AVAHO

CHICAGO – A chemotherapy-free regimen has produced promising early response and survival outcomes in patients with a particularly poor-prognosis subtype of diffuse large B-cell lymphoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

The overall response rate was 86% after two cycles of combined rituximab, lenalidomide, and ibrutinib – or RLI – in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) of the non–germinal center (non-GCB) subtype, said Jason Westin, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center in Houston.

The response rate increased to 96% after subsequent cycles of RLI plus standard chemotherapy, said Dr.Westin, who added that the rates of progression-free and overall survival at 1 year were also 96% in the investigator initiated, single-arm, open-label, phase 2 study, called Smart Start.

That looks quite favorable, compared with what’s been achieved in previous studies in this poor-prognosis group of patients, Dr. Westin said during a podium presentation of Smart Start data, though he cautioned against direct comparison to historical studies and added that further follow-up is needed.

“Our survival outcomes appear excellent with about a year’s worth of follow-up,” he said during his presentation. “I’d say the novel/novel combinations, with and without chemotherapy, are feasible for large cell, and next step studies are warranted.”

Jasmine M. Zain, MD, of City of Hope Comprehensive Cancer Center, said these results so far raise the possibility of an effective chemotherapy-free treatment regimen for aggressive lymphomas.

“This regimen, particularly for non-GCB subtypes, is extremely promising,” Dr. Zain said during a podium discussion of the study. “I think we were all oohing and aahing over the results, and it could possibly even be practice changing.”

Moving to a nonchemotherapy regimen could raise new questions for treatment of non-GCB and possibly also GCB subtypes of DLBCL, such as when the treatments could be stopped, or whether a maintenance approach would be useful, she added.

The Smart Start study enrolled a total of 60 patients with non-GCB DLBCL. The patients received RLI for two 21-day cycles, followed by another six cycles of RLI plus chemotherapy, which was either EPOCH or CHOP, at the investigators’ discretion.

“With a median follow-up of 362 days, we’ve had three progression events,” Dr. Westin said in his discussion of the preliminary efficacy results.

Adverse events were similar to what would be expected for standard chemotherapy, according to Dr. Westin, except for rash, which was seen mainly in cycles one and two.

There were two deaths on study protocol, including one fatal fungal infection that investigators attributed to high dose corticosteroids and RLI. There were no subsequent fungal infections after a protocol amendment prohibiting corticosteroids during the RLI-only cycles, according to the investigators’ report.

The high response rates following the initial lead-in phase made investigators wonder what would happen without subsequent chemotherapy, Dr. Westin told attendees during his oral presentation. In one case, a 74-year-old man did complete the two lead-in cycles of RLI and declined further therapy.

“He’s now nearly 2 years out, without any additional therapy, and has not relapsed to date,” Dr. Westin said. “This is, again, with 6 weeks worth of RLI therapy.”

Final results and minimal residual disease data from the Smart Start study will be presented at a conference later in 2019, Dr. Westin said.

The study received research support and funding from the ASCO Conquer Cancer Foundation. The trial drug and support were provided by Celgene and Janssen. Dr. Westin reported disclosures related to Celgene, Genentech/Abbvie, Kite Pharma, Kite/Gilead, Novartis, ProNAi, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Janssen, and Karyopharm Therapeutics.

SOURCE: Westin J et al. ASCO 2019, Abstract 7508.

CHICAGO – A chemotherapy-free regimen has produced promising early response and survival outcomes in patients with a particularly poor-prognosis subtype of diffuse large B-cell lymphoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

The overall response rate was 86% after two cycles of combined rituximab, lenalidomide, and ibrutinib – or RLI – in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) of the non–germinal center (non-GCB) subtype, said Jason Westin, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center in Houston.

The response rate increased to 96% after subsequent cycles of RLI plus standard chemotherapy, said Dr.Westin, who added that the rates of progression-free and overall survival at 1 year were also 96% in the investigator initiated, single-arm, open-label, phase 2 study, called Smart Start.

That looks quite favorable, compared with what’s been achieved in previous studies in this poor-prognosis group of patients, Dr. Westin said during a podium presentation of Smart Start data, though he cautioned against direct comparison to historical studies and added that further follow-up is needed.

“Our survival outcomes appear excellent with about a year’s worth of follow-up,” he said during his presentation. “I’d say the novel/novel combinations, with and without chemotherapy, are feasible for large cell, and next step studies are warranted.”

Jasmine M. Zain, MD, of City of Hope Comprehensive Cancer Center, said these results so far raise the possibility of an effective chemotherapy-free treatment regimen for aggressive lymphomas.

“This regimen, particularly for non-GCB subtypes, is extremely promising,” Dr. Zain said during a podium discussion of the study. “I think we were all oohing and aahing over the results, and it could possibly even be practice changing.”

Moving to a nonchemotherapy regimen could raise new questions for treatment of non-GCB and possibly also GCB subtypes of DLBCL, such as when the treatments could be stopped, or whether a maintenance approach would be useful, she added.

The Smart Start study enrolled a total of 60 patients with non-GCB DLBCL. The patients received RLI for two 21-day cycles, followed by another six cycles of RLI plus chemotherapy, which was either EPOCH or CHOP, at the investigators’ discretion.

“With a median follow-up of 362 days, we’ve had three progression events,” Dr. Westin said in his discussion of the preliminary efficacy results.

Adverse events were similar to what would be expected for standard chemotherapy, according to Dr. Westin, except for rash, which was seen mainly in cycles one and two.

There were two deaths on study protocol, including one fatal fungal infection that investigators attributed to high dose corticosteroids and RLI. There were no subsequent fungal infections after a protocol amendment prohibiting corticosteroids during the RLI-only cycles, according to the investigators’ report.

The high response rates following the initial lead-in phase made investigators wonder what would happen without subsequent chemotherapy, Dr. Westin told attendees during his oral presentation. In one case, a 74-year-old man did complete the two lead-in cycles of RLI and declined further therapy.

“He’s now nearly 2 years out, without any additional therapy, and has not relapsed to date,” Dr. Westin said. “This is, again, with 6 weeks worth of RLI therapy.”

Final results and minimal residual disease data from the Smart Start study will be presented at a conference later in 2019, Dr. Westin said.

The study received research support and funding from the ASCO Conquer Cancer Foundation. The trial drug and support were provided by Celgene and Janssen. Dr. Westin reported disclosures related to Celgene, Genentech/Abbvie, Kite Pharma, Kite/Gilead, Novartis, ProNAi, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Janssen, and Karyopharm Therapeutics.

SOURCE: Westin J et al. ASCO 2019, Abstract 7508.

CHICAGO – A chemotherapy-free regimen has produced promising early response and survival outcomes in patients with a particularly poor-prognosis subtype of diffuse large B-cell lymphoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.

The overall response rate was 86% after two cycles of combined rituximab, lenalidomide, and ibrutinib – or RLI – in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) of the non–germinal center (non-GCB) subtype, said Jason Westin, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center in Houston.

The response rate increased to 96% after subsequent cycles of RLI plus standard chemotherapy, said Dr.Westin, who added that the rates of progression-free and overall survival at 1 year were also 96% in the investigator initiated, single-arm, open-label, phase 2 study, called Smart Start.

That looks quite favorable, compared with what’s been achieved in previous studies in this poor-prognosis group of patients, Dr. Westin said during a podium presentation of Smart Start data, though he cautioned against direct comparison to historical studies and added that further follow-up is needed.

“Our survival outcomes appear excellent with about a year’s worth of follow-up,” he said during his presentation. “I’d say the novel/novel combinations, with and without chemotherapy, are feasible for large cell, and next step studies are warranted.”

Jasmine M. Zain, MD, of City of Hope Comprehensive Cancer Center, said these results so far raise the possibility of an effective chemotherapy-free treatment regimen for aggressive lymphomas.

“This regimen, particularly for non-GCB subtypes, is extremely promising,” Dr. Zain said during a podium discussion of the study. “I think we were all oohing and aahing over the results, and it could possibly even be practice changing.”

Moving to a nonchemotherapy regimen could raise new questions for treatment of non-GCB and possibly also GCB subtypes of DLBCL, such as when the treatments could be stopped, or whether a maintenance approach would be useful, she added.

The Smart Start study enrolled a total of 60 patients with non-GCB DLBCL. The patients received RLI for two 21-day cycles, followed by another six cycles of RLI plus chemotherapy, which was either EPOCH or CHOP, at the investigators’ discretion.

“With a median follow-up of 362 days, we’ve had three progression events,” Dr. Westin said in his discussion of the preliminary efficacy results.

Adverse events were similar to what would be expected for standard chemotherapy, according to Dr. Westin, except for rash, which was seen mainly in cycles one and two.

There were two deaths on study protocol, including one fatal fungal infection that investigators attributed to high dose corticosteroids and RLI. There were no subsequent fungal infections after a protocol amendment prohibiting corticosteroids during the RLI-only cycles, according to the investigators’ report.

The high response rates following the initial lead-in phase made investigators wonder what would happen without subsequent chemotherapy, Dr. Westin told attendees during his oral presentation. In one case, a 74-year-old man did complete the two lead-in cycles of RLI and declined further therapy.

“He’s now nearly 2 years out, without any additional therapy, and has not relapsed to date,” Dr. Westin said. “This is, again, with 6 weeks worth of RLI therapy.”

Final results and minimal residual disease data from the Smart Start study will be presented at a conference later in 2019, Dr. Westin said.

The study received research support and funding from the ASCO Conquer Cancer Foundation. The trial drug and support were provided by Celgene and Janssen. Dr. Westin reported disclosures related to Celgene, Genentech/Abbvie, Kite Pharma, Kite/Gilead, Novartis, ProNAi, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Janssen, and Karyopharm Therapeutics.

SOURCE: Westin J et al. ASCO 2019, Abstract 7508.

Cancer survivors have significantly higher out-of-pocket medical costs than those with no history of cancer, and a quarter of those survivors have some type of material hardship related to their diagnosis, according to the Centers for Disease Control and Prevention.

Along with those material financial hardships – the need to borrow money, go into debt, or declare bankruptcy – more than 34% of cancer survivors aged 18-64 years experienced psychological financial hardship, defined as worry about large medical bills, in 2011 and 2016, Donatus U. Ekwueme, PhD, and his associates reported in the Morbidity and Mortality Weekly Report.

Cancer survivors spend 60% more out of pocket than those with no cancer history: $1,000 a year from 2011 to 2016, compared with $622 for adults without a history of cancer. Spending was lowest among younger people (18-39 years) and increased with age, but the prevalence of both material and psychological hardships was highest in the middle age group (40-49 years) and lowest in the oldest group (50-64 years), they said.

Women had higher out-of-pocket costs than men, although the difference was smaller for those with cancer ($1,023 vs. $976) than for those without ($721 vs. $519). Material and psychological hardships were both more common among women, said Dr. Ekwueme of the CDC’s National Center for Chronic Disease Prevention and Health Promotion, Atlanta, and his associates.

Mean out-of-pocket spending was much higher for cancer survivors with private health insurance ($1,114) than for survivors with public insurance ($471), but material hardship was much more prevalent among those with public insurance (33.1% vs. 21.9%). Rates of psychological hardship, however, were much closer: 35.9% for those with public insurance and 32.5% for those with private insurance, the investigators said.

“The number of Americans with a history of cancer is projected to increase in the next decade, and the economic burden associated with living with a cancer diagnosis will likely increase as well,” they wrote, and interventions such as “systematic screening for financial hardship at cancer diagnosis and throughout the cancer care trajectory [are needed] to minimize financial hardship for cancer survivors.”

The analysis was based on data for 123,771 adults aged 18-64 years from the Medical Expenditure Panel Survey. Out-of-pocket costs were calculated using data from 2011 to 2016, with all costs adjusted to 2016 dollars, but the hardship calculations involved data from only 2011 and 2016.

rfranki@mdedge.com

SOURCE: Ekwueme DU et al. MMWR 2019 Jun 7;68(22):494-9.

Cancer survivors have significantly higher out-of-pocket medical costs than those with no history of cancer, and a quarter of those survivors have some type of material hardship related to their diagnosis, according to the Centers for Disease Control and Prevention.

Along with those material financial hardships – the need to borrow money, go into debt, or declare bankruptcy – more than 34% of cancer survivors aged 18-64 years experienced psychological financial hardship, defined as worry about large medical bills, in 2011 and 2016, Donatus U. Ekwueme, PhD, and his associates reported in the Morbidity and Mortality Weekly Report.

Cancer survivors spend 60% more out of pocket than those with no cancer history: $1,000 a year from 2011 to 2016, compared with $622 for adults without a history of cancer. Spending was lowest among younger people (18-39 years) and increased with age, but the prevalence of both material and psychological hardships was highest in the middle age group (40-49 years) and lowest in the oldest group (50-64 years), they said.

Women had higher out-of-pocket costs than men, although the difference was smaller for those with cancer ($1,023 vs. $976) than for those without ($721 vs. $519). Material and psychological hardships were both more common among women, said Dr. Ekwueme of the CDC’s National Center for Chronic Disease Prevention and Health Promotion, Atlanta, and his associates.

Mean out-of-pocket spending was much higher for cancer survivors with private health insurance ($1,114) than for survivors with public insurance ($471), but material hardship was much more prevalent among those with public insurance (33.1% vs. 21.9%). Rates of psychological hardship, however, were much closer: 35.9% for those with public insurance and 32.5% for those with private insurance, the investigators said.

“The number of Americans with a history of cancer is projected to increase in the next decade, and the economic burden associated with living with a cancer diagnosis will likely increase as well,” they wrote, and interventions such as “systematic screening for financial hardship at cancer diagnosis and throughout the cancer care trajectory [are needed] to minimize financial hardship for cancer survivors.”

The analysis was based on data for 123,771 adults aged 18-64 years from the Medical Expenditure Panel Survey. Out-of-pocket costs were calculated using data from 2011 to 2016, with all costs adjusted to 2016 dollars, but the hardship calculations involved data from only 2011 and 2016.

rfranki@mdedge.com

SOURCE: Ekwueme DU et al. MMWR 2019 Jun 7;68(22):494-9.

Cancer survivors have significantly higher out-of-pocket medical costs than those with no history of cancer, and a quarter of those survivors have some type of material hardship related to their diagnosis, according to the Centers for Disease Control and Prevention.

Along with those material financial hardships – the need to borrow money, go into debt, or declare bankruptcy – more than 34% of cancer survivors aged 18-64 years experienced psychological financial hardship, defined as worry about large medical bills, in 2011 and 2016, Donatus U. Ekwueme, PhD, and his associates reported in the Morbidity and Mortality Weekly Report.

Cancer survivors spend 60% more out of pocket than those with no cancer history: $1,000 a year from 2011 to 2016, compared with $622 for adults without a history of cancer. Spending was lowest among younger people (18-39 years) and increased with age, but the prevalence of both material and psychological hardships was highest in the middle age group (40-49 years) and lowest in the oldest group (50-64 years), they said.

Women had higher out-of-pocket costs than men, although the difference was smaller for those with cancer ($1,023 vs. $976) than for those without ($721 vs. $519). Material and psychological hardships were both more common among women, said Dr. Ekwueme of the CDC’s National Center for Chronic Disease Prevention and Health Promotion, Atlanta, and his associates.

Mean out-of-pocket spending was much higher for cancer survivors with private health insurance ($1,114) than for survivors with public insurance ($471), but material hardship was much more prevalent among those with public insurance (33.1% vs. 21.9%). Rates of psychological hardship, however, were much closer: 35.9% for those with public insurance and 32.5% for those with private insurance, the investigators said.

“The number of Americans with a history of cancer is projected to increase in the next decade, and the economic burden associated with living with a cancer diagnosis will likely increase as well,” they wrote, and interventions such as “systematic screening for financial hardship at cancer diagnosis and throughout the cancer care trajectory [are needed] to minimize financial hardship for cancer survivors.”

The analysis was based on data for 123,771 adults aged 18-64 years from the Medical Expenditure Panel Survey. Out-of-pocket costs were calculated using data from 2011 to 2016, with all costs adjusted to 2016 dollars, but the hardship calculations involved data from only 2011 and 2016.

rfranki@mdedge.com

SOURCE: Ekwueme DU et al. MMWR 2019 Jun 7;68(22):494-9.

CHICAGO – A fixed-duration venetoclax-obinutuzumab regimen is safe and provides a superior outcome versus standard chlorambucil-obinutuzumab in elderly patients with untreated chronic lymphocytic leukemia (CLL) and comorbidities, results of a randomized phase 3 trial showed.

At 24 months, progression-free survival was 88.2% for the venetoclax-obinutuzumab regimen, versus 64.1% for chlorambucil-obinutuzumab (hazard ratio, 0.35; 95% confidence interval, 0.23-0.53; P less than .0001) in CLL-14, an open-label, multinational trial presented at the annual meeting of the American Society of Clinical Oncology.

The regimen, given for just 12 28-day cycles, also achieved the highest rate of minimal residual disease (MRD)-negative responses ever seen in a randomized prospective CLL study, according to investigator Kirsten Fischer, MD, of the University of Cologne in Germany.

“We really think that these unprecedented MRD negativity levels will eventually translate into an improved overall survival,” Dr. Fischer said during an oral abstract presentation.

Matthew Steven Davids, MD, of Dana-Farber Cancer Institute/Harvard Medical School, Boston, said venetoclax plus obinutuzumab offers the potential for 1-year, time-limited therapy, which limits concerns over long-term adherence and has the potential for cost savings, should the therapy prove to be highly durable with further follow-up.

“A limitation of the study is that the comparator arm – chlorambucil plus obinutuzumab – is directly applicable to only a relatively small subset of our older and frailer CLL patients,” Dr. Davids said during a podium discussion of the results.

“But nonetheless, venetoclax plus obinutuzumab is a promising, time-limited regimen, and CLL14 is an immediately practice-changing study for frontline CLL treatment,” he added.

The regimen stands in contrast to ibrutinib, which offers durable responses but requires continuous dosing, and FCR (fludarabine, cyclophosphamide, and rituximab), a time-limited therapy with curative potential that is restricted to younger patients with IGHV-mutated CLL, according to Dr. Davids.

In CLL-14, 432 patients were randomized 1:1 to receive venetoclax-obinutuzumab for six cycles followed by venetoclax for six cycles, or chlorambucil-obinutuzumab for six cycles followed by chlorambucil for six cycles. The median age was 72 years in the venetoclax-obinutuzumab arm and 71 years in the chlorambucil-obinutuzumab arm.

The overall response rate was 85% for venetoclax-obinutuzumab and 71% for chlorambucil-obinutuzumab (P = .0007), Dr. Fischer reported at the meeting.

The improvement in progression-free survival seen in the overall study population was also seen in patients with TP53 deletions or mutations, and in those with unmutated IGHV, Dr. Fischer reported.

Rates of MRD negativity in peripheral blood were 76% versus 35% for the venetoclax- and chlorambucil-containing combinations, respectively (P less than .001), and similarly, MRD negativity in bone marrow was 57% versus 17% (P less than .001), she said.

There were no significant differences in the rates of grade 3 or 4 neutropenia, which occurred in 52.8% of the venetoclax–obinutuzumab treated patients and 48.1% of the chlorambucil-obinutuzumab treated patients, or in grade 3 or 4 infections, which occurred in 17.5% and 15.0%, respectively, according to a report, published simultaneously in the New England Journal of Medicine (2019;380:2225-36).

Likewise, all-cause mortality was not significantly different between the arms, at 9.3% and 7.9%, respectively.

F. Hoffmann-La Roche and AbbVie supported the study. Dr. Fischer reported travel, accommodations, or expenses from Roche in her abstract disclosure.

SOURCE: Fischer K et al. ASCO 2019, Abstract 7502.

CHICAGO – A fixed-duration venetoclax-obinutuzumab regimen is safe and provides a superior outcome versus standard chlorambucil-obinutuzumab in elderly patients with untreated chronic lymphocytic leukemia (CLL) and comorbidities, results of a randomized phase 3 trial showed.

At 24 months, progression-free survival was 88.2% for the venetoclax-obinutuzumab regimen, versus 64.1% for chlorambucil-obinutuzumab (hazard ratio, 0.35; 95% confidence interval, 0.23-0.53; P less than .0001) in CLL-14, an open-label, multinational trial presented at the annual meeting of the American Society of Clinical Oncology.

The regimen, given for just 12 28-day cycles, also achieved the highest rate of minimal residual disease (MRD)-negative responses ever seen in a randomized prospective CLL study, according to investigator Kirsten Fischer, MD, of the University of Cologne in Germany.

“We really think that these unprecedented MRD negativity levels will eventually translate into an improved overall survival,” Dr. Fischer said during an oral abstract presentation.

Matthew Steven Davids, MD, of Dana-Farber Cancer Institute/Harvard Medical School, Boston, said venetoclax plus obinutuzumab offers the potential for 1-year, time-limited therapy, which limits concerns over long-term adherence and has the potential for cost savings, should the therapy prove to be highly durable with further follow-up.

“A limitation of the study is that the comparator arm – chlorambucil plus obinutuzumab – is directly applicable to only a relatively small subset of our older and frailer CLL patients,” Dr. Davids said during a podium discussion of the results.

“But nonetheless, venetoclax plus obinutuzumab is a promising, time-limited regimen, and CLL14 is an immediately practice-changing study for frontline CLL treatment,” he added.

The regimen stands in contrast to ibrutinib, which offers durable responses but requires continuous dosing, and FCR (fludarabine, cyclophosphamide, and rituximab), a time-limited therapy with curative potential that is restricted to younger patients with IGHV-mutated CLL, according to Dr. Davids.

In CLL-14, 432 patients were randomized 1:1 to receive venetoclax-obinutuzumab for six cycles followed by venetoclax for six cycles, or chlorambucil-obinutuzumab for six cycles followed by chlorambucil for six cycles. The median age was 72 years in the venetoclax-obinutuzumab arm and 71 years in the chlorambucil-obinutuzumab arm.

The overall response rate was 85% for venetoclax-obinutuzumab and 71% for chlorambucil-obinutuzumab (P = .0007), Dr. Fischer reported at the meeting.

The improvement in progression-free survival seen in the overall study population was also seen in patients with TP53 deletions or mutations, and in those with unmutated IGHV, Dr. Fischer reported.

Rates of MRD negativity in peripheral blood were 76% versus 35% for the venetoclax- and chlorambucil-containing combinations, respectively (P less than .001), and similarly, MRD negativity in bone marrow was 57% versus 17% (P less than .001), she said.

There were no significant differences in the rates of grade 3 or 4 neutropenia, which occurred in 52.8% of the venetoclax–obinutuzumab treated patients and 48.1% of the chlorambucil-obinutuzumab treated patients, or in grade 3 or 4 infections, which occurred in 17.5% and 15.0%, respectively, according to a report, published simultaneously in the New England Journal of Medicine (2019;380:2225-36).

Likewise, all-cause mortality was not significantly different between the arms, at 9.3% and 7.9%, respectively.

F. Hoffmann-La Roche and AbbVie supported the study. Dr. Fischer reported travel, accommodations, or expenses from Roche in her abstract disclosure.

SOURCE: Fischer K et al. ASCO 2019, Abstract 7502.

CHICAGO – A fixed-duration venetoclax-obinutuzumab regimen is safe and provides a superior outcome versus standard chlorambucil-obinutuzumab in elderly patients with untreated chronic lymphocytic leukemia (CLL) and comorbidities, results of a randomized phase 3 trial showed.

At 24 months, progression-free survival was 88.2% for the venetoclax-obinutuzumab regimen, versus 64.1% for chlorambucil-obinutuzumab (hazard ratio, 0.35; 95% confidence interval, 0.23-0.53; P less than .0001) in CLL-14, an open-label, multinational trial presented at the annual meeting of the American Society of Clinical Oncology.

The regimen, given for just 12 28-day cycles, also achieved the highest rate of minimal residual disease (MRD)-negative responses ever seen in a randomized prospective CLL study, according to investigator Kirsten Fischer, MD, of the University of Cologne in Germany.

“We really think that these unprecedented MRD negativity levels will eventually translate into an improved overall survival,” Dr. Fischer said during an oral abstract presentation.

Matthew Steven Davids, MD, of Dana-Farber Cancer Institute/Harvard Medical School, Boston, said venetoclax plus obinutuzumab offers the potential for 1-year, time-limited therapy, which limits concerns over long-term adherence and has the potential for cost savings, should the therapy prove to be highly durable with further follow-up.

“A limitation of the study is that the comparator arm – chlorambucil plus obinutuzumab – is directly applicable to only a relatively small subset of our older and frailer CLL patients,” Dr. Davids said during a podium discussion of the results.

“But nonetheless, venetoclax plus obinutuzumab is a promising, time-limited regimen, and CLL14 is an immediately practice-changing study for frontline CLL treatment,” he added.

The regimen stands in contrast to ibrutinib, which offers durable responses but requires continuous dosing, and FCR (fludarabine, cyclophosphamide, and rituximab), a time-limited therapy with curative potential that is restricted to younger patients with IGHV-mutated CLL, according to Dr. Davids.

In CLL-14, 432 patients were randomized 1:1 to receive venetoclax-obinutuzumab for six cycles followed by venetoclax for six cycles, or chlorambucil-obinutuzumab for six cycles followed by chlorambucil for six cycles. The median age was 72 years in the venetoclax-obinutuzumab arm and 71 years in the chlorambucil-obinutuzumab arm.

The overall response rate was 85% for venetoclax-obinutuzumab and 71% for chlorambucil-obinutuzumab (P = .0007), Dr. Fischer reported at the meeting.

The improvement in progression-free survival seen in the overall study population was also seen in patients with TP53 deletions or mutations, and in those with unmutated IGHV, Dr. Fischer reported.

Rates of MRD negativity in peripheral blood were 76% versus 35% for the venetoclax- and chlorambucil-containing combinations, respectively (P less than .001), and similarly, MRD negativity in bone marrow was 57% versus 17% (P less than .001), she said.

There were no significant differences in the rates of grade 3 or 4 neutropenia, which occurred in 52.8% of the venetoclax–obinutuzumab treated patients and 48.1% of the chlorambucil-obinutuzumab treated patients, or in grade 3 or 4 infections, which occurred in 17.5% and 15.0%, respectively, according to a report, published simultaneously in the New England Journal of Medicine (2019;380:2225-36).

Likewise, all-cause mortality was not significantly different between the arms, at 9.3% and 7.9%, respectively.

F. Hoffmann-La Roche and AbbVie supported the study. Dr. Fischer reported travel, accommodations, or expenses from Roche in her abstract disclosure.

SOURCE: Fischer K et al. ASCO 2019, Abstract 7502.

In 2013, the CDC published guidelines to help state, tribal, local, and territorial public health agencies apply a systematic approach when responding to inquiries about suspected cancer clusters.

But since then, the CDC says, there have been technical and scientific advances that may be useful—so it is time to update Investigating Suspected Cancer Clusters and Responding to Community Concerns: Guidelines from CDC and the Council of State and Territorial Epidemiologists.

The CDC is working with the Agency for Toxic Substances and Disease Registry (ATSDR) to update the 2013 guidelines to ensure that users have access to current scientific tools and approaches. The new version will include input from subject matter experts, public health agencies, the public, and other stakeholders.

“We don’t yet know how the guidelines will change,” the CDC says. Once they are written, though, the public will have the opportunity to comment. In the meantime, the public and interested organizations are invited to participate by submitting written views, information, recommendations, and data. The CDC and ATSDR are looking for answers to questions such as, “What are the best approaches to respond to community concerns about potential cancer clusters?” and “What gaps and challenges exist in the 2013 guidelines? What are possible solutions to overcoming them?” Comments will be posted on https://www.regulations.gov.

The request for comment was posted May 15 in the Federal Register and will be available for public comment through July 15, 2019. For more information and to provide comment, visit https://www.federalregister.gov/documents/2019/05/15/2019-09998/updating-federal-guidelines-used-by-public-health-agencies-to-assess-and-respond-to-potential-cancer.

In 2013, the CDC published guidelines to help state, tribal, local, and territorial public health agencies apply a systematic approach when responding to inquiries about suspected cancer clusters.

But since then, the CDC says, there have been technical and scientific advances that may be useful—so it is time to update Investigating Suspected Cancer Clusters and Responding to Community Concerns: Guidelines from CDC and the Council of State and Territorial Epidemiologists.

The CDC is working with the Agency for Toxic Substances and Disease Registry (ATSDR) to update the 2013 guidelines to ensure that users have access to current scientific tools and approaches. The new version will include input from subject matter experts, public health agencies, the public, and other stakeholders.

“We don’t yet know how the guidelines will change,” the CDC says. Once they are written, though, the public will have the opportunity to comment. In the meantime, the public and interested organizations are invited to participate by submitting written views, information, recommendations, and data. The CDC and ATSDR are looking for answers to questions such as, “What are the best approaches to respond to community concerns about potential cancer clusters?” and “What gaps and challenges exist in the 2013 guidelines? What are possible solutions to overcoming them?” Comments will be posted on https://www.regulations.gov.

The request for comment was posted May 15 in the Federal Register and will be available for public comment through July 15, 2019. For more information and to provide comment, visit https://www.federalregister.gov/documents/2019/05/15/2019-09998/updating-federal-guidelines-used-by-public-health-agencies-to-assess-and-respond-to-potential-cancer.

In 2013, the CDC published guidelines to help state, tribal, local, and territorial public health agencies apply a systematic approach when responding to inquiries about suspected cancer clusters.

But since then, the CDC says, there have been technical and scientific advances that may be useful—so it is time to update Investigating Suspected Cancer Clusters and Responding to Community Concerns: Guidelines from CDC and the Council of State and Territorial Epidemiologists.

The CDC is working with the Agency for Toxic Substances and Disease Registry (ATSDR) to update the 2013 guidelines to ensure that users have access to current scientific tools and approaches. The new version will include input from subject matter experts, public health agencies, the public, and other stakeholders.

“We don’t yet know how the guidelines will change,” the CDC says. Once they are written, though, the public will have the opportunity to comment. In the meantime, the public and interested organizations are invited to participate by submitting written views, information, recommendations, and data. The CDC and ATSDR are looking for answers to questions such as, “What are the best approaches to respond to community concerns about potential cancer clusters?” and “What gaps and challenges exist in the 2013 guidelines? What are possible solutions to overcoming them?” Comments will be posted on https://www.regulations.gov.

The request for comment was posted May 15 in the Federal Register and will be available for public comment through July 15, 2019. For more information and to provide comment, visit https://www.federalregister.gov/documents/2019/05/15/2019-09998/updating-federal-guidelines-used-by-public-health-agencies-to-assess-and-respond-to-potential-cancer.

CHICAGO – For colorectal cancer patients with liver metastases, laparoscopic surgery has short-term advantages over open surgery, including fewer complications and better quality of life as compared to open surgery. Now, there are data to show that long-term outcomes with the laparoscopic approach aren’t any worse with the laparoscopic approach.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Åsmund Avdem Fretland, MD, discusses results of the 280-patient randomized OSLO-COMET study, including 5-year survival of 56% for the laparoscopic approach, and similarly, 57% for the open procedure.

Based on lower morbidity, and now similar life expectancy, more centers should be doing laparoscopic procedures for liver metastases, said Dr. Fretland, a surgeon in the department of HPB surgery at Oslo University Hospital.

For now, however, open surgery appears to be the dominant approach. According to a recent survey, just 22% of U.S. patients with colorectal liver metastases have laparoscopic surgery.

More data could help. Dr. Fretland said in the interview that more randomized trials are underway aimed at evaluating the long-term outcomes of laparoscopic versus open procedures.

Dr. Fretland reported honoraria from Olympus Medical Systems.

CHICAGO – For colorectal cancer patients with liver metastases, laparoscopic surgery has short-term advantages over open surgery, including fewer complications and better quality of life as compared to open surgery. Now, there are data to show that long-term outcomes with the laparoscopic approach aren’t any worse with the laparoscopic approach.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Åsmund Avdem Fretland, MD, discusses results of the 280-patient randomized OSLO-COMET study, including 5-year survival of 56% for the laparoscopic approach, and similarly, 57% for the open procedure.

Based on lower morbidity, and now similar life expectancy, more centers should be doing laparoscopic procedures for liver metastases, said Dr. Fretland, a surgeon in the department of HPB surgery at Oslo University Hospital.

For now, however, open surgery appears to be the dominant approach. According to a recent survey, just 22% of U.S. patients with colorectal liver metastases have laparoscopic surgery.

More data could help. Dr. Fretland said in the interview that more randomized trials are underway aimed at evaluating the long-term outcomes of laparoscopic versus open procedures.

Dr. Fretland reported honoraria from Olympus Medical Systems.

CHICAGO – For colorectal cancer patients with liver metastases, laparoscopic surgery has short-term advantages over open surgery, including fewer complications and better quality of life as compared to open surgery. Now, there are data to show that long-term outcomes with the laparoscopic approach aren’t any worse with the laparoscopic approach.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Åsmund Avdem Fretland, MD, discusses results of the 280-patient randomized OSLO-COMET study, including 5-year survival of 56% for the laparoscopic approach, and similarly, 57% for the open procedure.

Based on lower morbidity, and now similar life expectancy, more centers should be doing laparoscopic procedures for liver metastases, said Dr. Fretland, a surgeon in the department of HPB surgery at Oslo University Hospital.

For now, however, open surgery appears to be the dominant approach. According to a recent survey, just 22% of U.S. patients with colorectal liver metastases have laparoscopic surgery.

More data could help. Dr. Fretland said in the interview that more randomized trials are underway aimed at evaluating the long-term outcomes of laparoscopic versus open procedures.

Dr. Fretland reported honoraria from Olympus Medical Systems.

Colorectal cancer (CRC) ranks among the most common causes of cancer and cancer-related death in the US. The US Multi-Society Task Force (USMSTF) on Colorectal Cancer thus strongly endorsed using several available screening options.¹ The published guidelines largely rely on age to define the target population (Table 1). For average-risk individuals, national and Veterans Health Administration (VHA) guidelines currently recommend CRC screening in individuals aged between 50 and 75 years with a life expectancy of > 5 years.¹

Although case-control studies also point to a potential benefit in persons aged > 75 years,^2,3 the USMSTF cited less convincing evidence and suggested an individualized approach that should consider relative cancer risk and comorbidity burden. Such an approach is supported by modeling studies, which suggest reduced benefit and increased risk of screening with increasing age. The reduced benefit also is significantly affected by comorbidity and relative cancer risk.⁴ The VHA has successfully implemented CRC screening, capturing the majority of eligible patients based on age criteria. A recent survey showed that more than three-quarters of veterans between age 50 and 75 years had undergone some screening test for CRC as part of routine preventive care. Colonoscopy clearly emerged as the dominant modality chosen for CRC screening and accounted for nearly 84% of these screening tests.⁵ Consistent with these data, a case-control study confirmed that the widespread implementation of colonoscopy as CRC screening method reduced cancer-related mortality in veterans for cases of left but not right-sided colon cancer.⁶

With calls to expand the age range of CRC screening beyond aged 75 years, we decided to assess survival rates of a cohort of veterans who underwent a screening or surveillance colonoscopy between 2008 and 2014.⁷ The goals were to characterize the portion of the cohort that had died, the time between a screening colonoscopy and death, the portion of deaths that were aged ≥ 80 years, and the causes of the deaths. In addition, we focused on a subgroup of the cohort, defined by death within 2 years after the index colonoscopy, to identify predictors of early death that were independent of age.

Methods

We queried the endoscopy reporting system (EndoWorks; Olympus America, Center Valley, PA) for all colonoscopies performed by 2 of 14 physicians at the George Wahlen VA Medical Center (GWVAMC) in Salt Lake City, Utah, who performed endoscopic procedures between January 1, 2008 and December 1, 2014. These physicians had focused their clinical practice exclusively on elective outpatient colonoscopies and accounted for 37.4% of the examinations at GWVAMC during the study period. All colonoscopy requests were triaged and assigned based on availability of open and appropriate procedure time slots without direct physician-specific referral, thus reducing the chance of skewing results. The reports were filtered through a text search to focus on examinations that listed screening or surveillance as indication. The central patient electronic health record was then reviewed to extract basic demographic data, survival status (as of August 1, 2018), and survival time in years after the index or subsequent colonoscopy. For deceased veterans, the age at the time of death, cause of death, and comorbidities were queried.

This study compared cases and control across the study. Cases were persons who clearly died early (defined as > 2 years following the index examination). They were matched with controls who lived for ≥ 5 years after their colonoscopy. These periods were selected because the USMSTF recommended that CRC screening or surveillance colonoscopy should be discontinued in persons with a life expectancy of < 5 years, and most study patients underwent their index procedure ≥ 5 years before August 2018. Cases and controls underwent a colonoscopy in the same year and were matched for age, sex, and presence of underlying inflammatory bowel disease (IBD). For cases and controls, we identified the ordering health care provider specialty, (ie, primary care, gastroenterology, or other).

In addition, we reviewed the encounter linked to the order and abstracted relevant comorbidities listed at that time, noted the use of anticoagulants, opioid analgesics, and benzodiazepines. The comorbidity burden was quantified using the Charlson Comorbidity Index.⁸ In addition, we denoted the presence of psychiatric problems (eg, anxiety, depression, bipolar disease, psychosis, substance abuse), the diagnosis of atrial fibrillation (AF) or other cardiac arrhythmias, and whether the patient had previously been treated for a malignancy that was in apparent clinical remission. Finally, we searched for routine laboratory tests at the time of this visit or, when not obtained, within 6 months of the encounter, and abstracted serum creatinine, hemoglobin (Hgb), platelet number, serum protein, and albumin. In clinical practice, cutoff values of test results are often more helpful in decision making. We, therefore, dichotomized results for Hgb (cutoff: 10 g/dL), creatinine (cutoff: 2 mg/dL), and albumin (cutoff: 3.2 mg/dL).

Descriptive and analytical statistics were obtained with Stata Version 14.1 (College Station, TX). Unless indicated otherwise, continuous data are shown as mean with 95% CIs. For dichotomous data, we used percentages with their 95% CIs. Analytic statistics were performed with the t test for continuous variables and the 2-tailed test for proportions. A P < .05 was considered a significant difference. To determine independent predictors of early death, we performed a logistic regression analysis with results being expressed as odds ratio with 95% CIs. Survival status was chosen as a dependent variable, and we entered variables that significantly correlated with survival in the bivariate analysis as independent variables.

The study was designed and conducted as a quality improvement project to assess colonoscopy performance and outcomes with the Salt Lake City Specialty Care Center of Innovation (COI), one of 5 regional COIs with an operational mission to improve health care access, utilization, and quality. Our work related to colonoscopy and access within the COI region, including Salt Lake City, has been reviewed and acknowledged by the GWVAMC Institutional Review Board as quality improvement. Andrew Gawron has an operational appointment in the GWVAMC COI, which is part of a US Department of Veterans Affairs (VA) central office initiative established in 2015. The COIs are charged with identifying best practices within the VA and applying those practices throughout the COI region. This local project to identify practice patterns and outcomes locally was sponsored by the GWVAMC COI with a focus to generate information to improve colonoscopy referral quality in patients at Salt Lake City and inform regional and national efforts in this domain.

Results

During the study period, 4,879 veterans (96.9% male) underwent at least 1 colonoscopy for screening or surveillance by 1 of the 2 providers. A total of 306 persons (6.3%) were aged > 80 years. The indication for surveillance colonoscopies included IBD in 78 (1.6%) veterans 2 of whom were women. The mean (SD) follow-up period between the index colonoscopy and study closure or death was 7.4 years (1.7). During the study time, 1,439 persons underwent a repeat examination for surveillance. The percentage of veterans with at least 1 additional colonoscopy after the index test was significantly higher in patients with known IBD compared with those without IBD (78.2% vs 28.7%; P < .01).

Between the index colonoscopy and August 2018, 974 patients (20.0%) died (Figure). The mean (SD) time between the colonoscopy and recorded year of death was 4.4 years (4.1). The fraction of women in the cohort that died (n = 18) was lower compared with 132 for the group of persons still alive (1.8% vs 3.4%; P < .05). The fraction of veterans with IBD who died by August 2018 did not differ from that of patients with IBD in the cohort of individuals who survived (19.2% vs 20.0%; P = .87). The cohort of veterans who died before study closure included 107 persons who were aged > 80 years at the time of their index colonoscopy, which is significantly more than in the cohort of persons still alive (11.0% vs 5.1%; P < .01).

Cause of Death

In 209 of the 974 (21.5%) veteran deaths a cause was recorded. Malignancies accounted for 88 of the deaths (42.1%), and CRCs were responsible for 14 (6.7%) deaths (Table 2). In 8 of these patients, the cancer had been identified at an advanced stage, not allowing for curative therapy. One patient had been asked to return for a repeat test as residual fecal matter did not allow proper visualization. He died 1 year later due to complications of sepsis after colonic perforation caused by a proximal colon cancer. Five patients underwent surgery with curative intent but suffered recurrences. In addition to malignancies, advanced diseases, such as cardiovascular, bronchopulmonary illnesses, and infections, were other commonly listed causes of death.

We also abstracted comorbidities that were known at the time of death or the most recent encounter within the VHA system. Hypertension was most commonly listed (549) followed by a current or prior diagnosis of malignancies (355) and diabetes mellitus (DM) (Table 3). Prostate cancer was the most commonly diagnosed malignancy (80), 17 of whom had a second malignancy. CRC accounted for 54 of the malignancies, 1 of which developed in a patient with long-standing ulcerative colitis, 2 were a manifestation of a known hereditary cancer syndrome (Lynch syndrome), and the remaining 51 cases were various cancers without known predisposition. The diagnosis of CRC was made during the study period in 29 veterans. In the remaining 25 patients, the colonoscopy was performed as a surveillance examination after previous surgery for CRC.

Potential Predictors of Early Death

To better define potential predictors of early death, we focused on the 258 persons (5.3%) who died within 2 years after the index procedure and paired them with matched controls. One patient underwent a colonoscopy for surveillance of previously treated cancer and was excluded due to very advanced age, as no matched control could be identified. The mean (SD) age of this male-predominant cohort was 68.2 (9.6) vs 67.9 (9.4) years for cases and controls, respectively. At the time of referral for the test, 29 persons (11.3%) were aged > 80 years, which is significantly more than seen for the overall cohort with 306 (6.3%; P < .001). While primary care providers accounted for most referrals in cases (85.2%) and controls (93.0%), the fraction of veterans referred by gastroenterologists or other specialty care providers was significantly higher in the case group compared with that in the controls (14.8% vs 7.0%; P < .05).

In our age-matched analysis, we examined other potential factors that could influence survival. The burden of comorbid conditions summarized in the Charlson Comorbidity Index significantly correlated with survival status (Table 4). As this composite index does not include psychiatric conditions, we separately examined the impact of anxiety, depression, bipolar disease, psychotic disorders, and substance abuse. The diagnoses of depression and substance use disorders (SUDs) were associated with higher rates of early death. Considering concerns about SUDs, we also assessed the association between prescription for opioids or benzodiazepines and survival status, which showed a marginal correlation. Anticoagulant use, a likely surrogate for cardiovascular disorders, were more commonly listed in the cases than they were in the controls.

Looking at specific comorbid conditions, significant problems affecting key organ systems from heart to lung, liver, kidneys, or brain (dementia) were all predictors of poor outcome. Similarly, DM with secondary complication correlated with early death after the index procedure. In contrast, a history of prior myocardial infarction, prior cancer treatment without evidence of persistent or recurrent disease, or prior peptic ulcer disease did not differ between cases and controls. Focusing on routine blood tests, we noted marginal, but statistically different results for Hgb, serum creatinine, and albumin in cases compared with controls.

Next we performed a logistic regression to identify independent predictors of survival status. The referring provider specialty, Charlson Comorbidity Index, the diagnosis of a SUD, current benzodiazepine use, and significant anemia or hypoalbuminemia independently predicted death within 2 years of the index examination (Table 5). Considering the composite nature of the Charlson Comorbidity Index, we separately examined the relative importance of different comorbid conditions using a logistic regression analysis. Consistent with the univariate analyses, a known malignancy; severe liver, lung, or kidney disease; and DM with secondary complications were associated with poor outcome. Only arrhythmias other than AF were independent marginal predictors of early death, whereas other variables related to cardiac performance did not reach the level of significance (Table 6). As was true for our analysis examining the composite comorbidity index, the diagnosis of a SUD remained significant as a predictor of death within 2 years of the index colonoscopy.

Discussion

This retrospective analysis followed patients for a mean time of 7 years after a colonoscopy for CRC screening or polyp surveillance. We noted a high rate of all-cause mortality, with 20% of the cohort dying within the period studied. Malignancies, cardiovascular diseases, and advanced lung diseases were most commonly listed causes of death. As expected, CRC was among the 3 most common malignancies and was the cause of death in 6.7% of the group with sufficiently detailed information. While these results fall within the expected range for the mortality related to CRC,⁹ the results do not allow us to assess the impact of screening, which has been shown to decrease cancer-related mortality in veterans.⁶ This was limited because the sample size was too small to assess the impact of screening and the cause of death was ascertained for a small percentage of the sample.

Although our findings are limited to a subset of patients seen in a single center, they suggest the importance of appropriate eligibility criteria for screening tests, as also defined in national guidelines.¹ As a key anchoring point that describes the target population, age contributed to the rate of relatively early death after the index procedure. Consistent with previously published data, we saw a significant impact of comorbid diseases.^10,11 However, our findings go beyond prior reports and show the important impact of psychiatric disease burden, most important the role of SUDs. The predictive value of a summary score, such as the Charlson Comorbidity Index, supports the idea of a cumulative impact, with an increasing disease burden decreasing life expectancy.^10-14 It is important to consider the ongoing impact of such coexisting illnesses. Our analysis shows, the mere history of prior problems did not independently predict survival status in our cohort.

Although age is the key anchoring point that defines the target population for CRC screening programs, the benefit of earlier cancer detection or, in the context of colonoscopy with polypectomy, cancer prevention comes with a delay. Thus, cancer risk, procedural risk, and life expectancy should all be weighed when discussing and deciding on the appropriateness of CRC screening. When we disregard inherited cancer syndromes, CRC is clearly a disease of the second half of life with the incidence increasing with age.¹⁵ However, other disease burdens rise, which may affects the risk of screening and treatment should cancer be found.

Using our understanding of disease development, researchers have introduced the concept of time to benefit or lag time to help decisions about screening strategies. The period defines the likely time for a precursor or early form of cancer potentially detected by screening to manifest as a clinically relevant lesion. This lag time becomes an especially important consideration in screening of older and/or chronically ill adults with life expectancies that may be close to or even less than the time to benefit.¹⁶ Modeling studies suggest that 1,000 flexible sigmoidoscopy screenings are needed to prevent 1 cancer that would manifest about 10 years after the index examination.^17,18 The mean life expectancy of a healthy person aged 75 years exceeds 10 years but drops with comorbidity burden. Consistent with these considerations, an analysis of Medicare claims data concluded that individuals with ≥ 3 significant comorbidities do not derive any benefit from screening colonoscopy.¹⁴ Looking at the impact of comorbidities, mathematical models concluded that colorectal cancer screening should not be continued in persons with moderate or severe comorbid conditions aged 66 years and 72 years, respectively.¹⁹ In contrast, modeling results suggest a benefit of continued screening up to and even above the age of 80 years if persons have an increased cancer risk and if there are no confounding comorbidities.⁴

Life expectancy and time to benefit describe probabilities. Although such probabilities are relevant in public policy decision, providers and patients may struggle with probabilistic thinking when faced with decisions that involve probabilities of individual health care vs population health care. Both are concerned about the seemingly gloomy or pessimistic undertone of discussing life expectancy and the inherent uncertainty of prognostic tools.^20,21 Prior research indicates that this reluctance translates into clinical practice. When faced with vignettes, most clinicians would offer CRC screening to healthy persons aged 80 years with rates falling when the description included a significant comorbid burden; however, more than 40% would still consider screening in octogenarians with poor health.²²

Consistent with these responses to theoretical scenarios, CRC screening of veterans dropped with age but was still continued in persons with significant comorbidity.²³ Large studies of the veteran population suggest that about 10% of veterans aged > 70 years have chronic medical problems that limit their life expectancy to < 5 years; nonetheless, more than 40% of this cohort underwent colonoscopies for CRC screening.^24,25 Interestingly, more illness burden and more clinical encounters translated into more screening examinations in older sick veterans compared with that of the cohort of healthier older persons, suggesting an impact of clinical reminders and the key role of age as the main anchoring variable.²³

Ongoing screening despite limited or even no benefit is not unique to CRC. Using validated tools, Pollock and colleagues showed comparable screening rates for breast and prostate cancer when they examined cohorts at either high or low risk of early mortality.²⁶ Similar results have been reported in veterans with about one-third of elderly males with poor life expectancy still undergoing prostate cancer screening.²⁷ Interestingly, inappropriate screening is more common in nonacademic centers and influenced by provider characteristics: nurse practitioner, physician assistants, older attending physicians and male physicians were more likely to order such tests.^27,28

Limitations

In this study, we examined a cohort of veterans enrolled in CRC screening within a single institution and obtained survival data for a mean follow-up of > 7 years. We also restricted our study to patients undergoing examinations that explicitly listed screening as indication or polyp surveillance for the test. However, inclusion was based on the indication listed in the report, which may differ from the intent of the ordering provider. Reporting systems often come with default settings, which may skew data. Comorbidities for the entire cohort of veterans who died within the time frame of the study were extracted from the chart without controlling for time-dependent changes, which may more appropriately describe the comorbidity burden at the time of the test. Using a case-control design, we addressed this potential caveat and included only illnesses recorded in the encounter linked to the colonoscopy order. Despite these limitations, our results highlight the importance to more effectively define and target appropriate candidates for CRC screening.

Conclusion

This study shows that age is a simple but not sufficiently accurate criterion to define potential candidates for CRC screening. As automated reminders often prompt discussions about and referral to screening examinations, we should develop algorithms that estimate the individual cancer risk and/or integrate an automatically calculated comorbidity index with these alerts or insert such a tool into order-sets. In addition, providers and patients need to be educated about the rationale and need for a more comprehensive approach to CRC screening that considers anticipated life expectancy. On an individual and health system level, our goal should be to reduce overall mortality rather than only cancer-specific death rates.

Colorectal cancer (CRC) ranks among the most common causes of cancer and cancer-related death in the US. The US Multi-Society Task Force (USMSTF) on Colorectal Cancer thus strongly endorsed using several available screening options.¹ The published guidelines largely rely on age to define the target population (Table 1). For average-risk individuals, national and Veterans Health Administration (VHA) guidelines currently recommend CRC screening in individuals aged between 50 and 75 years with a life expectancy of > 5 years.¹

Although case-control studies also point to a potential benefit in persons aged > 75 years,^2,3 the USMSTF cited less convincing evidence and suggested an individualized approach that should consider relative cancer risk and comorbidity burden. Such an approach is supported by modeling studies, which suggest reduced benefit and increased risk of screening with increasing age. The reduced benefit also is significantly affected by comorbidity and relative cancer risk.⁴ The VHA has successfully implemented CRC screening, capturing the majority of eligible patients based on age criteria. A recent survey showed that more than three-quarters of veterans between age 50 and 75 years had undergone some screening test for CRC as part of routine preventive care. Colonoscopy clearly emerged as the dominant modality chosen for CRC screening and accounted for nearly 84% of these screening tests.⁵ Consistent with these data, a case-control study confirmed that the widespread implementation of colonoscopy as CRC screening method reduced cancer-related mortality in veterans for cases of left but not right-sided colon cancer.⁶

With calls to expand the age range of CRC screening beyond aged 75 years, we decided to assess survival rates of a cohort of veterans who underwent a screening or surveillance colonoscopy between 2008 and 2014.⁷ The goals were to characterize the portion of the cohort that had died, the time between a screening colonoscopy and death, the portion of deaths that were aged ≥ 80 years, and the causes of the deaths. In addition, we focused on a subgroup of the cohort, defined by death within 2 years after the index colonoscopy, to identify predictors of early death that were independent of age.

Methods

We queried the endoscopy reporting system (EndoWorks; Olympus America, Center Valley, PA) for all colonoscopies performed by 2 of 14 physicians at the George Wahlen VA Medical Center (GWVAMC) in Salt Lake City, Utah, who performed endoscopic procedures between January 1, 2008 and December 1, 2014. These physicians had focused their clinical practice exclusively on elective outpatient colonoscopies and accounted for 37.4% of the examinations at GWVAMC during the study period. All colonoscopy requests were triaged and assigned based on availability of open and appropriate procedure time slots without direct physician-specific referral, thus reducing the chance of skewing results. The reports were filtered through a text search to focus on examinations that listed screening or surveillance as indication. The central patient electronic health record was then reviewed to extract basic demographic data, survival status (as of August 1, 2018), and survival time in years after the index or subsequent colonoscopy. For deceased veterans, the age at the time of death, cause of death, and comorbidities were queried.

This study compared cases and control across the study. Cases were persons who clearly died early (defined as > 2 years following the index examination). They were matched with controls who lived for ≥ 5 years after their colonoscopy. These periods were selected because the USMSTF recommended that CRC screening or surveillance colonoscopy should be discontinued in persons with a life expectancy of < 5 years, and most study patients underwent their index procedure ≥ 5 years before August 2018. Cases and controls underwent a colonoscopy in the same year and were matched for age, sex, and presence of underlying inflammatory bowel disease (IBD). For cases and controls, we identified the ordering health care provider specialty, (ie, primary care, gastroenterology, or other).

In addition, we reviewed the encounter linked to the order and abstracted relevant comorbidities listed at that time, noted the use of anticoagulants, opioid analgesics, and benzodiazepines. The comorbidity burden was quantified using the Charlson Comorbidity Index.⁸ In addition, we denoted the presence of psychiatric problems (eg, anxiety, depression, bipolar disease, psychosis, substance abuse), the diagnosis of atrial fibrillation (AF) or other cardiac arrhythmias, and whether the patient had previously been treated for a malignancy that was in apparent clinical remission. Finally, we searched for routine laboratory tests at the time of this visit or, when not obtained, within 6 months of the encounter, and abstracted serum creatinine, hemoglobin (Hgb), platelet number, serum protein, and albumin. In clinical practice, cutoff values of test results are often more helpful in decision making. We, therefore, dichotomized results for Hgb (cutoff: 10 g/dL), creatinine (cutoff: 2 mg/dL), and albumin (cutoff: 3.2 mg/dL).

Descriptive and analytical statistics were obtained with Stata Version 14.1 (College Station, TX). Unless indicated otherwise, continuous data are shown as mean with 95% CIs. For dichotomous data, we used percentages with their 95% CIs. Analytic statistics were performed with the t test for continuous variables and the 2-tailed test for proportions. A P < .05 was considered a significant difference. To determine independent predictors of early death, we performed a logistic regression analysis with results being expressed as odds ratio with 95% CIs. Survival status was chosen as a dependent variable, and we entered variables that significantly correlated with survival in the bivariate analysis as independent variables.

The study was designed and conducted as a quality improvement project to assess colonoscopy performance and outcomes with the Salt Lake City Specialty Care Center of Innovation (COI), one of 5 regional COIs with an operational mission to improve health care access, utilization, and quality. Our work related to colonoscopy and access within the COI region, including Salt Lake City, has been reviewed and acknowledged by the GWVAMC Institutional Review Board as quality improvement. Andrew Gawron has an operational appointment in the GWVAMC COI, which is part of a US Department of Veterans Affairs (VA) central office initiative established in 2015. The COIs are charged with identifying best practices within the VA and applying those practices throughout the COI region. This local project to identify practice patterns and outcomes locally was sponsored by the GWVAMC COI with a focus to generate information to improve colonoscopy referral quality in patients at Salt Lake City and inform regional and national efforts in this domain.

Results

During the study period, 4,879 veterans (96.9% male) underwent at least 1 colonoscopy for screening or surveillance by 1 of the 2 providers. A total of 306 persons (6.3%) were aged > 80 years. The indication for surveillance colonoscopies included IBD in 78 (1.6%) veterans 2 of whom were women. The mean (SD) follow-up period between the index colonoscopy and study closure or death was 7.4 years (1.7). During the study time, 1,439 persons underwent a repeat examination for surveillance. The percentage of veterans with at least 1 additional colonoscopy after the index test was significantly higher in patients with known IBD compared with those without IBD (78.2% vs 28.7%; P < .01).

Between the index colonoscopy and August 2018, 974 patients (20.0%) died (Figure). The mean (SD) time between the colonoscopy and recorded year of death was 4.4 years (4.1). The fraction of women in the cohort that died (n = 18) was lower compared with 132 for the group of persons still alive (1.8% vs 3.4%; P < .05). The fraction of veterans with IBD who died by August 2018 did not differ from that of patients with IBD in the cohort of individuals who survived (19.2% vs 20.0%; P = .87). The cohort of veterans who died before study closure included 107 persons who were aged > 80 years at the time of their index colonoscopy, which is significantly more than in the cohort of persons still alive (11.0% vs 5.1%; P < .01).

Cause of Death

In 209 of the 974 (21.5%) veteran deaths a cause was recorded. Malignancies accounted for 88 of the deaths (42.1%), and CRCs were responsible for 14 (6.7%) deaths (Table 2). In 8 of these patients, the cancer had been identified at an advanced stage, not allowing for curative therapy. One patient had been asked to return for a repeat test as residual fecal matter did not allow proper visualization. He died 1 year later due to complications of sepsis after colonic perforation caused by a proximal colon cancer. Five patients underwent surgery with curative intent but suffered recurrences. In addition to malignancies, advanced diseases, such as cardiovascular, bronchopulmonary illnesses, and infections, were other commonly listed causes of death.

We also abstracted comorbidities that were known at the time of death or the most recent encounter within the VHA system. Hypertension was most commonly listed (549) followed by a current or prior diagnosis of malignancies (355) and diabetes mellitus (DM) (Table 3). Prostate cancer was the most commonly diagnosed malignancy (80), 17 of whom had a second malignancy. CRC accounted for 54 of the malignancies, 1 of which developed in a patient with long-standing ulcerative colitis, 2 were a manifestation of a known hereditary cancer syndrome (Lynch syndrome), and the remaining 51 cases were various cancers without known predisposition. The diagnosis of CRC was made during the study period in 29 veterans. In the remaining 25 patients, the colonoscopy was performed as a surveillance examination after previous surgery for CRC.

Potential Predictors of Early Death

To better define potential predictors of early death, we focused on the 258 persons (5.3%) who died within 2 years after the index procedure and paired them with matched controls. One patient underwent a colonoscopy for surveillance of previously treated cancer and was excluded due to very advanced age, as no matched control could be identified. The mean (SD) age of this male-predominant cohort was 68.2 (9.6) vs 67.9 (9.4) years for cases and controls, respectively. At the time of referral for the test, 29 persons (11.3%) were aged > 80 years, which is significantly more than seen for the overall cohort with 306 (6.3%; P < .001). While primary care providers accounted for most referrals in cases (85.2%) and controls (93.0%), the fraction of veterans referred by gastroenterologists or other specialty care providers was significantly higher in the case group compared with that in the controls (14.8% vs 7.0%; P < .05).

In our age-matched analysis, we examined other potential factors that could influence survival. The burden of comorbid conditions summarized in the Charlson Comorbidity Index significantly correlated with survival status (Table 4). As this composite index does not include psychiatric conditions, we separately examined the impact of anxiety, depression, bipolar disease, psychotic disorders, and substance abuse. The diagnoses of depression and substance use disorders (SUDs) were associated with higher rates of early death. Considering concerns about SUDs, we also assessed the association between prescription for opioids or benzodiazepines and survival status, which showed a marginal correlation. Anticoagulant use, a likely surrogate for cardiovascular disorders, were more commonly listed in the cases than they were in the controls.

Looking at specific comorbid conditions, significant problems affecting key organ systems from heart to lung, liver, kidneys, or brain (dementia) were all predictors of poor outcome. Similarly, DM with secondary complication correlated with early death after the index procedure. In contrast, a history of prior myocardial infarction, prior cancer treatment without evidence of persistent or recurrent disease, or prior peptic ulcer disease did not differ between cases and controls. Focusing on routine blood tests, we noted marginal, but statistically different results for Hgb, serum creatinine, and albumin in cases compared with controls.

Next we performed a logistic regression to identify independent predictors of survival status. The referring provider specialty, Charlson Comorbidity Index, the diagnosis of a SUD, current benzodiazepine use, and significant anemia or hypoalbuminemia independently predicted death within 2 years of the index examination (Table 5). Considering the composite nature of the Charlson Comorbidity Index, we separately examined the relative importance of different comorbid conditions using a logistic regression analysis. Consistent with the univariate analyses, a known malignancy; severe liver, lung, or kidney disease; and DM with secondary complications were associated with poor outcome. Only arrhythmias other than AF were independent marginal predictors of early death, whereas other variables related to cardiac performance did not reach the level of significance (Table 6). As was true for our analysis examining the composite comorbidity index, the diagnosis of a SUD remained significant as a predictor of death within 2 years of the index colonoscopy.

Discussion

This retrospective analysis followed patients for a mean time of 7 years after a colonoscopy for CRC screening or polyp surveillance. We noted a high rate of all-cause mortality, with 20% of the cohort dying within the period studied. Malignancies, cardiovascular diseases, and advanced lung diseases were most commonly listed causes of death. As expected, CRC was among the 3 most common malignancies and was the cause of death in 6.7% of the group with sufficiently detailed information. While these results fall within the expected range for the mortality related to CRC,⁹ the results do not allow us to assess the impact of screening, which has been shown to decrease cancer-related mortality in veterans.⁶ This was limited because the sample size was too small to assess the impact of screening and the cause of death was ascertained for a small percentage of the sample.

Although our findings are limited to a subset of patients seen in a single center, they suggest the importance of appropriate eligibility criteria for screening tests, as also defined in national guidelines.¹ As a key anchoring point that describes the target population, age contributed to the rate of relatively early death after the index procedure. Consistent with previously published data, we saw a significant impact of comorbid diseases.^10,11 However, our findings go beyond prior reports and show the important impact of psychiatric disease burden, most important the role of SUDs. The predictive value of a summary score, such as the Charlson Comorbidity Index, supports the idea of a cumulative impact, with an increasing disease burden decreasing life expectancy.^10-14 It is important to consider the ongoing impact of such coexisting illnesses. Our analysis shows, the mere history of prior problems did not independently predict survival status in our cohort.

Although age is the key anchoring point that defines the target population for CRC screening programs, the benefit of earlier cancer detection or, in the context of colonoscopy with polypectomy, cancer prevention comes with a delay. Thus, cancer risk, procedural risk, and life expectancy should all be weighed when discussing and deciding on the appropriateness of CRC screening. When we disregard inherited cancer syndromes, CRC is clearly a disease of the second half of life with the incidence increasing with age.¹⁵ However, other disease burdens rise, which may affects the risk of screening and treatment should cancer be found.

Using our understanding of disease development, researchers have introduced the concept of time to benefit or lag time to help decisions about screening strategies. The period defines the likely time for a precursor or early form of cancer potentially detected by screening to manifest as a clinically relevant lesion. This lag time becomes an especially important consideration in screening of older and/or chronically ill adults with life expectancies that may be close to or even less than the time to benefit.¹⁶ Modeling studies suggest that 1,000 flexible sigmoidoscopy screenings are needed to prevent 1 cancer that would manifest about 10 years after the index examination.^17,18 The mean life expectancy of a healthy person aged 75 years exceeds 10 years but drops with comorbidity burden. Consistent with these considerations, an analysis of Medicare claims data concluded that individuals with ≥ 3 significant comorbidities do not derive any benefit from screening colonoscopy.¹⁴ Looking at the impact of comorbidities, mathematical models concluded that colorectal cancer screening should not be continued in persons with moderate or severe comorbid conditions aged 66 years and 72 years, respectively.¹⁹ In contrast, modeling results suggest a benefit of continued screening up to and even above the age of 80 years if persons have an increased cancer risk and if there are no confounding comorbidities.⁴

Life expectancy and time to benefit describe probabilities. Although such probabilities are relevant in public policy decision, providers and patients may struggle with probabilistic thinking when faced with decisions that involve probabilities of individual health care vs population health care. Both are concerned about the seemingly gloomy or pessimistic undertone of discussing life expectancy and the inherent uncertainty of prognostic tools.^20,21 Prior research indicates that this reluctance translates into clinical practice. When faced with vignettes, most clinicians would offer CRC screening to healthy persons aged 80 years with rates falling when the description included a significant comorbid burden; however, more than 40% would still consider screening in octogenarians with poor health.²²

Consistent with these responses to theoretical scenarios, CRC screening of veterans dropped with age but was still continued in persons with significant comorbidity.²³ Large studies of the veteran population suggest that about 10% of veterans aged > 70 years have chronic medical problems that limit their life expectancy to < 5 years; nonetheless, more than 40% of this cohort underwent colonoscopies for CRC screening.^24,25 Interestingly, more illness burden and more clinical encounters translated into more screening examinations in older sick veterans compared with that of the cohort of healthier older persons, suggesting an impact of clinical reminders and the key role of age as the main anchoring variable.²³

Ongoing screening despite limited or even no benefit is not unique to CRC. Using validated tools, Pollock and colleagues showed comparable screening rates for breast and prostate cancer when they examined cohorts at either high or low risk of early mortality.²⁶ Similar results have been reported in veterans with about one-third of elderly males with poor life expectancy still undergoing prostate cancer screening.²⁷ Interestingly, inappropriate screening is more common in nonacademic centers and influenced by provider characteristics: nurse practitioner, physician assistants, older attending physicians and male physicians were more likely to order such tests.^27,28

Limitations

In this study, we examined a cohort of veterans enrolled in CRC screening within a single institution and obtained survival data for a mean follow-up of > 7 years. We also restricted our study to patients undergoing examinations that explicitly listed screening as indication or polyp surveillance for the test. However, inclusion was based on the indication listed in the report, which may differ from the intent of the ordering provider. Reporting systems often come with default settings, which may skew data. Comorbidities for the entire cohort of veterans who died within the time frame of the study were extracted from the chart without controlling for time-dependent changes, which may more appropriately describe the comorbidity burden at the time of the test. Using a case-control design, we addressed this potential caveat and included only illnesses recorded in the encounter linked to the colonoscopy order. Despite these limitations, our results highlight the importance to more effectively define and target appropriate candidates for CRC screening.

Conclusion

This study shows that age is a simple but not sufficiently accurate criterion to define potential candidates for CRC screening. As automated reminders often prompt discussions about and referral to screening examinations, we should develop algorithms that estimate the individual cancer risk and/or integrate an automatically calculated comorbidity index with these alerts or insert such a tool into order-sets. In addition, providers and patients need to be educated about the rationale and need for a more comprehensive approach to CRC screening that considers anticipated life expectancy. On an individual and health system level, our goal should be to reduce overall mortality rather than only cancer-specific death rates.

Colorectal cancer (CRC) ranks among the most common causes of cancer and cancer-related death in the US. The US Multi-Society Task Force (USMSTF) on Colorectal Cancer thus strongly endorsed using several available screening options.¹ The published guidelines largely rely on age to define the target population (Table 1). For average-risk individuals, national and Veterans Health Administration (VHA) guidelines currently recommend CRC screening in individuals aged between 50 and 75 years with a life expectancy of > 5 years.¹

Although case-control studies also point to a potential benefit in persons aged > 75 years,^2,3 the USMSTF cited less convincing evidence and suggested an individualized approach that should consider relative cancer risk and comorbidity burden. Such an approach is supported by modeling studies, which suggest reduced benefit and increased risk of screening with increasing age. The reduced benefit also is significantly affected by comorbidity and relative cancer risk.⁴ The VHA has successfully implemented CRC screening, capturing the majority of eligible patients based on age criteria. A recent survey showed that more than three-quarters of veterans between age 50 and 75 years had undergone some screening test for CRC as part of routine preventive care. Colonoscopy clearly emerged as the dominant modality chosen for CRC screening and accounted for nearly 84% of these screening tests.⁵ Consistent with these data, a case-control study confirmed that the widespread implementation of colonoscopy as CRC screening method reduced cancer-related mortality in veterans for cases of left but not right-sided colon cancer.⁶

With calls to expand the age range of CRC screening beyond aged 75 years, we decided to assess survival rates of a cohort of veterans who underwent a screening or surveillance colonoscopy between 2008 and 2014.⁷ The goals were to characterize the portion of the cohort that had died, the time between a screening colonoscopy and death, the portion of deaths that were aged ≥ 80 years, and the causes of the deaths. In addition, we focused on a subgroup of the cohort, defined by death within 2 years after the index colonoscopy, to identify predictors of early death that were independent of age.

Methods

We queried the endoscopy reporting system (EndoWorks; Olympus America, Center Valley, PA) for all colonoscopies performed by 2 of 14 physicians at the George Wahlen VA Medical Center (GWVAMC) in Salt Lake City, Utah, who performed endoscopic procedures between January 1, 2008 and December 1, 2014. These physicians had focused their clinical practice exclusively on elective outpatient colonoscopies and accounted for 37.4% of the examinations at GWVAMC during the study period. All colonoscopy requests were triaged and assigned based on availability of open and appropriate procedure time slots without direct physician-specific referral, thus reducing the chance of skewing results. The reports were filtered through a text search to focus on examinations that listed screening or surveillance as indication. The central patient electronic health record was then reviewed to extract basic demographic data, survival status (as of August 1, 2018), and survival time in years after the index or subsequent colonoscopy. For deceased veterans, the age at the time of death, cause of death, and comorbidities were queried.

This study compared cases and control across the study. Cases were persons who clearly died early (defined as > 2 years following the index examination). They were matched with controls who lived for ≥ 5 years after their colonoscopy. These periods were selected because the USMSTF recommended that CRC screening or surveillance colonoscopy should be discontinued in persons with a life expectancy of < 5 years, and most study patients underwent their index procedure ≥ 5 years before August 2018. Cases and controls underwent a colonoscopy in the same year and were matched for age, sex, and presence of underlying inflammatory bowel disease (IBD). For cases and controls, we identified the ordering health care provider specialty, (ie, primary care, gastroenterology, or other).

In addition, we reviewed the encounter linked to the order and abstracted relevant comorbidities listed at that time, noted the use of anticoagulants, opioid analgesics, and benzodiazepines. The comorbidity burden was quantified using the Charlson Comorbidity Index.⁸ In addition, we denoted the presence of psychiatric problems (eg, anxiety, depression, bipolar disease, psychosis, substance abuse), the diagnosis of atrial fibrillation (AF) or other cardiac arrhythmias, and whether the patient had previously been treated for a malignancy that was in apparent clinical remission. Finally, we searched for routine laboratory tests at the time of this visit or, when not obtained, within 6 months of the encounter, and abstracted serum creatinine, hemoglobin (Hgb), platelet number, serum protein, and albumin. In clinical practice, cutoff values of test results are often more helpful in decision making. We, therefore, dichotomized results for Hgb (cutoff: 10 g/dL), creatinine (cutoff: 2 mg/dL), and albumin (cutoff: 3.2 mg/dL).

Descriptive and analytical statistics were obtained with Stata Version 14.1 (College Station, TX). Unless indicated otherwise, continuous data are shown as mean with 95% CIs. For dichotomous data, we used percentages with their 95% CIs. Analytic statistics were performed with the t test for continuous variables and the 2-tailed test for proportions. A P < .05 was considered a significant difference. To determine independent predictors of early death, we performed a logistic regression analysis with results being expressed as odds ratio with 95% CIs. Survival status was chosen as a dependent variable, and we entered variables that significantly correlated with survival in the bivariate analysis as independent variables.

The study was designed and conducted as a quality improvement project to assess colonoscopy performance and outcomes with the Salt Lake City Specialty Care Center of Innovation (COI), one of 5 regional COIs with an operational mission to improve health care access, utilization, and quality. Our work related to colonoscopy and access within the COI region, including Salt Lake City, has been reviewed and acknowledged by the GWVAMC Institutional Review Board as quality improvement. Andrew Gawron has an operational appointment in the GWVAMC COI, which is part of a US Department of Veterans Affairs (VA) central office initiative established in 2015. The COIs are charged with identifying best practices within the VA and applying those practices throughout the COI region. This local project to identify practice patterns and outcomes locally was sponsored by the GWVAMC COI with a focus to generate information to improve colonoscopy referral quality in patients at Salt Lake City and inform regional and national efforts in this domain.

Results

During the study period, 4,879 veterans (96.9% male) underwent at least 1 colonoscopy for screening or surveillance by 1 of the 2 providers. A total of 306 persons (6.3%) were aged > 80 years. The indication for surveillance colonoscopies included IBD in 78 (1.6%) veterans 2 of whom were women. The mean (SD) follow-up period between the index colonoscopy and study closure or death was 7.4 years (1.7). During the study time, 1,439 persons underwent a repeat examination for surveillance. The percentage of veterans with at least 1 additional colonoscopy after the index test was significantly higher in patients with known IBD compared with those without IBD (78.2% vs 28.7%; P < .01).

Between the index colonoscopy and August 2018, 974 patients (20.0%) died (Figure). The mean (SD) time between the colonoscopy and recorded year of death was 4.4 years (4.1). The fraction of women in the cohort that died (n = 18) was lower compared with 132 for the group of persons still alive (1.8% vs 3.4%; P < .05). The fraction of veterans with IBD who died by August 2018 did not differ from that of patients with IBD in the cohort of individuals who survived (19.2% vs 20.0%; P = .87). The cohort of veterans who died before study closure included 107 persons who were aged > 80 years at the time of their index colonoscopy, which is significantly more than in the cohort of persons still alive (11.0% vs 5.1%; P < .01).

Cause of Death

In 209 of the 974 (21.5%) veteran deaths a cause was recorded. Malignancies accounted for 88 of the deaths (42.1%), and CRCs were responsible for 14 (6.7%) deaths (Table 2). In 8 of these patients, the cancer had been identified at an advanced stage, not allowing for curative therapy. One patient had been asked to return for a repeat test as residual fecal matter did not allow proper visualization. He died 1 year later due to complications of sepsis after colonic perforation caused by a proximal colon cancer. Five patients underwent surgery with curative intent but suffered recurrences. In addition to malignancies, advanced diseases, such as cardiovascular, bronchopulmonary illnesses, and infections, were other commonly listed causes of death.

We also abstracted comorbidities that were known at the time of death or the most recent encounter within the VHA system. Hypertension was most commonly listed (549) followed by a current or prior diagnosis of malignancies (355) and diabetes mellitus (DM) (Table 3). Prostate cancer was the most commonly diagnosed malignancy (80), 17 of whom had a second malignancy. CRC accounted for 54 of the malignancies, 1 of which developed in a patient with long-standing ulcerative colitis, 2 were a manifestation of a known hereditary cancer syndrome (Lynch syndrome), and the remaining 51 cases were various cancers without known predisposition. The diagnosis of CRC was made during the study period in 29 veterans. In the remaining 25 patients, the colonoscopy was performed as a surveillance examination after previous surgery for CRC.

Potential Predictors of Early Death

To better define potential predictors of early death, we focused on the 258 persons (5.3%) who died within 2 years after the index procedure and paired them with matched controls. One patient underwent a colonoscopy for surveillance of previously treated cancer and was excluded due to very advanced age, as no matched control could be identified. The mean (SD) age of this male-predominant cohort was 68.2 (9.6) vs 67.9 (9.4) years for cases and controls, respectively. At the time of referral for the test, 29 persons (11.3%) were aged > 80 years, which is significantly more than seen for the overall cohort with 306 (6.3%; P < .001). While primary care providers accounted for most referrals in cases (85.2%) and controls (93.0%), the fraction of veterans referred by gastroenterologists or other specialty care providers was significantly higher in the case group compared with that in the controls (14.8% vs 7.0%; P < .05).

In our age-matched analysis, we examined other potential factors that could influence survival. The burden of comorbid conditions summarized in the Charlson Comorbidity Index significantly correlated with survival status (Table 4). As this composite index does not include psychiatric conditions, we separately examined the impact of anxiety, depression, bipolar disease, psychotic disorders, and substance abuse. The diagnoses of depression and substance use disorders (SUDs) were associated with higher rates of early death. Considering concerns about SUDs, we also assessed the association between prescription for opioids or benzodiazepines and survival status, which showed a marginal correlation. Anticoagulant use, a likely surrogate for cardiovascular disorders, were more commonly listed in the cases than they were in the controls.

Looking at specific comorbid conditions, significant problems affecting key organ systems from heart to lung, liver, kidneys, or brain (dementia) were all predictors of poor outcome. Similarly, DM with secondary complication correlated with early death after the index procedure. In contrast, a history of prior myocardial infarction, prior cancer treatment without evidence of persistent or recurrent disease, or prior peptic ulcer disease did not differ between cases and controls. Focusing on routine blood tests, we noted marginal, but statistically different results for Hgb, serum creatinine, and albumin in cases compared with controls.

Next we performed a logistic regression to identify independent predictors of survival status. The referring provider specialty, Charlson Comorbidity Index, the diagnosis of a SUD, current benzodiazepine use, and significant anemia or hypoalbuminemia independently predicted death within 2 years of the index examination (Table 5). Considering the composite nature of the Charlson Comorbidity Index, we separately examined the relative importance of different comorbid conditions using a logistic regression analysis. Consistent with the univariate analyses, a known malignancy; severe liver, lung, or kidney disease; and DM with secondary complications were associated with poor outcome. Only arrhythmias other than AF were independent marginal predictors of early death, whereas other variables related to cardiac performance did not reach the level of significance (Table 6). As was true for our analysis examining the composite comorbidity index, the diagnosis of a SUD remained significant as a predictor of death within 2 years of the index colonoscopy.

Discussion

This retrospective analysis followed patients for a mean time of 7 years after a colonoscopy for CRC screening or polyp surveillance. We noted a high rate of all-cause mortality, with 20% of the cohort dying within the period studied. Malignancies, cardiovascular diseases, and advanced lung diseases were most commonly listed causes of death. As expected, CRC was among the 3 most common malignancies and was the cause of death in 6.7% of the group with sufficiently detailed information. While these results fall within the expected range for the mortality related to CRC,⁹ the results do not allow us to assess the impact of screening, which has been shown to decrease cancer-related mortality in veterans.⁶ This was limited because the sample size was too small to assess the impact of screening and the cause of death was ascertained for a small percentage of the sample.

Although our findings are limited to a subset of patients seen in a single center, they suggest the importance of appropriate eligibility criteria for screening tests, as also defined in national guidelines.¹ As a key anchoring point that describes the target population, age contributed to the rate of relatively early death after the index procedure. Consistent with previously published data, we saw a significant impact of comorbid diseases.^10,11 However, our findings go beyond prior reports and show the important impact of psychiatric disease burden, most important the role of SUDs. The predictive value of a summary score, such as the Charlson Comorbidity Index, supports the idea of a cumulative impact, with an increasing disease burden decreasing life expectancy.^10-14 It is important to consider the ongoing impact of such coexisting illnesses. Our analysis shows, the mere history of prior problems did not independently predict survival status in our cohort.

Although age is the key anchoring point that defines the target population for CRC screening programs, the benefit of earlier cancer detection or, in the context of colonoscopy with polypectomy, cancer prevention comes with a delay. Thus, cancer risk, procedural risk, and life expectancy should all be weighed when discussing and deciding on the appropriateness of CRC screening. When we disregard inherited cancer syndromes, CRC is clearly a disease of the second half of life with the incidence increasing with age.¹⁵ However, other disease burdens rise, which may affects the risk of screening and treatment should cancer be found.

Using our understanding of disease development, researchers have introduced the concept of time to benefit or lag time to help decisions about screening strategies. The period defines the likely time for a precursor or early form of cancer potentially detected by screening to manifest as a clinically relevant lesion. This lag time becomes an especially important consideration in screening of older and/or chronically ill adults with life expectancies that may be close to or even less than the time to benefit.¹⁶ Modeling studies suggest that 1,000 flexible sigmoidoscopy screenings are needed to prevent 1 cancer that would manifest about 10 years after the index examination.^17,18 The mean life expectancy of a healthy person aged 75 years exceeds 10 years but drops with comorbidity burden. Consistent with these considerations, an analysis of Medicare claims data concluded that individuals with ≥ 3 significant comorbidities do not derive any benefit from screening colonoscopy.¹⁴ Looking at the impact of comorbidities, mathematical models concluded that colorectal cancer screening should not be continued in persons with moderate or severe comorbid conditions aged 66 years and 72 years, respectively.¹⁹ In contrast, modeling results suggest a benefit of continued screening up to and even above the age of 80 years if persons have an increased cancer risk and if there are no confounding comorbidities.⁴

Life expectancy and time to benefit describe probabilities. Although such probabilities are relevant in public policy decision, providers and patients may struggle with probabilistic thinking when faced with decisions that involve probabilities of individual health care vs population health care. Both are concerned about the seemingly gloomy or pessimistic undertone of discussing life expectancy and the inherent uncertainty of prognostic tools.^20,21 Prior research indicates that this reluctance translates into clinical practice. When faced with vignettes, most clinicians would offer CRC screening to healthy persons aged 80 years with rates falling when the description included a significant comorbid burden; however, more than 40% would still consider screening in octogenarians with poor health.²²

Consistent with these responses to theoretical scenarios, CRC screening of veterans dropped with age but was still continued in persons with significant comorbidity.²³ Large studies of the veteran population suggest that about 10% of veterans aged > 70 years have chronic medical problems that limit their life expectancy to < 5 years; nonetheless, more than 40% of this cohort underwent colonoscopies for CRC screening.^24,25 Interestingly, more illness burden and more clinical encounters translated into more screening examinations in older sick veterans compared with that of the cohort of healthier older persons, suggesting an impact of clinical reminders and the key role of age as the main anchoring variable.²³

Ongoing screening despite limited or even no benefit is not unique to CRC. Using validated tools, Pollock and colleagues showed comparable screening rates for breast and prostate cancer when they examined cohorts at either high or low risk of early mortality.²⁶ Similar results have been reported in veterans with about one-third of elderly males with poor life expectancy still undergoing prostate cancer screening.²⁷ Interestingly, inappropriate screening is more common in nonacademic centers and influenced by provider characteristics: nurse practitioner, physician assistants, older attending physicians and male physicians were more likely to order such tests.^27,28

Limitations

In this study, we examined a cohort of veterans enrolled in CRC screening within a single institution and obtained survival data for a mean follow-up of > 7 years. We also restricted our study to patients undergoing examinations that explicitly listed screening as indication or polyp surveillance for the test. However, inclusion was based on the indication listed in the report, which may differ from the intent of the ordering provider. Reporting systems often come with default settings, which may skew data. Comorbidities for the entire cohort of veterans who died within the time frame of the study were extracted from the chart without controlling for time-dependent changes, which may more appropriately describe the comorbidity burden at the time of the test. Using a case-control design, we addressed this potential caveat and included only illnesses recorded in the encounter linked to the colonoscopy order. Despite these limitations, our results highlight the importance to more effectively define and target appropriate candidates for CRC screening.

Conclusion

This study shows that age is a simple but not sufficiently accurate criterion to define potential candidates for CRC screening. As automated reminders often prompt discussions about and referral to screening examinations, we should develop algorithms that estimate the individual cancer risk and/or integrate an automatically calculated comorbidity index with these alerts or insert such a tool into order-sets. In addition, providers and patients need to be educated about the rationale and need for a more comprehensive approach to CRC screening that considers anticipated life expectancy. On an individual and health system level, our goal should be to reduce overall mortality rather than only cancer-specific death rates.

CHICAGO – In gastric and gastroesophageal junction (GEJ) cancers, positive for PD-L1, treatment with the PD-1 inhibitor pembrolizumab offered comparable survival with fewer side effects, according to results of a phase 3 randomized clinical trial.

The checkpoint inhibitor also demonstrated a clinically meaningful improvement in patients who had high levels of PD-L1 expression, with a 2-year survival rate of 39% versus 22% for patients receiving the standard chemotherapy, which consisted of a platinum and a fluoropyrimidine, according to Josep Tabernero, MD, PhD, lead author of the KEYNOTE-062 study.

By contrast, the study failed to demonstrate that pembrolizumab immunotherapy combined with that chemotherapy backbone was superior to chemotherapy alone on survival endpoints, said Dr. Tabernero, Head of the Medical Oncology Department at the Vall d’Hebron Barcelona University Hospital and Institute of Oncology, Spain.

“There are several factors we are evaluating,” Dr. Tabernero said here in a press conference at the annual meeting of the American Society of Clinical Oncology (ASCO). “We still have to do more studies to understand why, with this chemotherapy backbone, we don’t see a clear synergistic effect for superiority in overall survival.”

Nevertheless, these findings make pembrolizumab a “preferred treatment” for many patients, particularly in light of its “substantially improved safety profile” versus chemotherapy, said ASCO Senior Vice President and Chief Medical Officer Richard L. Schilsky, MD.

“What I take away from this study is that for patients with advanced gastric and gastroesophageal cancer, pembrolizumab should really in many cases replace chemotherapy as a first-line treatment for this population,” Dr. Schilsky said in a press conference. “It’s certainly not worse, and it may well be better.”

The KEYNOTE-062 study included 763 patients with HER2-negative, PD-L1-positive advanced gastric or GEJ cancers randomized to one of three arms: pembrolizumab alone for up to 35 cycles, pembrolizumab for up to 35 cycles plus chemotherapy, or placebo plus chemotherapy.

Pembrolizumab alone was not inferior compared to chemotherapy, with median overall survival rates of 10.5 and 11.1 months, respectively (HR, 0.91; 99.2% CI, 0.69-1.18), Dr. Tabernero reported.

Overall survival appeared to be prolonged in patients with high levels of PD-L1 expression, defined as a combined positive score (CPS) of 10 or greater. The median survival in that subgroup was 17.4 months for those receiving pembrolizumab, and just 10.8 months for chemotherapy. However, the design of the study precluded an analysis of statistical significance for this finding, according to Dr. Tabernero.

Looking at the overall study population, pembrolizumab plus chemotherapy did not improve survival versus chemotherapy alone, he added, reporting median overall survivals of 12.5 and 11.1 months, respectively (P = .046).

Subgroup analysis suggested that Asian patients derived particular benefit from pembrolizumab as compared to chemotherapy, though Dr. Tabernero cautioned against overinterpretation of the finding, saying that it could be due to biology, or could be a statistical anomaly.

Funding for the study came from Merck & Co., Inc. Dr. Tabernero reported disclosures related to Bayer, Boehringer Ingelheim, Lilly, MSD, Merck Serono, Novartis, Sanofi, and others.

SOURCE: Tabernero J, et al. ASCO 2019. Abstract LBA4007.

CHICAGO – In gastric and gastroesophageal junction (GEJ) cancers, positive for PD-L1, treatment with the PD-1 inhibitor pembrolizumab offered comparable survival with fewer side effects, according to results of a phase 3 randomized clinical trial.

The checkpoint inhibitor also demonstrated a clinically meaningful improvement in patients who had high levels of PD-L1 expression, with a 2-year survival rate of 39% versus 22% for patients receiving the standard chemotherapy, which consisted of a platinum and a fluoropyrimidine, according to Josep Tabernero, MD, PhD, lead author of the KEYNOTE-062 study.

By contrast, the study failed to demonstrate that pembrolizumab immunotherapy combined with that chemotherapy backbone was superior to chemotherapy alone on survival endpoints, said Dr. Tabernero, Head of the Medical Oncology Department at the Vall d’Hebron Barcelona University Hospital and Institute of Oncology, Spain.

“There are several factors we are evaluating,” Dr. Tabernero said here in a press conference at the annual meeting of the American Society of Clinical Oncology (ASCO). “We still have to do more studies to understand why, with this chemotherapy backbone, we don’t see a clear synergistic effect for superiority in overall survival.”

Nevertheless, these findings make pembrolizumab a “preferred treatment” for many patients, particularly in light of its “substantially improved safety profile” versus chemotherapy, said ASCO Senior Vice President and Chief Medical Officer Richard L. Schilsky, MD.

“What I take away from this study is that for patients with advanced gastric and gastroesophageal cancer, pembrolizumab should really in many cases replace chemotherapy as a first-line treatment for this population,” Dr. Schilsky said in a press conference. “It’s certainly not worse, and it may well be better.”

The KEYNOTE-062 study included 763 patients with HER2-negative, PD-L1-positive advanced gastric or GEJ cancers randomized to one of three arms: pembrolizumab alone for up to 35 cycles, pembrolizumab for up to 35 cycles plus chemotherapy, or placebo plus chemotherapy.

Pembrolizumab alone was not inferior compared to chemotherapy, with median overall survival rates of 10.5 and 11.1 months, respectively (HR, 0.91; 99.2% CI, 0.69-1.18), Dr. Tabernero reported.

Overall survival appeared to be prolonged in patients with high levels of PD-L1 expression, defined as a combined positive score (CPS) of 10 or greater. The median survival in that subgroup was 17.4 months for those receiving pembrolizumab, and just 10.8 months for chemotherapy. However, the design of the study precluded an analysis of statistical significance for this finding, according to Dr. Tabernero.

Looking at the overall study population, pembrolizumab plus chemotherapy did not improve survival versus chemotherapy alone, he added, reporting median overall survivals of 12.5 and 11.1 months, respectively (P = .046).

Subgroup analysis suggested that Asian patients derived particular benefit from pembrolizumab as compared to chemotherapy, though Dr. Tabernero cautioned against overinterpretation of the finding, saying that it could be due to biology, or could be a statistical anomaly.

Funding for the study came from Merck & Co., Inc. Dr. Tabernero reported disclosures related to Bayer, Boehringer Ingelheim, Lilly, MSD, Merck Serono, Novartis, Sanofi, and others.

SOURCE: Tabernero J, et al. ASCO 2019. Abstract LBA4007.

CHICAGO – In gastric and gastroesophageal junction (GEJ) cancers, positive for PD-L1, treatment with the PD-1 inhibitor pembrolizumab offered comparable survival with fewer side effects, according to results of a phase 3 randomized clinical trial.

The checkpoint inhibitor also demonstrated a clinically meaningful improvement in patients who had high levels of PD-L1 expression, with a 2-year survival rate of 39% versus 22% for patients receiving the standard chemotherapy, which consisted of a platinum and a fluoropyrimidine, according to Josep Tabernero, MD, PhD, lead author of the KEYNOTE-062 study.

By contrast, the study failed to demonstrate that pembrolizumab immunotherapy combined with that chemotherapy backbone was superior to chemotherapy alone on survival endpoints, said Dr. Tabernero, Head of the Medical Oncology Department at the Vall d’Hebron Barcelona University Hospital and Institute of Oncology, Spain.

“There are several factors we are evaluating,” Dr. Tabernero said here in a press conference at the annual meeting of the American Society of Clinical Oncology (ASCO). “We still have to do more studies to understand why, with this chemotherapy backbone, we don’t see a clear synergistic effect for superiority in overall survival.”

Nevertheless, these findings make pembrolizumab a “preferred treatment” for many patients, particularly in light of its “substantially improved safety profile” versus chemotherapy, said ASCO Senior Vice President and Chief Medical Officer Richard L. Schilsky, MD.

“What I take away from this study is that for patients with advanced gastric and gastroesophageal cancer, pembrolizumab should really in many cases replace chemotherapy as a first-line treatment for this population,” Dr. Schilsky said in a press conference. “It’s certainly not worse, and it may well be better.”

The KEYNOTE-062 study included 763 patients with HER2-negative, PD-L1-positive advanced gastric or GEJ cancers randomized to one of three arms: pembrolizumab alone for up to 35 cycles, pembrolizumab for up to 35 cycles plus chemotherapy, or placebo plus chemotherapy.

Pembrolizumab alone was not inferior compared to chemotherapy, with median overall survival rates of 10.5 and 11.1 months, respectively (HR, 0.91; 99.2% CI, 0.69-1.18), Dr. Tabernero reported.

Overall survival appeared to be prolonged in patients with high levels of PD-L1 expression, defined as a combined positive score (CPS) of 10 or greater. The median survival in that subgroup was 17.4 months for those receiving pembrolizumab, and just 10.8 months for chemotherapy. However, the design of the study precluded an analysis of statistical significance for this finding, according to Dr. Tabernero.

Looking at the overall study population, pembrolizumab plus chemotherapy did not improve survival versus chemotherapy alone, he added, reporting median overall survivals of 12.5 and 11.1 months, respectively (P = .046).

Subgroup analysis suggested that Asian patients derived particular benefit from pembrolizumab as compared to chemotherapy, though Dr. Tabernero cautioned against overinterpretation of the finding, saying that it could be due to biology, or could be a statistical anomaly.

Funding for the study came from Merck & Co., Inc. Dr. Tabernero reported disclosures related to Bayer, Boehringer Ingelheim, Lilly, MSD, Merck Serono, Novartis, Sanofi, and others.

SOURCE: Tabernero J, et al. ASCO 2019. Abstract LBA4007.

Two recent studies that assess the Food and Drug Administration’s accelerated approval process for cancer drugs suggest the agency is using inadequate measures to determine clinical value for patients.

Artfoliophoto/Thinkstock

In the first study, lead investigator Emerson Y. Chen, MD, of Oregon Health & Science University, Portland, and colleagues conducted a retrospective analysis of all drugs approved by the FDA on the basis of response rate – the percentage of patients who experience tumor shrinkage – from Jan. 1, 2006, to Sept. 30, 2018. The data set consisted of 59 oncology drugs with 85 unique indications approved by the FDA for advanced-stage metastatic cancer on the basis of a response rate (RR) endpoint during the study period.

Of the 85 indications, 32 were granted regular approval immediately with limited postmarketing efficacy requirements and 53 (62%) were granted accelerated approval. Of the accelerated approvals, 29 (55%) were later converted to regular approval.

The median RR for the 85 indications was 41%, and the median sample size of such RR trials was 117 patients, according to the analysis published in JAMA Internal Medicine.

Among all approvals, 14 of 85 (16%) had an RR less than 20%, 28 of 85 (33%) had an RR less than 30%, and 40 of 85 (47%) had an RR less than 40%.

Most approved drugs had an RR ranging from 20% to 59%, the study found. Of 81 available indications, the median complete response rate – defined as the percentage of patients with no visible disease and normalization of lymph nodes – was 6%. (Complete response data were not reported for four drug indications.)

The investigators found that many of the drugs studied have remained on the market for years without subsequent confirmatory data. For example, when the accelerated approvals based on RR were converted to full approval, 23 of 29 were made on the basis of surrogate endpoints (progression-free survival or RR), 7 of 29 were made on the basis of RR, and just 6 of 29 were made on the basis of overall survival (OS).

The findings suggest that most cancer drugs approved by the FDA based on RR have less than transformational response rates, and that such indications do not have confirmed clinical benefit, the study authors wrote.

While in some settings, a response can equal prognostic value regarding overall survival, the authors wrote that “the ability of RR to serve as a validated surrogate for OS varies among cancer types and is generally poor.”

In the second study, researchers found that confirmatory trials for only one-fifth of cancer drug indications approved via the FDA’s accelerated approval route demonstrated improvements in overall patient survival.

Lead investigator Bishal Gyawali, MD, PhD, of Queen’s University, Kingston, Ont., and colleagues examined FDA data on recent drugs and indications that received accelerated approval and were later granted full approval.

For their analysis, the investigators reviewed the FDA’s database of postmarketing requirements and commitments, as well as PubMed, to determine the current status of postmarket trials for indications labeled as “ongoing” in the original FDA data.

Of 93 cancer drug indications for which accelerated approval was granted from Dec. 11, 1992, to May 31, 2017, the FDA reported clinical benefit was adequately confirmed in 51 indications. Of these confirmations, 15 demonstrated improvement in overall survival.

In their updated analysis, the investigators determined that confirmatory trials for 19 of the 93 (20%) cancer drug approvals reported an improvement in OS, 19 trials (20%) reported improvement in the same surrogate used in the preapproval trial, and 20 trials (21%) reported improvement in a different surrogate, according to the study, also published in JAMA Internal Medicine.

Additionally, results showed that 5 confirmatory trials were delayed, 10 trials were pending, and 9 trials were ongoing.

For three recent accelerated approvals, the primary endpoints were not met in the confirmatory trials, but one of the indications still received full approval.

The findings raise several concerns about the accelerated cancer drug pathway, including whether the same surrogate efficacy measure should be used as verification of drug benefit, according to the investigators. Conversely, using a different surrogate endpoint than the original measure can cause confusion among physicians and patients about whether the cancer drug improves survival or quality of life, information that is essential in the benefit-risk evaluation for clinical decision making.

That a number of the confirmatory trials examined were delayed or pending emphasize the considerable time that can elapse between drug approval and confirmatory trial completion, they added.

“Timely planning and completion of postmarketing trials is necessary for proper implementation of the accelerated approval pathway, and the FDA should minimize the period during which patients and physicians are using drugs approved through accelerated pathways without rigorous data on their ultimate clinical benefit,” the authors wrote in the analysis.

Dr. Chen, lead author of the RR study, said both studies call into question what criteria is optimal when assessing cancer drug value, while ensuring such measurements are not too high to achieve – preventing useful drugs to market – but also not too low – allowing drugs with marginal benefit into the market.

“There has been tremendous drug development within the oncology space, and it is always important to look back to reassess and see if the process [matches] the original vision so that we can correct any misuse or concerns,” Dr. Chen said in an interview.

Dr. Chen said his study indicates the RR endpoint has been misused in scenarios with low response rate, common cancer, and/or situations with already available therapies. In the study by Dr. Gyawali, the results suggest many drugs approved on the basis of a surrogate endpoint (RR or progression-free survival) ultimately do not demonstrate survival benefit confirmation or patient-reported benefit, Dr. Chen said.

“We hope that readers of these JAMA IM studies and the accompanying commentaries will recognize that there could be a set of guidance criteria from regulatory agencies or oncology organizations to recommend use of surrogate endpoints in special situations: high response rate of the drug, very rare cancer, or highly innovative therapy not yet seen before,” he said. “The use of surrogate endpoints to justify these therapies must also have postmarketing confirmation of survival or patient-reported benefit.”

The study led by Dr. Chen was supported by the Laura and John Arnold Foundation. Dr Chen reported receiving lecture honorarium from Horizon CME; another coauthor reported receiving honorarium from universities, medical centers, and publishers. The study led by Dr. Gyawali was supported by the Arnold Ventures; one of the coauthors reported receiving grant support from the Harvard-MIT Center for Regulatory Science and the Engelberg Foundation, as well as unrelated research funding from the FDA.

agallegos@mdedge.com

SOURCES: Chen EY et al. JAMA Intern Med. 2019 May 28. doi: 10.1001/jamainternmed.2019.0583; Gyawali B et al. JAMA Intern Med. 2019 May 28. doi: 10.1001/jamainternmed.2019.0462.

Two recent studies that assess the Food and Drug Administration’s accelerated approval process for cancer drugs suggest the agency is using inadequate measures to determine clinical value for patients.

Artfoliophoto/Thinkstock

In the first study, lead investigator Emerson Y. Chen, MD, of Oregon Health & Science University, Portland, and colleagues conducted a retrospective analysis of all drugs approved by the FDA on the basis of response rate – the percentage of patients who experience tumor shrinkage – from Jan. 1, 2006, to Sept. 30, 2018. The data set consisted of 59 oncology drugs with 85 unique indications approved by the FDA for advanced-stage metastatic cancer on the basis of a response rate (RR) endpoint during the study period.

Of the 85 indications, 32 were granted regular approval immediately with limited postmarketing efficacy requirements and 53 (62%) were granted accelerated approval. Of the accelerated approvals, 29 (55%) were later converted to regular approval.

The median RR for the 85 indications was 41%, and the median sample size of such RR trials was 117 patients, according to the analysis published in JAMA Internal Medicine.

Among all approvals, 14 of 85 (16%) had an RR less than 20%, 28 of 85 (33%) had an RR less than 30%, and 40 of 85 (47%) had an RR less than 40%.

Most approved drugs had an RR ranging from 20% to 59%, the study found. Of 81 available indications, the median complete response rate – defined as the percentage of patients with no visible disease and normalization of lymph nodes – was 6%. (Complete response data were not reported for four drug indications.)

The investigators found that many of the drugs studied have remained on the market for years without subsequent confirmatory data. For example, when the accelerated approvals based on RR were converted to full approval, 23 of 29 were made on the basis of surrogate endpoints (progression-free survival or RR), 7 of 29 were made on the basis of RR, and just 6 of 29 were made on the basis of overall survival (OS).

The findings suggest that most cancer drugs approved by the FDA based on RR have less than transformational response rates, and that such indications do not have confirmed clinical benefit, the study authors wrote.

While in some settings, a response can equal prognostic value regarding overall survival, the authors wrote that “the ability of RR to serve as a validated surrogate for OS varies among cancer types and is generally poor.”

In the second study, researchers found that confirmatory trials for only one-fifth of cancer drug indications approved via the FDA’s accelerated approval route demonstrated improvements in overall patient survival.

Lead investigator Bishal Gyawali, MD, PhD, of Queen’s University, Kingston, Ont., and colleagues examined FDA data on recent drugs and indications that received accelerated approval and were later granted full approval.

For their analysis, the investigators reviewed the FDA’s database of postmarketing requirements and commitments, as well as PubMed, to determine the current status of postmarket trials for indications labeled as “ongoing” in the original FDA data.

Of 93 cancer drug indications for which accelerated approval was granted from Dec. 11, 1992, to May 31, 2017, the FDA reported clinical benefit was adequately confirmed in 51 indications. Of these confirmations, 15 demonstrated improvement in overall survival.

In their updated analysis, the investigators determined that confirmatory trials for 19 of the 93 (20%) cancer drug approvals reported an improvement in OS, 19 trials (20%) reported improvement in the same surrogate used in the preapproval trial, and 20 trials (21%) reported improvement in a different surrogate, according to the study, also published in JAMA Internal Medicine.

Additionally, results showed that 5 confirmatory trials were delayed, 10 trials were pending, and 9 trials were ongoing.

For three recent accelerated approvals, the primary endpoints were not met in the confirmatory trials, but one of the indications still received full approval.

The findings raise several concerns about the accelerated cancer drug pathway, including whether the same surrogate efficacy measure should be used as verification of drug benefit, according to the investigators. Conversely, using a different surrogate endpoint than the original measure can cause confusion among physicians and patients about whether the cancer drug improves survival or quality of life, information that is essential in the benefit-risk evaluation for clinical decision making.

That a number of the confirmatory trials examined were delayed or pending emphasize the considerable time that can elapse between drug approval and confirmatory trial completion, they added.

“Timely planning and completion of postmarketing trials is necessary for proper implementation of the accelerated approval pathway, and the FDA should minimize the period during which patients and physicians are using drugs approved through accelerated pathways without rigorous data on their ultimate clinical benefit,” the authors wrote in the analysis.

Dr. Chen, lead author of the RR study, said both studies call into question what criteria is optimal when assessing cancer drug value, while ensuring such measurements are not too high to achieve – preventing useful drugs to market – but also not too low – allowing drugs with marginal benefit into the market.

“There has been tremendous drug development within the oncology space, and it is always important to look back to reassess and see if the process [matches] the original vision so that we can correct any misuse or concerns,” Dr. Chen said in an interview.

Dr. Chen said his study indicates the RR endpoint has been misused in scenarios with low response rate, common cancer, and/or situations with already available therapies. In the study by Dr. Gyawali, the results suggest many drugs approved on the basis of a surrogate endpoint (RR or progression-free survival) ultimately do not demonstrate survival benefit confirmation or patient-reported benefit, Dr. Chen said.

“We hope that readers of these JAMA IM studies and the accompanying commentaries will recognize that there could be a set of guidance criteria from regulatory agencies or oncology organizations to recommend use of surrogate endpoints in special situations: high response rate of the drug, very rare cancer, or highly innovative therapy not yet seen before,” he said. “The use of surrogate endpoints to justify these therapies must also have postmarketing confirmation of survival or patient-reported benefit.”

The study led by Dr. Chen was supported by the Laura and John Arnold Foundation. Dr Chen reported receiving lecture honorarium from Horizon CME; another coauthor reported receiving honorarium from universities, medical centers, and publishers. The study led by Dr. Gyawali was supported by the Arnold Ventures; one of the coauthors reported receiving grant support from the Harvard-MIT Center for Regulatory Science and the Engelberg Foundation, as well as unrelated research funding from the FDA.

agallegos@mdedge.com

SOURCES: Chen EY et al. JAMA Intern Med. 2019 May 28. doi: 10.1001/jamainternmed.2019.0583; Gyawali B et al. JAMA Intern Med. 2019 May 28. doi: 10.1001/jamainternmed.2019.0462.

Two recent studies that assess the Food and Drug Administration’s accelerated approval process for cancer drugs suggest the agency is using inadequate measures to determine clinical value for patients.

Artfoliophoto/Thinkstock

In the first study, lead investigator Emerson Y. Chen, MD, of Oregon Health & Science University, Portland, and colleagues conducted a retrospective analysis of all drugs approved by the FDA on the basis of response rate – the percentage of patients who experience tumor shrinkage – from Jan. 1, 2006, to Sept. 30, 2018. The data set consisted of 59 oncology drugs with 85 unique indications approved by the FDA for advanced-stage metastatic cancer on the basis of a response rate (RR) endpoint during the study period.

Of the 85 indications, 32 were granted regular approval immediately with limited postmarketing efficacy requirements and 53 (62%) were granted accelerated approval. Of the accelerated approvals, 29 (55%) were later converted to regular approval.

The median RR for the 85 indications was 41%, and the median sample size of such RR trials was 117 patients, according to the analysis published in JAMA Internal Medicine.

Among all approvals, 14 of 85 (16%) had an RR less than 20%, 28 of 85 (33%) had an RR less than 30%, and 40 of 85 (47%) had an RR less than 40%.

Most approved drugs had an RR ranging from 20% to 59%, the study found. Of 81 available indications, the median complete response rate – defined as the percentage of patients with no visible disease and normalization of lymph nodes – was 6%. (Complete response data were not reported for four drug indications.)

The investigators found that many of the drugs studied have remained on the market for years without subsequent confirmatory data. For example, when the accelerated approvals based on RR were converted to full approval, 23 of 29 were made on the basis of surrogate endpoints (progression-free survival or RR), 7 of 29 were made on the basis of RR, and just 6 of 29 were made on the basis of overall survival (OS).

The findings suggest that most cancer drugs approved by the FDA based on RR have less than transformational response rates, and that such indications do not have confirmed clinical benefit, the study authors wrote.

While in some settings, a response can equal prognostic value regarding overall survival, the authors wrote that “the ability of RR to serve as a validated surrogate for OS varies among cancer types and is generally poor.”

In the second study, researchers found that confirmatory trials for only one-fifth of cancer drug indications approved via the FDA’s accelerated approval route demonstrated improvements in overall patient survival.

Lead investigator Bishal Gyawali, MD, PhD, of Queen’s University, Kingston, Ont., and colleagues examined FDA data on recent drugs and indications that received accelerated approval and were later granted full approval.

For their analysis, the investigators reviewed the FDA’s database of postmarketing requirements and commitments, as well as PubMed, to determine the current status of postmarket trials for indications labeled as “ongoing” in the original FDA data.

Of 93 cancer drug indications for which accelerated approval was granted from Dec. 11, 1992, to May 31, 2017, the FDA reported clinical benefit was adequately confirmed in 51 indications. Of these confirmations, 15 demonstrated improvement in overall survival.

In their updated analysis, the investigators determined that confirmatory trials for 19 of the 93 (20%) cancer drug approvals reported an improvement in OS, 19 trials (20%) reported improvement in the same surrogate used in the preapproval trial, and 20 trials (21%) reported improvement in a different surrogate, according to the study, also published in JAMA Internal Medicine.

Additionally, results showed that 5 confirmatory trials were delayed, 10 trials were pending, and 9 trials were ongoing.

For three recent accelerated approvals, the primary endpoints were not met in the confirmatory trials, but one of the indications still received full approval.

The findings raise several concerns about the accelerated cancer drug pathway, including whether the same surrogate efficacy measure should be used as verification of drug benefit, according to the investigators. Conversely, using a different surrogate endpoint than the original measure can cause confusion among physicians and patients about whether the cancer drug improves survival or quality of life, information that is essential in the benefit-risk evaluation for clinical decision making.

That a number of the confirmatory trials examined were delayed or pending emphasize the considerable time that can elapse between drug approval and confirmatory trial completion, they added.

“Timely planning and completion of postmarketing trials is necessary for proper implementation of the accelerated approval pathway, and the FDA should minimize the period during which patients and physicians are using drugs approved through accelerated pathways without rigorous data on their ultimate clinical benefit,” the authors wrote in the analysis.

Dr. Chen, lead author of the RR study, said both studies call into question what criteria is optimal when assessing cancer drug value, while ensuring such measurements are not too high to achieve – preventing useful drugs to market – but also not too low – allowing drugs with marginal benefit into the market.

“There has been tremendous drug development within the oncology space, and it is always important to look back to reassess and see if the process [matches] the original vision so that we can correct any misuse or concerns,” Dr. Chen said in an interview.

Dr. Chen said his study indicates the RR endpoint has been misused in scenarios with low response rate, common cancer, and/or situations with already available therapies. In the study by Dr. Gyawali, the results suggest many drugs approved on the basis of a surrogate endpoint (RR or progression-free survival) ultimately do not demonstrate survival benefit confirmation or patient-reported benefit, Dr. Chen said.

“We hope that readers of these JAMA IM studies and the accompanying commentaries will recognize that there could be a set of guidance criteria from regulatory agencies or oncology organizations to recommend use of surrogate endpoints in special situations: high response rate of the drug, very rare cancer, or highly innovative therapy not yet seen before,” he said. “The use of surrogate endpoints to justify these therapies must also have postmarketing confirmation of survival or patient-reported benefit.”

The study led by Dr. Chen was supported by the Laura and John Arnold Foundation. Dr Chen reported receiving lecture honorarium from Horizon CME; another coauthor reported receiving honorarium from universities, medical centers, and publishers. The study led by Dr. Gyawali was supported by the Arnold Ventures; one of the coauthors reported receiving grant support from the Harvard-MIT Center for Regulatory Science and the Engelberg Foundation, as well as unrelated research funding from the FDA.

agallegos@mdedge.com

SOURCES: Chen EY et al. JAMA Intern Med. 2019 May 28. doi: 10.1001/jamainternmed.2019.0583; Gyawali B et al. JAMA Intern Med. 2019 May 28. doi: 10.1001/jamainternmed.2019.0462.

For patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT), adding daratumumab to lenalidomide and dexamethasone provides better outcomes than standard therapy alone, based on an interim analysis from the phase 3 MAIA trial.

A greater proportion of patients in the daratumumab group had complete responses and were alive without disease progression after a median follow-up of 28 months, reported lead author Thierry Facon, MD, of the University of Lille (France) and colleagues, who also noted that daratumumab was associated with higher rates of grade 3 or 4 pneumonia, neutropenia, and lymphopenia.

“For patients who are ineligible for stem-cell transplantation, multiagent regimens, including alkylating agents, glucocorticoids, immunomodulatory drugs, proteasome inhibitors, and new agents, are the standard of care,” the investigators wrote in the New England Journal of Medicine.

The findings from MAIA add clarity to the efficacy and safety of daratumumab in this setting, building on previous phase 3 myeloma trials in the same area, such as ALCYONE, CASTOR, and POLLUX, the investigators noted.

MAIA was an open-label, international trial involving 737 patients with newly diagnosed multiple myeloma who were ineligible for ASCT. Patients were randomized in a 1:1 ratio to receive either daratumumab, lenalidomide, and dexamethasone (daratumumab group; n = 368) or lenalidomide and dexamethasone alone (control group; n = 369).

On a 28-day cycle, all patients received oral lenalidomide 25 mg on days 1-21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22. Patients in the daratumumab group received intravenous daratumumab dosed at 16 mg/kg once a week for cycles 1 and 2, every 2 weeks for cycles 3-6, and then every 4 weeks thereafter. Treatment was continued until unacceptable toxic effects or disease progression occurred.

The primary end point was progression-free survival (PFS). Various secondary end points were also evaluated, including time to progression, complete responses, overall survival, and others.

Among the 737 randomized patients, 729 ultimately underwent treatment. The median patient age was 73 years.

Generally, efficacy measures favored adding daratumumab. After a median follow-up of 28.0 months, disease progression or death had occurred in 26.4% of patients in the daratumumab group, compared with 38.8% in the control group.

The median PFS was not reached in the daratumumab group, compared with 31.9 months in the control group. There was a 44% lower risk of disease progression or death among patients who received daratumumab, compared with the control group (hazard ratio, 0.56, P less than .001).

This PFS trend was consistent across most subgroups, including those for sex, age, and race, with the exception of patients with baseline hepatic impairment.

Additional efficacy measures added weight to the apparent benefit of adding daratumumab. For instance, more patients in the daratumumab group achieved a complete response or better (47.6% vs. 24.9%) and were negative for minimum residual disease (24.2% vs. 7.3%).

In terms of safety, more patients in the daratumumab group than the control group developed grade 3 or higher neutropenia (50% vs. 35.3%), lymphopenia (15.1% vs. 10.7%), infections (32.1% vs. 23.3%) or pneumonia (13.7% vs. 7.9%).

In contrast, grade 3 or 4 anemia was less common in the daratumumab group than the control group (11.8% vs. 19.7%). Overall, the rate of serious adverse events was similar for both groups (approximately 63%), as was the rate of adverse events resulting in death (approximately 6%-7%).

“In this trial involving patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, the addition of daratumumab to lenalidomide and dexamethasone resulted in significantly longer progression-free survival, a higher response rate, an increased depth of response, and a longer duration of response than lenalidomide and dexamethasone alone,” the investigators concluded.

The study was funded by Janssen Research and Development. The investigators reported relationships with Janssen, Celgene, Takeda, Sanofi, and other companies.

SOURCE: Facon T et al. N Engl J Med. 2019;380:2104-15.

For patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT), adding daratumumab to lenalidomide and dexamethasone provides better outcomes than standard therapy alone, based on an interim analysis from the phase 3 MAIA trial.

A greater proportion of patients in the daratumumab group had complete responses and were alive without disease progression after a median follow-up of 28 months, reported lead author Thierry Facon, MD, of the University of Lille (France) and colleagues, who also noted that daratumumab was associated with higher rates of grade 3 or 4 pneumonia, neutropenia, and lymphopenia.

“For patients who are ineligible for stem-cell transplantation, multiagent regimens, including alkylating agents, glucocorticoids, immunomodulatory drugs, proteasome inhibitors, and new agents, are the standard of care,” the investigators wrote in the New England Journal of Medicine.

The findings from MAIA add clarity to the efficacy and safety of daratumumab in this setting, building on previous phase 3 myeloma trials in the same area, such as ALCYONE, CASTOR, and POLLUX, the investigators noted.

MAIA was an open-label, international trial involving 737 patients with newly diagnosed multiple myeloma who were ineligible for ASCT. Patients were randomized in a 1:1 ratio to receive either daratumumab, lenalidomide, and dexamethasone (daratumumab group; n = 368) or lenalidomide and dexamethasone alone (control group; n = 369).

On a 28-day cycle, all patients received oral lenalidomide 25 mg on days 1-21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22. Patients in the daratumumab group received intravenous daratumumab dosed at 16 mg/kg once a week for cycles 1 and 2, every 2 weeks for cycles 3-6, and then every 4 weeks thereafter. Treatment was continued until unacceptable toxic effects or disease progression occurred.

The primary end point was progression-free survival (PFS). Various secondary end points were also evaluated, including time to progression, complete responses, overall survival, and others.

Among the 737 randomized patients, 729 ultimately underwent treatment. The median patient age was 73 years.

Generally, efficacy measures favored adding daratumumab. After a median follow-up of 28.0 months, disease progression or death had occurred in 26.4% of patients in the daratumumab group, compared with 38.8% in the control group.

The median PFS was not reached in the daratumumab group, compared with 31.9 months in the control group. There was a 44% lower risk of disease progression or death among patients who received daratumumab, compared with the control group (hazard ratio, 0.56, P less than .001).

This PFS trend was consistent across most subgroups, including those for sex, age, and race, with the exception of patients with baseline hepatic impairment.

Additional efficacy measures added weight to the apparent benefit of adding daratumumab. For instance, more patients in the daratumumab group achieved a complete response or better (47.6% vs. 24.9%) and were negative for minimum residual disease (24.2% vs. 7.3%).

In terms of safety, more patients in the daratumumab group than the control group developed grade 3 or higher neutropenia (50% vs. 35.3%), lymphopenia (15.1% vs. 10.7%), infections (32.1% vs. 23.3%) or pneumonia (13.7% vs. 7.9%).

In contrast, grade 3 or 4 anemia was less common in the daratumumab group than the control group (11.8% vs. 19.7%). Overall, the rate of serious adverse events was similar for both groups (approximately 63%), as was the rate of adverse events resulting in death (approximately 6%-7%).

“In this trial involving patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, the addition of daratumumab to lenalidomide and dexamethasone resulted in significantly longer progression-free survival, a higher response rate, an increased depth of response, and a longer duration of response than lenalidomide and dexamethasone alone,” the investigators concluded.

The study was funded by Janssen Research and Development. The investigators reported relationships with Janssen, Celgene, Takeda, Sanofi, and other companies.

SOURCE: Facon T et al. N Engl J Med. 2019;380:2104-15.

For patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT), adding daratumumab to lenalidomide and dexamethasone provides better outcomes than standard therapy alone, based on an interim analysis from the phase 3 MAIA trial.

A greater proportion of patients in the daratumumab group had complete responses and were alive without disease progression after a median follow-up of 28 months, reported lead author Thierry Facon, MD, of the University of Lille (France) and colleagues, who also noted that daratumumab was associated with higher rates of grade 3 or 4 pneumonia, neutropenia, and lymphopenia.

“For patients who are ineligible for stem-cell transplantation, multiagent regimens, including alkylating agents, glucocorticoids, immunomodulatory drugs, proteasome inhibitors, and new agents, are the standard of care,” the investigators wrote in the New England Journal of Medicine.

The findings from MAIA add clarity to the efficacy and safety of daratumumab in this setting, building on previous phase 3 myeloma trials in the same area, such as ALCYONE, CASTOR, and POLLUX, the investigators noted.

MAIA was an open-label, international trial involving 737 patients with newly diagnosed multiple myeloma who were ineligible for ASCT. Patients were randomized in a 1:1 ratio to receive either daratumumab, lenalidomide, and dexamethasone (daratumumab group; n = 368) or lenalidomide and dexamethasone alone (control group; n = 369).

On a 28-day cycle, all patients received oral lenalidomide 25 mg on days 1-21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22. Patients in the daratumumab group received intravenous daratumumab dosed at 16 mg/kg once a week for cycles 1 and 2, every 2 weeks for cycles 3-6, and then every 4 weeks thereafter. Treatment was continued until unacceptable toxic effects or disease progression occurred.

The primary end point was progression-free survival (PFS). Various secondary end points were also evaluated, including time to progression, complete responses, overall survival, and others.

Among the 737 randomized patients, 729 ultimately underwent treatment. The median patient age was 73 years.

Generally, efficacy measures favored adding daratumumab. After a median follow-up of 28.0 months, disease progression or death had occurred in 26.4% of patients in the daratumumab group, compared with 38.8% in the control group.

The median PFS was not reached in the daratumumab group, compared with 31.9 months in the control group. There was a 44% lower risk of disease progression or death among patients who received daratumumab, compared with the control group (hazard ratio, 0.56, P less than .001).

This PFS trend was consistent across most subgroups, including those for sex, age, and race, with the exception of patients with baseline hepatic impairment.

Additional efficacy measures added weight to the apparent benefit of adding daratumumab. For instance, more patients in the daratumumab group achieved a complete response or better (47.6% vs. 24.9%) and were negative for minimum residual disease (24.2% vs. 7.3%).

In terms of safety, more patients in the daratumumab group than the control group developed grade 3 or higher neutropenia (50% vs. 35.3%), lymphopenia (15.1% vs. 10.7%), infections (32.1% vs. 23.3%) or pneumonia (13.7% vs. 7.9%).

In contrast, grade 3 or 4 anemia was less common in the daratumumab group than the control group (11.8% vs. 19.7%). Overall, the rate of serious adverse events was similar for both groups (approximately 63%), as was the rate of adverse events resulting in death (approximately 6%-7%).

“In this trial involving patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, the addition of daratumumab to lenalidomide and dexamethasone resulted in significantly longer progression-free survival, a higher response rate, an increased depth of response, and a longer duration of response than lenalidomide and dexamethasone alone,” the investigators concluded.

The study was funded by Janssen Research and Development. The investigators reported relationships with Janssen, Celgene, Takeda, Sanofi, and other companies.

SOURCE: Facon T et al. N Engl J Med. 2019;380:2104-15.

The cost of oral cancer drugs increased by almost 6% over inflation from 2010 to 2018, leading to increases in out-of-pocket costs for Medicare patients despite reductions in the Part D coverage gap, according to an analysis of formulary and pricing data.

Point-of-sale prices for the 49 oral cancer drugs available before 2018 rose by 40.4% from 2010 to 2018 – an annual increase of 5.8% above the rate of inflation, Stacie B. Dusetzina, PhD, of Vanderbilt University, Nashville, Tenn., and associates reported in JAMA. Another five drugs with data that first became available in 2018 were not included in the cost-increase calculations.

The largest overall increase, 306% (16.2% above inflation per year), belonged to gefitinib (Iressa). Its point-of-sale price rose from $1,960 a month in 2010 to $7,960 in 2018. The award for largest reduction – only two others had a decrease – goes to the only generic available, imatinib. Its monthly cost dropped 44% (–28.1% below inflation per year) from $8,570 in 2016 to $4,822 in 2018, the investigators said (JAMA 2019 May 28;321[20]:2025-7).

Annual out-of-pocket spending for the 13 drugs available for the entire study period increased from $8,794 in 2010 to an expected $10,470 in 2019. Medicare patients’ out-of-pocket costs for those 13 cancer drugs in 2019 are expected to range from $7,220 for lapatinib to $15,472 for lenalidomide, they reported.

“Savings expected through closing the Part D coverage gap or through other policy changes, such as point-of-sale rebates, will be unlikely to offer financial protections to patients needing anticancer drugs. Moreover, because beneficiaries pay a percentage of the drug’s price and have no out-of-pocket spending limits on Part D, even large price decreases may not provide sufficient financial relief to patients requiring long-term anticancer drug use,” Dr. Dusetzina and associates wrote.

The study was supported by the Commonwealth Fund and the Leukemia and Lymphoma Society. The investigators reported receiving grant funding from the study funders.

rfranki@mdedge.com

The cost of oral cancer drugs increased by almost 6% over inflation from 2010 to 2018, leading to increases in out-of-pocket costs for Medicare patients despite reductions in the Part D coverage gap, according to an analysis of formulary and pricing data.

Point-of-sale prices for the 49 oral cancer drugs available before 2018 rose by 40.4% from 2010 to 2018 – an annual increase of 5.8% above the rate of inflation, Stacie B. Dusetzina, PhD, of Vanderbilt University, Nashville, Tenn., and associates reported in JAMA. Another five drugs with data that first became available in 2018 were not included in the cost-increase calculations.

The largest overall increase, 306% (16.2% above inflation per year), belonged to gefitinib (Iressa). Its point-of-sale price rose from $1,960 a month in 2010 to $7,960 in 2018. The award for largest reduction – only two others had a decrease – goes to the only generic available, imatinib. Its monthly cost dropped 44% (–28.1% below inflation per year) from $8,570 in 2016 to $4,822 in 2018, the investigators said (JAMA 2019 May 28;321[20]:2025-7).

Annual out-of-pocket spending for the 13 drugs available for the entire study period increased from $8,794 in 2010 to an expected $10,470 in 2019. Medicare patients’ out-of-pocket costs for those 13 cancer drugs in 2019 are expected to range from $7,220 for lapatinib to $15,472 for lenalidomide, they reported.

“Savings expected through closing the Part D coverage gap or through other policy changes, such as point-of-sale rebates, will be unlikely to offer financial protections to patients needing anticancer drugs. Moreover, because beneficiaries pay a percentage of the drug’s price and have no out-of-pocket spending limits on Part D, even large price decreases may not provide sufficient financial relief to patients requiring long-term anticancer drug use,” Dr. Dusetzina and associates wrote.

The study was supported by the Commonwealth Fund and the Leukemia and Lymphoma Society. The investigators reported receiving grant funding from the study funders.

rfranki@mdedge.com

The cost of oral cancer drugs increased by almost 6% over inflation from 2010 to 2018, leading to increases in out-of-pocket costs for Medicare patients despite reductions in the Part D coverage gap, according to an analysis of formulary and pricing data.

Point-of-sale prices for the 49 oral cancer drugs available before 2018 rose by 40.4% from 2010 to 2018 – an annual increase of 5.8% above the rate of inflation, Stacie B. Dusetzina, PhD, of Vanderbilt University, Nashville, Tenn., and associates reported in JAMA. Another five drugs with data that first became available in 2018 were not included in the cost-increase calculations.

The largest overall increase, 306% (16.2% above inflation per year), belonged to gefitinib (Iressa). Its point-of-sale price rose from $1,960 a month in 2010 to $7,960 in 2018. The award for largest reduction – only two others had a decrease – goes to the only generic available, imatinib. Its monthly cost dropped 44% (–28.1% below inflation per year) from $8,570 in 2016 to $4,822 in 2018, the investigators said (JAMA 2019 May 28;321[20]:2025-7).

Annual out-of-pocket spending for the 13 drugs available for the entire study period increased from $8,794 in 2010 to an expected $10,470 in 2019. Medicare patients’ out-of-pocket costs for those 13 cancer drugs in 2019 are expected to range from $7,220 for lapatinib to $15,472 for lenalidomide, they reported.

“Savings expected through closing the Part D coverage gap or through other policy changes, such as point-of-sale rebates, will be unlikely to offer financial protections to patients needing anticancer drugs. Moreover, because beneficiaries pay a percentage of the drug’s price and have no out-of-pocket spending limits on Part D, even large price decreases may not provide sufficient financial relief to patients requiring long-term anticancer drug use,” Dr. Dusetzina and associates wrote.

The study was supported by the Commonwealth Fund and the Leukemia and Lymphoma Society. The investigators reported receiving grant funding from the study funders.

rfranki@mdedge.com