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Sharon Worcester is an award-winning medical journalist for MDedge News. She has been with the company since 1996, first as the Southeast Bureau Chief (1996-2009) when the company was known as International Medical News Group, then as a freelance writer (2010-2015) before returning as a reporter in 2015. She previously worked as a daily newspaper reporter covering health and local government. Sharon currently reports primarily on oncology and hematology. She has a BA from Eckerd College and an MA in Mass Communication/Print Journalism from the University of Florida. Connect with her via LinkedIn and follow her on twitter @SW_MedReporter.
CDC: Trivalent adjuvanted influenza vaccine aIIV3 safe in elderly adults
ATLANTA – according to an analysis of reports to the Vaccine Adverse Event Reporting System (VAERS) during July 2016 through March 2018.
VAERS received 630 reports related to the vaccine (aIIV3; FLUAD) during the study period, of which 521 involved adults aged 65 years and older.
“Eighteen (3%) were serious reports, including two death reports (0.4%), all in adults aged [at least] 65 years,” Penina Haber and her colleagues at the Immunization Safety Office at the Centers for Disease Control and Prevention reported in a poster at the International Conference on Emerging Infectious Diseases.
The deaths included a 75-year-old man who died from Sjögren’s syndrome and a 65-year-old man who died from a myocardial infarction. The other serious events included five neurologic disorders (two cases of Guillain-Barré syndrome and one each of Bell’s palsy, Bickerstaff encephalitis, and lower-extremity weakness), five musculoskeletal and connective tissue disorders (three with shoulder pain and two with arm pain), three general disorders and administration site conditions (two cases of fever/chills and one case of cellulitis/bursitis), and one case each of a gastrointestinal disorder (acute diarrhea/gastroenteritis), an injury (a fall), and a skin/subcutaneous tissue disorder (keratosis pilaris rubra), according to the investigators.
There were no reports of anaphylaxis.
For the sake of comparison, the investigators also looked at reports associated with IIV3-HD and IIV3/IIV4 vaccines in adults aged 65 years and older during the same time period; they found that patient characteristics and reported events were similar for all the vaccines. For example, the percentages of reports involving patients aged 65 years and older were 65% or 66% for each, and those involving patients aged 75-84 years were 27%-29%. Further, 0.2%-0.6% of reports for each vaccine involved death.
The most frequently reported events for aIIV3, IIV3-HD, and IIV3/IIV4, respectively, were extremity pain (21%, 17%, and 15%, respectively), injection site erythema (18%, 19%, and 15%), and injection site pain (15%, 16%, and 16%), they said.
The aIIV3 vaccine – the first seasonal inactivated trivalent influenza vaccine produced from three influenza virus strains (two subtype A strains and one type B strain) – was approved by the Food and Drug Administration in 2015 for adults aged 65 years and older. It was the first influenza vaccine containing the adjuvant MF59 – a purified oil-in-water emulsion of squalene oil added to boost immune response in that population. Its safety was assessed in 15 randomized, controlled clinical studies, and several trials in older adults supported its efficacy and safety over nonadjuvanted influenza vaccines, the investigators reported. They noted that the Advisory Committee on Immunization Practices (ACIP) recommended the vaccine as an option for routine use in adults aged 65 years and older during the 2016-2017 flu seasons.
For the 2018-2019 flu season, ACIP determined that “For persons aged ≥65 years, any age-appropriate IIV formulation (standard-dose or high-dose, trivalent or quadrivalent, unadjuvanted or adjuvanted) or RIV4 are acceptable options.”
The findings of the analysis of the 2017-2018 flu season data are consistent with prelicensure studies, Ms. Haber and her colleagues concluded, noting that data mining did not detect disproportional reporting of any unexpected adverse event.
“[There were] no safety concerns following aIIV3 when compared to the nonadjuvanted influenza vaccines (IIV3-HD or IIV3/IIV4),” they wrote, adding that the “CDC and FDA will continue to monitor and ensure the safety of aIIV3.”
Ms. Haber reported having no disclosures
SOURCE: Haber P et al. ICEID 2018, Board 320.
ATLANTA – according to an analysis of reports to the Vaccine Adverse Event Reporting System (VAERS) during July 2016 through March 2018.
VAERS received 630 reports related to the vaccine (aIIV3; FLUAD) during the study period, of which 521 involved adults aged 65 years and older.
“Eighteen (3%) were serious reports, including two death reports (0.4%), all in adults aged [at least] 65 years,” Penina Haber and her colleagues at the Immunization Safety Office at the Centers for Disease Control and Prevention reported in a poster at the International Conference on Emerging Infectious Diseases.
The deaths included a 75-year-old man who died from Sjögren’s syndrome and a 65-year-old man who died from a myocardial infarction. The other serious events included five neurologic disorders (two cases of Guillain-Barré syndrome and one each of Bell’s palsy, Bickerstaff encephalitis, and lower-extremity weakness), five musculoskeletal and connective tissue disorders (three with shoulder pain and two with arm pain), three general disorders and administration site conditions (two cases of fever/chills and one case of cellulitis/bursitis), and one case each of a gastrointestinal disorder (acute diarrhea/gastroenteritis), an injury (a fall), and a skin/subcutaneous tissue disorder (keratosis pilaris rubra), according to the investigators.
There were no reports of anaphylaxis.
For the sake of comparison, the investigators also looked at reports associated with IIV3-HD and IIV3/IIV4 vaccines in adults aged 65 years and older during the same time period; they found that patient characteristics and reported events were similar for all the vaccines. For example, the percentages of reports involving patients aged 65 years and older were 65% or 66% for each, and those involving patients aged 75-84 years were 27%-29%. Further, 0.2%-0.6% of reports for each vaccine involved death.
The most frequently reported events for aIIV3, IIV3-HD, and IIV3/IIV4, respectively, were extremity pain (21%, 17%, and 15%, respectively), injection site erythema (18%, 19%, and 15%), and injection site pain (15%, 16%, and 16%), they said.
The aIIV3 vaccine – the first seasonal inactivated trivalent influenza vaccine produced from three influenza virus strains (two subtype A strains and one type B strain) – was approved by the Food and Drug Administration in 2015 for adults aged 65 years and older. It was the first influenza vaccine containing the adjuvant MF59 – a purified oil-in-water emulsion of squalene oil added to boost immune response in that population. Its safety was assessed in 15 randomized, controlled clinical studies, and several trials in older adults supported its efficacy and safety over nonadjuvanted influenza vaccines, the investigators reported. They noted that the Advisory Committee on Immunization Practices (ACIP) recommended the vaccine as an option for routine use in adults aged 65 years and older during the 2016-2017 flu seasons.
For the 2018-2019 flu season, ACIP determined that “For persons aged ≥65 years, any age-appropriate IIV formulation (standard-dose or high-dose, trivalent or quadrivalent, unadjuvanted or adjuvanted) or RIV4 are acceptable options.”
The findings of the analysis of the 2017-2018 flu season data are consistent with prelicensure studies, Ms. Haber and her colleagues concluded, noting that data mining did not detect disproportional reporting of any unexpected adverse event.
“[There were] no safety concerns following aIIV3 when compared to the nonadjuvanted influenza vaccines (IIV3-HD or IIV3/IIV4),” they wrote, adding that the “CDC and FDA will continue to monitor and ensure the safety of aIIV3.”
Ms. Haber reported having no disclosures
SOURCE: Haber P et al. ICEID 2018, Board 320.
ATLANTA – according to an analysis of reports to the Vaccine Adverse Event Reporting System (VAERS) during July 2016 through March 2018.
VAERS received 630 reports related to the vaccine (aIIV3; FLUAD) during the study period, of which 521 involved adults aged 65 years and older.
“Eighteen (3%) were serious reports, including two death reports (0.4%), all in adults aged [at least] 65 years,” Penina Haber and her colleagues at the Immunization Safety Office at the Centers for Disease Control and Prevention reported in a poster at the International Conference on Emerging Infectious Diseases.
The deaths included a 75-year-old man who died from Sjögren’s syndrome and a 65-year-old man who died from a myocardial infarction. The other serious events included five neurologic disorders (two cases of Guillain-Barré syndrome and one each of Bell’s palsy, Bickerstaff encephalitis, and lower-extremity weakness), five musculoskeletal and connective tissue disorders (three with shoulder pain and two with arm pain), three general disorders and administration site conditions (two cases of fever/chills and one case of cellulitis/bursitis), and one case each of a gastrointestinal disorder (acute diarrhea/gastroenteritis), an injury (a fall), and a skin/subcutaneous tissue disorder (keratosis pilaris rubra), according to the investigators.
There were no reports of anaphylaxis.
For the sake of comparison, the investigators also looked at reports associated with IIV3-HD and IIV3/IIV4 vaccines in adults aged 65 years and older during the same time period; they found that patient characteristics and reported events were similar for all the vaccines. For example, the percentages of reports involving patients aged 65 years and older were 65% or 66% for each, and those involving patients aged 75-84 years were 27%-29%. Further, 0.2%-0.6% of reports for each vaccine involved death.
The most frequently reported events for aIIV3, IIV3-HD, and IIV3/IIV4, respectively, were extremity pain (21%, 17%, and 15%, respectively), injection site erythema (18%, 19%, and 15%), and injection site pain (15%, 16%, and 16%), they said.
The aIIV3 vaccine – the first seasonal inactivated trivalent influenza vaccine produced from three influenza virus strains (two subtype A strains and one type B strain) – was approved by the Food and Drug Administration in 2015 for adults aged 65 years and older. It was the first influenza vaccine containing the adjuvant MF59 – a purified oil-in-water emulsion of squalene oil added to boost immune response in that population. Its safety was assessed in 15 randomized, controlled clinical studies, and several trials in older adults supported its efficacy and safety over nonadjuvanted influenza vaccines, the investigators reported. They noted that the Advisory Committee on Immunization Practices (ACIP) recommended the vaccine as an option for routine use in adults aged 65 years and older during the 2016-2017 flu seasons.
For the 2018-2019 flu season, ACIP determined that “For persons aged ≥65 years, any age-appropriate IIV formulation (standard-dose or high-dose, trivalent or quadrivalent, unadjuvanted or adjuvanted) or RIV4 are acceptable options.”
The findings of the analysis of the 2017-2018 flu season data are consistent with prelicensure studies, Ms. Haber and her colleagues concluded, noting that data mining did not detect disproportional reporting of any unexpected adverse event.
“[There were] no safety concerns following aIIV3 when compared to the nonadjuvanted influenza vaccines (IIV3-HD or IIV3/IIV4),” they wrote, adding that the “CDC and FDA will continue to monitor and ensure the safety of aIIV3.”
Ms. Haber reported having no disclosures
SOURCE: Haber P et al. ICEID 2018, Board 320.
REPORTING FROM ICEID 2018
Key clinical point: No new or unexpected adverse events were reported among the 630 reports related to the vaccine during the study period, of which 521 involved adults aged 65 years and older.
Major finding: Of 521 reports, 18 were serious, and there were two deaths.
Study details: A review of 521 reports to the Vaccine Adverse Event Reporting System in 2017-2018.
Disclosures: Ms. Haber reported having no disclosures.
Source: Haber P et al. ICEID 2018, Board 320.
PCV13 moderately effective in older adults
ATLANTA – (IPD) caused by PCV13 vaccine serotypes in adults aged 65 years and older, according to a case-control study involving Medicare beneficiaries.
Conversely, the 23-valent pneumococcal polysaccharide vaccine (PPSV23) showed limited effectiveness against serotypes unique to that vaccine in the study, which included 699 cases and more than 10,000 controls, Olivia Almendares, an epidemiologist at the Centers for Disease Control and Prevention, Atlanta, and her colleagues reported in a poster at the International Conference on Emerging Infectious Diseases.
“Vaccine efficacy against PCV13 [plus 6C type, which has cross-reactivity with serotype 6A] was 47% in those who received PCV13 vaccine only,” Ms. Almendares said in an interview, noting that efficacy was 26% against serotype 3 and 67% against other PCV13 serotypes (plus 6C). “Vaccine efficacy against PPSV23-unique types was 36% for those who received only PPSV23.”
Neither vaccine showed effectiveness against serotypes not included in the respective vaccines, she said.
The findings are timely given that the Advisory Committee on Immunization Practices (ACIP) is reevaluating its PCV13 recommendation for adults aged 65 years and older, she added.
“Specifically, ACIP is addressing whether PCV13 should be recommended routinely for all immunocompetent adults aged 65 and older given sustained indirect effects,” she said, explaining that, in 2014 when ACIP recommended routine use of the vaccine in series with PPSV23 for adults aged 65 years and older, the committee recognized that herd immunity effects from PCV13 use in children might eventually limit the utility of this recommendation, and therefore it proposed reevaluation and revision as needed after 4 years.
For the current study, she and her colleagues linked IPD cases in persons aged 65 years and older, which were identified through Active Bacterial Core surveillance during 2015-2016, to records for Centers for Medicare & Medicaid Services (CMS) beneficiaries. Vaccination and medical histories were obtained through medical records, and vaccine effectiveness was estimated as one minus the odds ratio for vaccination with PCV13 only or PPSV23 only versus neither vaccine using conditional logistic regression, with adjustment for sex and underlying medical conditions.
Of 2,246 IPD cases, 1,017 (45%) were matched to Medicare beneficiaries, and 699 were included in the analysis after those with noncontinuous enrollment in Medicare, long-term care residence, and missing census tract data were excluded. The cases were matched based on age, census tract of residence, and length of Medicare enrollment to 10,152 matched controls identified through CMS.
IPD associated with PCV13 (plus type 6C) accounted for 164 (23% of cases), of which 88 (12% of cases) involved serotype 3, and invasive pneumococcal disease associated with PPSV23 accounted for 350 cases (50%), she said.
PCV13 vaccine was given alone in 14% and 18% of cases and controls, respectively; PPSV23 alone was given in 22% and 21% of case patients and controls, respectively; and both vaccines were given in 8% of cases and controls.
Compared with controls, case patients were more likely to be of nonwhite race (16% vs. 11%), to have more than one chronic medical condition (88% vs. 58%), and to have one or more immunocompromising conditions (54% vs. 32%), she and her colleagues reported.
“PCV13 showed moderate overall effectiveness in preventing IPD caused by PCV13 (including 6C), but effectiveness may be lower for serotype 3 than for other PCV13 types,” she said.
“These results are in agreement with those from CAPiTA – a large clinical trial conducted in the Netherlands, which showed PCV13 to be effective against IPD caused by vaccine serotypes among community-dwelling adults aged 65 and older,” she noted. “Additionally, data from CDC surveillance suggest that PCV13-serotype [invasive pneumococcal disease] among children and adults aged 65 and older has declined dramatically following PCV13 introduction for children in 2010, as predicted.”
In fact, among adults aged 65 years and older, PCV13-serotype invasive pneumococcal disease declined by 40% after the vaccine was introduced in children. This corresponds to a change in the annual PCV13-serotype incidence from 14 cases per 100,000 population in 2010 to five cases per 100,000 population in 2014, she said; she added that IPD incidence plateaued in 2014-2016 with vaccine serotypes contributing to a small proportion of overall IPD burden among adults aged 65 years and older.
ACIP’s reevaluation of the PCV13 recommendation is ongoing and will be addressed at upcoming meetings.
“As part of the review process, we look at changes in disease incidence focusing primarily on invasive pneumococcal disease and noninvasive pneumonia, vaccine efficacy and effectiveness, and vaccine safety,” she said. She noted that ACIP currently has no plans to consider revising PCV13 recommendations for adults who have immunocompromising conditions, for whom PCV13 has been recommended since 2012.
Ms. Almendares reported having no disclosures.
SOURCE: Almendares O et al. ICEID 2018, Board 376.
ATLANTA – (IPD) caused by PCV13 vaccine serotypes in adults aged 65 years and older, according to a case-control study involving Medicare beneficiaries.
Conversely, the 23-valent pneumococcal polysaccharide vaccine (PPSV23) showed limited effectiveness against serotypes unique to that vaccine in the study, which included 699 cases and more than 10,000 controls, Olivia Almendares, an epidemiologist at the Centers for Disease Control and Prevention, Atlanta, and her colleagues reported in a poster at the International Conference on Emerging Infectious Diseases.
“Vaccine efficacy against PCV13 [plus 6C type, which has cross-reactivity with serotype 6A] was 47% in those who received PCV13 vaccine only,” Ms. Almendares said in an interview, noting that efficacy was 26% against serotype 3 and 67% against other PCV13 serotypes (plus 6C). “Vaccine efficacy against PPSV23-unique types was 36% for those who received only PPSV23.”
Neither vaccine showed effectiveness against serotypes not included in the respective vaccines, she said.
The findings are timely given that the Advisory Committee on Immunization Practices (ACIP) is reevaluating its PCV13 recommendation for adults aged 65 years and older, she added.
“Specifically, ACIP is addressing whether PCV13 should be recommended routinely for all immunocompetent adults aged 65 and older given sustained indirect effects,” she said, explaining that, in 2014 when ACIP recommended routine use of the vaccine in series with PPSV23 for adults aged 65 years and older, the committee recognized that herd immunity effects from PCV13 use in children might eventually limit the utility of this recommendation, and therefore it proposed reevaluation and revision as needed after 4 years.
For the current study, she and her colleagues linked IPD cases in persons aged 65 years and older, which were identified through Active Bacterial Core surveillance during 2015-2016, to records for Centers for Medicare & Medicaid Services (CMS) beneficiaries. Vaccination and medical histories were obtained through medical records, and vaccine effectiveness was estimated as one minus the odds ratio for vaccination with PCV13 only or PPSV23 only versus neither vaccine using conditional logistic regression, with adjustment for sex and underlying medical conditions.
Of 2,246 IPD cases, 1,017 (45%) were matched to Medicare beneficiaries, and 699 were included in the analysis after those with noncontinuous enrollment in Medicare, long-term care residence, and missing census tract data were excluded. The cases were matched based on age, census tract of residence, and length of Medicare enrollment to 10,152 matched controls identified through CMS.
IPD associated with PCV13 (plus type 6C) accounted for 164 (23% of cases), of which 88 (12% of cases) involved serotype 3, and invasive pneumococcal disease associated with PPSV23 accounted for 350 cases (50%), she said.
PCV13 vaccine was given alone in 14% and 18% of cases and controls, respectively; PPSV23 alone was given in 22% and 21% of case patients and controls, respectively; and both vaccines were given in 8% of cases and controls.
Compared with controls, case patients were more likely to be of nonwhite race (16% vs. 11%), to have more than one chronic medical condition (88% vs. 58%), and to have one or more immunocompromising conditions (54% vs. 32%), she and her colleagues reported.
“PCV13 showed moderate overall effectiveness in preventing IPD caused by PCV13 (including 6C), but effectiveness may be lower for serotype 3 than for other PCV13 types,” she said.
“These results are in agreement with those from CAPiTA – a large clinical trial conducted in the Netherlands, which showed PCV13 to be effective against IPD caused by vaccine serotypes among community-dwelling adults aged 65 and older,” she noted. “Additionally, data from CDC surveillance suggest that PCV13-serotype [invasive pneumococcal disease] among children and adults aged 65 and older has declined dramatically following PCV13 introduction for children in 2010, as predicted.”
In fact, among adults aged 65 years and older, PCV13-serotype invasive pneumococcal disease declined by 40% after the vaccine was introduced in children. This corresponds to a change in the annual PCV13-serotype incidence from 14 cases per 100,000 population in 2010 to five cases per 100,000 population in 2014, she said; she added that IPD incidence plateaued in 2014-2016 with vaccine serotypes contributing to a small proportion of overall IPD burden among adults aged 65 years and older.
ACIP’s reevaluation of the PCV13 recommendation is ongoing and will be addressed at upcoming meetings.
“As part of the review process, we look at changes in disease incidence focusing primarily on invasive pneumococcal disease and noninvasive pneumonia, vaccine efficacy and effectiveness, and vaccine safety,” she said. She noted that ACIP currently has no plans to consider revising PCV13 recommendations for adults who have immunocompromising conditions, for whom PCV13 has been recommended since 2012.
Ms. Almendares reported having no disclosures.
SOURCE: Almendares O et al. ICEID 2018, Board 376.
ATLANTA – (IPD) caused by PCV13 vaccine serotypes in adults aged 65 years and older, according to a case-control study involving Medicare beneficiaries.
Conversely, the 23-valent pneumococcal polysaccharide vaccine (PPSV23) showed limited effectiveness against serotypes unique to that vaccine in the study, which included 699 cases and more than 10,000 controls, Olivia Almendares, an epidemiologist at the Centers for Disease Control and Prevention, Atlanta, and her colleagues reported in a poster at the International Conference on Emerging Infectious Diseases.
“Vaccine efficacy against PCV13 [plus 6C type, which has cross-reactivity with serotype 6A] was 47% in those who received PCV13 vaccine only,” Ms. Almendares said in an interview, noting that efficacy was 26% against serotype 3 and 67% against other PCV13 serotypes (plus 6C). “Vaccine efficacy against PPSV23-unique types was 36% for those who received only PPSV23.”
Neither vaccine showed effectiveness against serotypes not included in the respective vaccines, she said.
The findings are timely given that the Advisory Committee on Immunization Practices (ACIP) is reevaluating its PCV13 recommendation for adults aged 65 years and older, she added.
“Specifically, ACIP is addressing whether PCV13 should be recommended routinely for all immunocompetent adults aged 65 and older given sustained indirect effects,” she said, explaining that, in 2014 when ACIP recommended routine use of the vaccine in series with PPSV23 for adults aged 65 years and older, the committee recognized that herd immunity effects from PCV13 use in children might eventually limit the utility of this recommendation, and therefore it proposed reevaluation and revision as needed after 4 years.
For the current study, she and her colleagues linked IPD cases in persons aged 65 years and older, which were identified through Active Bacterial Core surveillance during 2015-2016, to records for Centers for Medicare & Medicaid Services (CMS) beneficiaries. Vaccination and medical histories were obtained through medical records, and vaccine effectiveness was estimated as one minus the odds ratio for vaccination with PCV13 only or PPSV23 only versus neither vaccine using conditional logistic regression, with adjustment for sex and underlying medical conditions.
Of 2,246 IPD cases, 1,017 (45%) were matched to Medicare beneficiaries, and 699 were included in the analysis after those with noncontinuous enrollment in Medicare, long-term care residence, and missing census tract data were excluded. The cases were matched based on age, census tract of residence, and length of Medicare enrollment to 10,152 matched controls identified through CMS.
IPD associated with PCV13 (plus type 6C) accounted for 164 (23% of cases), of which 88 (12% of cases) involved serotype 3, and invasive pneumococcal disease associated with PPSV23 accounted for 350 cases (50%), she said.
PCV13 vaccine was given alone in 14% and 18% of cases and controls, respectively; PPSV23 alone was given in 22% and 21% of case patients and controls, respectively; and both vaccines were given in 8% of cases and controls.
Compared with controls, case patients were more likely to be of nonwhite race (16% vs. 11%), to have more than one chronic medical condition (88% vs. 58%), and to have one or more immunocompromising conditions (54% vs. 32%), she and her colleagues reported.
“PCV13 showed moderate overall effectiveness in preventing IPD caused by PCV13 (including 6C), but effectiveness may be lower for serotype 3 than for other PCV13 types,” she said.
“These results are in agreement with those from CAPiTA – a large clinical trial conducted in the Netherlands, which showed PCV13 to be effective against IPD caused by vaccine serotypes among community-dwelling adults aged 65 and older,” she noted. “Additionally, data from CDC surveillance suggest that PCV13-serotype [invasive pneumococcal disease] among children and adults aged 65 and older has declined dramatically following PCV13 introduction for children in 2010, as predicted.”
In fact, among adults aged 65 years and older, PCV13-serotype invasive pneumococcal disease declined by 40% after the vaccine was introduced in children. This corresponds to a change in the annual PCV13-serotype incidence from 14 cases per 100,000 population in 2010 to five cases per 100,000 population in 2014, she said; she added that IPD incidence plateaued in 2014-2016 with vaccine serotypes contributing to a small proportion of overall IPD burden among adults aged 65 years and older.
ACIP’s reevaluation of the PCV13 recommendation is ongoing and will be addressed at upcoming meetings.
“As part of the review process, we look at changes in disease incidence focusing primarily on invasive pneumococcal disease and noninvasive pneumonia, vaccine efficacy and effectiveness, and vaccine safety,” she said. She noted that ACIP currently has no plans to consider revising PCV13 recommendations for adults who have immunocompromising conditions, for whom PCV13 has been recommended since 2012.
Ms. Almendares reported having no disclosures.
SOURCE: Almendares O et al. ICEID 2018, Board 376.
REPORTING FROM ICEID 2018
Breast cancer risk in type 2 diabetes related to adiposity
ORLANDO – findings from meta-analyses suggest.
In one meta-analysis of data from 21 prospective studies with a total of nearly 15.2 million women, 325,117 breast cancer cases, and a mean follow-up time of 8 years (nearly 33 million person-years), the risk of breast cancer was significantly greater among patients with diabetes than it was among patients without diabetes (summary relative risk, 1.11), Maria Bota reported at the annual scientific sessions of the American Diabetes Association.
However, there was substantial unexplained heterogeneity of results across the individual studies (I2 = 82%), said Ms. Bota, a faculty member at the International Prevention Research Institute, Lyon, France.
“When the analysis was restricted to the 12 studies that adjusted for [body mass index], the summary relative risk decreased to 1.09 and the heterogeneity also decreased to a moderate value of 32%; when the analysis was restricted to the 9 studies that did not adjust for BMI, the summary relative risk increased to 1.14 again, and the heterogeneity increased even more to 91%,” she said.
In an analysis that combined the results of the nine studies that did not adjust for BMI along with crude relative risks from studies that reported both crude and BMI-adjusted relative risks (17 studies in all), the SRR was 1.12, and heterogeneity among the studies was high at 84%.
Additionally, an analysis by menopausal status based on four studies that reported breast cancer in both pre- and postmenopausal women showed SRRs for breast cancer of 0.97 (a 3% decrease in risk) and 1.14 among diabetic vs. nondiabetic premenopausal women and postmenopausal women, respectively, she said, noting that heterogeneity was low (I2 = 0%) among the premenopausal breast cancer study groups and high (I2 = 70%) among the postmenopausal study groups.
The findings provide evidence for a moderately increased risk of breast cancer in women with T2DM, Ms. Bota said.
“However, the effect of the adjustment or lack of adjustment on the heterogeneity suggests that the higher risk of breast cancer in women with diabetes may not be due to diabetes itself, but to adiposity,” she said, adding that “this hypothesis is equally supported by our subgroup analysis according to menopausal status because we saw that the risk of breast cancer was only associated with diabetes in postmenopausal women and this pattern resembles the pattern of the risk of breast cancer associated with adiposity, which is also only increased in postmenopausal women.”
This study was limited by insufficient data for investigating the sources of heterogeneity, she said.
“Therefore we propose ... future pooled analyses based on individual data from good quality prospective studies in order to increase the study power and to do some detailed analysis of the links between adiposity, diabetes, and breast cancer,” she concluded, adding that new studies to examine those relationships only in premenopausal women are also needed
In a separate meta-analysis, she and her colleagues, including Peter Boyle, PhD, president of the International Prevention Research Institute, assessed the association between insulin treatment and breast cancer risk in patients with diabetes.
“The long-acting insulin analogues glargine and detemir have been shown in some studies to be associated with increased risk of breast cancer, and other studies have shown no association between the use of these two compounds and the risk of breast cancer,” Dr. Boyle said in a separate presentation at the ADA meeting. “It was important to sort out a little bit what was going on in the literature.”
Overall, the meta-analysis of data from 12 longitudinal cohort studies – including more than 6,000 cases of breast cancer – showed a slight increase in breast cancer risk in patients taking long-acting insulin (SRR, 1.13) with “a relatively reasonable” level of heterogeneity (I2 = 23%).
“But we see that the story is not that simple,” he said.
For example, some studies included only patients who were prescribed insulin for the first time after the study began (new users), some included only patients who were prescribed insulin before the study began (prevalent users), and some included both (ever users), which may have introduced bias in the results, he explained.
Studies of glargine included 4,168 breast cancer cases over a total of 1,418,743 person-years of observation, and studies of detemir included fewer than 2,047 breast cancer cases (not all studies reported case numbers). Among both new users of glargine and detemir, the SRR was 1.12, suggesting no real association between either glargine or detemir use and breast cancer, he said.
“One important take-home message is that you have to be careful that these pharmaco-epidemiological studies, even when working with the same database, may have conflicting results ... so we still need more robust standards in methods for [such] studies,” he concluded.
Ms. Bota reported having no disclosures. The study presented by Dr. Boyle was funded by Sanofi. Dr. Boyle is president of a charity that has received donations from Pfizer, Roche, Novartis, and Lilly.
SOURCE: Bota M. ADA 2018, Abstract 180-OR; Boyle P. ADA 2018, Abstract 133-OR.
ORLANDO – findings from meta-analyses suggest.
In one meta-analysis of data from 21 prospective studies with a total of nearly 15.2 million women, 325,117 breast cancer cases, and a mean follow-up time of 8 years (nearly 33 million person-years), the risk of breast cancer was significantly greater among patients with diabetes than it was among patients without diabetes (summary relative risk, 1.11), Maria Bota reported at the annual scientific sessions of the American Diabetes Association.
However, there was substantial unexplained heterogeneity of results across the individual studies (I2 = 82%), said Ms. Bota, a faculty member at the International Prevention Research Institute, Lyon, France.
“When the analysis was restricted to the 12 studies that adjusted for [body mass index], the summary relative risk decreased to 1.09 and the heterogeneity also decreased to a moderate value of 32%; when the analysis was restricted to the 9 studies that did not adjust for BMI, the summary relative risk increased to 1.14 again, and the heterogeneity increased even more to 91%,” she said.
In an analysis that combined the results of the nine studies that did not adjust for BMI along with crude relative risks from studies that reported both crude and BMI-adjusted relative risks (17 studies in all), the SRR was 1.12, and heterogeneity among the studies was high at 84%.
Additionally, an analysis by menopausal status based on four studies that reported breast cancer in both pre- and postmenopausal women showed SRRs for breast cancer of 0.97 (a 3% decrease in risk) and 1.14 among diabetic vs. nondiabetic premenopausal women and postmenopausal women, respectively, she said, noting that heterogeneity was low (I2 = 0%) among the premenopausal breast cancer study groups and high (I2 = 70%) among the postmenopausal study groups.
The findings provide evidence for a moderately increased risk of breast cancer in women with T2DM, Ms. Bota said.
“However, the effect of the adjustment or lack of adjustment on the heterogeneity suggests that the higher risk of breast cancer in women with diabetes may not be due to diabetes itself, but to adiposity,” she said, adding that “this hypothesis is equally supported by our subgroup analysis according to menopausal status because we saw that the risk of breast cancer was only associated with diabetes in postmenopausal women and this pattern resembles the pattern of the risk of breast cancer associated with adiposity, which is also only increased in postmenopausal women.”
This study was limited by insufficient data for investigating the sources of heterogeneity, she said.
“Therefore we propose ... future pooled analyses based on individual data from good quality prospective studies in order to increase the study power and to do some detailed analysis of the links between adiposity, diabetes, and breast cancer,” she concluded, adding that new studies to examine those relationships only in premenopausal women are also needed
In a separate meta-analysis, she and her colleagues, including Peter Boyle, PhD, president of the International Prevention Research Institute, assessed the association between insulin treatment and breast cancer risk in patients with diabetes.
“The long-acting insulin analogues glargine and detemir have been shown in some studies to be associated with increased risk of breast cancer, and other studies have shown no association between the use of these two compounds and the risk of breast cancer,” Dr. Boyle said in a separate presentation at the ADA meeting. “It was important to sort out a little bit what was going on in the literature.”
Overall, the meta-analysis of data from 12 longitudinal cohort studies – including more than 6,000 cases of breast cancer – showed a slight increase in breast cancer risk in patients taking long-acting insulin (SRR, 1.13) with “a relatively reasonable” level of heterogeneity (I2 = 23%).
“But we see that the story is not that simple,” he said.
For example, some studies included only patients who were prescribed insulin for the first time after the study began (new users), some included only patients who were prescribed insulin before the study began (prevalent users), and some included both (ever users), which may have introduced bias in the results, he explained.
Studies of glargine included 4,168 breast cancer cases over a total of 1,418,743 person-years of observation, and studies of detemir included fewer than 2,047 breast cancer cases (not all studies reported case numbers). Among both new users of glargine and detemir, the SRR was 1.12, suggesting no real association between either glargine or detemir use and breast cancer, he said.
“One important take-home message is that you have to be careful that these pharmaco-epidemiological studies, even when working with the same database, may have conflicting results ... so we still need more robust standards in methods for [such] studies,” he concluded.
Ms. Bota reported having no disclosures. The study presented by Dr. Boyle was funded by Sanofi. Dr. Boyle is president of a charity that has received donations from Pfizer, Roche, Novartis, and Lilly.
SOURCE: Bota M. ADA 2018, Abstract 180-OR; Boyle P. ADA 2018, Abstract 133-OR.
ORLANDO – findings from meta-analyses suggest.
In one meta-analysis of data from 21 prospective studies with a total of nearly 15.2 million women, 325,117 breast cancer cases, and a mean follow-up time of 8 years (nearly 33 million person-years), the risk of breast cancer was significantly greater among patients with diabetes than it was among patients without diabetes (summary relative risk, 1.11), Maria Bota reported at the annual scientific sessions of the American Diabetes Association.
However, there was substantial unexplained heterogeneity of results across the individual studies (I2 = 82%), said Ms. Bota, a faculty member at the International Prevention Research Institute, Lyon, France.
“When the analysis was restricted to the 12 studies that adjusted for [body mass index], the summary relative risk decreased to 1.09 and the heterogeneity also decreased to a moderate value of 32%; when the analysis was restricted to the 9 studies that did not adjust for BMI, the summary relative risk increased to 1.14 again, and the heterogeneity increased even more to 91%,” she said.
In an analysis that combined the results of the nine studies that did not adjust for BMI along with crude relative risks from studies that reported both crude and BMI-adjusted relative risks (17 studies in all), the SRR was 1.12, and heterogeneity among the studies was high at 84%.
Additionally, an analysis by menopausal status based on four studies that reported breast cancer in both pre- and postmenopausal women showed SRRs for breast cancer of 0.97 (a 3% decrease in risk) and 1.14 among diabetic vs. nondiabetic premenopausal women and postmenopausal women, respectively, she said, noting that heterogeneity was low (I2 = 0%) among the premenopausal breast cancer study groups and high (I2 = 70%) among the postmenopausal study groups.
The findings provide evidence for a moderately increased risk of breast cancer in women with T2DM, Ms. Bota said.
“However, the effect of the adjustment or lack of adjustment on the heterogeneity suggests that the higher risk of breast cancer in women with diabetes may not be due to diabetes itself, but to adiposity,” she said, adding that “this hypothesis is equally supported by our subgroup analysis according to menopausal status because we saw that the risk of breast cancer was only associated with diabetes in postmenopausal women and this pattern resembles the pattern of the risk of breast cancer associated with adiposity, which is also only increased in postmenopausal women.”
This study was limited by insufficient data for investigating the sources of heterogeneity, she said.
“Therefore we propose ... future pooled analyses based on individual data from good quality prospective studies in order to increase the study power and to do some detailed analysis of the links between adiposity, diabetes, and breast cancer,” she concluded, adding that new studies to examine those relationships only in premenopausal women are also needed
In a separate meta-analysis, she and her colleagues, including Peter Boyle, PhD, president of the International Prevention Research Institute, assessed the association between insulin treatment and breast cancer risk in patients with diabetes.
“The long-acting insulin analogues glargine and detemir have been shown in some studies to be associated with increased risk of breast cancer, and other studies have shown no association between the use of these two compounds and the risk of breast cancer,” Dr. Boyle said in a separate presentation at the ADA meeting. “It was important to sort out a little bit what was going on in the literature.”
Overall, the meta-analysis of data from 12 longitudinal cohort studies – including more than 6,000 cases of breast cancer – showed a slight increase in breast cancer risk in patients taking long-acting insulin (SRR, 1.13) with “a relatively reasonable” level of heterogeneity (I2 = 23%).
“But we see that the story is not that simple,” he said.
For example, some studies included only patients who were prescribed insulin for the first time after the study began (new users), some included only patients who were prescribed insulin before the study began (prevalent users), and some included both (ever users), which may have introduced bias in the results, he explained.
Studies of glargine included 4,168 breast cancer cases over a total of 1,418,743 person-years of observation, and studies of detemir included fewer than 2,047 breast cancer cases (not all studies reported case numbers). Among both new users of glargine and detemir, the SRR was 1.12, suggesting no real association between either glargine or detemir use and breast cancer, he said.
“One important take-home message is that you have to be careful that these pharmaco-epidemiological studies, even when working with the same database, may have conflicting results ... so we still need more robust standards in methods for [such] studies,” he concluded.
Ms. Bota reported having no disclosures. The study presented by Dr. Boyle was funded by Sanofi. Dr. Boyle is president of a charity that has received donations from Pfizer, Roche, Novartis, and Lilly.
SOURCE: Bota M. ADA 2018, Abstract 180-OR; Boyle P. ADA 2018, Abstract 133-OR.
REPORTING FROM ADA 2018
Key clinical point: Adiposity accounts for the increased risk of breast cancer among women with diabetes.
Major finding: An analysis of 12 studies that adjusted for BMI showed a summary relative risk for breast cancer of 1.09 in diabetic versus nondiabetic women, with moderate study heterogeneity.
Study details: Meta-analyses including 21 and 12 studies, respectively.
Disclosures: Ms. Bota reported having no disclosures. The study presented by Dr. Boyle was funded by Sanofi. Dr. Boyle is president of a charity that has received donations from Pfizer, Roche, Novartis, and Lilly.
Source: Bota M. ADA 2018, Abstract 180-OR; Boyle P. ADA 2018, Abstract 133-OR.
FDA approves oral dacomitinib for some metastatic NSCLC
The Food and Drug Administration has approved dacomitinib tablets (VIZIMPRO) for the first-line treatment of metastatic non-small cell lung cancer in patients with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations.
The second-generation, irreversible EGFR tyrosine kinase inhibitor (TKI) has a recommended dose of 45 mg once daily with or without food.
The approval is based on the randomized, active-controlled 452-patient ARCHER 1050 trial, in which the drug showed improvement in progression-free survival (PFS) versus gefitinib. The median PFS was 14.7 in the dacomitinib arm, compared with 9.2 months in the gefitinib arm (hazard ratio 0.59).
ARCHER 1050 trial participants had good performance status, no prior therapy for metastatic disease or recurrent disease and were disease-free for at least 12 months following systemic non-EGFR TKI-containing therapy. Dacomitinib and gefitinib were given once-daily at 45 mg and 250 mg oral doses, respectively, until disease progression or unacceptable toxicity.
No improvement was seen in overall response rate or overall survival with dacomitinib vs. gefitinib.
Of 394 patients who received dacomitinib, 27% experienced serious adverse reactions – most often diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus, according to the FDA. Those that most often lead to discontinuation were diarrhea and interstitial lung disease. Prescribing information for dacomitinib contains warnings and precautions for interstitial lung disease, diarrhea, and dermatologic adverse reactions.
The Food and Drug Administration has approved dacomitinib tablets (VIZIMPRO) for the first-line treatment of metastatic non-small cell lung cancer in patients with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations.
The second-generation, irreversible EGFR tyrosine kinase inhibitor (TKI) has a recommended dose of 45 mg once daily with or without food.
The approval is based on the randomized, active-controlled 452-patient ARCHER 1050 trial, in which the drug showed improvement in progression-free survival (PFS) versus gefitinib. The median PFS was 14.7 in the dacomitinib arm, compared with 9.2 months in the gefitinib arm (hazard ratio 0.59).
ARCHER 1050 trial participants had good performance status, no prior therapy for metastatic disease or recurrent disease and were disease-free for at least 12 months following systemic non-EGFR TKI-containing therapy. Dacomitinib and gefitinib were given once-daily at 45 mg and 250 mg oral doses, respectively, until disease progression or unacceptable toxicity.
No improvement was seen in overall response rate or overall survival with dacomitinib vs. gefitinib.
Of 394 patients who received dacomitinib, 27% experienced serious adverse reactions – most often diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus, according to the FDA. Those that most often lead to discontinuation were diarrhea and interstitial lung disease. Prescribing information for dacomitinib contains warnings and precautions for interstitial lung disease, diarrhea, and dermatologic adverse reactions.
The Food and Drug Administration has approved dacomitinib tablets (VIZIMPRO) for the first-line treatment of metastatic non-small cell lung cancer in patients with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations.
The second-generation, irreversible EGFR tyrosine kinase inhibitor (TKI) has a recommended dose of 45 mg once daily with or without food.
The approval is based on the randomized, active-controlled 452-patient ARCHER 1050 trial, in which the drug showed improvement in progression-free survival (PFS) versus gefitinib. The median PFS was 14.7 in the dacomitinib arm, compared with 9.2 months in the gefitinib arm (hazard ratio 0.59).
ARCHER 1050 trial participants had good performance status, no prior therapy for metastatic disease or recurrent disease and were disease-free for at least 12 months following systemic non-EGFR TKI-containing therapy. Dacomitinib and gefitinib were given once-daily at 45 mg and 250 mg oral doses, respectively, until disease progression or unacceptable toxicity.
No improvement was seen in overall response rate or overall survival with dacomitinib vs. gefitinib.
Of 394 patients who received dacomitinib, 27% experienced serious adverse reactions – most often diarrhea, rash, paronychia, stomatitis, decreased appetite, dry skin, decreased weight, alopecia, cough, and pruritus, according to the FDA. Those that most often lead to discontinuation were diarrhea and interstitial lung disease. Prescribing information for dacomitinib contains warnings and precautions for interstitial lung disease, diarrhea, and dermatologic adverse reactions.
PACIFIC trial: Durvalumab improves both OS and PFS in stage III NSCLC
TORONTO – The programmed death-ligand 1 (PD-L1) inhibitor durvalumab significantly improves overall survival in patients with stage III unresectable non–small-cell lung cancer without progression after chemoradiotherapy, according to updated results from the global phase 3 PACIFIC study.
The findings, presented at the World Conference on Lung Cancer, follow a prior report from the study showing improved progression-free survival (PFS) in durvalumab-treated patients (stratified hazard ratio, 0.52), and together these survival benefits mark the first major advance in this disease setting in decades,” Scott J. Antonia, MD, reported at the conference, sponsored by the International Association for the Study of Lung Cancer (IASLC).
“The fact is this is a new standard of care treatment for the patients with this disease,” he said, adding that “in all likelihood we are improving the cure rate for the patients with this disease.”
The findings were published simultaneously in the New England Journal of Medicine.
Overall survival at a median follow-up of 25.2 months in 473 patients randomized to receive durvalumab was significantly greater than among 236 who received placebo (stratified HR, 0.68; median survival not reached vs. 28.7 months in the groups, respectively), said Dr. Antonia of the H. Lee Moffitt Cancer Center and Research Institute, and professor of oncologic sciences at the University of South Florida, Tampa.
Durvalumab also improved overall survival in all prespecified subgroups, and PFS was similar to that in previous reports (stratified HR 0.51; median of 17.2 vs. 5.6 months with durvalumab and placebo, respectively), he said, noting that “interestingly, patients who were nonsmokers did benefit from durvalumab.”
This is notable because prior research suggests that never-smokers with advanced stage cancer have less of a chance of responding to immunotherapy (although they should still be offered immunotherapy), he explained.
“Also interestingly, it appears as if cisplatin was the better drug to use in the conventional therapy portion of the treatment,” he said.
Durvalumab also provided continued improvement vs. placebo in time to death or distant metastasis (stratified HR, 0.53), time to second progression (stratified HR, 0.58), time to first subsequent therapy or death (stratified HR, 0.58), and time to second subsequent therapy or death (stratified HR, 0.63).
Study subjects were patients with World Health Organization Performance Status scores of 0 or 1 with any PD-L1 tumor status, who received at least two cycles of conventional standard-of-care platinum-based chemoradiotherapy (CRT). They were randomized between May 2014 and April 2016 – at 1-42 days after CRT – to receive intravenous durvalumab at a dose of 10 mg/kg given intravenously every 2 weeks or placebo, and were stratified by age, gender, and smoking history.
Durvalumab was well tolerated; 30.5% and 26.1% of treatment and placebo patients, respectively, had grade 3/4 adverse events, and 15.4% and 9.8%, respectively, discontinued because of adverse events.
“There were no new safety signals with this longer follow-up,” Dr. Antonia said.
After study treatment ended, 41% and 54% in the groups, respectively, received additional anticancer therapy, and 8% and 22.4%, respectively, received additional immunotherapy, he noted.
The results are not only statistically significant, but clinically meaningful, and they offer new hope for patients with a disease that, in those who receive chemoradiotherapy, has a 3-year survival rate of only about 27%, he said.
During a press briefing at the conference, moderator Frances Shepherd, MD, a medical oncologist at Princess Margaret Cancer Centre in Toronto and a past president of the International Association for the Study of Lung Cancer, called the results “very exciting” given that this type of cancer represents about a third of all lung cancers and therefore affects an “enormous number of patients in Canada and globally.”
The PACIFIC trial was sponsored by AstraZeneca. Dr. Antonia reported being a speaker or advisory board member or receiving funding support from AstraZeneca and numerous other companies. Dr. Shepherd reported receiving honoraria and support from AstraZeneca and others. She is a speaker or advisory board member for Eli Lilly, AstraZeneca, and Merck, and she has ownership Interest in Eli Lilly and AstraZeneca.
SOURCE: Antonia S et al., WCLC 2018 Abstract PL02.01.
TORONTO – The programmed death-ligand 1 (PD-L1) inhibitor durvalumab significantly improves overall survival in patients with stage III unresectable non–small-cell lung cancer without progression after chemoradiotherapy, according to updated results from the global phase 3 PACIFIC study.
The findings, presented at the World Conference on Lung Cancer, follow a prior report from the study showing improved progression-free survival (PFS) in durvalumab-treated patients (stratified hazard ratio, 0.52), and together these survival benefits mark the first major advance in this disease setting in decades,” Scott J. Antonia, MD, reported at the conference, sponsored by the International Association for the Study of Lung Cancer (IASLC).
“The fact is this is a new standard of care treatment for the patients with this disease,” he said, adding that “in all likelihood we are improving the cure rate for the patients with this disease.”
The findings were published simultaneously in the New England Journal of Medicine.
Overall survival at a median follow-up of 25.2 months in 473 patients randomized to receive durvalumab was significantly greater than among 236 who received placebo (stratified HR, 0.68; median survival not reached vs. 28.7 months in the groups, respectively), said Dr. Antonia of the H. Lee Moffitt Cancer Center and Research Institute, and professor of oncologic sciences at the University of South Florida, Tampa.
Durvalumab also improved overall survival in all prespecified subgroups, and PFS was similar to that in previous reports (stratified HR 0.51; median of 17.2 vs. 5.6 months with durvalumab and placebo, respectively), he said, noting that “interestingly, patients who were nonsmokers did benefit from durvalumab.”
This is notable because prior research suggests that never-smokers with advanced stage cancer have less of a chance of responding to immunotherapy (although they should still be offered immunotherapy), he explained.
“Also interestingly, it appears as if cisplatin was the better drug to use in the conventional therapy portion of the treatment,” he said.
Durvalumab also provided continued improvement vs. placebo in time to death or distant metastasis (stratified HR, 0.53), time to second progression (stratified HR, 0.58), time to first subsequent therapy or death (stratified HR, 0.58), and time to second subsequent therapy or death (stratified HR, 0.63).
Study subjects were patients with World Health Organization Performance Status scores of 0 or 1 with any PD-L1 tumor status, who received at least two cycles of conventional standard-of-care platinum-based chemoradiotherapy (CRT). They were randomized between May 2014 and April 2016 – at 1-42 days after CRT – to receive intravenous durvalumab at a dose of 10 mg/kg given intravenously every 2 weeks or placebo, and were stratified by age, gender, and smoking history.
Durvalumab was well tolerated; 30.5% and 26.1% of treatment and placebo patients, respectively, had grade 3/4 adverse events, and 15.4% and 9.8%, respectively, discontinued because of adverse events.
“There were no new safety signals with this longer follow-up,” Dr. Antonia said.
After study treatment ended, 41% and 54% in the groups, respectively, received additional anticancer therapy, and 8% and 22.4%, respectively, received additional immunotherapy, he noted.
The results are not only statistically significant, but clinically meaningful, and they offer new hope for patients with a disease that, in those who receive chemoradiotherapy, has a 3-year survival rate of only about 27%, he said.
During a press briefing at the conference, moderator Frances Shepherd, MD, a medical oncologist at Princess Margaret Cancer Centre in Toronto and a past president of the International Association for the Study of Lung Cancer, called the results “very exciting” given that this type of cancer represents about a third of all lung cancers and therefore affects an “enormous number of patients in Canada and globally.”
The PACIFIC trial was sponsored by AstraZeneca. Dr. Antonia reported being a speaker or advisory board member or receiving funding support from AstraZeneca and numerous other companies. Dr. Shepherd reported receiving honoraria and support from AstraZeneca and others. She is a speaker or advisory board member for Eli Lilly, AstraZeneca, and Merck, and she has ownership Interest in Eli Lilly and AstraZeneca.
SOURCE: Antonia S et al., WCLC 2018 Abstract PL02.01.
TORONTO – The programmed death-ligand 1 (PD-L1) inhibitor durvalumab significantly improves overall survival in patients with stage III unresectable non–small-cell lung cancer without progression after chemoradiotherapy, according to updated results from the global phase 3 PACIFIC study.
The findings, presented at the World Conference on Lung Cancer, follow a prior report from the study showing improved progression-free survival (PFS) in durvalumab-treated patients (stratified hazard ratio, 0.52), and together these survival benefits mark the first major advance in this disease setting in decades,” Scott J. Antonia, MD, reported at the conference, sponsored by the International Association for the Study of Lung Cancer (IASLC).
“The fact is this is a new standard of care treatment for the patients with this disease,” he said, adding that “in all likelihood we are improving the cure rate for the patients with this disease.”
The findings were published simultaneously in the New England Journal of Medicine.
Overall survival at a median follow-up of 25.2 months in 473 patients randomized to receive durvalumab was significantly greater than among 236 who received placebo (stratified HR, 0.68; median survival not reached vs. 28.7 months in the groups, respectively), said Dr. Antonia of the H. Lee Moffitt Cancer Center and Research Institute, and professor of oncologic sciences at the University of South Florida, Tampa.
Durvalumab also improved overall survival in all prespecified subgroups, and PFS was similar to that in previous reports (stratified HR 0.51; median of 17.2 vs. 5.6 months with durvalumab and placebo, respectively), he said, noting that “interestingly, patients who were nonsmokers did benefit from durvalumab.”
This is notable because prior research suggests that never-smokers with advanced stage cancer have less of a chance of responding to immunotherapy (although they should still be offered immunotherapy), he explained.
“Also interestingly, it appears as if cisplatin was the better drug to use in the conventional therapy portion of the treatment,” he said.
Durvalumab also provided continued improvement vs. placebo in time to death or distant metastasis (stratified HR, 0.53), time to second progression (stratified HR, 0.58), time to first subsequent therapy or death (stratified HR, 0.58), and time to second subsequent therapy or death (stratified HR, 0.63).
Study subjects were patients with World Health Organization Performance Status scores of 0 or 1 with any PD-L1 tumor status, who received at least two cycles of conventional standard-of-care platinum-based chemoradiotherapy (CRT). They were randomized between May 2014 and April 2016 – at 1-42 days after CRT – to receive intravenous durvalumab at a dose of 10 mg/kg given intravenously every 2 weeks or placebo, and were stratified by age, gender, and smoking history.
Durvalumab was well tolerated; 30.5% and 26.1% of treatment and placebo patients, respectively, had grade 3/4 adverse events, and 15.4% and 9.8%, respectively, discontinued because of adverse events.
“There were no new safety signals with this longer follow-up,” Dr. Antonia said.
After study treatment ended, 41% and 54% in the groups, respectively, received additional anticancer therapy, and 8% and 22.4%, respectively, received additional immunotherapy, he noted.
The results are not only statistically significant, but clinically meaningful, and they offer new hope for patients with a disease that, in those who receive chemoradiotherapy, has a 3-year survival rate of only about 27%, he said.
During a press briefing at the conference, moderator Frances Shepherd, MD, a medical oncologist at Princess Margaret Cancer Centre in Toronto and a past president of the International Association for the Study of Lung Cancer, called the results “very exciting” given that this type of cancer represents about a third of all lung cancers and therefore affects an “enormous number of patients in Canada and globally.”
The PACIFIC trial was sponsored by AstraZeneca. Dr. Antonia reported being a speaker or advisory board member or receiving funding support from AstraZeneca and numerous other companies. Dr. Shepherd reported receiving honoraria and support from AstraZeneca and others. She is a speaker or advisory board member for Eli Lilly, AstraZeneca, and Merck, and she has ownership Interest in Eli Lilly and AstraZeneca.
SOURCE: Antonia S et al., WCLC 2018 Abstract PL02.01.
REPORTING FROM WCLC 2018
Key clinical point: Durvalumab improves survival in stage III unresectable NSCLC patients without progression after CRT.
Major finding: Median overall survival not reached vs. 28.7 months for durvalumab compared with placebo (stratified HR, 0.58).
Study details: The global, randomized, placebo-controlled phase 3 PACIFIC trial of 709 patients.
Disclosures: The PACIFIC trial was sponsored by AstraZeneca. Dr. Antonia reported being a speaker or advisory board member or receiving funding support from AstraZeneca and numerous other companies. Dr. Shepherd reported receiving honoraria and support from AstraZeneca and others. She is a speaker or advisory board member for Eli Lilly, AstraZeneca, and Merck, and she has ownership Interest in Eli Lilly and AstraZeneca.
Source: Antonia S et al. WCLC 2018 Abstract PL02.01.
Prognostic factors guide mantle cell treatment decisions
CHICAGO – The treatment options for patients with mantle cell lymphoma (MCL) vary based on age, but several prognostic factors can help guide treatment decision making in all patients, according to Kristie A. Blum, MD.
These include age, disease stage, disease sites, Mantle Cell Lymphoma International Prognostic Index (MIPI), biologic factors, and histology, Dr. Blum said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.
Age
“I think the most important thing to recognize is there really isn’t any randomized transplant data for patients that are over 65. … There are very few transplant studies for patients [aged] 66-70,” said Dr. Blum, acting professor of hematology and medical oncology at Emory University in Atlanta.
The SWOG 0213 study did examine rituximab-hyperCVAD (R-HCVAD) in this age group, and showed that it has higher toxicity and lower efficacy in older versus younger patients, she said.
“Of course this is not typically a transplant approach, but an intensive-therapy approach,” she said, noting that progression-free and overall survival in patients aged 66-70 years were just 29% and 57%, respectively (Ann Oncol. 2013 Jun; 24[6]:1587-93).
The CALGB 59909 and 50403 studies of chemoimmunotherapy and autologous stem cell transplant (ASCT), with or without bortezomib, included only adults up to age 70.
“So while most of us think that transplant is probably okay and safe in patients up to 70, the question is what induction regimen to use,” she said.
Dr. Blum noted that a retrospective study from the Mayo Clinic looked at all 63 patients aged 65 years and older with MCL who underwent ASCT there (including 22 patients over age 70), and most (60%) were treated with R-CHOP. Just 19% received cytarabine-based regimens (Blood. 2017:130:4536).
Median overall survival after ASCT was 5 years, and median relapse-free survival was 3.2 years.
Stage
Like age, disease stage in MCL patients has not been well studied, Dr. Blum said.
“Most of the randomized transplant studies have been conducted in patients stage II-IV, so we don’t have a lot of data about the early-stage patients,” she said, adding, however, that there are some retrospective data on radiation therapy for stage I-II MCL in older adults.
An International Lymphoma Radiation Oncology Group study of 179 patients, for example, showed that overall survival was “really the same whether they got chemo, chemo plus radiation, or radiation alone,” she said.
The 10-year freedom from progression was 46%, 43%, and 31%, respectively (P = .64).
Location
“What about where the disease presents? We’ve all heard about indolent mantle cell – so there’s this leukemic ‘non-nodal’ variant that’s been described,” she said, noting that this variant has a chronic lymphocytic leukemia–like presentation (no nodal disease, blood and marrow involvement, and splenic involvement). “And they tend to be SOX11-negative with mutated [immunoglobulin variable region heavy chain gene].”
Another variant involves primarily nodal disease that typically presents without elevated white blood cell count, with low Ki-67 (10% or lower), with SOX11 positivity, and without TP53 mutations.
“But I would caution you that this is really not very well defined; there’s no clear marker that predicts for indolent disease,” Dr. Blum said. “If you have one of these patients and you’re thinking about observing them, my experience has been that the most important thing to do is make sure you look at their [gastrointestinal] tract. I’ve had a lot of these patients progress with colon masses over time.”
MIPI
MIPI is basically a risk score calculated based on age, performance status, lactate dehydrogenase levels, and white cell count, she said.
MIPI less than 5.70 indicates low risk, MIPI of 5.70-6.2 is considered intermediate risk, and MIPI greater than 6.2 is considered high risk. High-risk patients who were transplanted in one study had a median overall survival of about 2.8 years and a median time to treatment failure of 1.4 years (J Clin Oncol. 2014 May 1;32[13]:1338-46). Even among patients under age 65 with high risk, the median time to treatment failure was 2 years, she said.
“So I do wonder, are we really helping these patients by transplanting them?” she added. “Similarly, the low-risk patients had a median time to treatment failure of 6 years; I wonder if they didn’t need a transplant.”
Biology
Ki-67 protein, a cellular marker for proliferation, is another important prognostic factor. A European Mantle Cell network study showed that median overall survival for patients with a Ki-67 proliferation index of less than 30% was not reached, and 5-year survival was 75%. At the same time, the median overall survival (OS) for those with Ki-67 proliferation index of 30% or greater was just 3.4 years, and 5-year OS was only 41% (J Clin Oncol. 2016 Apr 20;34[12]:1386-94).
The prognostic effect was independent of induction treatment, Dr. Blum said.
Combining MIPI and the Ki-67 index (MIPI-C) provides further value in defining a very high-risk group; those with both high MIPI and high Ki-67 had a median overall survival of only 1.5 years, and those with both, but who were under age 65, had median OS of only 1.7 years.
Histology
Patients with blastoid MCL variants were shown in that same study to have median OS of about 2.8 years, compared with 8 years in those with nonblastoid variants. The 5-year OS and progression-free survival (PFS) for blastoid variants were 35% and 29%, respectively, and for nonblastoid variants were 68% and 44%, respectively.
“But when you look at this with respect to the Ki-67 – so those patients that were called nonblastoid, that had a high Ki-67 index – their median overall survival is still lower at 5 years,” she said, noting that median OS was not reached in blastic variant (low-Ki-67) patients. “So it seems like the prognostic effect of cytology is largely explained by the Ki-67 index.”
In terms of karyotype, several studies have shown that complex karyotype is associated with poorer outcomes. One recent multicenter study of 274 patients showed that median OS in 53 patients with at least three cytogenetic abnormalities versus the remaining patients was 4.5 years vs. 11.6 years, and median PFS was 1.9 vs. 4.4 years (Cancer. 2018 Jun 1;124[11]:2306-15).
TP53 deletions (which affect about 20% of MCL patients) and mutations (which affect about 10%), are also useful prognostic factors, she said, noting that each is associated with inferior outcomes, and in one study patients with both appeared to have the worst outcomes (Blood. 2017;130:1903-10).
Another study showed that high TP53 staining (greater than 50% positive) is also associated with inferior outcomes, including reduced time to treatment failure and lower overall survival (Blood. 2018;131:417-20).
Finally, the most important factor is the patient’s wishes, Dr. Blum said, noting that she has “a lot of long discussions with these patients.”
“I consider all of these factors with each patient that I see with mantle cell,” she said.
Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.
CHICAGO – The treatment options for patients with mantle cell lymphoma (MCL) vary based on age, but several prognostic factors can help guide treatment decision making in all patients, according to Kristie A. Blum, MD.
These include age, disease stage, disease sites, Mantle Cell Lymphoma International Prognostic Index (MIPI), biologic factors, and histology, Dr. Blum said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.
Age
“I think the most important thing to recognize is there really isn’t any randomized transplant data for patients that are over 65. … There are very few transplant studies for patients [aged] 66-70,” said Dr. Blum, acting professor of hematology and medical oncology at Emory University in Atlanta.
The SWOG 0213 study did examine rituximab-hyperCVAD (R-HCVAD) in this age group, and showed that it has higher toxicity and lower efficacy in older versus younger patients, she said.
“Of course this is not typically a transplant approach, but an intensive-therapy approach,” she said, noting that progression-free and overall survival in patients aged 66-70 years were just 29% and 57%, respectively (Ann Oncol. 2013 Jun; 24[6]:1587-93).
The CALGB 59909 and 50403 studies of chemoimmunotherapy and autologous stem cell transplant (ASCT), with or without bortezomib, included only adults up to age 70.
“So while most of us think that transplant is probably okay and safe in patients up to 70, the question is what induction regimen to use,” she said.
Dr. Blum noted that a retrospective study from the Mayo Clinic looked at all 63 patients aged 65 years and older with MCL who underwent ASCT there (including 22 patients over age 70), and most (60%) were treated with R-CHOP. Just 19% received cytarabine-based regimens (Blood. 2017:130:4536).
Median overall survival after ASCT was 5 years, and median relapse-free survival was 3.2 years.
Stage
Like age, disease stage in MCL patients has not been well studied, Dr. Blum said.
“Most of the randomized transplant studies have been conducted in patients stage II-IV, so we don’t have a lot of data about the early-stage patients,” she said, adding, however, that there are some retrospective data on radiation therapy for stage I-II MCL in older adults.
An International Lymphoma Radiation Oncology Group study of 179 patients, for example, showed that overall survival was “really the same whether they got chemo, chemo plus radiation, or radiation alone,” she said.
The 10-year freedom from progression was 46%, 43%, and 31%, respectively (P = .64).
Location
“What about where the disease presents? We’ve all heard about indolent mantle cell – so there’s this leukemic ‘non-nodal’ variant that’s been described,” she said, noting that this variant has a chronic lymphocytic leukemia–like presentation (no nodal disease, blood and marrow involvement, and splenic involvement). “And they tend to be SOX11-negative with mutated [immunoglobulin variable region heavy chain gene].”
Another variant involves primarily nodal disease that typically presents without elevated white blood cell count, with low Ki-67 (10% or lower), with SOX11 positivity, and without TP53 mutations.
“But I would caution you that this is really not very well defined; there’s no clear marker that predicts for indolent disease,” Dr. Blum said. “If you have one of these patients and you’re thinking about observing them, my experience has been that the most important thing to do is make sure you look at their [gastrointestinal] tract. I’ve had a lot of these patients progress with colon masses over time.”
MIPI
MIPI is basically a risk score calculated based on age, performance status, lactate dehydrogenase levels, and white cell count, she said.
MIPI less than 5.70 indicates low risk, MIPI of 5.70-6.2 is considered intermediate risk, and MIPI greater than 6.2 is considered high risk. High-risk patients who were transplanted in one study had a median overall survival of about 2.8 years and a median time to treatment failure of 1.4 years (J Clin Oncol. 2014 May 1;32[13]:1338-46). Even among patients under age 65 with high risk, the median time to treatment failure was 2 years, she said.
“So I do wonder, are we really helping these patients by transplanting them?” she added. “Similarly, the low-risk patients had a median time to treatment failure of 6 years; I wonder if they didn’t need a transplant.”
Biology
Ki-67 protein, a cellular marker for proliferation, is another important prognostic factor. A European Mantle Cell network study showed that median overall survival for patients with a Ki-67 proliferation index of less than 30% was not reached, and 5-year survival was 75%. At the same time, the median overall survival (OS) for those with Ki-67 proliferation index of 30% or greater was just 3.4 years, and 5-year OS was only 41% (J Clin Oncol. 2016 Apr 20;34[12]:1386-94).
The prognostic effect was independent of induction treatment, Dr. Blum said.
Combining MIPI and the Ki-67 index (MIPI-C) provides further value in defining a very high-risk group; those with both high MIPI and high Ki-67 had a median overall survival of only 1.5 years, and those with both, but who were under age 65, had median OS of only 1.7 years.
Histology
Patients with blastoid MCL variants were shown in that same study to have median OS of about 2.8 years, compared with 8 years in those with nonblastoid variants. The 5-year OS and progression-free survival (PFS) for blastoid variants were 35% and 29%, respectively, and for nonblastoid variants were 68% and 44%, respectively.
“But when you look at this with respect to the Ki-67 – so those patients that were called nonblastoid, that had a high Ki-67 index – their median overall survival is still lower at 5 years,” she said, noting that median OS was not reached in blastic variant (low-Ki-67) patients. “So it seems like the prognostic effect of cytology is largely explained by the Ki-67 index.”
In terms of karyotype, several studies have shown that complex karyotype is associated with poorer outcomes. One recent multicenter study of 274 patients showed that median OS in 53 patients with at least three cytogenetic abnormalities versus the remaining patients was 4.5 years vs. 11.6 years, and median PFS was 1.9 vs. 4.4 years (Cancer. 2018 Jun 1;124[11]:2306-15).
TP53 deletions (which affect about 20% of MCL patients) and mutations (which affect about 10%), are also useful prognostic factors, she said, noting that each is associated with inferior outcomes, and in one study patients with both appeared to have the worst outcomes (Blood. 2017;130:1903-10).
Another study showed that high TP53 staining (greater than 50% positive) is also associated with inferior outcomes, including reduced time to treatment failure and lower overall survival (Blood. 2018;131:417-20).
Finally, the most important factor is the patient’s wishes, Dr. Blum said, noting that she has “a lot of long discussions with these patients.”
“I consider all of these factors with each patient that I see with mantle cell,” she said.
Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.
CHICAGO – The treatment options for patients with mantle cell lymphoma (MCL) vary based on age, but several prognostic factors can help guide treatment decision making in all patients, according to Kristie A. Blum, MD.
These include age, disease stage, disease sites, Mantle Cell Lymphoma International Prognostic Index (MIPI), biologic factors, and histology, Dr. Blum said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.
Age
“I think the most important thing to recognize is there really isn’t any randomized transplant data for patients that are over 65. … There are very few transplant studies for patients [aged] 66-70,” said Dr. Blum, acting professor of hematology and medical oncology at Emory University in Atlanta.
The SWOG 0213 study did examine rituximab-hyperCVAD (R-HCVAD) in this age group, and showed that it has higher toxicity and lower efficacy in older versus younger patients, she said.
“Of course this is not typically a transplant approach, but an intensive-therapy approach,” she said, noting that progression-free and overall survival in patients aged 66-70 years were just 29% and 57%, respectively (Ann Oncol. 2013 Jun; 24[6]:1587-93).
The CALGB 59909 and 50403 studies of chemoimmunotherapy and autologous stem cell transplant (ASCT), with or without bortezomib, included only adults up to age 70.
“So while most of us think that transplant is probably okay and safe in patients up to 70, the question is what induction regimen to use,” she said.
Dr. Blum noted that a retrospective study from the Mayo Clinic looked at all 63 patients aged 65 years and older with MCL who underwent ASCT there (including 22 patients over age 70), and most (60%) were treated with R-CHOP. Just 19% received cytarabine-based regimens (Blood. 2017:130:4536).
Median overall survival after ASCT was 5 years, and median relapse-free survival was 3.2 years.
Stage
Like age, disease stage in MCL patients has not been well studied, Dr. Blum said.
“Most of the randomized transplant studies have been conducted in patients stage II-IV, so we don’t have a lot of data about the early-stage patients,” she said, adding, however, that there are some retrospective data on radiation therapy for stage I-II MCL in older adults.
An International Lymphoma Radiation Oncology Group study of 179 patients, for example, showed that overall survival was “really the same whether they got chemo, chemo plus radiation, or radiation alone,” she said.
The 10-year freedom from progression was 46%, 43%, and 31%, respectively (P = .64).
Location
“What about where the disease presents? We’ve all heard about indolent mantle cell – so there’s this leukemic ‘non-nodal’ variant that’s been described,” she said, noting that this variant has a chronic lymphocytic leukemia–like presentation (no nodal disease, blood and marrow involvement, and splenic involvement). “And they tend to be SOX11-negative with mutated [immunoglobulin variable region heavy chain gene].”
Another variant involves primarily nodal disease that typically presents without elevated white blood cell count, with low Ki-67 (10% or lower), with SOX11 positivity, and without TP53 mutations.
“But I would caution you that this is really not very well defined; there’s no clear marker that predicts for indolent disease,” Dr. Blum said. “If you have one of these patients and you’re thinking about observing them, my experience has been that the most important thing to do is make sure you look at their [gastrointestinal] tract. I’ve had a lot of these patients progress with colon masses over time.”
MIPI
MIPI is basically a risk score calculated based on age, performance status, lactate dehydrogenase levels, and white cell count, she said.
MIPI less than 5.70 indicates low risk, MIPI of 5.70-6.2 is considered intermediate risk, and MIPI greater than 6.2 is considered high risk. High-risk patients who were transplanted in one study had a median overall survival of about 2.8 years and a median time to treatment failure of 1.4 years (J Clin Oncol. 2014 May 1;32[13]:1338-46). Even among patients under age 65 with high risk, the median time to treatment failure was 2 years, she said.
“So I do wonder, are we really helping these patients by transplanting them?” she added. “Similarly, the low-risk patients had a median time to treatment failure of 6 years; I wonder if they didn’t need a transplant.”
Biology
Ki-67 protein, a cellular marker for proliferation, is another important prognostic factor. A European Mantle Cell network study showed that median overall survival for patients with a Ki-67 proliferation index of less than 30% was not reached, and 5-year survival was 75%. At the same time, the median overall survival (OS) for those with Ki-67 proliferation index of 30% or greater was just 3.4 years, and 5-year OS was only 41% (J Clin Oncol. 2016 Apr 20;34[12]:1386-94).
The prognostic effect was independent of induction treatment, Dr. Blum said.
Combining MIPI and the Ki-67 index (MIPI-C) provides further value in defining a very high-risk group; those with both high MIPI and high Ki-67 had a median overall survival of only 1.5 years, and those with both, but who were under age 65, had median OS of only 1.7 years.
Histology
Patients with blastoid MCL variants were shown in that same study to have median OS of about 2.8 years, compared with 8 years in those with nonblastoid variants. The 5-year OS and progression-free survival (PFS) for blastoid variants were 35% and 29%, respectively, and for nonblastoid variants were 68% and 44%, respectively.
“But when you look at this with respect to the Ki-67 – so those patients that were called nonblastoid, that had a high Ki-67 index – their median overall survival is still lower at 5 years,” she said, noting that median OS was not reached in blastic variant (low-Ki-67) patients. “So it seems like the prognostic effect of cytology is largely explained by the Ki-67 index.”
In terms of karyotype, several studies have shown that complex karyotype is associated with poorer outcomes. One recent multicenter study of 274 patients showed that median OS in 53 patients with at least three cytogenetic abnormalities versus the remaining patients was 4.5 years vs. 11.6 years, and median PFS was 1.9 vs. 4.4 years (Cancer. 2018 Jun 1;124[11]:2306-15).
TP53 deletions (which affect about 20% of MCL patients) and mutations (which affect about 10%), are also useful prognostic factors, she said, noting that each is associated with inferior outcomes, and in one study patients with both appeared to have the worst outcomes (Blood. 2017;130:1903-10).
Another study showed that high TP53 staining (greater than 50% positive) is also associated with inferior outcomes, including reduced time to treatment failure and lower overall survival (Blood. 2018;131:417-20).
Finally, the most important factor is the patient’s wishes, Dr. Blum said, noting that she has “a lot of long discussions with these patients.”
“I consider all of these factors with each patient that I see with mantle cell,” she said.
Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.
REPORTING FROM MHM 2018
NELSON trial: CT Screening reduces lung cancer deaths
TORONTO – Computed tomography screening among asymptomatic men at high risk for lung cancer reduced lung cancer deaths by a highly statistically significant 26% at 10 years and appeared to reduce lung cancer mortality risk even more in women in the population-based, NELSON trial.
The findings from this large controlled trial encompassing more than 27,000 CT scans in 15,792 individuals support those from the National Lung Screening Trials (NLST), published in 2011, and should “inform and direct future CT screening programs worldwide,” according to Harry de Koning, MD, who presented the findings at the World Conference on Lung Cancer.
Participants were randomized to CT screening at baseline, 1, 3, and 5.5 years after randomization, or to a control group that received usual care. Overall 157 lung cancer deaths occurred in the screening arm vs. 250 in the control arm. Detection rates varied between 0.8% and 1.1% across screenings (0.9% overall), and the positive predictive value of screening was 41%, Dr. de Koning of Erasmus Medical Center, Rotterdam, the Netherlands, said at the meeting sponsored by the International Association for the Study of Lung Cancer.
Notably, 69% of the 243 lung cancers detected by screening were detected at stage 1A or 1B, compared with 10%-12% being detected at stage 4 in about 50% of control patients and based on registry data in the Netherlands.
“There’s huge importance of this early detection in the screening arm,” Dr. de Koning said.
Additionally, an analysis of a subset of those with lung cancer showed a significant threefold increase in surgical treatment among the screened patients vs. those in the control arm who developed lung cancer (67.7% vs. 24.5%), he said.
CT screening reduced the risk of death from lung cancer by 9% to 41% in men over the course of the study, with an overall reduction of 26% at 10 years, and in a smaller subset of women, the rate-ratio of dying from lung cancer varied from 0.39 to 0.61 at different years of follow-up, he said, noting that this suggests a “significant and even larger reduction” in women.
Study participants were individuals aged 50-74 years in the Netherlands and Leuven, Belgium, who were considered at high risk for lung cancer based on responses to a general questionnaire. Participants’ records were linked with national registries with 100% coverage regarding cancer diagnosis and date and cause of death, and medical records for deceased lung cancer patients were reviewed by a blinded expert panel through 2013, and for the remaining study years cause of death as reported by Statistics Netherlands was used. Compliance among those randomized to the screening group was 86%, Dr. de Koning said.
“These findings show that CT screenings are an effective way to assess lung nodules in people at high risk for lung cancer, often leading to detection of suspicious nodules and subsequent surgical intervention at relatively low rates and with few false positives, and can positively increase the chances of cure in this devastating disease,” Dr. de Koning said in a press statement. “It is the second-largest trial in the world, with an even more favorable outcome than the first trial, the NLST, showed. These results should be used to inform and direct future CT screening in the world.”
During a press briefing, in response to a question about whether lung cancer screening should be offered more widely, he said that yes, countries – including the United States – should take note that “now two large-scale trials show large benefit.”
Dr. de Koning reported having no disclosures.
TORONTO – Computed tomography screening among asymptomatic men at high risk for lung cancer reduced lung cancer deaths by a highly statistically significant 26% at 10 years and appeared to reduce lung cancer mortality risk even more in women in the population-based, NELSON trial.
The findings from this large controlled trial encompassing more than 27,000 CT scans in 15,792 individuals support those from the National Lung Screening Trials (NLST), published in 2011, and should “inform and direct future CT screening programs worldwide,” according to Harry de Koning, MD, who presented the findings at the World Conference on Lung Cancer.
Participants were randomized to CT screening at baseline, 1, 3, and 5.5 years after randomization, or to a control group that received usual care. Overall 157 lung cancer deaths occurred in the screening arm vs. 250 in the control arm. Detection rates varied between 0.8% and 1.1% across screenings (0.9% overall), and the positive predictive value of screening was 41%, Dr. de Koning of Erasmus Medical Center, Rotterdam, the Netherlands, said at the meeting sponsored by the International Association for the Study of Lung Cancer.
Notably, 69% of the 243 lung cancers detected by screening were detected at stage 1A or 1B, compared with 10%-12% being detected at stage 4 in about 50% of control patients and based on registry data in the Netherlands.
“There’s huge importance of this early detection in the screening arm,” Dr. de Koning said.
Additionally, an analysis of a subset of those with lung cancer showed a significant threefold increase in surgical treatment among the screened patients vs. those in the control arm who developed lung cancer (67.7% vs. 24.5%), he said.
CT screening reduced the risk of death from lung cancer by 9% to 41% in men over the course of the study, with an overall reduction of 26% at 10 years, and in a smaller subset of women, the rate-ratio of dying from lung cancer varied from 0.39 to 0.61 at different years of follow-up, he said, noting that this suggests a “significant and even larger reduction” in women.
Study participants were individuals aged 50-74 years in the Netherlands and Leuven, Belgium, who were considered at high risk for lung cancer based on responses to a general questionnaire. Participants’ records were linked with national registries with 100% coverage regarding cancer diagnosis and date and cause of death, and medical records for deceased lung cancer patients were reviewed by a blinded expert panel through 2013, and for the remaining study years cause of death as reported by Statistics Netherlands was used. Compliance among those randomized to the screening group was 86%, Dr. de Koning said.
“These findings show that CT screenings are an effective way to assess lung nodules in people at high risk for lung cancer, often leading to detection of suspicious nodules and subsequent surgical intervention at relatively low rates and with few false positives, and can positively increase the chances of cure in this devastating disease,” Dr. de Koning said in a press statement. “It is the second-largest trial in the world, with an even more favorable outcome than the first trial, the NLST, showed. These results should be used to inform and direct future CT screening in the world.”
During a press briefing, in response to a question about whether lung cancer screening should be offered more widely, he said that yes, countries – including the United States – should take note that “now two large-scale trials show large benefit.”
Dr. de Koning reported having no disclosures.
TORONTO – Computed tomography screening among asymptomatic men at high risk for lung cancer reduced lung cancer deaths by a highly statistically significant 26% at 10 years and appeared to reduce lung cancer mortality risk even more in women in the population-based, NELSON trial.
The findings from this large controlled trial encompassing more than 27,000 CT scans in 15,792 individuals support those from the National Lung Screening Trials (NLST), published in 2011, and should “inform and direct future CT screening programs worldwide,” according to Harry de Koning, MD, who presented the findings at the World Conference on Lung Cancer.
Participants were randomized to CT screening at baseline, 1, 3, and 5.5 years after randomization, or to a control group that received usual care. Overall 157 lung cancer deaths occurred in the screening arm vs. 250 in the control arm. Detection rates varied between 0.8% and 1.1% across screenings (0.9% overall), and the positive predictive value of screening was 41%, Dr. de Koning of Erasmus Medical Center, Rotterdam, the Netherlands, said at the meeting sponsored by the International Association for the Study of Lung Cancer.
Notably, 69% of the 243 lung cancers detected by screening were detected at stage 1A or 1B, compared with 10%-12% being detected at stage 4 in about 50% of control patients and based on registry data in the Netherlands.
“There’s huge importance of this early detection in the screening arm,” Dr. de Koning said.
Additionally, an analysis of a subset of those with lung cancer showed a significant threefold increase in surgical treatment among the screened patients vs. those in the control arm who developed lung cancer (67.7% vs. 24.5%), he said.
CT screening reduced the risk of death from lung cancer by 9% to 41% in men over the course of the study, with an overall reduction of 26% at 10 years, and in a smaller subset of women, the rate-ratio of dying from lung cancer varied from 0.39 to 0.61 at different years of follow-up, he said, noting that this suggests a “significant and even larger reduction” in women.
Study participants were individuals aged 50-74 years in the Netherlands and Leuven, Belgium, who were considered at high risk for lung cancer based on responses to a general questionnaire. Participants’ records were linked with national registries with 100% coverage regarding cancer diagnosis and date and cause of death, and medical records for deceased lung cancer patients were reviewed by a blinded expert panel through 2013, and for the remaining study years cause of death as reported by Statistics Netherlands was used. Compliance among those randomized to the screening group was 86%, Dr. de Koning said.
“These findings show that CT screenings are an effective way to assess lung nodules in people at high risk for lung cancer, often leading to detection of suspicious nodules and subsequent surgical intervention at relatively low rates and with few false positives, and can positively increase the chances of cure in this devastating disease,” Dr. de Koning said in a press statement. “It is the second-largest trial in the world, with an even more favorable outcome than the first trial, the NLST, showed. These results should be used to inform and direct future CT screening in the world.”
During a press briefing, in response to a question about whether lung cancer screening should be offered more widely, he said that yes, countries – including the United States – should take note that “now two large-scale trials show large benefit.”
Dr. de Koning reported having no disclosures.
REPORTING FROM WCLC 2018
Key clinical point: CT screening among high-risk patients significantly reduces lung cancer mortality.
Major finding: CT screening in high-risk patients reduced lung cancer deaths by 26% in men, 39%-61% in women.
Study details: A population-based controlled trial of 15,792 individuals.
Disclosures: Dr. de Koning reported having no disclosures.
Neoadjuvant combo yields high pathologic response in NSCLC
TORONTO – Neoadjuvant combined chemotherapy and immunotherapy (CT-IO) yielded high pathologic response rates for locally advanced, potentially resectable non-small cell lung cancer in the phase 2 multicenter study Nadim study.
All 30 adults with stage IIIA N2 non-small cell lung cancer (NSCLC) who enrolled in the ongoing single-arm, open-label study and have undergone surgery to date, had resectable tumors following neoadjuvant treatment, Mariano Provencio, MD, of Hospital Puerta de Hierro, Madrid, Spain, reported at the World Conference on Lung Cancer.
The complete and partial response rates following the treatment were 10% and 60%, respectively, and the remaining patients had stable disease, Dr. Provencio said, noting that an additional 10 enrolled patients have completed treatment and are awaiting resection, and another 3 are still completing treatment.
The overall major pathologic response rate was 80%, including 75% with complete remission, he said at the conference, which was sponsored by the International Association for the Study of Lung Cancer.
“With a median follow-up of 4 months, no patients suffered any recurrence,” he said. “We have been unable to identify any significant factor related to the response, but we still do not have information about biomarkers.”
The study participants had a median age of 64 years, most (73%) were men, and all were current or former smokers. All received the planned neoadjuvant doses, which included 3 cycles of intravenous nivolumab at a dose of 360 mg every 3 weeks, plus 200 mg/m2 of paclitaxel and carboplatin at AUC 6 every 3 weeks.
“The most important toxicity was hematological toxicity related to chemotherapy; there were very few episodes of non-hematological toxicity,” he said.
Tumors were then assessed, and surgery–lobectomy in 90% of cases–was performed in the 3rd or 4th week after day 21 of the third neoadjuvant treatment cycle.
“There were no intraoperative complications, and 7 patients experienced some postoperative complications, but there was no postoperative mortality,” he said.
Adjuvant treatment included 240 mg of intravenous nivolumab every 2 weeks for 4 months and then 480 mg every 4 weeks for 8 months after resection.
The primary end-point of the study is 24-month progression-free survival.
CT-IO has a high response rate and longer survival in unselected patients with metastatic NSCLC, but there were previously no data about this combination in the neoadjuvant setting, Dr. Provencio said.
The findings of this ongoing study are limited by their preliminary nature and the related lack of information about overall survival and biomarkers, Dr. Provencio said.
“But the higher complete remission and major pathological response rates make this a promising future treatment in stage 3 [NSCLC,] he said.
Indeed, the Nadim study thus far has shown “an amazing result that needs to be verified ... [there is] no prospective proof yet in this context that major pathologic response is parlayed with improved [progression-free survival] or [overall survival],” said discussant Corey Langer, MD, professor of medicine and director of thoracic oncology at the University of Pennsylvania, Philadelphia. “We need to track the late sequelae and [central nervous system] recurrences.”
Dr. Provencio reported relationships with AstraZeneca, Bristol-Meyers Squibb, Fabre, Merck, Pierre, Roche, and Bristol-Meyers Squibb. Dr. Langer reported relationships with numerous companies and organizations.
SOURCE: Provencio, Mario et al., WCLC 2018 Abstract OA01.05.
TORONTO – Neoadjuvant combined chemotherapy and immunotherapy (CT-IO) yielded high pathologic response rates for locally advanced, potentially resectable non-small cell lung cancer in the phase 2 multicenter study Nadim study.
All 30 adults with stage IIIA N2 non-small cell lung cancer (NSCLC) who enrolled in the ongoing single-arm, open-label study and have undergone surgery to date, had resectable tumors following neoadjuvant treatment, Mariano Provencio, MD, of Hospital Puerta de Hierro, Madrid, Spain, reported at the World Conference on Lung Cancer.
The complete and partial response rates following the treatment were 10% and 60%, respectively, and the remaining patients had stable disease, Dr. Provencio said, noting that an additional 10 enrolled patients have completed treatment and are awaiting resection, and another 3 are still completing treatment.
The overall major pathologic response rate was 80%, including 75% with complete remission, he said at the conference, which was sponsored by the International Association for the Study of Lung Cancer.
“With a median follow-up of 4 months, no patients suffered any recurrence,” he said. “We have been unable to identify any significant factor related to the response, but we still do not have information about biomarkers.”
The study participants had a median age of 64 years, most (73%) were men, and all were current or former smokers. All received the planned neoadjuvant doses, which included 3 cycles of intravenous nivolumab at a dose of 360 mg every 3 weeks, plus 200 mg/m2 of paclitaxel and carboplatin at AUC 6 every 3 weeks.
“The most important toxicity was hematological toxicity related to chemotherapy; there were very few episodes of non-hematological toxicity,” he said.
Tumors were then assessed, and surgery–lobectomy in 90% of cases–was performed in the 3rd or 4th week after day 21 of the third neoadjuvant treatment cycle.
“There were no intraoperative complications, and 7 patients experienced some postoperative complications, but there was no postoperative mortality,” he said.
Adjuvant treatment included 240 mg of intravenous nivolumab every 2 weeks for 4 months and then 480 mg every 4 weeks for 8 months after resection.
The primary end-point of the study is 24-month progression-free survival.
CT-IO has a high response rate and longer survival in unselected patients with metastatic NSCLC, but there were previously no data about this combination in the neoadjuvant setting, Dr. Provencio said.
The findings of this ongoing study are limited by their preliminary nature and the related lack of information about overall survival and biomarkers, Dr. Provencio said.
“But the higher complete remission and major pathological response rates make this a promising future treatment in stage 3 [NSCLC,] he said.
Indeed, the Nadim study thus far has shown “an amazing result that needs to be verified ... [there is] no prospective proof yet in this context that major pathologic response is parlayed with improved [progression-free survival] or [overall survival],” said discussant Corey Langer, MD, professor of medicine and director of thoracic oncology at the University of Pennsylvania, Philadelphia. “We need to track the late sequelae and [central nervous system] recurrences.”
Dr. Provencio reported relationships with AstraZeneca, Bristol-Meyers Squibb, Fabre, Merck, Pierre, Roche, and Bristol-Meyers Squibb. Dr. Langer reported relationships with numerous companies and organizations.
SOURCE: Provencio, Mario et al., WCLC 2018 Abstract OA01.05.
TORONTO – Neoadjuvant combined chemotherapy and immunotherapy (CT-IO) yielded high pathologic response rates for locally advanced, potentially resectable non-small cell lung cancer in the phase 2 multicenter study Nadim study.
All 30 adults with stage IIIA N2 non-small cell lung cancer (NSCLC) who enrolled in the ongoing single-arm, open-label study and have undergone surgery to date, had resectable tumors following neoadjuvant treatment, Mariano Provencio, MD, of Hospital Puerta de Hierro, Madrid, Spain, reported at the World Conference on Lung Cancer.
The complete and partial response rates following the treatment were 10% and 60%, respectively, and the remaining patients had stable disease, Dr. Provencio said, noting that an additional 10 enrolled patients have completed treatment and are awaiting resection, and another 3 are still completing treatment.
The overall major pathologic response rate was 80%, including 75% with complete remission, he said at the conference, which was sponsored by the International Association for the Study of Lung Cancer.
“With a median follow-up of 4 months, no patients suffered any recurrence,” he said. “We have been unable to identify any significant factor related to the response, but we still do not have information about biomarkers.”
The study participants had a median age of 64 years, most (73%) were men, and all were current or former smokers. All received the planned neoadjuvant doses, which included 3 cycles of intravenous nivolumab at a dose of 360 mg every 3 weeks, plus 200 mg/m2 of paclitaxel and carboplatin at AUC 6 every 3 weeks.
“The most important toxicity was hematological toxicity related to chemotherapy; there were very few episodes of non-hematological toxicity,” he said.
Tumors were then assessed, and surgery–lobectomy in 90% of cases–was performed in the 3rd or 4th week after day 21 of the third neoadjuvant treatment cycle.
“There were no intraoperative complications, and 7 patients experienced some postoperative complications, but there was no postoperative mortality,” he said.
Adjuvant treatment included 240 mg of intravenous nivolumab every 2 weeks for 4 months and then 480 mg every 4 weeks for 8 months after resection.
The primary end-point of the study is 24-month progression-free survival.
CT-IO has a high response rate and longer survival in unselected patients with metastatic NSCLC, but there were previously no data about this combination in the neoadjuvant setting, Dr. Provencio said.
The findings of this ongoing study are limited by their preliminary nature and the related lack of information about overall survival and biomarkers, Dr. Provencio said.
“But the higher complete remission and major pathological response rates make this a promising future treatment in stage 3 [NSCLC,] he said.
Indeed, the Nadim study thus far has shown “an amazing result that needs to be verified ... [there is] no prospective proof yet in this context that major pathologic response is parlayed with improved [progression-free survival] or [overall survival],” said discussant Corey Langer, MD, professor of medicine and director of thoracic oncology at the University of Pennsylvania, Philadelphia. “We need to track the late sequelae and [central nervous system] recurrences.”
Dr. Provencio reported relationships with AstraZeneca, Bristol-Meyers Squibb, Fabre, Merck, Pierre, Roche, and Bristol-Meyers Squibb. Dr. Langer reported relationships with numerous companies and organizations.
SOURCE: Provencio, Mario et al., WCLC 2018 Abstract OA01.05.
REPORTING FROM WCLC 2018
Key clinical point: Neoadjuvant CT-IO yielded high pathologic response rates for stage IIIA N2 NSCLC.
Major finding: The major pathologic response rate was 80%, including 10% with a complete response.
Study details: A phase 2, single-arm, open-label study of 30 patients.
Disclosures: Dr. Provencio reported relationships with AstraZeneca, Bristol-Meyers Squibb, Fabre, Merck, Pierre, Roche, and Bristol-Meyers Squibb. Dr. Langer reported relationships with numerous companies and organizations.
Source: Provencio, Mario et al., WCLC 2018 Abstract OA01.05.
CGP guides cancer patient management, facilitates trial enrollment
TORONTO – according to findings from a retrospective study of 46 patients who were followed for 3 years after CGP.
A total of 263 genomic alterations were identified in the patients, leading to a change of therapy in 26% of cases and referral to a clinical trial in 13%, Kimberly Rohan, APN, reported at the World Conference on Lung Cancer.
The 13% referral rate was surprising, “because that’s way above the national average for enrollment in a clinical trial,” Ms. Rohan, of the Edward Cancer Center in Naperville, Ill., said during a press briefing at the meeting, sponsored by the International Association for the Study of Lung Cancer.
“Among those diagnosed with lung cancer, 6% were referred to clinical trials and 34% had a change of therapy,” she said, noting that all but one of the patients had non–small cell lung cancer, and the other had small cell lung cancer and many alterations.
Of note, three patients enrolled in hospice care based on the findings; sometimes, palliative care is the most appropriate option, and this information helps patients and their families make those decisions, Ms. Rohan said.
Patients were tested between 2014 and 2017, and the review looked at the number of genomic alterations identified in each, what treatments were associated with potential clinical trial benefits, what therapies were associated with lack of response, and the effects of the CGP findings on decision making.
An important next step is to work with payors to get them to pay for CGP testing, she said. “These tests are expensive so a lot of [insurance companies] don’t want to pay for them, but this data will help support the fact that [these tests] do allow better treatments for patients and allow patients to make better decisions for themselves in regard to treatment.”
Ms. Rohan is a speaker or advisory board member for Merck, Genentech, and AstraZeneca.
TORONTO – according to findings from a retrospective study of 46 patients who were followed for 3 years after CGP.
A total of 263 genomic alterations were identified in the patients, leading to a change of therapy in 26% of cases and referral to a clinical trial in 13%, Kimberly Rohan, APN, reported at the World Conference on Lung Cancer.
The 13% referral rate was surprising, “because that’s way above the national average for enrollment in a clinical trial,” Ms. Rohan, of the Edward Cancer Center in Naperville, Ill., said during a press briefing at the meeting, sponsored by the International Association for the Study of Lung Cancer.
“Among those diagnosed with lung cancer, 6% were referred to clinical trials and 34% had a change of therapy,” she said, noting that all but one of the patients had non–small cell lung cancer, and the other had small cell lung cancer and many alterations.
Of note, three patients enrolled in hospice care based on the findings; sometimes, palliative care is the most appropriate option, and this information helps patients and their families make those decisions, Ms. Rohan said.
Patients were tested between 2014 and 2017, and the review looked at the number of genomic alterations identified in each, what treatments were associated with potential clinical trial benefits, what therapies were associated with lack of response, and the effects of the CGP findings on decision making.
An important next step is to work with payors to get them to pay for CGP testing, she said. “These tests are expensive so a lot of [insurance companies] don’t want to pay for them, but this data will help support the fact that [these tests] do allow better treatments for patients and allow patients to make better decisions for themselves in regard to treatment.”
Ms. Rohan is a speaker or advisory board member for Merck, Genentech, and AstraZeneca.
TORONTO – according to findings from a retrospective study of 46 patients who were followed for 3 years after CGP.
A total of 263 genomic alterations were identified in the patients, leading to a change of therapy in 26% of cases and referral to a clinical trial in 13%, Kimberly Rohan, APN, reported at the World Conference on Lung Cancer.
The 13% referral rate was surprising, “because that’s way above the national average for enrollment in a clinical trial,” Ms. Rohan, of the Edward Cancer Center in Naperville, Ill., said during a press briefing at the meeting, sponsored by the International Association for the Study of Lung Cancer.
“Among those diagnosed with lung cancer, 6% were referred to clinical trials and 34% had a change of therapy,” she said, noting that all but one of the patients had non–small cell lung cancer, and the other had small cell lung cancer and many alterations.
Of note, three patients enrolled in hospice care based on the findings; sometimes, palliative care is the most appropriate option, and this information helps patients and their families make those decisions, Ms. Rohan said.
Patients were tested between 2014 and 2017, and the review looked at the number of genomic alterations identified in each, what treatments were associated with potential clinical trial benefits, what therapies were associated with lack of response, and the effects of the CGP findings on decision making.
An important next step is to work with payors to get them to pay for CGP testing, she said. “These tests are expensive so a lot of [insurance companies] don’t want to pay for them, but this data will help support the fact that [these tests] do allow better treatments for patients and allow patients to make better decisions for themselves in regard to treatment.”
Ms. Rohan is a speaker or advisory board member for Merck, Genentech, and AstraZeneca.
REPORTING FROM WCLC 2018
Key clinical point: Comprehensive genetic profiling (GCP) is useful for guiding the care of cancer patients.
Major finding: CGP led to a change of therapy in 26% of cases and referral to a clinical trial in 13% of cases.
Study details: A retrospective study of CGP for 46 cancer patients.
Disclosures: Ms. Rohan is a speaker or advisory board member for Merck, Genentech, and AstraZeneca.
AYA cancer: Bridging the divide
and older adult patients, a trend that has been going on for decades. But clinicians and researchers are getting serious about an important question: Why?
“This is a very heterogeneous group of disorders,” Rabi Hanna, MD, a pediatric hematologist and oncologist, and director of pediatric bone marrow transplantation at Cleveland Clinic Children’s Hospital, Ohio, said in an interview.
He is referring to the cancers that affect adolescents and young adults (AYAs), who are broadly defined as patients aged 15-39 years.
“A few cancers, such as [acute lymphoblastic leukemia], are more common in children, and others, such as breast cancer, are more common in adults; biology may be different in the adolescent and young adult patients, which may lead to different outcomes,” Dr. Hanna said.
In addition, the psychosocial needs in this age group differ vastly from those of other groups, he said.
“Many of these patients are in college or have just started their families, so we have to pay attention more to financial toxicities and fertility, for example,” he said.
Another factor that likely contributes to the disparities between AYAs and other populations with cancer is the relative lack of clinical trial involvement among AYAs. That’s a point on which Dr. Hanna and many other experts agree.
A recent series of articles published in Blood addressed these and other issues, including whether AYAs with ALL or aggressive B-cell non-Hodgkin lymphomas (NHLs) should be treated as children or adults, treatment strategies for those with acute myeloid leukemias, management of Hodgkin lymphoma, and psychosocial challenges and health-related quality of life (QOL) of AYAs with hematologic malignancies.
“Hematological malignancies occurring in AYAs represent a unique challenge because of their special biological features and distinctive therapeutic requirements, as well as the unique medical, social, and psychological characteristics of this patient population,” Jorge Cortes, MD, an assistant editor for Blood, wrote in an introduction to the series.
“Unfortunately, not much has been done to explore unique molecular and biological features of AYA hematologic malignancies. The discussion on the management of AYAs frequently centers on whether these patients should be treated in a pediatric setting or an adult setting, or with regimens designed for children or for adults. Clinical trials specifically designed for AYAs are scanty,” noted Dr. Cortes, who directs the chronic myeloid leukemia (CML) and acute myeloid leukemia programs (AML) at the University of Texas MD Anderson Cancer Center, Houston.
Treatment approach and setting
In the Blood article on ALL in AYAs, Nicolas Boissel, MD, and André Baruchel, MD, note that the use of “fully pediatric protocols” in patients aged 15-20 years is supported by numerous studies, and that in young adults, evidence increasingly supports “pediatric-inspired or even fully pediatric approaches” as they have been shown to dramatically improve outcomes, with long-term survival rates nearing 70% (2018;132:351-61).
Patients in these age groups require specific programs that take into account factors such as care access and trial access, increased risk of acute toxicities, and treatment adherence, which can be particularly problematic in AYAs, they concluded.
Kristen O’Dwyer, MD, and her colleagues, in their article on AML treatment in AYAs, argue that based on “the distinguishing characteristics of AYAs with AML,” neither the pediatric nor adult approaches are ideally suited for them.
Rather, AYA-specific approaches merit consideration, they concluded (Blood 2018;132:362-68).
Similarly, Kieron Dunleavy, MD, and Thomas G. Gross, MD, note in an article on managing aggressive B-cell NHLs in AYAs that a “remarkable divide” in the treatment of patients under age 18 years with lymphoma versus their young adult counterparts underscores the need for collaboration in developing consensus regarding treatment of AYAs (Blood 2018;132:369-75).
But recent findings from a study by Paul C. Nathan, MD, and his colleagues focuses more on where that treatment should take place (J Natl Cancer Inst. 2018 Jul 19. doi: 10.1093/jnci/djy119).
The study provides new insights into the understanding of treatment differences for adolescents seen in pediatric vs. adult cancer facilities. And the findings suggest that the trade-off for improved outcomes among those treated in the pediatric setting – as emerging literature demonstrates – is higher resource use and cost, Helen M. Parsons, PhD, and her colleagues wrote in an accompanying editorial (J Natl Cancer Inst. 2018 Jul 19. doi: 10.1093/jnci/djy123).
Among 1,356 patients aged 15-17 years who were diagnosed with cancer between 1996 and 2010, the cost of care was higher when treatment took place in a pediatric setting vs. an adult institution. This was driven in part by higher hospitalization rates and longer hospital stays, the investigators found.
“Additionally, adolescents treated in the pediatric setting tended to seek more [emergency department] care immediately before diagnosis and during the initial treatment phase; these adolescents also used more home care services during initial treatment and survivorship,” Dr. Parsons and her colleagues wrote.
This was true across different diagnoses, including leukemias, lymphomas, sarcomas, and germ cell tumors, but only during the initial treatment phase.
The findings of higher inpatient days in the pediatric setting is not surprising given that induction therapies for pediatric ALL are generally more complex and intensive than therapies commonly used in adults with ALL, and given that pediatric cancer hospitals tend to have a wider array of services, including psychosocial and family support services.
“What is less clear is why individuals seen in pediatric settings have higher rates of ED care directly before diagnosis and during the initial treatment phase ... more work on this topic is needed to more fully understand these patterns,” they wrote, adding that “the finding that adolescents treated in pediatric institutions had higher resource use across diagnostic groups demonstrates that resource utilization may be driven just as much by care setting as diagnosis.”
Disease and developmental biology
As Dr. Hanna noted, biological differences and changes over time suggest that different age groups need varying approaches to treatment and may have different outcomes with the same treatments.
For example, the biology of AML is known to change with age, Dr. Dwyer and her colleagues said, explaining that a recent European study showed that in 5,564 patients with de novo AML, the frequency of favorable cytogenetics was low in infants, increased in children and young adults, and decreased again in middle age and older age (Cancer. 2016 Dec 15;122[24]:3821-30).
“Normal karyotype increases in prevalence from 13.7% in infants to approximately 25% in children, 44% in AYAs, and 50% in adults. Most unfavorable cytogenetic abnormalities are rare across all age groups, though complex cytogenetics are relatively more frequent in infants, decrease in frequency in AYAs, and then increase in frequency beyond AYA,” Dr. Dwyer and her colleagues wrote, noting that it also is becoming more apparent that age influences the presence of AML-related molecular abnormalities.
The authors argue that recognition of age-related differences in disease biology “will provide the best opportunity to improve the clinical outcomes that have been static for decades.”
Dr. Boissel and Dr. Baruchel also note that the “black hole” of understanding of ALL biology in AYAs that characterized the last 15 years has been “nearly brought to light and revealed a continuum between childhood and adult ALL.”
One example of this involves data from the NOPHO-ALL-2008 trial, showing that the proportion of patients with intrachromosomal amplification of the long arm of chromosome 21 (iAMP21), which is a rare event occurring in about 2% of children with ALL, is more frequent in older children and adolescents and is associated with higher relapse risk that is only partially diminished by intensified treatment.
In NOPHO-2008, iAMP21 occurred in 1.5% of patients aged 1-9 years, 5.8% of those aged 10-17 years, and 12% of those aged 17-45 years. The authors provided numerous other examples of such age-related differences in disease biology and concluded that “risk stratification based on recent biology findings and sequential [minimum residual disease] evaluations should now be implemented, as well as new therapeutic options including immunotherapy and targeted therapies, at best within the setting of integrated pediatric and AYA protocols.”
Psychosocial factors
The “financial toxicity” mentioned by Dr. Hanna – the high cost of care, lost work time, and delays in reaching educational and career goals, for example – is a major factor that must be addressed in this population, but there are also many others.
“Cancer is a non-normative event for AYAs. It is extremely disruptive to them physically, psychologically, and vocationally ... and this poses significant challenges,” John M. Salsman, PhD, director of clinical research in AYA oncology at Wake Forest University, Winston-Salem, N.C., said in an interview.
These patients not only have 5-year survival rates that haven’t improved in tandem with those in pediatric and adult populations over the last 3 decades, but in addition to the financial toxicity and strain, they also have higher rates of depression and anxiety, including fear of recurrence, he added.
“Quality of life is incredibly important, and these things need to be addressed because of the developmental changes AYAs are navigating; there are issues of positive body image, family and career decisions ... These are challenging for anyone, and when you throw a cancer diagnosis into the mix they become disproportionately so,” he said.
In a 2014 study, he and his colleagues found that AYAs with cancer had poorer physical and emotional quality of life when compared with matched controls, but better social quality of life. The latter finding was surprising, and highlights the “critical importance” of the social dimension in AYAs’ lives.
“Patient after patient will say ‘I found out who my real friends are,’ ” Dr. Salsman said. “There’s this refinement and deepening of the social network among some posttreatment survivors.”
Dr. Salsman and his colleagues are using those findings to develop interventions that can maximize self care in posttreatment survivorship – a time when AYAs may feel they have a new lease on life and may be more motivated to adhere to recommendations and take care of themselves.
A randomized controlled pilot study incorporating social media apps and other technologies to build on the positive social components of their lives in promoting physical activity interventions, for example, is underway.
Another intervention targets emotional well-being via web-based tools to increase positive affect. A proof-of-concept study showed that the approach is feasible and well received, and efforts are underway to plan a larger-scale randomized controlled trial, he said.
Dr. Salsman also praised the PRISM (Promoting Resilience in Stress Management) tool developed by researchers at Seattle Children’s Hospital.
PRISM was created to help AYAs with cancer and other illnesses learn coping skills to manage stress after their diagnosis, and to boost quality of life beyond treatment. A digital app has also been developed to be used in conjunction with the program.
Trial enrollment
In his editorial introducing the Blood series on AYAs and cancer, Dr. Cortes noted a paucity of clinical trials specifically designed for this population.
“At the time of this writing, I could identify four therapeutic trials registered at www.clinicaltrials.gov that appeared to be somewhat specifically designed for AYAs (some included children also),” he wrote, adding that “enrollment of AYAs in clinical trials in cancer in general has been suboptimal at best.”
The dismal numbers with respect to enrollment of AYAs with cancer in clinical trials may be related in part to treatment setting, Dr. Salsman said.
Data suggest that the majority of AYAs with cancer are treated in community-based practices rather than comprehensive cancer centers, where the bulk of research is being done, he explained.
The bottom line is that more research involving AYAs is needed, as is greater understanding of why enrollment is so much lower among AYA patients, Dr. Hanna said, noting that in 2017, The American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (FOCR) released a statement recommending that pediatric patients be considered for enrollment in later-phase trials for cancer types that span both adults and children.
Individuals aged 12 years and older should routinely be included in such trials as their drug metabolism is similar to that of adults, and inclusion of younger patients may also be appropriate if they are part of the population impacted by the disease, depending on specific disease biology, action of the drug, and available safety information, the organizations said.
Officials at the Food and Drug Administration are considering that possibility, Dr. Hanna said.
Attention to the disparities in survival improvements and trial involvement among AYAs with cancer, compared with other age groups, has definitely increased in recent years, Dr. Salsman added, noting that in addition to ASCO and FOCR, several other organizations are working to address the problem.
About 5 years ago, the National Clinical Trials Network formed a working group that developed a number of specific objectives for incorporating more AYAs into cancer trials and finding better ways to study this population; the Institute of Medicine held a forum on the care of AYAs with cancer; and the National Cancer Institute (NCI) held a state-of-the-science meeting that focused on identifying strategic priorities for AYA oncology, he noted.
An article in Cancer provides a summary of the progress toward the priorities identified during the NCI meeting, which convened five working groups to address various topics, including clinical trial enrollment (Cancer. 2016 Apr 1;122[7]:988-99).
Dr. Hanna added that groups such as the Southwest Oncology Group (SWOG) and Children’s Oncology Group (COG) also have AYA committees now.
“One of the success stories of working together between SWOG and COG was the intergroup study C10403 for patients with ALL. And now there are efforts for an intergroup AYA-AML task force to include representatives from each of the cooperative groups that historically coordinated myeloid disease clinical trials – COG, SWOG, Alliance, and ECOG-ACRIN,” he said.
In fact, all of the National Clinical Trials Network groups have some initiative in place to address AYA concerns, said Dr. Salsman, who chairs the ECOG-ACRIN AYA oncology subcommittee.
Despite these efforts, and many others, long-term survival improvements among AYAs with cancer still fall short, compared with those of other age groups.
What’s next?
Among the recommendations of the authors of the AYA series in Blood is a call for assessing AYA-specific therapy in future clinical trials, as well as improved collaboration between adult and pediatric teams with involvement of multidisciplinary teams.
Many centers are already working on models for collaborative care, Dr. Salsman said, citing the Fort Worth AYA Oncology Coalition led by medical director Karen Albritton, MD, as an example of a program that has been successful in “getting stakeholders on the same page, helping them have a shared vision, and working to maximize improvements in outcomes.”
Patients are also taking the lead in demanding better care and attention to their psychosocial needs, Dr. Hanna said. In the case of the community-powered advocacy organization Critical Mass, they succeeded in getting lawmakers to introduce a bill in the U.S. House of Representatives that would allow college students to defer loan payments while undergoing cancer treatment.
and older adult patients, a trend that has been going on for decades. But clinicians and researchers are getting serious about an important question: Why?
“This is a very heterogeneous group of disorders,” Rabi Hanna, MD, a pediatric hematologist and oncologist, and director of pediatric bone marrow transplantation at Cleveland Clinic Children’s Hospital, Ohio, said in an interview.
He is referring to the cancers that affect adolescents and young adults (AYAs), who are broadly defined as patients aged 15-39 years.
“A few cancers, such as [acute lymphoblastic leukemia], are more common in children, and others, such as breast cancer, are more common in adults; biology may be different in the adolescent and young adult patients, which may lead to different outcomes,” Dr. Hanna said.
In addition, the psychosocial needs in this age group differ vastly from those of other groups, he said.
“Many of these patients are in college or have just started their families, so we have to pay attention more to financial toxicities and fertility, for example,” he said.
Another factor that likely contributes to the disparities between AYAs and other populations with cancer is the relative lack of clinical trial involvement among AYAs. That’s a point on which Dr. Hanna and many other experts agree.
A recent series of articles published in Blood addressed these and other issues, including whether AYAs with ALL or aggressive B-cell non-Hodgkin lymphomas (NHLs) should be treated as children or adults, treatment strategies for those with acute myeloid leukemias, management of Hodgkin lymphoma, and psychosocial challenges and health-related quality of life (QOL) of AYAs with hematologic malignancies.
“Hematological malignancies occurring in AYAs represent a unique challenge because of their special biological features and distinctive therapeutic requirements, as well as the unique medical, social, and psychological characteristics of this patient population,” Jorge Cortes, MD, an assistant editor for Blood, wrote in an introduction to the series.
“Unfortunately, not much has been done to explore unique molecular and biological features of AYA hematologic malignancies. The discussion on the management of AYAs frequently centers on whether these patients should be treated in a pediatric setting or an adult setting, or with regimens designed for children or for adults. Clinical trials specifically designed for AYAs are scanty,” noted Dr. Cortes, who directs the chronic myeloid leukemia (CML) and acute myeloid leukemia programs (AML) at the University of Texas MD Anderson Cancer Center, Houston.
Treatment approach and setting
In the Blood article on ALL in AYAs, Nicolas Boissel, MD, and André Baruchel, MD, note that the use of “fully pediatric protocols” in patients aged 15-20 years is supported by numerous studies, and that in young adults, evidence increasingly supports “pediatric-inspired or even fully pediatric approaches” as they have been shown to dramatically improve outcomes, with long-term survival rates nearing 70% (2018;132:351-61).
Patients in these age groups require specific programs that take into account factors such as care access and trial access, increased risk of acute toxicities, and treatment adherence, which can be particularly problematic in AYAs, they concluded.
Kristen O’Dwyer, MD, and her colleagues, in their article on AML treatment in AYAs, argue that based on “the distinguishing characteristics of AYAs with AML,” neither the pediatric nor adult approaches are ideally suited for them.
Rather, AYA-specific approaches merit consideration, they concluded (Blood 2018;132:362-68).
Similarly, Kieron Dunleavy, MD, and Thomas G. Gross, MD, note in an article on managing aggressive B-cell NHLs in AYAs that a “remarkable divide” in the treatment of patients under age 18 years with lymphoma versus their young adult counterparts underscores the need for collaboration in developing consensus regarding treatment of AYAs (Blood 2018;132:369-75).
But recent findings from a study by Paul C. Nathan, MD, and his colleagues focuses more on where that treatment should take place (J Natl Cancer Inst. 2018 Jul 19. doi: 10.1093/jnci/djy119).
The study provides new insights into the understanding of treatment differences for adolescents seen in pediatric vs. adult cancer facilities. And the findings suggest that the trade-off for improved outcomes among those treated in the pediatric setting – as emerging literature demonstrates – is higher resource use and cost, Helen M. Parsons, PhD, and her colleagues wrote in an accompanying editorial (J Natl Cancer Inst. 2018 Jul 19. doi: 10.1093/jnci/djy123).
Among 1,356 patients aged 15-17 years who were diagnosed with cancer between 1996 and 2010, the cost of care was higher when treatment took place in a pediatric setting vs. an adult institution. This was driven in part by higher hospitalization rates and longer hospital stays, the investigators found.
“Additionally, adolescents treated in the pediatric setting tended to seek more [emergency department] care immediately before diagnosis and during the initial treatment phase; these adolescents also used more home care services during initial treatment and survivorship,” Dr. Parsons and her colleagues wrote.
This was true across different diagnoses, including leukemias, lymphomas, sarcomas, and germ cell tumors, but only during the initial treatment phase.
The findings of higher inpatient days in the pediatric setting is not surprising given that induction therapies for pediatric ALL are generally more complex and intensive than therapies commonly used in adults with ALL, and given that pediatric cancer hospitals tend to have a wider array of services, including psychosocial and family support services.
“What is less clear is why individuals seen in pediatric settings have higher rates of ED care directly before diagnosis and during the initial treatment phase ... more work on this topic is needed to more fully understand these patterns,” they wrote, adding that “the finding that adolescents treated in pediatric institutions had higher resource use across diagnostic groups demonstrates that resource utilization may be driven just as much by care setting as diagnosis.”
Disease and developmental biology
As Dr. Hanna noted, biological differences and changes over time suggest that different age groups need varying approaches to treatment and may have different outcomes with the same treatments.
For example, the biology of AML is known to change with age, Dr. Dwyer and her colleagues said, explaining that a recent European study showed that in 5,564 patients with de novo AML, the frequency of favorable cytogenetics was low in infants, increased in children and young adults, and decreased again in middle age and older age (Cancer. 2016 Dec 15;122[24]:3821-30).
“Normal karyotype increases in prevalence from 13.7% in infants to approximately 25% in children, 44% in AYAs, and 50% in adults. Most unfavorable cytogenetic abnormalities are rare across all age groups, though complex cytogenetics are relatively more frequent in infants, decrease in frequency in AYAs, and then increase in frequency beyond AYA,” Dr. Dwyer and her colleagues wrote, noting that it also is becoming more apparent that age influences the presence of AML-related molecular abnormalities.
The authors argue that recognition of age-related differences in disease biology “will provide the best opportunity to improve the clinical outcomes that have been static for decades.”
Dr. Boissel and Dr. Baruchel also note that the “black hole” of understanding of ALL biology in AYAs that characterized the last 15 years has been “nearly brought to light and revealed a continuum between childhood and adult ALL.”
One example of this involves data from the NOPHO-ALL-2008 trial, showing that the proportion of patients with intrachromosomal amplification of the long arm of chromosome 21 (iAMP21), which is a rare event occurring in about 2% of children with ALL, is more frequent in older children and adolescents and is associated with higher relapse risk that is only partially diminished by intensified treatment.
In NOPHO-2008, iAMP21 occurred in 1.5% of patients aged 1-9 years, 5.8% of those aged 10-17 years, and 12% of those aged 17-45 years. The authors provided numerous other examples of such age-related differences in disease biology and concluded that “risk stratification based on recent biology findings and sequential [minimum residual disease] evaluations should now be implemented, as well as new therapeutic options including immunotherapy and targeted therapies, at best within the setting of integrated pediatric and AYA protocols.”
Psychosocial factors
The “financial toxicity” mentioned by Dr. Hanna – the high cost of care, lost work time, and delays in reaching educational and career goals, for example – is a major factor that must be addressed in this population, but there are also many others.
“Cancer is a non-normative event for AYAs. It is extremely disruptive to them physically, psychologically, and vocationally ... and this poses significant challenges,” John M. Salsman, PhD, director of clinical research in AYA oncology at Wake Forest University, Winston-Salem, N.C., said in an interview.
These patients not only have 5-year survival rates that haven’t improved in tandem with those in pediatric and adult populations over the last 3 decades, but in addition to the financial toxicity and strain, they also have higher rates of depression and anxiety, including fear of recurrence, he added.
“Quality of life is incredibly important, and these things need to be addressed because of the developmental changes AYAs are navigating; there are issues of positive body image, family and career decisions ... These are challenging for anyone, and when you throw a cancer diagnosis into the mix they become disproportionately so,” he said.
In a 2014 study, he and his colleagues found that AYAs with cancer had poorer physical and emotional quality of life when compared with matched controls, but better social quality of life. The latter finding was surprising, and highlights the “critical importance” of the social dimension in AYAs’ lives.
“Patient after patient will say ‘I found out who my real friends are,’ ” Dr. Salsman said. “There’s this refinement and deepening of the social network among some posttreatment survivors.”
Dr. Salsman and his colleagues are using those findings to develop interventions that can maximize self care in posttreatment survivorship – a time when AYAs may feel they have a new lease on life and may be more motivated to adhere to recommendations and take care of themselves.
A randomized controlled pilot study incorporating social media apps and other technologies to build on the positive social components of their lives in promoting physical activity interventions, for example, is underway.
Another intervention targets emotional well-being via web-based tools to increase positive affect. A proof-of-concept study showed that the approach is feasible and well received, and efforts are underway to plan a larger-scale randomized controlled trial, he said.
Dr. Salsman also praised the PRISM (Promoting Resilience in Stress Management) tool developed by researchers at Seattle Children’s Hospital.
PRISM was created to help AYAs with cancer and other illnesses learn coping skills to manage stress after their diagnosis, and to boost quality of life beyond treatment. A digital app has also been developed to be used in conjunction with the program.
Trial enrollment
In his editorial introducing the Blood series on AYAs and cancer, Dr. Cortes noted a paucity of clinical trials specifically designed for this population.
“At the time of this writing, I could identify four therapeutic trials registered at www.clinicaltrials.gov that appeared to be somewhat specifically designed for AYAs (some included children also),” he wrote, adding that “enrollment of AYAs in clinical trials in cancer in general has been suboptimal at best.”
The dismal numbers with respect to enrollment of AYAs with cancer in clinical trials may be related in part to treatment setting, Dr. Salsman said.
Data suggest that the majority of AYAs with cancer are treated in community-based practices rather than comprehensive cancer centers, where the bulk of research is being done, he explained.
The bottom line is that more research involving AYAs is needed, as is greater understanding of why enrollment is so much lower among AYA patients, Dr. Hanna said, noting that in 2017, The American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (FOCR) released a statement recommending that pediatric patients be considered for enrollment in later-phase trials for cancer types that span both adults and children.
Individuals aged 12 years and older should routinely be included in such trials as their drug metabolism is similar to that of adults, and inclusion of younger patients may also be appropriate if they are part of the population impacted by the disease, depending on specific disease biology, action of the drug, and available safety information, the organizations said.
Officials at the Food and Drug Administration are considering that possibility, Dr. Hanna said.
Attention to the disparities in survival improvements and trial involvement among AYAs with cancer, compared with other age groups, has definitely increased in recent years, Dr. Salsman added, noting that in addition to ASCO and FOCR, several other organizations are working to address the problem.
About 5 years ago, the National Clinical Trials Network formed a working group that developed a number of specific objectives for incorporating more AYAs into cancer trials and finding better ways to study this population; the Institute of Medicine held a forum on the care of AYAs with cancer; and the National Cancer Institute (NCI) held a state-of-the-science meeting that focused on identifying strategic priorities for AYA oncology, he noted.
An article in Cancer provides a summary of the progress toward the priorities identified during the NCI meeting, which convened five working groups to address various topics, including clinical trial enrollment (Cancer. 2016 Apr 1;122[7]:988-99).
Dr. Hanna added that groups such as the Southwest Oncology Group (SWOG) and Children’s Oncology Group (COG) also have AYA committees now.
“One of the success stories of working together between SWOG and COG was the intergroup study C10403 for patients with ALL. And now there are efforts for an intergroup AYA-AML task force to include representatives from each of the cooperative groups that historically coordinated myeloid disease clinical trials – COG, SWOG, Alliance, and ECOG-ACRIN,” he said.
In fact, all of the National Clinical Trials Network groups have some initiative in place to address AYA concerns, said Dr. Salsman, who chairs the ECOG-ACRIN AYA oncology subcommittee.
Despite these efforts, and many others, long-term survival improvements among AYAs with cancer still fall short, compared with those of other age groups.
What’s next?
Among the recommendations of the authors of the AYA series in Blood is a call for assessing AYA-specific therapy in future clinical trials, as well as improved collaboration between adult and pediatric teams with involvement of multidisciplinary teams.
Many centers are already working on models for collaborative care, Dr. Salsman said, citing the Fort Worth AYA Oncology Coalition led by medical director Karen Albritton, MD, as an example of a program that has been successful in “getting stakeholders on the same page, helping them have a shared vision, and working to maximize improvements in outcomes.”
Patients are also taking the lead in demanding better care and attention to their psychosocial needs, Dr. Hanna said. In the case of the community-powered advocacy organization Critical Mass, they succeeded in getting lawmakers to introduce a bill in the U.S. House of Representatives that would allow college students to defer loan payments while undergoing cancer treatment.
and older adult patients, a trend that has been going on for decades. But clinicians and researchers are getting serious about an important question: Why?
“This is a very heterogeneous group of disorders,” Rabi Hanna, MD, a pediatric hematologist and oncologist, and director of pediatric bone marrow transplantation at Cleveland Clinic Children’s Hospital, Ohio, said in an interview.
He is referring to the cancers that affect adolescents and young adults (AYAs), who are broadly defined as patients aged 15-39 years.
“A few cancers, such as [acute lymphoblastic leukemia], are more common in children, and others, such as breast cancer, are more common in adults; biology may be different in the adolescent and young adult patients, which may lead to different outcomes,” Dr. Hanna said.
In addition, the psychosocial needs in this age group differ vastly from those of other groups, he said.
“Many of these patients are in college or have just started their families, so we have to pay attention more to financial toxicities and fertility, for example,” he said.
Another factor that likely contributes to the disparities between AYAs and other populations with cancer is the relative lack of clinical trial involvement among AYAs. That’s a point on which Dr. Hanna and many other experts agree.
A recent series of articles published in Blood addressed these and other issues, including whether AYAs with ALL or aggressive B-cell non-Hodgkin lymphomas (NHLs) should be treated as children or adults, treatment strategies for those with acute myeloid leukemias, management of Hodgkin lymphoma, and psychosocial challenges and health-related quality of life (QOL) of AYAs with hematologic malignancies.
“Hematological malignancies occurring in AYAs represent a unique challenge because of their special biological features and distinctive therapeutic requirements, as well as the unique medical, social, and psychological characteristics of this patient population,” Jorge Cortes, MD, an assistant editor for Blood, wrote in an introduction to the series.
“Unfortunately, not much has been done to explore unique molecular and biological features of AYA hematologic malignancies. The discussion on the management of AYAs frequently centers on whether these patients should be treated in a pediatric setting or an adult setting, or with regimens designed for children or for adults. Clinical trials specifically designed for AYAs are scanty,” noted Dr. Cortes, who directs the chronic myeloid leukemia (CML) and acute myeloid leukemia programs (AML) at the University of Texas MD Anderson Cancer Center, Houston.
Treatment approach and setting
In the Blood article on ALL in AYAs, Nicolas Boissel, MD, and André Baruchel, MD, note that the use of “fully pediatric protocols” in patients aged 15-20 years is supported by numerous studies, and that in young adults, evidence increasingly supports “pediatric-inspired or even fully pediatric approaches” as they have been shown to dramatically improve outcomes, with long-term survival rates nearing 70% (2018;132:351-61).
Patients in these age groups require specific programs that take into account factors such as care access and trial access, increased risk of acute toxicities, and treatment adherence, which can be particularly problematic in AYAs, they concluded.
Kristen O’Dwyer, MD, and her colleagues, in their article on AML treatment in AYAs, argue that based on “the distinguishing characteristics of AYAs with AML,” neither the pediatric nor adult approaches are ideally suited for them.
Rather, AYA-specific approaches merit consideration, they concluded (Blood 2018;132:362-68).
Similarly, Kieron Dunleavy, MD, and Thomas G. Gross, MD, note in an article on managing aggressive B-cell NHLs in AYAs that a “remarkable divide” in the treatment of patients under age 18 years with lymphoma versus their young adult counterparts underscores the need for collaboration in developing consensus regarding treatment of AYAs (Blood 2018;132:369-75).
But recent findings from a study by Paul C. Nathan, MD, and his colleagues focuses more on where that treatment should take place (J Natl Cancer Inst. 2018 Jul 19. doi: 10.1093/jnci/djy119).
The study provides new insights into the understanding of treatment differences for adolescents seen in pediatric vs. adult cancer facilities. And the findings suggest that the trade-off for improved outcomes among those treated in the pediatric setting – as emerging literature demonstrates – is higher resource use and cost, Helen M. Parsons, PhD, and her colleagues wrote in an accompanying editorial (J Natl Cancer Inst. 2018 Jul 19. doi: 10.1093/jnci/djy123).
Among 1,356 patients aged 15-17 years who were diagnosed with cancer between 1996 and 2010, the cost of care was higher when treatment took place in a pediatric setting vs. an adult institution. This was driven in part by higher hospitalization rates and longer hospital stays, the investigators found.
“Additionally, adolescents treated in the pediatric setting tended to seek more [emergency department] care immediately before diagnosis and during the initial treatment phase; these adolescents also used more home care services during initial treatment and survivorship,” Dr. Parsons and her colleagues wrote.
This was true across different diagnoses, including leukemias, lymphomas, sarcomas, and germ cell tumors, but only during the initial treatment phase.
The findings of higher inpatient days in the pediatric setting is not surprising given that induction therapies for pediatric ALL are generally more complex and intensive than therapies commonly used in adults with ALL, and given that pediatric cancer hospitals tend to have a wider array of services, including psychosocial and family support services.
“What is less clear is why individuals seen in pediatric settings have higher rates of ED care directly before diagnosis and during the initial treatment phase ... more work on this topic is needed to more fully understand these patterns,” they wrote, adding that “the finding that adolescents treated in pediatric institutions had higher resource use across diagnostic groups demonstrates that resource utilization may be driven just as much by care setting as diagnosis.”
Disease and developmental biology
As Dr. Hanna noted, biological differences and changes over time suggest that different age groups need varying approaches to treatment and may have different outcomes with the same treatments.
For example, the biology of AML is known to change with age, Dr. Dwyer and her colleagues said, explaining that a recent European study showed that in 5,564 patients with de novo AML, the frequency of favorable cytogenetics was low in infants, increased in children and young adults, and decreased again in middle age and older age (Cancer. 2016 Dec 15;122[24]:3821-30).
“Normal karyotype increases in prevalence from 13.7% in infants to approximately 25% in children, 44% in AYAs, and 50% in adults. Most unfavorable cytogenetic abnormalities are rare across all age groups, though complex cytogenetics are relatively more frequent in infants, decrease in frequency in AYAs, and then increase in frequency beyond AYA,” Dr. Dwyer and her colleagues wrote, noting that it also is becoming more apparent that age influences the presence of AML-related molecular abnormalities.
The authors argue that recognition of age-related differences in disease biology “will provide the best opportunity to improve the clinical outcomes that have been static for decades.”
Dr. Boissel and Dr. Baruchel also note that the “black hole” of understanding of ALL biology in AYAs that characterized the last 15 years has been “nearly brought to light and revealed a continuum between childhood and adult ALL.”
One example of this involves data from the NOPHO-ALL-2008 trial, showing that the proportion of patients with intrachromosomal amplification of the long arm of chromosome 21 (iAMP21), which is a rare event occurring in about 2% of children with ALL, is more frequent in older children and adolescents and is associated with higher relapse risk that is only partially diminished by intensified treatment.
In NOPHO-2008, iAMP21 occurred in 1.5% of patients aged 1-9 years, 5.8% of those aged 10-17 years, and 12% of those aged 17-45 years. The authors provided numerous other examples of such age-related differences in disease biology and concluded that “risk stratification based on recent biology findings and sequential [minimum residual disease] evaluations should now be implemented, as well as new therapeutic options including immunotherapy and targeted therapies, at best within the setting of integrated pediatric and AYA protocols.”
Psychosocial factors
The “financial toxicity” mentioned by Dr. Hanna – the high cost of care, lost work time, and delays in reaching educational and career goals, for example – is a major factor that must be addressed in this population, but there are also many others.
“Cancer is a non-normative event for AYAs. It is extremely disruptive to them physically, psychologically, and vocationally ... and this poses significant challenges,” John M. Salsman, PhD, director of clinical research in AYA oncology at Wake Forest University, Winston-Salem, N.C., said in an interview.
These patients not only have 5-year survival rates that haven’t improved in tandem with those in pediatric and adult populations over the last 3 decades, but in addition to the financial toxicity and strain, they also have higher rates of depression and anxiety, including fear of recurrence, he added.
“Quality of life is incredibly important, and these things need to be addressed because of the developmental changes AYAs are navigating; there are issues of positive body image, family and career decisions ... These are challenging for anyone, and when you throw a cancer diagnosis into the mix they become disproportionately so,” he said.
In a 2014 study, he and his colleagues found that AYAs with cancer had poorer physical and emotional quality of life when compared with matched controls, but better social quality of life. The latter finding was surprising, and highlights the “critical importance” of the social dimension in AYAs’ lives.
“Patient after patient will say ‘I found out who my real friends are,’ ” Dr. Salsman said. “There’s this refinement and deepening of the social network among some posttreatment survivors.”
Dr. Salsman and his colleagues are using those findings to develop interventions that can maximize self care in posttreatment survivorship – a time when AYAs may feel they have a new lease on life and may be more motivated to adhere to recommendations and take care of themselves.
A randomized controlled pilot study incorporating social media apps and other technologies to build on the positive social components of their lives in promoting physical activity interventions, for example, is underway.
Another intervention targets emotional well-being via web-based tools to increase positive affect. A proof-of-concept study showed that the approach is feasible and well received, and efforts are underway to plan a larger-scale randomized controlled trial, he said.
Dr. Salsman also praised the PRISM (Promoting Resilience in Stress Management) tool developed by researchers at Seattle Children’s Hospital.
PRISM was created to help AYAs with cancer and other illnesses learn coping skills to manage stress after their diagnosis, and to boost quality of life beyond treatment. A digital app has also been developed to be used in conjunction with the program.
Trial enrollment
In his editorial introducing the Blood series on AYAs and cancer, Dr. Cortes noted a paucity of clinical trials specifically designed for this population.
“At the time of this writing, I could identify four therapeutic trials registered at www.clinicaltrials.gov that appeared to be somewhat specifically designed for AYAs (some included children also),” he wrote, adding that “enrollment of AYAs in clinical trials in cancer in general has been suboptimal at best.”
The dismal numbers with respect to enrollment of AYAs with cancer in clinical trials may be related in part to treatment setting, Dr. Salsman said.
Data suggest that the majority of AYAs with cancer are treated in community-based practices rather than comprehensive cancer centers, where the bulk of research is being done, he explained.
The bottom line is that more research involving AYAs is needed, as is greater understanding of why enrollment is so much lower among AYA patients, Dr. Hanna said, noting that in 2017, The American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (FOCR) released a statement recommending that pediatric patients be considered for enrollment in later-phase trials for cancer types that span both adults and children.
Individuals aged 12 years and older should routinely be included in such trials as their drug metabolism is similar to that of adults, and inclusion of younger patients may also be appropriate if they are part of the population impacted by the disease, depending on specific disease biology, action of the drug, and available safety information, the organizations said.
Officials at the Food and Drug Administration are considering that possibility, Dr. Hanna said.
Attention to the disparities in survival improvements and trial involvement among AYAs with cancer, compared with other age groups, has definitely increased in recent years, Dr. Salsman added, noting that in addition to ASCO and FOCR, several other organizations are working to address the problem.
About 5 years ago, the National Clinical Trials Network formed a working group that developed a number of specific objectives for incorporating more AYAs into cancer trials and finding better ways to study this population; the Institute of Medicine held a forum on the care of AYAs with cancer; and the National Cancer Institute (NCI) held a state-of-the-science meeting that focused on identifying strategic priorities for AYA oncology, he noted.
An article in Cancer provides a summary of the progress toward the priorities identified during the NCI meeting, which convened five working groups to address various topics, including clinical trial enrollment (Cancer. 2016 Apr 1;122[7]:988-99).
Dr. Hanna added that groups such as the Southwest Oncology Group (SWOG) and Children’s Oncology Group (COG) also have AYA committees now.
“One of the success stories of working together between SWOG and COG was the intergroup study C10403 for patients with ALL. And now there are efforts for an intergroup AYA-AML task force to include representatives from each of the cooperative groups that historically coordinated myeloid disease clinical trials – COG, SWOG, Alliance, and ECOG-ACRIN,” he said.
In fact, all of the National Clinical Trials Network groups have some initiative in place to address AYA concerns, said Dr. Salsman, who chairs the ECOG-ACRIN AYA oncology subcommittee.
Despite these efforts, and many others, long-term survival improvements among AYAs with cancer still fall short, compared with those of other age groups.
What’s next?
Among the recommendations of the authors of the AYA series in Blood is a call for assessing AYA-specific therapy in future clinical trials, as well as improved collaboration between adult and pediatric teams with involvement of multidisciplinary teams.
Many centers are already working on models for collaborative care, Dr. Salsman said, citing the Fort Worth AYA Oncology Coalition led by medical director Karen Albritton, MD, as an example of a program that has been successful in “getting stakeholders on the same page, helping them have a shared vision, and working to maximize improvements in outcomes.”
Patients are also taking the lead in demanding better care and attention to their psychosocial needs, Dr. Hanna said. In the case of the community-powered advocacy organization Critical Mass, they succeeded in getting lawmakers to introduce a bill in the U.S. House of Representatives that would allow college students to defer loan payments while undergoing cancer treatment.