to provide us with information that can try to help us to identify patients to improve their outcome. Essentially, staging is to help direct therapy or provide prognosis for outcome, and the only way to do that is to test new systems or classifications in a prospective fashion. Indeed, that is what we are trying to do with this international effort.

This international effort, just as an aside, illustrates one of the challenges of all rare cancers, but particularly pediatrics. In pediatric mature B-cell NHL, both large-cell and Burkitt, we are now at a cure rate of about 90%. To make advances, we don't have enough patients seen in North America and Australia, and it requires international collaboration. This trial, to get 600 patients randomized, it will take 7 years with 14 countries participating—that is one of the challenges, certainly, we have with pediatric NHL. Also, we want to try to gain as much information as possible, not just to the effect of rituximab as Dr. Bollard said, but also to test other questions such as the role or the value in validating this new staging system.

To talk about the controversy of treatment, certainly we know that there is a very different approach in pediatrics. For many years, we have treated diffuse large B-cell lymphoma just like Burkitt. This is a very important delineation when you're seen by a medical oncologist because the treatment for diffuse large B-cell lymphoma is outpatient therapy, ie rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP). Treatment for Burkitt is inpatient with high doses of methotrexate, but other higher doses of the same agents used to treat diffuse large B-cell lymphoma. The question is, do we really need to treat all the pediatric diffuse large B-cell lymphoma with these aggressive Burkitt regimens? I think one of the things that is encouraging to me as a pediatric oncologist is that we are beginning to learn that the biology is very different. Though the disease looks the same under the microscope or by flow cytometry, when you look at it genetically it's quite different. We know now that the younger the patient is with diffuse large B-cell lymphoma, even though it looks for all intents and purposes like the same disease as seen in adults, when you look at the genetics, many times, as high as 30% of the time, it will be genetically the same as a Burkitt lymphoma. I think when you're talking about young patients we can easily justify treating them both the same because the biology would suggest that a good number of patients would need Burkitt therapy to be cured.

Now, that changes over time, so that it appears that sometime in young adulthood, maybe somewhere between 25 and 35 years of age, you don't see the genetic disease that looks like diffuse large B-cell lymphoma, but is genetically Burkitt lymphoma. As for the 18-year-old patient that Dr. Bollard was posing to me, I've had several patients like this. I go through the pluses and minuses of the therapy, inpatient vs outpatient, but also the potential long-term side effects. The outpatient therapy has potentially more long-term side effects as far as potential infertility and potential heart damage. Every time I have given the choice to the family and the patient, the teenager has always chosen the outpatient therapy that you would get as an adult, and the parents always say they would rather have the inpatient therapy, and that spending a couple of days in the hospital to try to reduce the chance of long-term damage is their choice. It's a very interesting dynamic and I think sometimes the issues that go into choice of treatment are quite variable. My personal opinion is that hopefully in the future we will be able to have a better understanding of biology, so that when we see these patients, be they 18 or 25 years old, we're not looking at what it looks like under the microscope or who they see, and what they're used to giving, but the biology will determine which therapy is more likely to cure them. Right now we don't have that ability in most of the patients.

DR. BOLLARD: Thank you, Dr. Gross. Again, another very comprehensive answer to a difficult question. I'm actually going to push this back to Dr. Cairo and then impose the same soon to be 18-year-old patient to you. This time, he's coming to you with relapsed diffuse large B-cell lymphoma. What are you going to tell him? Are you going to treat him today on pediatric protocols, or will you wait until tomorrow when he could have access to adult protocols?

DR. CAIRO: I think the results are relatively similar, but, in part, the answer to the question is of course based on what their original therapy was. If the original therapy was the pediatric-inspired type of treatment, I think there's a world of experience of what are some of the best pediatric-inspired regimens to use for retrieval. If, however, the original therapy was an adult-inspired regimen, then I think the options are open because the disease may not be as resistant in that setting; therefore, one would want to consider all the adult type of retrieval regimens in that case, because that group of patients—at least in the adult experience—tend to have disease that may be more responsive because they're not as resistant to the higher dose and multi-agent therapy that a pediatric-inspired regimen would have given them had they been treated that way.

DR. BOLLARD: I was also trying to ask you to speak to the access that an 18-year-old might have to novel therapies that a 17-year-old might not. How do you address that issue?

DR. CAIRO: That's an excellent question. I think that for first relapse or first induction failure most of the retrieval regimens, the first line regimens, that are available, either pediatric inspired or adult inspired, probably don't require an investigational agent that an 18-year-old might have access to if he was being treated on an adult type of regimen. However, I would strongly encourage an 18-year-old who failed one retrieval regimen to consider experimental therapy. There I think the access to new agents—if you're 18 or over—are so much greater that I would encourage them to be treated on an adult retrieval regimen, where some of the newer agents may be investigational, are not available to a pediatric program.

DR. BOLLARD: Thank you very much, Dr. Cairo. I have one last question on the B-cell diseases before I move to Dr. Lowe, and the last question goes to Dr. Gross. Would you recommend that a patient with relapsed Burkitt lymphoma—now increasingly rare—be treated with salvage chemotherapy and then autologous transplant or allogeneic stem cell transplant?  

DR. GROSS: As the others on this discussion know, we performed an analysis from data in the Center for International Blood and Marrow Transplant Research (CIBMTR), and the problem is that Burkitt lymphoma tends to reoccur so rapidly after transplant. The median time to relapse is 3 months after transplant. We could not find a difference in the outcome between autografts and allografts because of its early reoccurrence. That said, my personal opinion is, since we know that Burkitt lymphoma is a hematologically spread disease, that I always prefer a donor source where I know they're not going to have tumor cells in them, which is an allogeneic donor. I always prefer an allogeneic donor, because I know it's tumor-free, but also it gives us an opportunity, if the disease will stay under control long enough, to potentially get an immune response against any residual tumor. For that reason, I recommend an allogeneic donor if it can be found readily.

DR. BOLLARD: Thank you very much, Dr. Gross. Now, on to Dr. Lowe, and Dr. Lowe's particular area of expertise is in anaplastic large cell lymphoma (ALCL) and T-cell diseases. I was wondering if you could explain to me the difference between T-cell lymphoblastic lymphoma and T-cell acute lymphoblastic leukemia (ALL), specifically since the World Health Organization (WHO) groups these two disease entities together as T-lymphoblastic leukemia/lymphoma. If you could clarify that classification that would be very helpful.

DR. LOWE: As you well know, many physicians believe that T-cell lymphoblastic leukemia and T-cell lymphoblastic lymphoma are very similar diseases, but they are not exactly the same disease although we sometimes treat them very similar. We know that T-cells do not mature in bone marrow but rather they are thymic driven cells. Because of this, there are distinct differences between the leukemia and lymphoma. For example, we know that the genetics between the two—although in limited samples—are not always the same, including in prognostic. Just one example, loss of heterozygosity at 6Q has been shown to be prognostically important in lymphoblastic lymphoma but not in T-cell ALL. I think the real challenge is to figure out what the differences are. I think we could argue that potentially, T-ALL is stage four T-cell lymphoblastic lymphoma.

I think that the WHO classifying the two diseases as one entity with T-lymphoblastic leukemia/lymphoma has hindered a little in the advancement of recognizing the differences in that many people assume that they're the same disease. When you look up from a pathological standpoint and you say, well, they're clearly the same disease because they're listed as a single entity, and when you look up treatment, you say, well they're treated very similar, so they must be the same disease. I think that does us a little disservice in trying to advance the field forward, because I think getting lymphoblastic lymphoma samples, which is challenging, is extremely important to determine the genetic drivers of this disease.

DR. BOLLARD: Thank you very much, Dr. Lowe. I would also like you to discuss how ALCL differs between the pediatric and the adult populations, and how that dictates how you would treat those two patient populations.

DR. LOWE: So, ALCL really has a much shorter span in terms of its description pathologically. It was not described by itself until the mid 1980s. In the mid 1990s it started entering classification schemes. It wasn't until 2008 that the WHO separated out three distinct entities within ALCL. You have anaplastic lymphoma kinase (ALK)-positive ALCL, ALK-negative ALCL, and primary cutaneous ALCL. This is a great example where these three different entities have very different epidemiology, very different treatment strategies, and the fact that they are broken up has really helped move the field forward. For example, ALK-positive ALCL is really a disease of children, adolescents, and young adults. It's the most common ALCL by far in that age group. It's extremely rare to have an ALK-negative ALCL, and the pathological reason for the disease with ALK-positive ALCL is a translocation involving the ALK gene leads directly to oncogenesis.

Because of this, we have started to develop treatments that are designed to target this specific oncogenic driving translocation. This is in direct comparison to an ALK-negative ALCL, which is primarily a disease of older individuals, most commonly in their 50s and 60s. The outcome for this disease is consistently poorer than for ALK-positive disease. The treatment, while sometimes the same, is changing now that we have targets for the tyrosine kinase that is driving the ALK-positive ALCL. I think separating these two out has been a huge advantage in terms of figuring out what to do with pediatric ALCL because the 95 plus percent of ALCLs in pediatrics and young adults are ALK-positive.

Primary cutaneous ALCL is almost a completely different entity in and of itself, although it shares the same name. The primary cutaneous ALCLs are usually not treated on similar studies as the systemic forms of ALCL. The primary cutaneous form has different characteristics in terms of location, age, treatment, and natural course. The vast majority does not develop into systemic disease, and thus the treatment is very different. I think ALCL is a very good example where the different pathological entities have led to very different treatments based on what is driving the cancer.

DR. BOLLARD: Thanks, Dr. Lowe. I think that's very important to emphasize how ALK-positivity is more common in children than in adults, and the successes of crizotinib, even in phase 1 in pediatric patients with ALCL. My question now is given the success of this targeted agent in the relapse setting, even in phase 1, do you still see a role for allogeneic stem cell transplant for those patients who have relapsed after conventional therapy?

DR. LOWE: I do still see a role, but I'm not sure how much that role will shrink over time as we learn more and more about this disease. We know that there are very high risk patients that relapse or progress while receiving traditional chemotherapy. Those patients typically have achieved the best outcome with an allogeneic transplant. That said, I think crizotinib and other ALK inhibitors are changing the landscape of treatment for ALK-positive ALCL very fast. We know that some patients who are refractory to many other treatments go into remission with these drugs, and while I think that the role of allogeneic transplant is still there, I think that it may be changing over time. The other decision that I think will be difficult in terms of allogeneic transplant is for patients who receive ALK-inhibitors, like crizotinib, for initial treatment and then relapse. Many patients in that situation currently will end up having an allogenic transplant. However, one can argue that very much like chronic myeloid leukemia, these patients might be rescued without an allogeneic transplant using a second line ALK inhibitor. All of these things, obviously, we hope to know over time, but at this point in time are unknown.

DR. BOLLARD: Thank you very much. I'll take you out of the hot seat now. All of us talked about the concept of the importance of knowing the biology of what we're treating, and with the advent of novel targeted therapies, this concept of precision medicine is becoming increasingly important, ie, targeting the individual patient's tumor with the appropriate targeted agents for their tumor. This is maybe a question for Dr. Gross first, and then Dr. Cairo. What do you see are the challenges for being able to obtain the tissue from pediatric patients to perform these important and critical tests that will be needed as we move the field forward for the management of pediatric patients with NHL?

DR. GROSS: I think that the number one barrier is, as the technology improves to be able to make the essential diagnosis, we need less and less tissue for the pathologist. It becomes increasingly more of a challenge to obtain extra tissue because the standard of practice is to get just enough to make the diagnosis. Unless we can address this challenge, it's going to be extremely difficult.

DR. BOLLARD: Dr. Cairo, do you want to speak to that, since you recently completed a Children’s Oncology Group trial for Burkitt and diffuse large B-cell lymphoma?

DR. CAIRO: Thank you. I agree with Dr. Gross, and that particular trial, despite it being one of the primary objectives and also many of those patients actually had bone marrow involvement, which is the area that we access the easiest as the acute lymphoblastic leukemia colleagues have taught us. We still only were able to get 11 of some 90 patients entered on study, to have specimens sent. That being said, having just come back from the Fifth International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma, It appears that the Europeans have been much more successful in obtaining specimens for biology studies in particular, the future precision medicine-based trials. We should try to learn a little bit from our European colleagues, who seem to have a much higher percentage of getting specimens, and we need to make every effort, as Dr. Gross said of encouraging our colleagues, that this is as important as making the diagnosis. We face an uphill battle because of our high cure rate, the biology is often considered a second thought sometimes. Europeans are better than us at obtaining biological specimens and we need to compete to achieve the level that they have achieved in Europe.

DR. GROSS: It's almost a catch-22. We know from other diseases in pediatric oncology, but also in adult oncology, that once we are able to demonstrate that the biology will make a difference in the treatment and outcome of the patient, then we're able to get the tissue needed. I think a good example of that is neuroblastoma. However, we can't make those discoveries unless we get enough tissue to study. We're in this catch-22, we cannot demonstrate that the biology makes a difference, unless we will get the tissue for research.

DR. LOWE: I'd like to add one other point to this. I think the rarity of the diseases and the large number of centers that treat the patients also hinders obtaining pathological samples. Because pediatric NHL is a relatively rare disease, you can’t have a single champion for obtaining biology at one institution that can accomplish anything without many other institutions. It requires a large group effort which is more difficult than a single institution collecting colon cancer samples, for example, where you really only need one institution, one champion, one pathologist, and you have all the samples you need.

DR. BOLLARD: Thank you, Dr. Lowe. I really thank you all for speaking in a very detailed way about the importance of obtaining tumor tissue to perform these critical biologic studies, because I do feel that's an important issue to overcome for the future care of our pediatric patients with NHL. I would like to discuss late effects in our survivors. As Dr. Gross said, survival rates for patients with B-cell lymphomas are generally outstanding. Dr. Gross, do you feel that late effects are not something the NHL group has to worry about now that we have obviated the need for radiation, or not? And what are your feelings about trying to minimize these late effects even further?

DR. GROSS: The good news is that over time, we have been able to come up with regimens that are highly effective but have reduced the agents we know have the highest risk of late effects—radiation being the primary one, but also anthracyclines we have been able to reduce in the vast majority of the patients, and to keep alkylating agents in the vast majority of the patients to a level that most patients do not have infertility. The long-term side effects are becoming pretty minimal, but the question is, how low do they have to be to be acceptable? The goal would be cure without any long-term effects. As I said before, certainly we have paid the price in short-term effects. Our regimens are inpatient, and they can have quite severe short-term side effects such as mucositis. We've made great advances but I think there's still room to go.

DR. CAIRO: I agree, of course, with my colleague Dr. Gross. Again, when we look at large series of chronic health care conditions, certainly children with treated NHL still comes up as one showing over 40% to 50% of patients having one or two serious chronic health care conditions. We know the data are a little antiquated, because they include patients who were treated with different regimens in the 1970s and all of the 1980s. However, I think our goal continues to be to identify the most effective treatment regimen, but with the least toxic long-term complications for our patients. That struggle is very difficult because of the very high success rate we have today, and to identify without hurting that high success rate less toxic therapies will require a collaborative, multidisciplinary, international effort to reach that goal.

DR. BOLLARD: Thank you very much Drs. Cairo and Gross. Dr. Lowe, did you have any closing remarks on the late effects issues for the T-cell mediated diseases in particular?

DR. LOWE: I would absolutely agree with Dr. Gross and Dr. Cairo that this is an important issue. I think we in pediatrics do a good job at following our patients for long-term side effects and creating guidelines for screening for these long-term side effects. That said, I think as we start to talk about better and better therapy and even more and more targeted therapy, what we don't know about some of these targeted therapies is their 15 and 20 year long-term side effects. We obviously hope that there aren't any, and that's why we are moving toward these drugs, but again, surveillance of those long-term side effects will be extremely important, especially when you're talking about medications for young children.

DR. BOLLARD: I'd like to thank you all very much for participating in this expert roundtable discussion today. I think the overarching points are that prognoses at the current time for newly diagnosed pediatric patients with NHL range from 70% to over 90% even for patients with disseminated disease. The challenges that we need to overcome are how we can optimize our up front treatment to prevent relapse in all, because I think we've all reiterated the fact that the outcomes for those few patients who do relapse remains extremely poor. I think there is still controversy about how to manage patients with relapsed disease, and how to temper our therapies against long-term side effects of our surviving patients. Finally, I think with the advent of novel targeted agents, it is incredibly important for the optimal management of our current and future patients that we are able to access tumor tissues and perform the critical biologic studies that are required to develop an effective precision medicine approach for pediatric patients with NHL. I would like to again thank Dr. Cairo, Dr. Gross, and Dr. Lowe for their excellent answers to my, at times, difficult and challenging questions and I would like to thank the organizers of this expert roundtable discussion. I hope that in the next decade that we will see even greater advances for the patient population that we treat. Thank you very much.

References

1. Rosolen RA, Perkins SL, Pinkerton CR, et al. Revised International Pediatric Non-Hodgkin Lymphoma Staging System. J Clin Oncol. 2015;33(18):2112–2118.

2. Sandlund JT, Guillerman RP, Perkins SL, et al. International Pediatric Non-Hodgkin Lymphoma Response Criteria. J Clin Oncol. 2015;33(18)2106-2111.

Moderator: Catherine Bollard, MD, FRACP, FRCPA¹

Discussants: Mitchell S. Cairo, MD²; Eric J. Lowe, MD³; Thomas G. Gross, MD, PhD⁴

Address for correspondence: Catherine Bollard, MD, FRACP, FRCPA, 111 Michigan Avenue, NW, 5th Floor Main, Suite 5225, Washington, DC 20010

E-mail: [email protected] 

Biographical sketch: From The George Washington University, School of Medicine and Health Sciences, Washington, DC1; Westchester Medical Center, New York Medical College, Valhalla, NY2; Children’s Hospital of the King’s Daughters, Norfolk, VA3; Center for Global Health at the National Cancer Institute, Rockville, MD

DR. BOLLARD: My name is Dr. Catherine Bollard. I'm Chief of the Division of Allergy and Immunology at Children's National Health System and the Chair of the NHL Committee of the Children's Oncology Group. I hope that today we can provide some clarity and give you some of our first-hand expertise and experience regarding some of the challenges and controversies of treating pediatric patients with non-Hodgkin lymphoma (NHL). Here with me are Drs. Mitchell Cairo, Chief of Pediatric Hematology/Oncology and Stem Cell Transplantation at New York Medical College in the Maria Fareri Children's Hospital, Westchester Medical Center; Eric Lowe, Division Director for Pediatric Hematology/Oncology at the Children's Hospital of the King's Daughters; and Thomas Gross, Deputy Director for Science at the Center for Global Health at the National Cancer Institute.

I'd like to start the questioning, firstly to Dr. Cairo, who recently published with a group of leaders in the pediatric lymphoma field, new staging and response classifications. Dr. Cairo, I’d like you to highlight how these are different from the current classifications, and what you see are the strengths and the limitations at this time.

DR. CAIRO: Thank you, Cath. The original staging classification was developed in the late 1970s by Dr. Murphy while she was at St. Jude's hospital, and either goes by the name the Murphy Staging Classification or the St. Jude's Classification. That classification I think was quite useful at that time when we recognized really only a couple subtypes of NHL, as well as the capabilities we had in those days both imaging as well as further molecular identification as well as trying to identify sites of spread. As some 35 years have evolved, new pathological entities have been identified, much more precise imaging techniques, new methods of detecting more evidence of minimal disease, and also identifying new organ sites of involvement, allowed the creation of a multidisciplinary international task force to look at how we could enhance the original observations by the St. Jude's group.

As Dr. Bollard pointed out, we eventually, over 9 years of evidence-based review, came up with an enhanced staging classification called the International Pediatric NHL Staging System (IPNHLSS).¹ In this new system we account for new histological subtypes, allow for different organ distributions, improve on the new imaging techniques to identify areas of involvement, and also to more molecularly identify extent of disease. I think the advantages are stated above. The disadvantage is that like all staging systems it's a breathing document. It will require international collaboration. As time evolves, this staging system will of course need to be updated as we gain new experience.

Briefly, in terms of the response classification that also came out of the same international multidisciplinary task force that was led by Dr. Sandlund at St. Jude's²; there had never been a response criteria that had been focused entirely in childhood and adolescent NHL. The previous response criteria had been developed by adult NHL investigators, and there was a need to develop the first response criteria for pediatric NHL because of different histologies, different sites of sanctuary disease, and now obviously enhanced imaging capabilities. That also now has been named the International Pediatric Non-Hodgkin Lymphoma Response Criteria (IPNHLRC)—hopefully for harmonizing a response across new studies, but also a breathing document that is going to be limited as we gain new knowledge into how we can better assess response as new techniques are developed.

DR. BOLLARD: I thank you very much for your detailed response. My next question is actually to Dr. Gross, who is currently chairing the international study for upfront diffuse large B-cell lymphoma and Burkitt lymphoma in pediatric young adults. I would like you to speak to a couple of issues, and you can put it in the context of the current randomized trial, looking at rituximab vs no rituximab for this disease. I think firstly it would be useful for you to speak to the implications of this new classification system as we go forward with choosing new therapeutic strategies for these patients, and in particular I'd like to focus on the newly diagnosed diffuse large B-cell lymphoma patients who are in that adolescent/young adult range.

I would also be interested in your opinion regarding how you would manage a patient who is 17 years old but is going to turn 18 tomorrow, and he comes to you with newly diagnosed diffuse large B-cell lymphoma. As you know, the adult oncologists treat diffuse large B-cell lymphoma different to Burkitt lymphoma, and in pediatrics we generally treat these diseases the same. Do you tell this patient that you will treat him today on a pediatric regimen, or do you tell him to go tomorrow, when he's 18, to be treated by an adult oncologist? I would like you to justify your answer please.

DR. GROSS: First to discuss the implications of the new staging as it applies to the current international trial. As Dr. Cairo pointed out, this was developed through a literature review and evidence based analyses, but like any new staging system, the value of staging is to provide us with information that can try to help us to identify patients to improve their outcome. Essentially, staging is to help direct therapy or provide prognosis for outcome, and the only way to do that is to test new systems or classifications in a prospective fashion. Indeed, that is what we are trying to do with this international effort.

This international effort, just as an aside, illustrates one of the challenges of all rare cancers, but particularly pediatrics. In pediatric mature B-cell NHL, both large-cell and Burkitt, we are now at a cure rate of about 90%. To make advances, we don't have enough patients seen in North America and Australia, and it requires international collaboration. This trial, to get 600 patients randomized, it will take 7 years with 14 countries participating—that is one of the challenges, certainly, we have with pediatric NHL. Also, we want to try to gain as much information as possible, not just to the effect of rituximab as Dr. Bollard said, but also to test other questions such as the role or the value in validating this new staging system.

To talk about the controversy of treatment, certainly we know that there is a very different approach in pediatrics. For many years, we have treated diffuse large B-cell lymphoma just like Burkitt. This is a very important delineation when you're seen by a medical oncologist because the treatment for diffuse large B-cell lymphoma is outpatient therapy, ie rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP). Treatment for Burkitt is inpatient with high doses of methotrexate, but other higher doses of the same agents used to treat diffuse large B-cell lymphoma. The question is, do we really need to treat all the pediatric diffuse large B-cell lymphoma with these aggressive Burkitt regimens? I think one of the things that is encouraging to me as a pediatric oncologist is that we are beginning to learn that the biology is very different. Though the disease looks the same under the microscope or by flow cytometry, when you look at it genetically it's quite different. We know now that the younger the patient is with diffuse large B-cell lymphoma, even though it looks for all intents and purposes like the same disease as seen in adults, when you look at the genetics, many times, as high as 30% of the time, it will be genetically the same as a Burkitt lymphoma. I think when you're talking about young patients we can easily justify treating them both the same because the biology would suggest that a good number of patients would need Burkitt therapy to be cured.

Now, that changes over time, so that it appears that sometime in young adulthood, maybe somewhere between 25 and 35 years of age, you don't see the genetic disease that looks like diffuse large B-cell lymphoma, but is genetically Burkitt lymphoma. As for the 18-year-old patient that Dr. Bollard was posing to me, I've had several patients like this. I go through the pluses and minuses of the therapy, inpatient vs outpatient, but also the potential long-term side effects. The outpatient therapy has potentially more long-term side effects as far as potential infertility and potential heart damage. Every time I have given the choice to the family and the patient, the teenager has always chosen the outpatient therapy that you would get as an adult, and the parents always say they would rather have the inpatient therapy, and that spending a couple of days in the hospital to try to reduce the chance of long-term damage is their choice. It's a very interesting dynamic and I think sometimes the issues that go into choice of treatment are quite variable. My personal opinion is that hopefully in the future we will be able to have a better understanding of biology, so that when we see these patients, be they 18 or 25 years old, we're not looking at what it looks like under the microscope or who they see, and what they're used to giving, but the biology will determine which therapy is more likely to cure them. Right now we don't have that ability in most of the patients.

DR. BOLLARD: Thank you, Dr. Gross. Again, another very comprehensive answer to a difficult question. I'm actually going to push this back to Dr. Cairo and then impose the same soon to be 18-year-old patient to you. This time, he's coming to you with relapsed diffuse large B-cell lymphoma. What are you going to tell him? Are you going to treat him today on pediatric protocols, or will you wait until tomorrow when he could have access to adult protocols?

DR. CAIRO: I think the results are relatively similar, but, in part, the answer to the question is of course based on what their original therapy was. If the original therapy was the pediatric-inspired type of treatment, I think there's a world of experience of what are some of the best pediatric-inspired regimens to use for retrieval. If, however, the original therapy was an adult-inspired regimen, then I think the options are open because the disease may not be as resistant in that setting; therefore, one would want to consider all the adult type of retrieval regimens in that case, because that group of patients—at least in the adult experience—tend to have disease that may be more responsive because they're not as resistant to the higher dose and multi-agent therapy that a pediatric-inspired regimen would have given them had they been treated that way.

DR. BOLLARD: I was also trying to ask you to speak to the access that an 18-year-old might have to novel therapies that a 17-year-old might not. How do you address that issue?

DR. CAIRO: That's an excellent question. I think that for first relapse or first induction failure most of the retrieval regimens, the first line regimens, that are available, either pediatric inspired or adult inspired, probably don't require an investigational agent that an 18-year-old might have access to if he was being treated on an adult type of regimen. However, I would strongly encourage an 18-year-old who failed one retrieval regimen to consider experimental therapy. There I think the access to new agents—if you're 18 or over—are so much greater that I would encourage them to be treated on an adult retrieval regimen, where some of the newer agents may be investigational, are not available to a pediatric program.

DR. BOLLARD: Thank you very much, Dr. Cairo. I have one last question on the B-cell diseases before I move to Dr. Lowe, and the last question goes to Dr. Gross. Would you recommend that a patient with relapsed Burkitt lymphoma—now increasingly rare—be treated with salvage chemotherapy and then autologous transplant or allogeneic stem cell transplant?  

DR. GROSS: As the others on this discussion know, we performed an analysis from data in the Center for International Blood and Marrow Transplant Research (CIBMTR), and the problem is that Burkitt lymphoma tends to reoccur so rapidly after transplant. The median time to relapse is 3 months after transplant. We could not find a difference in the outcome between autografts and allografts because of its early reoccurrence. That said, my personal opinion is, since we know that Burkitt lymphoma is a hematologically spread disease, that I always prefer a donor source where I know they're not going to have tumor cells in them, which is an allogeneic donor. I always prefer an allogeneic donor, because I know it's tumor-free, but also it gives us an opportunity, if the disease will stay under control long enough, to potentially get an immune response against any residual tumor. For that reason, I recommend an allogeneic donor if it can be found readily.

DR. BOLLARD: Thank you very much, Dr. Gross. Now, on to Dr. Lowe, and Dr. Lowe's particular area of expertise is in anaplastic large cell lymphoma (ALCL) and T-cell diseases. I was wondering if you could explain to me the difference between T-cell lymphoblastic lymphoma and T-cell acute lymphoblastic leukemia (ALL), specifically since the World Health Organization (WHO) groups these two disease entities together as T-lymphoblastic leukemia/lymphoma. If you could clarify that classification that would be very helpful.

DR. LOWE: As you well know, many physicians believe that T-cell lymphoblastic leukemia and T-cell lymphoblastic lymphoma are very similar diseases, but they are not exactly the same disease although we sometimes treat them very similar. We know that T-cells do not mature in bone marrow but rather they are thymic driven cells. Because of this, there are distinct differences between the leukemia and lymphoma. For example, we know that the genetics between the two—although in limited samples—are not always the same, including in prognostic. Just one example, loss of heterozygosity at 6Q has been shown to be prognostically important in lymphoblastic lymphoma but not in T-cell ALL. I think the real challenge is to figure out what the differences are. I think we could argue that potentially, T-ALL is stage four T-cell lymphoblastic lymphoma.

I think that the WHO classifying the two diseases as one entity with T-lymphoblastic leukemia/lymphoma has hindered a little in the advancement of recognizing the differences in that many people assume that they're the same disease. When you look up from a pathological standpoint and you say, well, they're clearly the same disease because they're listed as a single entity, and when you look up treatment, you say, well they're treated very similar, so they must be the same disease. I think that does us a little disservice in trying to advance the field forward, because I think getting lymphoblastic lymphoma samples, which is challenging, is extremely important to determine the genetic drivers of this disease.

DR. BOLLARD: Thank you very much, Dr. Lowe. I would also like you to discuss how ALCL differs between the pediatric and the adult populations, and how that dictates how you would treat those two patient populations.

DR. LOWE: So, ALCL really has a much shorter span in terms of its description pathologically. It was not described by itself until the mid 1980s. In the mid 1990s it started entering classification schemes. It wasn't until 2008 that the WHO separated out three distinct entities within ALCL. You have anaplastic lymphoma kinase (ALK)-positive ALCL, ALK-negative ALCL, and primary cutaneous ALCL. This is a great example where these three different entities have very different epidemiology, very different treatment strategies, and the fact that they are broken up has really helped move the field forward. For example, ALK-positive ALCL is really a disease of children, adolescents, and young adults. It's the most common ALCL by far in that age group. It's extremely rare to have an ALK-negative ALCL, and the pathological reason for the disease with ALK-positive ALCL is a translocation involving the ALK gene leads directly to oncogenesis.

Because of this, we have started to develop treatments that are designed to target this specific oncogenic driving translocation. This is in direct comparison to an ALK-negative ALCL, which is primarily a disease of older individuals, most commonly in their 50s and 60s. The outcome for this disease is consistently poorer than for ALK-positive disease. The treatment, while sometimes the same, is changing now that we have targets for the tyrosine kinase that is driving the ALK-positive ALCL. I think separating these two out has been a huge advantage in terms of figuring out what to do with pediatric ALCL because the 95 plus percent of ALCLs in pediatrics and young adults are ALK-positive.

Primary cutaneous ALCL is almost a completely different entity in and of itself, although it shares the same name. The primary cutaneous ALCLs are usually not treated on similar studies as the systemic forms of ALCL. The primary cutaneous form has different characteristics in terms of location, age, treatment, and natural course. The vast majority does not develop into systemic disease, and thus the treatment is very different. I think ALCL is a very good example where the different pathological entities have led to very different treatments based on what is driving the cancer.

DR. BOLLARD: Thanks, Dr. Lowe. I think that's very important to emphasize how ALK-positivity is more common in children than in adults, and the successes of crizotinib, even in phase 1 in pediatric patients with ALCL. My question now is given the success of this targeted agent in the relapse setting, even in phase 1, do you still see a role for allogeneic stem cell transplant for those patients who have relapsed after conventional therapy?

DR. LOWE: I do still see a role, but I'm not sure how much that role will shrink over time as we learn more and more about this disease. We know that there are very high risk patients that relapse or progress while receiving traditional chemotherapy. Those patients typically have achieved the best outcome with an allogeneic transplant. That said, I think crizotinib and other ALK inhibitors are changing the landscape of treatment for ALK-positive ALCL very fast. We know that some patients who are refractory to many other treatments go into remission with these drugs, and while I think that the role of allogeneic transplant is still there, I think that it may be changing over time. The other decision that I think will be difficult in terms of allogeneic transplant is for patients who receive ALK-inhibitors, like crizotinib, for initial treatment and then relapse. Many patients in that situation currently will end up having an allogenic transplant. However, one can argue that very much like chronic myeloid leukemia, these patients might be rescued without an allogeneic transplant using a second line ALK inhibitor. All of these things, obviously, we hope to know over time, but at this point in time are unknown.

DR. BOLLARD: Thank you very much. I'll take you out of the hot seat now. All of us talked about the concept of the importance of knowing the biology of what we're treating, and with the advent of novel targeted therapies, this concept of precision medicine is becoming increasingly important, ie, targeting the individual patient's tumor with the appropriate targeted agents for their tumor. This is maybe a question for Dr. Gross first, and then Dr. Cairo. What do you see are the challenges for being able to obtain the tissue from pediatric patients to perform these important and critical tests that will be needed as we move the field forward for the management of pediatric patients with NHL?

DR. GROSS: I think that the number one barrier is, as the technology improves to be able to make the essential diagnosis, we need less and less tissue for the pathologist. It becomes increasingly more of a challenge to obtain extra tissue because the standard of practice is to get just enough to make the diagnosis. Unless we can address this challenge, it's going to be extremely difficult.

DR. BOLLARD: Dr. Cairo, do you want to speak to that, since you recently completed a Children’s Oncology Group trial for Burkitt and diffuse large B-cell lymphoma?

DR. CAIRO: Thank you. I agree with Dr. Gross, and that particular trial, despite it being one of the primary objectives and also many of those patients actually had bone marrow involvement, which is the area that we access the easiest as the acute lymphoblastic leukemia colleagues have taught us. We still only were able to get 11 of some 90 patients entered on study, to have specimens sent. That being said, having just come back from the Fifth International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma, It appears that the Europeans have been much more successful in obtaining specimens for biology studies in particular, the future precision medicine-based trials. We should try to learn a little bit from our European colleagues, who seem to have a much higher percentage of getting specimens, and we need to make every effort, as Dr. Gross said of encouraging our colleagues, that this is as important as making the diagnosis. We face an uphill battle because of our high cure rate, the biology is often considered a second thought sometimes. Europeans are better than us at obtaining biological specimens and we need to compete to achieve the level that they have achieved in Europe.

DR. GROSS: It's almost a catch-22. We know from other diseases in pediatric oncology, but also in adult oncology, that once we are able to demonstrate that the biology will make a difference in the treatment and outcome of the patient, then we're able to get the tissue needed. I think a good example of that is neuroblastoma. However, we can't make those discoveries unless we get enough tissue to study. We're in this catch-22, we cannot demonstrate that the biology makes a difference, unless we will get the tissue for research.

DR. LOWE: I'd like to add one other point to this. I think the rarity of the diseases and the large number of centers that treat the patients also hinders obtaining pathological samples. Because pediatric NHL is a relatively rare disease, you can’t have a single champion for obtaining biology at one institution that can accomplish anything without many other institutions. It requires a large group effort which is more difficult than a single institution collecting colon cancer samples, for example, where you really only need one institution, one champion, one pathologist, and you have all the samples you need.

DR. BOLLARD: Thank you, Dr. Lowe. I really thank you all for speaking in a very detailed way about the importance of obtaining tumor tissue to perform these critical biologic studies, because I do feel that's an important issue to overcome for the future care of our pediatric patients with NHL. I would like to discuss late effects in our survivors. As Dr. Gross said, survival rates for patients with B-cell lymphomas are generally outstanding. Dr. Gross, do you feel that late effects are not something the NHL group has to worry about now that we have obviated the need for radiation, or not? And what are your feelings about trying to minimize these late effects even further?

DR. GROSS: The good news is that over time, we have been able to come up with regimens that are highly effective but have reduced the agents we know have the highest risk of late effects—radiation being the primary one, but also anthracyclines we have been able to reduce in the vast majority of the patients, and to keep alkylating agents in the vast majority of the patients to a level that most patients do not have infertility. The long-term side effects are becoming pretty minimal, but the question is, how low do they have to be to be acceptable? The goal would be cure without any long-term effects. As I said before, certainly we have paid the price in short-term effects. Our regimens are inpatient, and they can have quite severe short-term side effects such as mucositis. We've made great advances but I think there's still room to go.

DR. CAIRO: I agree, of course, with my colleague Dr. Gross. Again, when we look at large series of chronic health care conditions, certainly children with treated NHL still comes up as one showing over 40% to 50% of patients having one or two serious chronic health care conditions. We know the data are a little antiquated, because they include patients who were treated with different regimens in the 1970s and all of the 1980s. However, I think our goal continues to be to identify the most effective treatment regimen, but with the least toxic long-term complications for our patients. That struggle is very difficult because of the very high success rate we have today, and to identify without hurting that high success rate less toxic therapies will require a collaborative, multidisciplinary, international effort to reach that goal.

DR. BOLLARD: Thank you very much Drs. Cairo and Gross. Dr. Lowe, did you have any closing remarks on the late effects issues for the T-cell mediated diseases in particular?

DR. LOWE: I would absolutely agree with Dr. Gross and Dr. Cairo that this is an important issue. I think we in pediatrics do a good job at following our patients for long-term side effects and creating guidelines for screening for these long-term side effects. That said, I think as we start to talk about better and better therapy and even more and more targeted therapy, what we don't know about some of these targeted therapies is their 15 and 20 year long-term side effects. We obviously hope that there aren't any, and that's why we are moving toward these drugs, but again, surveillance of those long-term side effects will be extremely important, especially when you're talking about medications for young children.

DR. BOLLARD: I'd like to thank you all very much for participating in this expert roundtable discussion today. I think the overarching points are that prognoses at the current time for newly diagnosed pediatric patients with NHL range from 70% to over 90% even for patients with disseminated disease. The challenges that we need to overcome are how we can optimize our up front treatment to prevent relapse in all, because I think we've all reiterated the fact that the outcomes for those few patients who do relapse remains extremely poor. I think there is still controversy about how to manage patients with relapsed disease, and how to temper our therapies against long-term side effects of our surviving patients. Finally, I think with the advent of novel targeted agents, it is incredibly important for the optimal management of our current and future patients that we are able to access tumor tissues and perform the critical biologic studies that are required to develop an effective precision medicine approach for pediatric patients with NHL. I would like to again thank Dr. Cairo, Dr. Gross, and Dr. Lowe for their excellent answers to my, at times, difficult and challenging questions and I would like to thank the organizers of this expert roundtable discussion. I hope that in the next decade that we will see even greater advances for the patient population that we treat. Thank you very much.

References

1. Rosolen RA, Perkins SL, Pinkerton CR, et al. Revised International Pediatric Non-Hodgkin Lymphoma Staging System. J Clin Oncol. 2015;33(18):2112–2118.

2. Sandlund JT, Guillerman RP, Perkins SL, et al. International Pediatric Non-Hodgkin Lymphoma Response Criteria. J Clin Oncol. 2015;33(18)2106-2111.

Moderator: Catherine Bollard, MD, FRACP, FRCPA¹

Discussants: Mitchell S. Cairo, MD²; Eric J. Lowe, MD³; Thomas G. Gross, MD, PhD⁴

Address for correspondence: Catherine Bollard, MD, FRACP, FRCPA, 111 Michigan Avenue, NW, 5th Floor Main, Suite 5225, Washington, DC 20010

E-mail: [email protected] 

Biographical sketch: From The George Washington University, School of Medicine and Health Sciences, Washington, DC1; Westchester Medical Center, New York Medical College, Valhalla, NY2; Children’s Hospital of the King’s Daughters, Norfolk, VA3; Center for Global Health at the National Cancer Institute, Rockville, MD

DR. BOLLARD: My name is Dr. Catherine Bollard. I'm Chief of the Division of Allergy and Immunology at Children's National Health System and the Chair of the NHL Committee of the Children's Oncology Group. I hope that today we can provide some clarity and give you some of our first-hand expertise and experience regarding some of the challenges and controversies of treating pediatric patients with non-Hodgkin lymphoma (NHL). Here with me are Drs. Mitchell Cairo, Chief of Pediatric Hematology/Oncology and Stem Cell Transplantation at New York Medical College in the Maria Fareri Children's Hospital, Westchester Medical Center; Eric Lowe, Division Director for Pediatric Hematology/Oncology at the Children's Hospital of the King's Daughters; and Thomas Gross, Deputy Director for Science at the Center for Global Health at the National Cancer Institute.

I'd like to start the questioning, firstly to Dr. Cairo, who recently published with a group of leaders in the pediatric lymphoma field, new staging and response classifications. Dr. Cairo, I’d like you to highlight how these are different from the current classifications, and what you see are the strengths and the limitations at this time.

DR. CAIRO: Thank you, Cath. The original staging classification was developed in the late 1970s by Dr. Murphy while she was at St. Jude's hospital, and either goes by the name the Murphy Staging Classification or the St. Jude's Classification. That classification I think was quite useful at that time when we recognized really only a couple subtypes of NHL, as well as the capabilities we had in those days both imaging as well as further molecular identification as well as trying to identify sites of spread. As some 35 years have evolved, new pathological entities have been identified, much more precise imaging techniques, new methods of detecting more evidence of minimal disease, and also identifying new organ sites of involvement, allowed the creation of a multidisciplinary international task force to look at how we could enhance the original observations by the St. Jude's group.

As Dr. Bollard pointed out, we eventually, over 9 years of evidence-based review, came up with an enhanced staging classification called the International Pediatric NHL Staging System (IPNHLSS).¹ In this new system we account for new histological subtypes, allow for different organ distributions, improve on the new imaging techniques to identify areas of involvement, and also to more molecularly identify extent of disease. I think the advantages are stated above. The disadvantage is that like all staging systems it's a breathing document. It will require international collaboration. As time evolves, this staging system will of course need to be updated as we gain new experience.

Briefly, in terms of the response classification that also came out of the same international multidisciplinary task force that was led by Dr. Sandlund at St. Jude's²; there had never been a response criteria that had been focused entirely in childhood and adolescent NHL. The previous response criteria had been developed by adult NHL investigators, and there was a need to develop the first response criteria for pediatric NHL because of different histologies, different sites of sanctuary disease, and now obviously enhanced imaging capabilities. That also now has been named the International Pediatric Non-Hodgkin Lymphoma Response Criteria (IPNHLRC)—hopefully for harmonizing a response across new studies, but also a breathing document that is going to be limited as we gain new knowledge into how we can better assess response as new techniques are developed.

DR. BOLLARD: I thank you very much for your detailed response. My next question is actually to Dr. Gross, who is currently chairing the international study for upfront diffuse large B-cell lymphoma and Burkitt lymphoma in pediatric young adults. I would like you to speak to a couple of issues, and you can put it in the context of the current randomized trial, looking at rituximab vs no rituximab for this disease. I think firstly it would be useful for you to speak to the implications of this new classification system as we go forward with choosing new therapeutic strategies for these patients, and in particular I'd like to focus on the newly diagnosed diffuse large B-cell lymphoma patients who are in that adolescent/young adult range.

I would also be interested in your opinion regarding how you would manage a patient who is 17 years old but is going to turn 18 tomorrow, and he comes to you with newly diagnosed diffuse large B-cell lymphoma. As you know, the adult oncologists treat diffuse large B-cell lymphoma different to Burkitt lymphoma, and in pediatrics we generally treat these diseases the same. Do you tell this patient that you will treat him today on a pediatric regimen, or do you tell him to go tomorrow, when he's 18, to be treated by an adult oncologist? I would like you to justify your answer please.

DR. GROSS: First to discuss the implications of the new staging as it applies to the current international trial. As Dr. Cairo pointed out, this was developed through a literature review and evidence based analyses, but like any new staging system, the value of staging is to provide us with information that can try to help us to identify patients to improve their outcome. Essentially, staging is to help direct therapy or provide prognosis for outcome, and the only way to do that is to test new systems or classifications in a prospective fashion. Indeed, that is what we are trying to do with this international effort.

This international effort, just as an aside, illustrates one of the challenges of all rare cancers, but particularly pediatrics. In pediatric mature B-cell NHL, both large-cell and Burkitt, we are now at a cure rate of about 90%. To make advances, we don't have enough patients seen in North America and Australia, and it requires international collaboration. This trial, to get 600 patients randomized, it will take 7 years with 14 countries participating—that is one of the challenges, certainly, we have with pediatric NHL. Also, we want to try to gain as much information as possible, not just to the effect of rituximab as Dr. Bollard said, but also to test other questions such as the role or the value in validating this new staging system.

To talk about the controversy of treatment, certainly we know that there is a very different approach in pediatrics. For many years, we have treated diffuse large B-cell lymphoma just like Burkitt. This is a very important delineation when you're seen by a medical oncologist because the treatment for diffuse large B-cell lymphoma is outpatient therapy, ie rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP). Treatment for Burkitt is inpatient with high doses of methotrexate, but other higher doses of the same agents used to treat diffuse large B-cell lymphoma. The question is, do we really need to treat all the pediatric diffuse large B-cell lymphoma with these aggressive Burkitt regimens? I think one of the things that is encouraging to me as a pediatric oncologist is that we are beginning to learn that the biology is very different. Though the disease looks the same under the microscope or by flow cytometry, when you look at it genetically it's quite different. We know now that the younger the patient is with diffuse large B-cell lymphoma, even though it looks for all intents and purposes like the same disease as seen in adults, when you look at the genetics, many times, as high as 30% of the time, it will be genetically the same as a Burkitt lymphoma. I think when you're talking about young patients we can easily justify treating them both the same because the biology would suggest that a good number of patients would need Burkitt therapy to be cured.

Now, that changes over time, so that it appears that sometime in young adulthood, maybe somewhere between 25 and 35 years of age, you don't see the genetic disease that looks like diffuse large B-cell lymphoma, but is genetically Burkitt lymphoma. As for the 18-year-old patient that Dr. Bollard was posing to me, I've had several patients like this. I go through the pluses and minuses of the therapy, inpatient vs outpatient, but also the potential long-term side effects. The outpatient therapy has potentially more long-term side effects as far as potential infertility and potential heart damage. Every time I have given the choice to the family and the patient, the teenager has always chosen the outpatient therapy that you would get as an adult, and the parents always say they would rather have the inpatient therapy, and that spending a couple of days in the hospital to try to reduce the chance of long-term damage is their choice. It's a very interesting dynamic and I think sometimes the issues that go into choice of treatment are quite variable. My personal opinion is that hopefully in the future we will be able to have a better understanding of biology, so that when we see these patients, be they 18 or 25 years old, we're not looking at what it looks like under the microscope or who they see, and what they're used to giving, but the biology will determine which therapy is more likely to cure them. Right now we don't have that ability in most of the patients.

DR. BOLLARD: Thank you, Dr. Gross. Again, another very comprehensive answer to a difficult question. I'm actually going to push this back to Dr. Cairo and then impose the same soon to be 18-year-old patient to you. This time, he's coming to you with relapsed diffuse large B-cell lymphoma. What are you going to tell him? Are you going to treat him today on pediatric protocols, or will you wait until tomorrow when he could have access to adult protocols?

DR. CAIRO: I think the results are relatively similar, but, in part, the answer to the question is of course based on what their original therapy was. If the original therapy was the pediatric-inspired type of treatment, I think there's a world of experience of what are some of the best pediatric-inspired regimens to use for retrieval. If, however, the original therapy was an adult-inspired regimen, then I think the options are open because the disease may not be as resistant in that setting; therefore, one would want to consider all the adult type of retrieval regimens in that case, because that group of patients—at least in the adult experience—tend to have disease that may be more responsive because they're not as resistant to the higher dose and multi-agent therapy that a pediatric-inspired regimen would have given them had they been treated that way.

DR. BOLLARD: I was also trying to ask you to speak to the access that an 18-year-old might have to novel therapies that a 17-year-old might not. How do you address that issue?

DR. CAIRO: That's an excellent question. I think that for first relapse or first induction failure most of the retrieval regimens, the first line regimens, that are available, either pediatric inspired or adult inspired, probably don't require an investigational agent that an 18-year-old might have access to if he was being treated on an adult type of regimen. However, I would strongly encourage an 18-year-old who failed one retrieval regimen to consider experimental therapy. There I think the access to new agents—if you're 18 or over—are so much greater that I would encourage them to be treated on an adult retrieval regimen, where some of the newer agents may be investigational, are not available to a pediatric program.

DR. BOLLARD: Thank you very much, Dr. Cairo. I have one last question on the B-cell diseases before I move to Dr. Lowe, and the last question goes to Dr. Gross. Would you recommend that a patient with relapsed Burkitt lymphoma—now increasingly rare—be treated with salvage chemotherapy and then autologous transplant or allogeneic stem cell transplant?  

DR. GROSS: As the others on this discussion know, we performed an analysis from data in the Center for International Blood and Marrow Transplant Research (CIBMTR), and the problem is that Burkitt lymphoma tends to reoccur so rapidly after transplant. The median time to relapse is 3 months after transplant. We could not find a difference in the outcome between autografts and allografts because of its early reoccurrence. That said, my personal opinion is, since we know that Burkitt lymphoma is a hematologically spread disease, that I always prefer a donor source where I know they're not going to have tumor cells in them, which is an allogeneic donor. I always prefer an allogeneic donor, because I know it's tumor-free, but also it gives us an opportunity, if the disease will stay under control long enough, to potentially get an immune response against any residual tumor. For that reason, I recommend an allogeneic donor if it can be found readily.

DR. BOLLARD: Thank you very much, Dr. Gross. Now, on to Dr. Lowe, and Dr. Lowe's particular area of expertise is in anaplastic large cell lymphoma (ALCL) and T-cell diseases. I was wondering if you could explain to me the difference between T-cell lymphoblastic lymphoma and T-cell acute lymphoblastic leukemia (ALL), specifically since the World Health Organization (WHO) groups these two disease entities together as T-lymphoblastic leukemia/lymphoma. If you could clarify that classification that would be very helpful.

DR. LOWE: As you well know, many physicians believe that T-cell lymphoblastic leukemia and T-cell lymphoblastic lymphoma are very similar diseases, but they are not exactly the same disease although we sometimes treat them very similar. We know that T-cells do not mature in bone marrow but rather they are thymic driven cells. Because of this, there are distinct differences between the leukemia and lymphoma. For example, we know that the genetics between the two—although in limited samples—are not always the same, including in prognostic. Just one example, loss of heterozygosity at 6Q has been shown to be prognostically important in lymphoblastic lymphoma but not in T-cell ALL. I think the real challenge is to figure out what the differences are. I think we could argue that potentially, T-ALL is stage four T-cell lymphoblastic lymphoma.

I think that the WHO classifying the two diseases as one entity with T-lymphoblastic leukemia/lymphoma has hindered a little in the advancement of recognizing the differences in that many people assume that they're the same disease. When you look up from a pathological standpoint and you say, well, they're clearly the same disease because they're listed as a single entity, and when you look up treatment, you say, well they're treated very similar, so they must be the same disease. I think that does us a little disservice in trying to advance the field forward, because I think getting lymphoblastic lymphoma samples, which is challenging, is extremely important to determine the genetic drivers of this disease.

DR. BOLLARD: Thank you very much, Dr. Lowe. I would also like you to discuss how ALCL differs between the pediatric and the adult populations, and how that dictates how you would treat those two patient populations.

DR. LOWE: So, ALCL really has a much shorter span in terms of its description pathologically. It was not described by itself until the mid 1980s. In the mid 1990s it started entering classification schemes. It wasn't until 2008 that the WHO separated out three distinct entities within ALCL. You have anaplastic lymphoma kinase (ALK)-positive ALCL, ALK-negative ALCL, and primary cutaneous ALCL. This is a great example where these three different entities have very different epidemiology, very different treatment strategies, and the fact that they are broken up has really helped move the field forward. For example, ALK-positive ALCL is really a disease of children, adolescents, and young adults. It's the most common ALCL by far in that age group. It's extremely rare to have an ALK-negative ALCL, and the pathological reason for the disease with ALK-positive ALCL is a translocation involving the ALK gene leads directly to oncogenesis.

Because of this, we have started to develop treatments that are designed to target this specific oncogenic driving translocation. This is in direct comparison to an ALK-negative ALCL, which is primarily a disease of older individuals, most commonly in their 50s and 60s. The outcome for this disease is consistently poorer than for ALK-positive disease. The treatment, while sometimes the same, is changing now that we have targets for the tyrosine kinase that is driving the ALK-positive ALCL. I think separating these two out has been a huge advantage in terms of figuring out what to do with pediatric ALCL because the 95 plus percent of ALCLs in pediatrics and young adults are ALK-positive.

Primary cutaneous ALCL is almost a completely different entity in and of itself, although it shares the same name. The primary cutaneous ALCLs are usually not treated on similar studies as the systemic forms of ALCL. The primary cutaneous form has different characteristics in terms of location, age, treatment, and natural course. The vast majority does not develop into systemic disease, and thus the treatment is very different. I think ALCL is a very good example where the different pathological entities have led to very different treatments based on what is driving the cancer.

DR. BOLLARD: Thanks, Dr. Lowe. I think that's very important to emphasize how ALK-positivity is more common in children than in adults, and the successes of crizotinib, even in phase 1 in pediatric patients with ALCL. My question now is given the success of this targeted agent in the relapse setting, even in phase 1, do you still see a role for allogeneic stem cell transplant for those patients who have relapsed after conventional therapy?

DR. LOWE: I do still see a role, but I'm not sure how much that role will shrink over time as we learn more and more about this disease. We know that there are very high risk patients that relapse or progress while receiving traditional chemotherapy. Those patients typically have achieved the best outcome with an allogeneic transplant. That said, I think crizotinib and other ALK inhibitors are changing the landscape of treatment for ALK-positive ALCL very fast. We know that some patients who are refractory to many other treatments go into remission with these drugs, and while I think that the role of allogeneic transplant is still there, I think that it may be changing over time. The other decision that I think will be difficult in terms of allogeneic transplant is for patients who receive ALK-inhibitors, like crizotinib, for initial treatment and then relapse. Many patients in that situation currently will end up having an allogenic transplant. However, one can argue that very much like chronic myeloid leukemia, these patients might be rescued without an allogeneic transplant using a second line ALK inhibitor. All of these things, obviously, we hope to know over time, but at this point in time are unknown.

DR. BOLLARD: Thank you very much. I'll take you out of the hot seat now. All of us talked about the concept of the importance of knowing the biology of what we're treating, and with the advent of novel targeted therapies, this concept of precision medicine is becoming increasingly important, ie, targeting the individual patient's tumor with the appropriate targeted agents for their tumor. This is maybe a question for Dr. Gross first, and then Dr. Cairo. What do you see are the challenges for being able to obtain the tissue from pediatric patients to perform these important and critical tests that will be needed as we move the field forward for the management of pediatric patients with NHL?

DR. GROSS: I think that the number one barrier is, as the technology improves to be able to make the essential diagnosis, we need less and less tissue for the pathologist. It becomes increasingly more of a challenge to obtain extra tissue because the standard of practice is to get just enough to make the diagnosis. Unless we can address this challenge, it's going to be extremely difficult.

DR. BOLLARD: Dr. Cairo, do you want to speak to that, since you recently completed a Children’s Oncology Group trial for Burkitt and diffuse large B-cell lymphoma?

DR. CAIRO: Thank you. I agree with Dr. Gross, and that particular trial, despite it being one of the primary objectives and also many of those patients actually had bone marrow involvement, which is the area that we access the easiest as the acute lymphoblastic leukemia colleagues have taught us. We still only were able to get 11 of some 90 patients entered on study, to have specimens sent. That being said, having just come back from the Fifth International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma, It appears that the Europeans have been much more successful in obtaining specimens for biology studies in particular, the future precision medicine-based trials. We should try to learn a little bit from our European colleagues, who seem to have a much higher percentage of getting specimens, and we need to make every effort, as Dr. Gross said of encouraging our colleagues, that this is as important as making the diagnosis. We face an uphill battle because of our high cure rate, the biology is often considered a second thought sometimes. Europeans are better than us at obtaining biological specimens and we need to compete to achieve the level that they have achieved in Europe.

DR. GROSS: It's almost a catch-22. We know from other diseases in pediatric oncology, but also in adult oncology, that once we are able to demonstrate that the biology will make a difference in the treatment and outcome of the patient, then we're able to get the tissue needed. I think a good example of that is neuroblastoma. However, we can't make those discoveries unless we get enough tissue to study. We're in this catch-22, we cannot demonstrate that the biology makes a difference, unless we will get the tissue for research.

DR. LOWE: I'd like to add one other point to this. I think the rarity of the diseases and the large number of centers that treat the patients also hinders obtaining pathological samples. Because pediatric NHL is a relatively rare disease, you can’t have a single champion for obtaining biology at one institution that can accomplish anything without many other institutions. It requires a large group effort which is more difficult than a single institution collecting colon cancer samples, for example, where you really only need one institution, one champion, one pathologist, and you have all the samples you need.

DR. BOLLARD: Thank you, Dr. Lowe. I really thank you all for speaking in a very detailed way about the importance of obtaining tumor tissue to perform these critical biologic studies, because I do feel that's an important issue to overcome for the future care of our pediatric patients with NHL. I would like to discuss late effects in our survivors. As Dr. Gross said, survival rates for patients with B-cell lymphomas are generally outstanding. Dr. Gross, do you feel that late effects are not something the NHL group has to worry about now that we have obviated the need for radiation, or not? And what are your feelings about trying to minimize these late effects even further?

DR. GROSS: The good news is that over time, we have been able to come up with regimens that are highly effective but have reduced the agents we know have the highest risk of late effects—radiation being the primary one, but also anthracyclines we have been able to reduce in the vast majority of the patients, and to keep alkylating agents in the vast majority of the patients to a level that most patients do not have infertility. The long-term side effects are becoming pretty minimal, but the question is, how low do they have to be to be acceptable? The goal would be cure without any long-term effects. As I said before, certainly we have paid the price in short-term effects. Our regimens are inpatient, and they can have quite severe short-term side effects such as mucositis. We've made great advances but I think there's still room to go.

DR. CAIRO: I agree, of course, with my colleague Dr. Gross. Again, when we look at large series of chronic health care conditions, certainly children with treated NHL still comes up as one showing over 40% to 50% of patients having one or two serious chronic health care conditions. We know the data are a little antiquated, because they include patients who were treated with different regimens in the 1970s and all of the 1980s. However, I think our goal continues to be to identify the most effective treatment regimen, but with the least toxic long-term complications for our patients. That struggle is very difficult because of the very high success rate we have today, and to identify without hurting that high success rate less toxic therapies will require a collaborative, multidisciplinary, international effort to reach that goal.

DR. BOLLARD: Thank you very much Drs. Cairo and Gross. Dr. Lowe, did you have any closing remarks on the late effects issues for the T-cell mediated diseases in particular?

DR. LOWE: I would absolutely agree with Dr. Gross and Dr. Cairo that this is an important issue. I think we in pediatrics do a good job at following our patients for long-term side effects and creating guidelines for screening for these long-term side effects. That said, I think as we start to talk about better and better therapy and even more and more targeted therapy, what we don't know about some of these targeted therapies is their 15 and 20 year long-term side effects. We obviously hope that there aren't any, and that's why we are moving toward these drugs, but again, surveillance of those long-term side effects will be extremely important, especially when you're talking about medications for young children.

DR. BOLLARD: I'd like to thank you all very much for participating in this expert roundtable discussion today. I think the overarching points are that prognoses at the current time for newly diagnosed pediatric patients with NHL range from 70% to over 90% even for patients with disseminated disease. The challenges that we need to overcome are how we can optimize our up front treatment to prevent relapse in all, because I think we've all reiterated the fact that the outcomes for those few patients who do relapse remains extremely poor. I think there is still controversy about how to manage patients with relapsed disease, and how to temper our therapies against long-term side effects of our surviving patients. Finally, I think with the advent of novel targeted agents, it is incredibly important for the optimal management of our current and future patients that we are able to access tumor tissues and perform the critical biologic studies that are required to develop an effective precision medicine approach for pediatric patients with NHL. I would like to again thank Dr. Cairo, Dr. Gross, and Dr. Lowe for their excellent answers to my, at times, difficult and challenging questions and I would like to thank the organizers of this expert roundtable discussion. I hope that in the next decade that we will see even greater advances for the patient population that we treat. Thank you very much.

References

1. Rosolen RA, Perkins SL, Pinkerton CR, et al. Revised International Pediatric Non-Hodgkin Lymphoma Staging System. J Clin Oncol. 2015;33(18):2112–2118.

2. Sandlund JT, Guillerman RP, Perkins SL, et al. International Pediatric Non-Hodgkin Lymphoma Response Criteria. J Clin Oncol. 2015;33(18)2106-2111.

Doctor consults with a cancer

patient and her father

Photo by Rhoda Baer

Results of a large study suggest that adolescent and young adult cancer survivors have an increased risk of hospitalization up to 34 years after their diagnosis.

Cancer survivors with the highest risk of hospitalization were those who had been diagnosed with leukemia, brain cancer, or Hodgkin lymphoma.

Kathrine Rugbjerg, PhD, and Jørgen H. Olsen, MD, of the Danish Cancer Society Research Center in Copenhagen, Denmark, reported these results in JAMA Oncology.

The pair examined the risk of hospitalization in 33,555 subjects who had cancer as adolescents or young adults and survived at least 5 years. The subjects were diagnosed from 1943 through 2004, when they were 15 to 39 years of age.

The researchers compared the cancer survivors to a cohort of 228,447 subjects from the general population who were matched to the cancer survivors by sex and year of birth.

All study subjects were followed up for hospitalizations in the Danish Patient Register through December 2010. The median follow-up was 14 years.

There were 53,032 hospitalizations among the cancer survivors, but only 38,423 were expected. So the standardized hospitalization rate ratio (RR) was 1.38.

The highest risks of hospitalization were for diseases of blood and blood-forming organs (RR=2.00), infectious and parasitic diseases (RR=1.69), and malignant neoplasms (RR=1.63).

The overall absolute excess risk of hospitalization for the cancer survivors was 2803 per 100,000 person-years. The highest absolute excess risks were for malignant neoplasms (18%), diseases of digestive organs (15%), and diseases of the circulatory system (14%).

The researchers said these results suggest that survivors of adolescent and young adult cancers face persistent risks for a broad range of somatic diseases that require hospitalization. And the morbidity pattern is highly dependent on the type of cancer being treated.

Doctor consults with a cancer

patient and her father

Photo by Rhoda Baer

Results of a large study suggest that adolescent and young adult cancer survivors have an increased risk of hospitalization up to 34 years after their diagnosis.

Cancer survivors with the highest risk of hospitalization were those who had been diagnosed with leukemia, brain cancer, or Hodgkin lymphoma.

Kathrine Rugbjerg, PhD, and Jørgen H. Olsen, MD, of the Danish Cancer Society Research Center in Copenhagen, Denmark, reported these results in JAMA Oncology.

The pair examined the risk of hospitalization in 33,555 subjects who had cancer as adolescents or young adults and survived at least 5 years. The subjects were diagnosed from 1943 through 2004, when they were 15 to 39 years of age.

The researchers compared the cancer survivors to a cohort of 228,447 subjects from the general population who were matched to the cancer survivors by sex and year of birth.

All study subjects were followed up for hospitalizations in the Danish Patient Register through December 2010. The median follow-up was 14 years.

There were 53,032 hospitalizations among the cancer survivors, but only 38,423 were expected. So the standardized hospitalization rate ratio (RR) was 1.38.

The highest risks of hospitalization were for diseases of blood and blood-forming organs (RR=2.00), infectious and parasitic diseases (RR=1.69), and malignant neoplasms (RR=1.63).

The overall absolute excess risk of hospitalization for the cancer survivors was 2803 per 100,000 person-years. The highest absolute excess risks were for malignant neoplasms (18%), diseases of digestive organs (15%), and diseases of the circulatory system (14%).

The researchers said these results suggest that survivors of adolescent and young adult cancers face persistent risks for a broad range of somatic diseases that require hospitalization. And the morbidity pattern is highly dependent on the type of cancer being treated.

Doctor consults with a cancer

patient and her father

Photo by Rhoda Baer

Results of a large study suggest that adolescent and young adult cancer survivors have an increased risk of hospitalization up to 34 years after their diagnosis.

Cancer survivors with the highest risk of hospitalization were those who had been diagnosed with leukemia, brain cancer, or Hodgkin lymphoma.

Kathrine Rugbjerg, PhD, and Jørgen H. Olsen, MD, of the Danish Cancer Society Research Center in Copenhagen, Denmark, reported these results in JAMA Oncology.

The pair examined the risk of hospitalization in 33,555 subjects who had cancer as adolescents or young adults and survived at least 5 years. The subjects were diagnosed from 1943 through 2004, when they were 15 to 39 years of age.

The researchers compared the cancer survivors to a cohort of 228,447 subjects from the general population who were matched to the cancer survivors by sex and year of birth.

All study subjects were followed up for hospitalizations in the Danish Patient Register through December 2010. The median follow-up was 14 years.

There were 53,032 hospitalizations among the cancer survivors, but only 38,423 were expected. So the standardized hospitalization rate ratio (RR) was 1.38.

The highest risks of hospitalization were for diseases of blood and blood-forming organs (RR=2.00), infectious and parasitic diseases (RR=1.69), and malignant neoplasms (RR=1.63).

The overall absolute excess risk of hospitalization for the cancer survivors was 2803 per 100,000 person-years. The highest absolute excess risks were for malignant neoplasms (18%), diseases of digestive organs (15%), and diseases of the circulatory system (14%).

The researchers said these results suggest that survivors of adolescent and young adult cancers face persistent risks for a broad range of somatic diseases that require hospitalization. And the morbidity pattern is highly dependent on the type of cancer being treated.

Preparing patient for radiation

Photo by Rhoda Baer

European researchers say they have quantified the risk of cardiovascular disease associated with treatments for Hodgkin lymphoma (HL).

The group analyzed the risks associated with specific doses of radiation and anthracycline exposure.

They believe their results, published in The Lancet Haematology, could help clinicians identify the optimal treatment regimen for each individual HL patient.

“These study results are exciting,” said Maja V. Maraldo, PhD, of Rigshospitalet in Copenhagen, Denmark.

“They should allow physicians to optimize the combination of systemic therapy and radiation and thereby balance the risks and benefits of different regimens in individual patients.”

Study details

Dr Maraldo and her colleagues analyzed data from patients who participated in 9 trials conducted by the European Organisation for Research and Treatment of Cancer (EORTC) and the Groupe d’Etude des Lymphomes de l’Adulte (GELA, now renamed LYSA) between 1964 and 2004.

In 2009 and 2010, the researchers mailed a Life Situation Questionnaire (LSQ) to the trial participants. The goal was to determine late-onset effects of HL and its treatment.

The team also reconstructed patients’ mean radiation doses to the heart and carotid arteries and the cumulative doses of anthracyclines and vinca-alkaloids they received. The incidence of cardiovascular disease was reported during follow-up and updated through the LSQ.

Patient data

The researchers were able to collect complete information on primary treatment for 6039 HL survivors. Of these patients, 2923 received the LSQ, and 1919 responded. The median follow-up was 9 years, and the patients’ median age at diagnosis was 30.

There were 1238 cardiovascular events in 703 patients, including 46 patients who died from such an event.

The events included ischemic heart disease (24%), congestive heart failure (21%), arrhythmia (17%), valvular disease (14%), disease of the arterial vessels (9%), stroke (6%), venous thromboembolism (5%), pericarditis (3%), peripheral vasculopathy (1%), other vascular events (1%), and other cardiac events (<1%).

Predictors of risk

The researchers found that the mean radiation dose to the heart, per 1 Gy increase, was a significant predictor of cardiovascular disease, with a hazard ratio of 1.015 (P=0.0014).

However, the mean radiation doses to the left internal carotid artery and the right internal carotid artery were not significant predictors of cardiovascular events (P=0.41 and 0.70, respectively).

The dose of anthracyclines, per 50 mg/m² increase in cumulative dose, was a significant predictor of cardiovascular disease, with a hazard ratio of 1.077 (P=0.0064).

But the cumulative dose of vinblastine or vincristine was not (P=0.77 and 0.36, respectively).

The researchers said a limitation of this study is that they were not able to assess the impact of cardiovascular risk factors such as smoking, hypertension, and diabetes because that information was not consistently available.

Still, the team believes their analyses quantified the effect of radiotherapy and anthracyclines on the risk of cardiovascular disease, and the findings should aid treatment decisions in HL.

Preparing patient for radiation

Photo by Rhoda Baer

European researchers say they have quantified the risk of cardiovascular disease associated with treatments for Hodgkin lymphoma (HL).

The group analyzed the risks associated with specific doses of radiation and anthracycline exposure.

They believe their results, published in The Lancet Haematology, could help clinicians identify the optimal treatment regimen for each individual HL patient.

“These study results are exciting,” said Maja V. Maraldo, PhD, of Rigshospitalet in Copenhagen, Denmark.

“They should allow physicians to optimize the combination of systemic therapy and radiation and thereby balance the risks and benefits of different regimens in individual patients.”

Study details

Dr Maraldo and her colleagues analyzed data from patients who participated in 9 trials conducted by the European Organisation for Research and Treatment of Cancer (EORTC) and the Groupe d’Etude des Lymphomes de l’Adulte (GELA, now renamed LYSA) between 1964 and 2004.

In 2009 and 2010, the researchers mailed a Life Situation Questionnaire (LSQ) to the trial participants. The goal was to determine late-onset effects of HL and its treatment.

The team also reconstructed patients’ mean radiation doses to the heart and carotid arteries and the cumulative doses of anthracyclines and vinca-alkaloids they received. The incidence of cardiovascular disease was reported during follow-up and updated through the LSQ.

Patient data

The researchers were able to collect complete information on primary treatment for 6039 HL survivors. Of these patients, 2923 received the LSQ, and 1919 responded. The median follow-up was 9 years, and the patients’ median age at diagnosis was 30.

There were 1238 cardiovascular events in 703 patients, including 46 patients who died from such an event.

The events included ischemic heart disease (24%), congestive heart failure (21%), arrhythmia (17%), valvular disease (14%), disease of the arterial vessels (9%), stroke (6%), venous thromboembolism (5%), pericarditis (3%), peripheral vasculopathy (1%), other vascular events (1%), and other cardiac events (<1%).

Predictors of risk

The researchers found that the mean radiation dose to the heart, per 1 Gy increase, was a significant predictor of cardiovascular disease, with a hazard ratio of 1.015 (P=0.0014).

However, the mean radiation doses to the left internal carotid artery and the right internal carotid artery were not significant predictors of cardiovascular events (P=0.41 and 0.70, respectively).

The dose of anthracyclines, per 50 mg/m² increase in cumulative dose, was a significant predictor of cardiovascular disease, with a hazard ratio of 1.077 (P=0.0064).

But the cumulative dose of vinblastine or vincristine was not (P=0.77 and 0.36, respectively).

The researchers said a limitation of this study is that they were not able to assess the impact of cardiovascular risk factors such as smoking, hypertension, and diabetes because that information was not consistently available.

Still, the team believes their analyses quantified the effect of radiotherapy and anthracyclines on the risk of cardiovascular disease, and the findings should aid treatment decisions in HL.

Preparing patient for radiation

Photo by Rhoda Baer

European researchers say they have quantified the risk of cardiovascular disease associated with treatments for Hodgkin lymphoma (HL).

The group analyzed the risks associated with specific doses of radiation and anthracycline exposure.

They believe their results, published in The Lancet Haematology, could help clinicians identify the optimal treatment regimen for each individual HL patient.

“These study results are exciting,” said Maja V. Maraldo, PhD, of Rigshospitalet in Copenhagen, Denmark.

“They should allow physicians to optimize the combination of systemic therapy and radiation and thereby balance the risks and benefits of different regimens in individual patients.”

Study details

Dr Maraldo and her colleagues analyzed data from patients who participated in 9 trials conducted by the European Organisation for Research and Treatment of Cancer (EORTC) and the Groupe d’Etude des Lymphomes de l’Adulte (GELA, now renamed LYSA) between 1964 and 2004.

In 2009 and 2010, the researchers mailed a Life Situation Questionnaire (LSQ) to the trial participants. The goal was to determine late-onset effects of HL and its treatment.

The team also reconstructed patients’ mean radiation doses to the heart and carotid arteries and the cumulative doses of anthracyclines and vinca-alkaloids they received. The incidence of cardiovascular disease was reported during follow-up and updated through the LSQ.

Patient data

The researchers were able to collect complete information on primary treatment for 6039 HL survivors. Of these patients, 2923 received the LSQ, and 1919 responded. The median follow-up was 9 years, and the patients’ median age at diagnosis was 30.

There were 1238 cardiovascular events in 703 patients, including 46 patients who died from such an event.

The events included ischemic heart disease (24%), congestive heart failure (21%), arrhythmia (17%), valvular disease (14%), disease of the arterial vessels (9%), stroke (6%), venous thromboembolism (5%), pericarditis (3%), peripheral vasculopathy (1%), other vascular events (1%), and other cardiac events (<1%).

Predictors of risk

The researchers found that the mean radiation dose to the heart, per 1 Gy increase, was a significant predictor of cardiovascular disease, with a hazard ratio of 1.015 (P=0.0014).

However, the mean radiation doses to the left internal carotid artery and the right internal carotid artery were not significant predictors of cardiovascular events (P=0.41 and 0.70, respectively).

The dose of anthracyclines, per 50 mg/m² increase in cumulative dose, was a significant predictor of cardiovascular disease, with a hazard ratio of 1.077 (P=0.0064).

But the cumulative dose of vinblastine or vincristine was not (P=0.77 and 0.36, respectively).

The researchers said a limitation of this study is that they were not able to assess the impact of cardiovascular risk factors such as smoking, hypertension, and diabetes because that information was not consistently available.

Still, the team believes their analyses quantified the effect of radiotherapy and anthracyclines on the risk of cardiovascular disease, and the findings should aid treatment decisions in HL.

Patient receiving dialysis

Photo by Anna Frodesiak

Patients with end-stage renal disease (ESRD) may have different cancer risks according to the treatment they are receiving, a new study suggests.

Researchers found that patients had a higher risk of developing infection-related and immune-related cancers—including Hodgkin and non-Hodgkin lymphoma (NHL)—after receiving a kidney transplant.

But patients had a higher risk of ESRD-related cancers when they were on dialysis.

Elizabeth Yanik, PhD, of the National Cancer Institute in Bethesda, Maryland, and her colleagues reported these results in the Journal of the American Society of Nephrology.

The researchers theorized that assessing patterns in ESRD patients across periods of dialysis and kidney transplant might inform cancer etiology.

So the team studied registry data on 202,195 kidney transplant candidates and recipients, comparing the incidence of cancers during kidney function intervals (time with a transplant) to the incidence during nonfunction intervals (waitlist or time after transplant failure [dialysis]). The analysis was adjusted for demographic characteristics.

Results showed the incidence of infection-related and immune-related cancers was higher during kidney function intervals than nonfunction intervals.

Cancers with a significantly higher incidence included Kaposi’s sarcoma (hazard ratio [HR]=9.1, P<0.001), NHL (HR=3.2, P<0.001), Hodgkin lymphoma (HR=3.0, P<0.001), lip cancer (HR=3.4, P<0.001), nonepithelial skin cancers (HR=3.8, P<0.001), melanoma (HR=1.9, P<0.001), prostate cancer (HR=1.2, P=0.003),  anal cancer (HR=1.8, P=0.01), other genital cancers (HR=1.5, P=0.03), lung cancer (HR=1.3 P<0.001), and pancreatic cancer (HR=1.5, P=0.004).

Dr Yanik and her colleagues noted that, of these cancers, NHL, anal cancer, lung cancer, melanoma, nonepithelial skin cancers, and pancreatic cancer consistently increased in incidence with each transition to a kidney function interval and decreased with each transition to a nonfunction interval.

And the 2 types of transitions were significant for NHL, lung cancer, melanoma, nonepithelial skin cancers, and pancreatic cancer.

The researchers also identified cancers with a significantly lower incidence during kidney function intervals. This included kidney cancer (HR=0.77, P<0.001), thyroid cancer (HR=0.67, P<0.001), breast cancer (HR=0.81, P=0.002), and liver cancer (HR=0.59, P=0.001).

The team noted that, among cancers with a lower incidence during kidney function intervals, kidney cancer, thyroid cancer, and myeloma consistently decreased in incidence with each transition to a kidney function interval and increased in incidence with each transition to a nonfunction interval. But both transitions were only significant for kidney and thyroid cancers.

“Our study indicates that the needs of individuals with end-stage renal disease, in terms of cancer prevention and cancer screening, will likely differ over time,” Dr Yanik said.

“Vigilance for kidney cancer and thyroid cancer may be of particular importance while these individuals are on dialysis. Extra consideration for screening for melanoma or lung cancer may be called for while taking immunosuppressant medications following a kidney transplant.”

Patient receiving dialysis

Photo by Anna Frodesiak

Patients with end-stage renal disease (ESRD) may have different cancer risks according to the treatment they are receiving, a new study suggests.

Researchers found that patients had a higher risk of developing infection-related and immune-related cancers—including Hodgkin and non-Hodgkin lymphoma (NHL)—after receiving a kidney transplant.

But patients had a higher risk of ESRD-related cancers when they were on dialysis.

Elizabeth Yanik, PhD, of the National Cancer Institute in Bethesda, Maryland, and her colleagues reported these results in the Journal of the American Society of Nephrology.

The researchers theorized that assessing patterns in ESRD patients across periods of dialysis and kidney transplant might inform cancer etiology.

So the team studied registry data on 202,195 kidney transplant candidates and recipients, comparing the incidence of cancers during kidney function intervals (time with a transplant) to the incidence during nonfunction intervals (waitlist or time after transplant failure [dialysis]). The analysis was adjusted for demographic characteristics.

Results showed the incidence of infection-related and immune-related cancers was higher during kidney function intervals than nonfunction intervals.

Cancers with a significantly higher incidence included Kaposi’s sarcoma (hazard ratio [HR]=9.1, P<0.001), NHL (HR=3.2, P<0.001), Hodgkin lymphoma (HR=3.0, P<0.001), lip cancer (HR=3.4, P<0.001), nonepithelial skin cancers (HR=3.8, P<0.001), melanoma (HR=1.9, P<0.001), prostate cancer (HR=1.2, P=0.003),  anal cancer (HR=1.8, P=0.01), other genital cancers (HR=1.5, P=0.03), lung cancer (HR=1.3 P<0.001), and pancreatic cancer (HR=1.5, P=0.004).

Dr Yanik and her colleagues noted that, of these cancers, NHL, anal cancer, lung cancer, melanoma, nonepithelial skin cancers, and pancreatic cancer consistently increased in incidence with each transition to a kidney function interval and decreased with each transition to a nonfunction interval.

And the 2 types of transitions were significant for NHL, lung cancer, melanoma, nonepithelial skin cancers, and pancreatic cancer.

The researchers also identified cancers with a significantly lower incidence during kidney function intervals. This included kidney cancer (HR=0.77, P<0.001), thyroid cancer (HR=0.67, P<0.001), breast cancer (HR=0.81, P=0.002), and liver cancer (HR=0.59, P=0.001).

The team noted that, among cancers with a lower incidence during kidney function intervals, kidney cancer, thyroid cancer, and myeloma consistently decreased in incidence with each transition to a kidney function interval and increased in incidence with each transition to a nonfunction interval. But both transitions were only significant for kidney and thyroid cancers.

“Our study indicates that the needs of individuals with end-stage renal disease, in terms of cancer prevention and cancer screening, will likely differ over time,” Dr Yanik said.

“Vigilance for kidney cancer and thyroid cancer may be of particular importance while these individuals are on dialysis. Extra consideration for screening for melanoma or lung cancer may be called for while taking immunosuppressant medications following a kidney transplant.”

Patient receiving dialysis

Photo by Anna Frodesiak

Patients with end-stage renal disease (ESRD) may have different cancer risks according to the treatment they are receiving, a new study suggests.

Researchers found that patients had a higher risk of developing infection-related and immune-related cancers—including Hodgkin and non-Hodgkin lymphoma (NHL)—after receiving a kidney transplant.

But patients had a higher risk of ESRD-related cancers when they were on dialysis.

Elizabeth Yanik, PhD, of the National Cancer Institute in Bethesda, Maryland, and her colleagues reported these results in the Journal of the American Society of Nephrology.

The researchers theorized that assessing patterns in ESRD patients across periods of dialysis and kidney transplant might inform cancer etiology.

So the team studied registry data on 202,195 kidney transplant candidates and recipients, comparing the incidence of cancers during kidney function intervals (time with a transplant) to the incidence during nonfunction intervals (waitlist or time after transplant failure [dialysis]). The analysis was adjusted for demographic characteristics.

Results showed the incidence of infection-related and immune-related cancers was higher during kidney function intervals than nonfunction intervals.

Cancers with a significantly higher incidence included Kaposi’s sarcoma (hazard ratio [HR]=9.1, P<0.001), NHL (HR=3.2, P<0.001), Hodgkin lymphoma (HR=3.0, P<0.001), lip cancer (HR=3.4, P<0.001), nonepithelial skin cancers (HR=3.8, P<0.001), melanoma (HR=1.9, P<0.001), prostate cancer (HR=1.2, P=0.003),  anal cancer (HR=1.8, P=0.01), other genital cancers (HR=1.5, P=0.03), lung cancer (HR=1.3 P<0.001), and pancreatic cancer (HR=1.5, P=0.004).

Dr Yanik and her colleagues noted that, of these cancers, NHL, anal cancer, lung cancer, melanoma, nonepithelial skin cancers, and pancreatic cancer consistently increased in incidence with each transition to a kidney function interval and decreased with each transition to a nonfunction interval.

And the 2 types of transitions were significant for NHL, lung cancer, melanoma, nonepithelial skin cancers, and pancreatic cancer.

The researchers also identified cancers with a significantly lower incidence during kidney function intervals. This included kidney cancer (HR=0.77, P<0.001), thyroid cancer (HR=0.67, P<0.001), breast cancer (HR=0.81, P=0.002), and liver cancer (HR=0.59, P=0.001).

The team noted that, among cancers with a lower incidence during kidney function intervals, kidney cancer, thyroid cancer, and myeloma consistently decreased in incidence with each transition to a kidney function interval and increased in incidence with each transition to a nonfunction interval. But both transitions were only significant for kidney and thyroid cancers.

“Our study indicates that the needs of individuals with end-stage renal disease, in terms of cancer prevention and cancer screening, will likely differ over time,” Dr Yanik said.

“Vigilance for kidney cancer and thyroid cancer may be of particular importance while these individuals are on dialysis. Extra consideration for screening for melanoma or lung cancer may be called for while taking immunosuppressant medications following a kidney transplant.”