AVAHO

Treating lung cancer with proton beam radiotherapy instead of conventional photon radiotherapy almost halves the dose to the heart, reducing the risk of cardiovascular events over the next several years, a cohort study suggests.

Photo courtesy of Dr. Tris Arscott

The findings were reported at the American Society for Radiation Oncology Annual Meeting 2020.

Patients with lung cancer often have underlying cardiac risk factors, noted lead investigator Timothy Kegelman, MD, PhD, of University of Pennsylvania in Philadelphia.

“The dose to the heart correlates with adverse cardiovascular events following radiation therapy. One strategy to minimize dose to the heart is proton beam radiation,” Dr. Kegelman said.

He and his colleagues retrospectively studied consecutive patients with locally advanced non–small cell lung cancer (NSCLC) treated with chemotherapy plus either proton beam radiotherapy or conventional photon radiotherapy.

The team used electronic health records to ascertain incidence of six cardiovascular events: MI, atrial fibrillation, coronary artery disease, heart failure, stroke, and transient ischemic attack. Patients who had previously experienced an event were not considered as part of the at-risk population for that specific event after radiotherapy.

Analyses were based on 98 patients who received proton beam radiotherapy and 104 patients who received conventional photon radiotherapy.

At baseline, the proton cohort was older, had a heavier smoking history, and had a higher prevalence of previous cardiovascular events (46.9% vs. 31.7%; P = .03).

The total median radiation dose was identical for the proton and photon groups (66.6 Gy), but the former group had significantly lower measures of cardiac radiation dose, including roughly half the mean dose to the heart (6.9 vs. 13.3 Gy).
 

Outcomes and next steps

At a median follow-up of 29 months, the proton beam radiotherapy group had a significantly lower incidence of transient ischemic attack, compared with the photon radiotherapy group (1.1% vs. 8.2%; P = .04).

The proton group also had numerically lower incidences of MI (2.3% vs. 9.0%; P = .06) and stroke (3.2% vs. 6.1%; P = .50).

The proton and photon groups were similar as far as the incidence of total cardiovascular events (53.1% vs. 47.1%; P = .48) and the 3-year overall survival rate (38.8% vs. 42.1%; P = .99).

“Our future studies aim to examine the potential relationships between grade of cardiac event and type of radiotherapy and dose to cardiac substructures,” Dr. Kegelman commented.

In addition, his institution is participating in RTOG 1308, a phase 3 trial comparing photon and proton beam radiotherapy in patients with inoperable lung cancer that will better assess cardiac-related morbidity and mortality. The trial is expected to be completed by the end of 2025.
 

Accumulating evidence

“This study adds to a growing body of evidence about the potential importance of heart dose in any radiation modality,” said Daniel Gomez, MD, MBA, of Memorial Sloan Kettering Cancer Center in New York, who was not involved in the study.

The RTOG 0617 trial and the Lung ART trial previously showed correlations between lower radiation dose to the heart and better survival in patients with lung cancer, Dr. Gomez noted.

“It’s been well established that protons can improve heart dose, and therefore it’s been inferred that they may improve outcomes, but the exact mechanisms remain unclear,” Dr. Gomez said.

Proton beam radiotherapy performed well in a single-arm, phase 2 trial among patients with unresectable NSCLC.

“The ongoing phase 3 trial is using a more modern proton technique and has a larger population, with a randomized study design. It will be much more informative,” Dr. Gomez predicted.

The current study did not receive specific funding. Dr. Kegelman disclosed no relevant conflicts of interest. Dr. Gomez disclosed honoraria from Varian.

SOURCE: Kegelman TP et al. ASTRO 2020, Abstract 1046.

Treating lung cancer with proton beam radiotherapy instead of conventional photon radiotherapy almost halves the dose to the heart, reducing the risk of cardiovascular events over the next several years, a cohort study suggests.

Photo courtesy of Dr. Tris Arscott

The findings were reported at the American Society for Radiation Oncology Annual Meeting 2020.

Patients with lung cancer often have underlying cardiac risk factors, noted lead investigator Timothy Kegelman, MD, PhD, of University of Pennsylvania in Philadelphia.

“The dose to the heart correlates with adverse cardiovascular events following radiation therapy. One strategy to minimize dose to the heart is proton beam radiation,” Dr. Kegelman said.

He and his colleagues retrospectively studied consecutive patients with locally advanced non–small cell lung cancer (NSCLC) treated with chemotherapy plus either proton beam radiotherapy or conventional photon radiotherapy.

The team used electronic health records to ascertain incidence of six cardiovascular events: MI, atrial fibrillation, coronary artery disease, heart failure, stroke, and transient ischemic attack. Patients who had previously experienced an event were not considered as part of the at-risk population for that specific event after radiotherapy.

Analyses were based on 98 patients who received proton beam radiotherapy and 104 patients who received conventional photon radiotherapy.

At baseline, the proton cohort was older, had a heavier smoking history, and had a higher prevalence of previous cardiovascular events (46.9% vs. 31.7%; P = .03).

The total median radiation dose was identical for the proton and photon groups (66.6 Gy), but the former group had significantly lower measures of cardiac radiation dose, including roughly half the mean dose to the heart (6.9 vs. 13.3 Gy).
 

Outcomes and next steps

At a median follow-up of 29 months, the proton beam radiotherapy group had a significantly lower incidence of transient ischemic attack, compared with the photon radiotherapy group (1.1% vs. 8.2%; P = .04).

The proton group also had numerically lower incidences of MI (2.3% vs. 9.0%; P = .06) and stroke (3.2% vs. 6.1%; P = .50).

The proton and photon groups were similar as far as the incidence of total cardiovascular events (53.1% vs. 47.1%; P = .48) and the 3-year overall survival rate (38.8% vs. 42.1%; P = .99).

“Our future studies aim to examine the potential relationships between grade of cardiac event and type of radiotherapy and dose to cardiac substructures,” Dr. Kegelman commented.

In addition, his institution is participating in RTOG 1308, a phase 3 trial comparing photon and proton beam radiotherapy in patients with inoperable lung cancer that will better assess cardiac-related morbidity and mortality. The trial is expected to be completed by the end of 2025.
 

Accumulating evidence

“This study adds to a growing body of evidence about the potential importance of heart dose in any radiation modality,” said Daniel Gomez, MD, MBA, of Memorial Sloan Kettering Cancer Center in New York, who was not involved in the study.

The RTOG 0617 trial and the Lung ART trial previously showed correlations between lower radiation dose to the heart and better survival in patients with lung cancer, Dr. Gomez noted.

“It’s been well established that protons can improve heart dose, and therefore it’s been inferred that they may improve outcomes, but the exact mechanisms remain unclear,” Dr. Gomez said.

Proton beam radiotherapy performed well in a single-arm, phase 2 trial among patients with unresectable NSCLC.

“The ongoing phase 3 trial is using a more modern proton technique and has a larger population, with a randomized study design. It will be much more informative,” Dr. Gomez predicted.

The current study did not receive specific funding. Dr. Kegelman disclosed no relevant conflicts of interest. Dr. Gomez disclosed honoraria from Varian.

SOURCE: Kegelman TP et al. ASTRO 2020, Abstract 1046.

Treating lung cancer with proton beam radiotherapy instead of conventional photon radiotherapy almost halves the dose to the heart, reducing the risk of cardiovascular events over the next several years, a cohort study suggests.

Photo courtesy of Dr. Tris Arscott

The findings were reported at the American Society for Radiation Oncology Annual Meeting 2020.

Patients with lung cancer often have underlying cardiac risk factors, noted lead investigator Timothy Kegelman, MD, PhD, of University of Pennsylvania in Philadelphia.

“The dose to the heart correlates with adverse cardiovascular events following radiation therapy. One strategy to minimize dose to the heart is proton beam radiation,” Dr. Kegelman said.

He and his colleagues retrospectively studied consecutive patients with locally advanced non–small cell lung cancer (NSCLC) treated with chemotherapy plus either proton beam radiotherapy or conventional photon radiotherapy.

The team used electronic health records to ascertain incidence of six cardiovascular events: MI, atrial fibrillation, coronary artery disease, heart failure, stroke, and transient ischemic attack. Patients who had previously experienced an event were not considered as part of the at-risk population for that specific event after radiotherapy.

Analyses were based on 98 patients who received proton beam radiotherapy and 104 patients who received conventional photon radiotherapy.

At baseline, the proton cohort was older, had a heavier smoking history, and had a higher prevalence of previous cardiovascular events (46.9% vs. 31.7%; P = .03).

The total median radiation dose was identical for the proton and photon groups (66.6 Gy), but the former group had significantly lower measures of cardiac radiation dose, including roughly half the mean dose to the heart (6.9 vs. 13.3 Gy).
 

Outcomes and next steps

At a median follow-up of 29 months, the proton beam radiotherapy group had a significantly lower incidence of transient ischemic attack, compared with the photon radiotherapy group (1.1% vs. 8.2%; P = .04).

The proton group also had numerically lower incidences of MI (2.3% vs. 9.0%; P = .06) and stroke (3.2% vs. 6.1%; P = .50).

The proton and photon groups were similar as far as the incidence of total cardiovascular events (53.1% vs. 47.1%; P = .48) and the 3-year overall survival rate (38.8% vs. 42.1%; P = .99).

“Our future studies aim to examine the potential relationships between grade of cardiac event and type of radiotherapy and dose to cardiac substructures,” Dr. Kegelman commented.

In addition, his institution is participating in RTOG 1308, a phase 3 trial comparing photon and proton beam radiotherapy in patients with inoperable lung cancer that will better assess cardiac-related morbidity and mortality. The trial is expected to be completed by the end of 2025.
 

Accumulating evidence

“This study adds to a growing body of evidence about the potential importance of heart dose in any radiation modality,” said Daniel Gomez, MD, MBA, of Memorial Sloan Kettering Cancer Center in New York, who was not involved in the study.

The RTOG 0617 trial and the Lung ART trial previously showed correlations between lower radiation dose to the heart and better survival in patients with lung cancer, Dr. Gomez noted.

“It’s been well established that protons can improve heart dose, and therefore it’s been inferred that they may improve outcomes, but the exact mechanisms remain unclear,” Dr. Gomez said.

Proton beam radiotherapy performed well in a single-arm, phase 2 trial among patients with unresectable NSCLC.

“The ongoing phase 3 trial is using a more modern proton technique and has a larger population, with a randomized study design. It will be much more informative,” Dr. Gomez predicted.

The current study did not receive specific funding. Dr. Kegelman disclosed no relevant conflicts of interest. Dr. Gomez disclosed honoraria from Varian.

SOURCE: Kegelman TP et al. ASTRO 2020, Abstract 1046.

Home administration of bortezomib (Velcade), as a once or twice-weekly subcutaneous self-injection is safe in patients with myeloma, significantly reducing hospital visits, and likely improving quality of life, a study shows.

The majority (43 of 52 patients) successfully self-administered bortezomib and completed the course. Also, hospital visits for those on the so-called Homecare programme reduced by 50%, with most visits comprising a fortnightly drug pickup from the drive-through pharmacy.

The work was presented as a poster by lead author and researcher, Kanchana De Abrew, hematology consultant at University Hospital Southampton NHS Foundation Trust, at this year’s virtual British Society of Haematology (BSH) meeting. De Abrew conducted the study while at Queen Alexandra Hospital, Portsmouth.

“We wanted to minimize patient visits to hospital because with travel time and waiting time, patients can easily find a visit takes up a whole morning, so this relates to their quality of life as well as having financial implications for patients,” Dr. De Abrew said in an interview. It also reduced the impact on day units and improved capacity for other services.

Dr. De Abrew noted that the study was conducted in the pre-COVID-19 era, but that the current enhanced threat of infection only served to reinforce the benefits of self-administration at home and avoiding unnecessary hospital visits.

“This project could easily be set up in other hospitals and some other centers have already contacted us about this. It might suit rural areas,” she added.
 

‘Safe and effective’

Dr. Matthew Jenner, consultant hematologist for University Hospital Southampton NHS Foundation Trust, who was not involved in the study, remarked that the study demonstrated another way to deliver bortezomib outside of hospital in addition to home care services that require trained nurses to administer treatment. “With a modest amount of training of the patient and family, it is both a safe and effective way of delivering treatment. This reduces hospital visits for the patient and frees up much needed capacity for heavily stretched chemotherapy units, creating space for other newer treatments that require hospital attendance.

“It is of benefit all round to both the patients undertaking self-administration and those who benefit from improved capacity,” added Dr. Jenner.
 

Avoiding hospital visits

Myeloma patients are already immunosuppressed prior to treatment and then this worsens once on treatment. Once they are sitting in a clinic environment they are surrounded by similarly immunosuppressed patients, so their risk is heightened further.

Figures suggest myeloma cases are on the increase. Annually, the United Kingdom sees around 5,800 new cases of myeloma and incidence increased by a significant 32% between the periods of 1993-1995 and 2015-2017. These figures were reflected in the patient numbers at the Queen Alexandra Hospital where the study was carried out. Many patients receive bortezomib, which forms the backbone of four National Institute for Health and Care Excellence (NICE) approved regimens.

“Patients are living longer so in the early 2000s patients had a life expectancy of 2-3 years, whereas now patients live for around 5 years. Also, the scope and lines of treatments have increased a lot. Over 50% of patients are likely to have bortezomib at some point in their management,” explained Dr. De Abrew.

Bortezomib is given once or twice weekly as a subcutaneous injection, and this usually continues for approximately 6-8 months with four to six cycles. Administering the drug in hospital requires around a half-hour slot placing considerable burden on the hematology day unit resources, and this can adversely affect the patient experience with waiting times and the need for frequent hospital visits.
 

Patient or relatives taught to self-administer at home

In 2017, clinical nurse specialists taught suitable patients to self-administer bortezomib in the Homecare protocol. Patients collected a 2-week supply of the drug. The protocol aimed to improve patient quality of life by reducing hospital visits, and increasing capacity in the hematology day unit. Since the start of the programme in 2017, the majority (71) of myeloma patients at Portsmouth have been treated through the Homecare program.

Dr. De Abrew conducted a retrospective review of patients who received bortezomib between January and October 2019 aimed at determining the effectiveness of the Homecare programme. To this end, she measured the proportion able to commence the Homecare protocol; the proportion successful in completing treatment on the Homecare protocol; the amount of additional clinical nurse specialist time required to support the Homecare protocol; and the number of associated adverse incidents.

A total of 52 bortezomib-treated patients were included in the study. Patients were excluded if they were on a different combination of drugs that required hospital visits, or inpatient care for other reasons. Three patients ceased the drug – two because of toxicity, and one because of rapid progression.  The average age of patients was 74 years, and 55.8% were using bortezomib as first-line, 36.5% second-line, and the remainder third-line or more.

The vast majority started the Homecare protocol (45/52), and 25 self-administered and 17 received a relative’s help. A total of 43 completed the self-administration protocol with two reverting to hospital assistance. Bortezomib was given for four to six cycles lasting around 6-8 months.

Clinical nurse specialists trained 38 patients for home care, with an average training time of 43 minutes. Two of these patients were considered unsuitable for self-administration. The remainder were trained by ward nurses or did not require training having received bortezomib previously.

A total of 20 patients required additional clinical nurse specialist time requiring an average of 55 minutes. Of those requiring additional support: Seven needed retraining; two needed the first dose delivered by a nurse specialist; two requested help from the hematology unit; and nine wanted general extra support – for example, help with injection site queries (usually administered to the abdominal area), reassurance during administration, syringe queries, administrative queries, and queries around spillages.

“Importantly, patients always have the phone number of the nurse specialist at hand. But most people managed okay, and even if they needed additional support they still got there,” remarked Dr. De Abrew.

In terms of adverse events, there were six in total. These included three reported spillages (with no harm caused), and three experienced injection site incidents (rash, pain). “We found a low number of reported adverse events,” she said.

Dr. De Abrew added that generally, many more medications were being converted to subcutaneous formulations in myeloma and other hematology conditions. “Perhaps these results could inform self-administration of other drugs. In hematology, we get so many new drugs come through every year, but we don’t get the increased resources to manage this in the day units. Broadening self-administration could really help with capacity as well as improve quality of life for the patients.

“These results show that it can be done!” she said. 

Dr. De Abrew declared no relevant conflicts of interest. Dr. Jenner declared receiving honoraria from Janssen, which manufactures branded Velcade (bortezomib).

A version of this story originally appeared on Medscape.com.

Home administration of bortezomib (Velcade), as a once or twice-weekly subcutaneous self-injection is safe in patients with myeloma, significantly reducing hospital visits, and likely improving quality of life, a study shows.

The majority (43 of 52 patients) successfully self-administered bortezomib and completed the course. Also, hospital visits for those on the so-called Homecare programme reduced by 50%, with most visits comprising a fortnightly drug pickup from the drive-through pharmacy.

The work was presented as a poster by lead author and researcher, Kanchana De Abrew, hematology consultant at University Hospital Southampton NHS Foundation Trust, at this year’s virtual British Society of Haematology (BSH) meeting. De Abrew conducted the study while at Queen Alexandra Hospital, Portsmouth.

“We wanted to minimize patient visits to hospital because with travel time and waiting time, patients can easily find a visit takes up a whole morning, so this relates to their quality of life as well as having financial implications for patients,” Dr. De Abrew said in an interview. It also reduced the impact on day units and improved capacity for other services.

Dr. De Abrew noted that the study was conducted in the pre-COVID-19 era, but that the current enhanced threat of infection only served to reinforce the benefits of self-administration at home and avoiding unnecessary hospital visits.

“This project could easily be set up in other hospitals and some other centers have already contacted us about this. It might suit rural areas,” she added.
 

‘Safe and effective’

Dr. Matthew Jenner, consultant hematologist for University Hospital Southampton NHS Foundation Trust, who was not involved in the study, remarked that the study demonstrated another way to deliver bortezomib outside of hospital in addition to home care services that require trained nurses to administer treatment. “With a modest amount of training of the patient and family, it is both a safe and effective way of delivering treatment. This reduces hospital visits for the patient and frees up much needed capacity for heavily stretched chemotherapy units, creating space for other newer treatments that require hospital attendance.

“It is of benefit all round to both the patients undertaking self-administration and those who benefit from improved capacity,” added Dr. Jenner.
 

Avoiding hospital visits

Myeloma patients are already immunosuppressed prior to treatment and then this worsens once on treatment. Once they are sitting in a clinic environment they are surrounded by similarly immunosuppressed patients, so their risk is heightened further.

Figures suggest myeloma cases are on the increase. Annually, the United Kingdom sees around 5,800 new cases of myeloma and incidence increased by a significant 32% between the periods of 1993-1995 and 2015-2017. These figures were reflected in the patient numbers at the Queen Alexandra Hospital where the study was carried out. Many patients receive bortezomib, which forms the backbone of four National Institute for Health and Care Excellence (NICE) approved regimens.

“Patients are living longer so in the early 2000s patients had a life expectancy of 2-3 years, whereas now patients live for around 5 years. Also, the scope and lines of treatments have increased a lot. Over 50% of patients are likely to have bortezomib at some point in their management,” explained Dr. De Abrew.

Bortezomib is given once or twice weekly as a subcutaneous injection, and this usually continues for approximately 6-8 months with four to six cycles. Administering the drug in hospital requires around a half-hour slot placing considerable burden on the hematology day unit resources, and this can adversely affect the patient experience with waiting times and the need for frequent hospital visits.
 

Patient or relatives taught to self-administer at home

In 2017, clinical nurse specialists taught suitable patients to self-administer bortezomib in the Homecare protocol. Patients collected a 2-week supply of the drug. The protocol aimed to improve patient quality of life by reducing hospital visits, and increasing capacity in the hematology day unit. Since the start of the programme in 2017, the majority (71) of myeloma patients at Portsmouth have been treated through the Homecare program.

Dr. De Abrew conducted a retrospective review of patients who received bortezomib between January and October 2019 aimed at determining the effectiveness of the Homecare programme. To this end, she measured the proportion able to commence the Homecare protocol; the proportion successful in completing treatment on the Homecare protocol; the amount of additional clinical nurse specialist time required to support the Homecare protocol; and the number of associated adverse incidents.

A total of 52 bortezomib-treated patients were included in the study. Patients were excluded if they were on a different combination of drugs that required hospital visits, or inpatient care for other reasons. Three patients ceased the drug – two because of toxicity, and one because of rapid progression.  The average age of patients was 74 years, and 55.8% were using bortezomib as first-line, 36.5% second-line, and the remainder third-line or more.

The vast majority started the Homecare protocol (45/52), and 25 self-administered and 17 received a relative’s help. A total of 43 completed the self-administration protocol with two reverting to hospital assistance. Bortezomib was given for four to six cycles lasting around 6-8 months.

Clinical nurse specialists trained 38 patients for home care, with an average training time of 43 minutes. Two of these patients were considered unsuitable for self-administration. The remainder were trained by ward nurses or did not require training having received bortezomib previously.

A total of 20 patients required additional clinical nurse specialist time requiring an average of 55 minutes. Of those requiring additional support: Seven needed retraining; two needed the first dose delivered by a nurse specialist; two requested help from the hematology unit; and nine wanted general extra support – for example, help with injection site queries (usually administered to the abdominal area), reassurance during administration, syringe queries, administrative queries, and queries around spillages.

“Importantly, patients always have the phone number of the nurse specialist at hand. But most people managed okay, and even if they needed additional support they still got there,” remarked Dr. De Abrew.

In terms of adverse events, there were six in total. These included three reported spillages (with no harm caused), and three experienced injection site incidents (rash, pain). “We found a low number of reported adverse events,” she said.

Dr. De Abrew added that generally, many more medications were being converted to subcutaneous formulations in myeloma and other hematology conditions. “Perhaps these results could inform self-administration of other drugs. In hematology, we get so many new drugs come through every year, but we don’t get the increased resources to manage this in the day units. Broadening self-administration could really help with capacity as well as improve quality of life for the patients.

“These results show that it can be done!” she said. 

Dr. De Abrew declared no relevant conflicts of interest. Dr. Jenner declared receiving honoraria from Janssen, which manufactures branded Velcade (bortezomib).

A version of this story originally appeared on Medscape.com.

Home administration of bortezomib (Velcade), as a once or twice-weekly subcutaneous self-injection is safe in patients with myeloma, significantly reducing hospital visits, and likely improving quality of life, a study shows.

The majority (43 of 52 patients) successfully self-administered bortezomib and completed the course. Also, hospital visits for those on the so-called Homecare programme reduced by 50%, with most visits comprising a fortnightly drug pickup from the drive-through pharmacy.

The work was presented as a poster by lead author and researcher, Kanchana De Abrew, hematology consultant at University Hospital Southampton NHS Foundation Trust, at this year’s virtual British Society of Haematology (BSH) meeting. De Abrew conducted the study while at Queen Alexandra Hospital, Portsmouth.

“We wanted to minimize patient visits to hospital because with travel time and waiting time, patients can easily find a visit takes up a whole morning, so this relates to their quality of life as well as having financial implications for patients,” Dr. De Abrew said in an interview. It also reduced the impact on day units and improved capacity for other services.

Dr. De Abrew noted that the study was conducted in the pre-COVID-19 era, but that the current enhanced threat of infection only served to reinforce the benefits of self-administration at home and avoiding unnecessary hospital visits.

“This project could easily be set up in other hospitals and some other centers have already contacted us about this. It might suit rural areas,” she added.
 

‘Safe and effective’

Dr. Matthew Jenner, consultant hematologist for University Hospital Southampton NHS Foundation Trust, who was not involved in the study, remarked that the study demonstrated another way to deliver bortezomib outside of hospital in addition to home care services that require trained nurses to administer treatment. “With a modest amount of training of the patient and family, it is both a safe and effective way of delivering treatment. This reduces hospital visits for the patient and frees up much needed capacity for heavily stretched chemotherapy units, creating space for other newer treatments that require hospital attendance.

“It is of benefit all round to both the patients undertaking self-administration and those who benefit from improved capacity,” added Dr. Jenner.
 

Avoiding hospital visits

Myeloma patients are already immunosuppressed prior to treatment and then this worsens once on treatment. Once they are sitting in a clinic environment they are surrounded by similarly immunosuppressed patients, so their risk is heightened further.

Figures suggest myeloma cases are on the increase. Annually, the United Kingdom sees around 5,800 new cases of myeloma and incidence increased by a significant 32% between the periods of 1993-1995 and 2015-2017. These figures were reflected in the patient numbers at the Queen Alexandra Hospital where the study was carried out. Many patients receive bortezomib, which forms the backbone of four National Institute for Health and Care Excellence (NICE) approved regimens.

“Patients are living longer so in the early 2000s patients had a life expectancy of 2-3 years, whereas now patients live for around 5 years. Also, the scope and lines of treatments have increased a lot. Over 50% of patients are likely to have bortezomib at some point in their management,” explained Dr. De Abrew.

Bortezomib is given once or twice weekly as a subcutaneous injection, and this usually continues for approximately 6-8 months with four to six cycles. Administering the drug in hospital requires around a half-hour slot placing considerable burden on the hematology day unit resources, and this can adversely affect the patient experience with waiting times and the need for frequent hospital visits.
 

Patient or relatives taught to self-administer at home

In 2017, clinical nurse specialists taught suitable patients to self-administer bortezomib in the Homecare protocol. Patients collected a 2-week supply of the drug. The protocol aimed to improve patient quality of life by reducing hospital visits, and increasing capacity in the hematology day unit. Since the start of the programme in 2017, the majority (71) of myeloma patients at Portsmouth have been treated through the Homecare program.

Dr. De Abrew conducted a retrospective review of patients who received bortezomib between January and October 2019 aimed at determining the effectiveness of the Homecare programme. To this end, she measured the proportion able to commence the Homecare protocol; the proportion successful in completing treatment on the Homecare protocol; the amount of additional clinical nurse specialist time required to support the Homecare protocol; and the number of associated adverse incidents.

A total of 52 bortezomib-treated patients were included in the study. Patients were excluded if they were on a different combination of drugs that required hospital visits, or inpatient care for other reasons. Three patients ceased the drug – two because of toxicity, and one because of rapid progression.  The average age of patients was 74 years, and 55.8% were using bortezomib as first-line, 36.5% second-line, and the remainder third-line or more.

The vast majority started the Homecare protocol (45/52), and 25 self-administered and 17 received a relative’s help. A total of 43 completed the self-administration protocol with two reverting to hospital assistance. Bortezomib was given for four to six cycles lasting around 6-8 months.

Clinical nurse specialists trained 38 patients for home care, with an average training time of 43 minutes. Two of these patients were considered unsuitable for self-administration. The remainder were trained by ward nurses or did not require training having received bortezomib previously.

A total of 20 patients required additional clinical nurse specialist time requiring an average of 55 minutes. Of those requiring additional support: Seven needed retraining; two needed the first dose delivered by a nurse specialist; two requested help from the hematology unit; and nine wanted general extra support – for example, help with injection site queries (usually administered to the abdominal area), reassurance during administration, syringe queries, administrative queries, and queries around spillages.

“Importantly, patients always have the phone number of the nurse specialist at hand. But most people managed okay, and even if they needed additional support they still got there,” remarked Dr. De Abrew.

In terms of adverse events, there were six in total. These included three reported spillages (with no harm caused), and three experienced injection site incidents (rash, pain). “We found a low number of reported adverse events,” she said.

Dr. De Abrew added that generally, many more medications were being converted to subcutaneous formulations in myeloma and other hematology conditions. “Perhaps these results could inform self-administration of other drugs. In hematology, we get so many new drugs come through every year, but we don’t get the increased resources to manage this in the day units. Broadening self-administration could really help with capacity as well as improve quality of life for the patients.

“These results show that it can be done!” she said. 

Dr. De Abrew declared no relevant conflicts of interest. Dr. Jenner declared receiving honoraria from Janssen, which manufactures branded Velcade (bortezomib).

A version of this story originally appeared on Medscape.com.

Ibrutinib showed significant impact on circulating malignant and nonmalignant immune cells and was found to restore healthy T-cell function in patients with chronic lymphocytic leukemia (CLL), according to the results of a comparative study of CLL patients and healthy controls.

Researchers compared circulating counts of 21 immune blood cell subsets throughout the first year of treatment in 55 patients with relapsed/refractory (R/R) CLL from the RESONATE trial and 50 previously untreated CLL patients from the RESONATE-2 trial with 20 untreated age-matched healthy donors, according to a report published online in Leukemia Research.

In addition, T-cell function was assessed in response to T-cell–receptor stimulation in 21 patients with R/R CLL, compared with 18 age-matched healthy donors, according to Isabelle G. Solman, MS, an employee of Translational Medicine, Pharmacyclics, Sunnyvale, Calif. and colleagues.
 

Positive indicators

Ibrutinib significantly decreased pathologically high circulating B cells, regulatory T cells, effector/memory CD4+ and CD8+ T cells (including exhausted and chronically activated T cells), natural killer (NK) T cells, and myeloid-derived suppressor cells; preserved naive T cells and NK cells; and increased circulating classical monocytes, according to the researchers.

Ibrutinib also significantly restored T-cell proliferative ability, degranulation, and cytokine secretion. Over the same period, ofatumumab or chlorambucil did not confer the same spectrum of normalization as ibrutinib in multiple immune subsets that were examined, they added.

“These results establish that ibrutinib has a significant and likely positive impact on circulating malignant and nonmalignant immune cells and restores healthy T-cell function,” the researchers indicated.

“Ibrutinib has a significant, progressively positive impact on both malignant and nonmalignant immune cells in CLL. These positive effects on circulating nonmalignant immune cells may contribute to long-term CLL disease control, overall health status, and decreased susceptibility to infection,” they concluded.

The study was funded by Pharmacyclics, an AbbVie Company. Ms. Solman is an employee of Translational Medicine, Pharmacyclics, Sunnyvale, Calif. as were several other authors.

[email protected]

SOURCE: Solman IG et al. Leuk Res. 2020;97. doi: 10.1016/j.leukres.2020.106432.

Ibrutinib showed significant impact on circulating malignant and nonmalignant immune cells and was found to restore healthy T-cell function in patients with chronic lymphocytic leukemia (CLL), according to the results of a comparative study of CLL patients and healthy controls.

Researchers compared circulating counts of 21 immune blood cell subsets throughout the first year of treatment in 55 patients with relapsed/refractory (R/R) CLL from the RESONATE trial and 50 previously untreated CLL patients from the RESONATE-2 trial with 20 untreated age-matched healthy donors, according to a report published online in Leukemia Research.

In addition, T-cell function was assessed in response to T-cell–receptor stimulation in 21 patients with R/R CLL, compared with 18 age-matched healthy donors, according to Isabelle G. Solman, MS, an employee of Translational Medicine, Pharmacyclics, Sunnyvale, Calif. and colleagues.
 

Positive indicators

Ibrutinib significantly decreased pathologically high circulating B cells, regulatory T cells, effector/memory CD4+ and CD8+ T cells (including exhausted and chronically activated T cells), natural killer (NK) T cells, and myeloid-derived suppressor cells; preserved naive T cells and NK cells; and increased circulating classical monocytes, according to the researchers.

Ibrutinib also significantly restored T-cell proliferative ability, degranulation, and cytokine secretion. Over the same period, ofatumumab or chlorambucil did not confer the same spectrum of normalization as ibrutinib in multiple immune subsets that were examined, they added.

“These results establish that ibrutinib has a significant and likely positive impact on circulating malignant and nonmalignant immune cells and restores healthy T-cell function,” the researchers indicated.

“Ibrutinib has a significant, progressively positive impact on both malignant and nonmalignant immune cells in CLL. These positive effects on circulating nonmalignant immune cells may contribute to long-term CLL disease control, overall health status, and decreased susceptibility to infection,” they concluded.

The study was funded by Pharmacyclics, an AbbVie Company. Ms. Solman is an employee of Translational Medicine, Pharmacyclics, Sunnyvale, Calif. as were several other authors.

[email protected]

SOURCE: Solman IG et al. Leuk Res. 2020;97. doi: 10.1016/j.leukres.2020.106432.

Ibrutinib showed significant impact on circulating malignant and nonmalignant immune cells and was found to restore healthy T-cell function in patients with chronic lymphocytic leukemia (CLL), according to the results of a comparative study of CLL patients and healthy controls.

Researchers compared circulating counts of 21 immune blood cell subsets throughout the first year of treatment in 55 patients with relapsed/refractory (R/R) CLL from the RESONATE trial and 50 previously untreated CLL patients from the RESONATE-2 trial with 20 untreated age-matched healthy donors, according to a report published online in Leukemia Research.

In addition, T-cell function was assessed in response to T-cell–receptor stimulation in 21 patients with R/R CLL, compared with 18 age-matched healthy donors, according to Isabelle G. Solman, MS, an employee of Translational Medicine, Pharmacyclics, Sunnyvale, Calif. and colleagues.
 

Positive indicators

Ibrutinib significantly decreased pathologically high circulating B cells, regulatory T cells, effector/memory CD4+ and CD8+ T cells (including exhausted and chronically activated T cells), natural killer (NK) T cells, and myeloid-derived suppressor cells; preserved naive T cells and NK cells; and increased circulating classical monocytes, according to the researchers.

Ibrutinib also significantly restored T-cell proliferative ability, degranulation, and cytokine secretion. Over the same period, ofatumumab or chlorambucil did not confer the same spectrum of normalization as ibrutinib in multiple immune subsets that were examined, they added.

“These results establish that ibrutinib has a significant and likely positive impact on circulating malignant and nonmalignant immune cells and restores healthy T-cell function,” the researchers indicated.

“Ibrutinib has a significant, progressively positive impact on both malignant and nonmalignant immune cells in CLL. These positive effects on circulating nonmalignant immune cells may contribute to long-term CLL disease control, overall health status, and decreased susceptibility to infection,” they concluded.

The study was funded by Pharmacyclics, an AbbVie Company. Ms. Solman is an employee of Translational Medicine, Pharmacyclics, Sunnyvale, Calif. as were several other authors.

[email protected]

SOURCE: Solman IG et al. Leuk Res. 2020;97. doi: 10.1016/j.leukres.2020.106432.

Precision medicine therapy proved feasible and superior to standard-of-care (SOC) chemotherapy in patients with acute myeloid leukemia in the Beat AML Master Clinical Trial.

The 30-day mortality rates were 3.7% versus 20.4% in 224 patients who enrolled in the Beat AML trial precision medicine substudies within 7 days of prospective genomic profiling and 103 who elected SOC chemotherapy, respectively, Amy Burd, PhD, vice president of research strategy for the Leukemia & Lymphoma Society, Rye Brook, N.Y. and her colleagues reported online in Nature Medicine.

Overall survival (OS) at a median of 7.1 months was also significantly longer with precision medicine than with SOC chemotherapy (median, 12.8 vs. 3.9 months), the investigators found.

In an additional 28 patients who selected an investigational therapy rather than a precision medicine strategy or SOC chemotherapy, median OS was not reached, and in 38 who chose palliative care, median OS was 0.6 months, they noted. Care type was unknown in two patients.

The results were similar after controlling for demographic, clinical, and molecular variables and did not change when patients with adverse events of special interest were excluded from the analysis or when only those with survival greater than 2 weeks were included in the analysis.

AML confers an adverse outcome in older adults and therefore is typically treated rapidly after diagnosis. This has precluded consideration of patients’ mutational profile for treatment decisions.

Beat AML, however, sought to prospectively assess the feasibility of quickly ascertaining cytogenetic and mutational data for the purpose of improving outcomes through targeted treatment.

“The study shows that delaying treatment up to 7 days is feasible and safe, and that patients who opted for the precision medicine approach experienced a lower early death rate and superior overall survival, compared with patients who opted for standard of care,” lead study author John C. Byrd, MD, the D. Warren Brown Chair of Leukemia Research of the Ohio State University, Columbus, noted in a press statement from the Leukemia & Lymphoma Society, which conducted the trial. “This patient-centric study shows that we can move away from chemotherapy treatment for patients who won’t respond or can’t withstand the harsh effects of the same chemotherapies we’ve been using for 40 years and match them with a treatment better suited for their individual cases.”

The ongoing Beat AML trial was launched by LLS in 2016 to assess various novel targeted therapies in newly diagnosed AML patients aged 60 years and older. Participants underwent next-generation genomic sequencing, were matched to the appropriate targeted therapy, and were given the option of enrolling on the relevant substudy or selecting an alternate treatment strategy. There are currently 11 substudies assessing novel therapies that have emerged in the wake of “significant progress in understanding the molecular pathogenesis of AML.”

The current findings represent outcomes in patients enrolled between Nov. 2016 and Jan. 2018. The patients had a mean age of 72 years, and those selecting precision medicine vs. SOC had similar demographic and genetic features, the authors noted.

LLS president and chief executive officer Louis J. DeGennaro, PhD, said the findings are practice changing and provide a template for studying precision medicine in other cancers.

“The study is changing significantly the way we look at treating patients with AML, showing that precision medicine ... can improve short- and long-term outcomes for patients with this deadly blood cancer,” he said in the LLS statement. “Further, BEAT AML has proven to be a viable model for other cancer clinical trials to emulate.”

In fact, the model has been applied to the recently launched Beat COVID trial, which looks at acalabrutinib in patients with hematologic cancers and COVID-19 infection, and other trials, including the LLS PedAL global precision medicine trial for children with relapsed acute leukemia, are planned.

“This study sets the path to establish the safety of precision medicine in AML and sets the stage to extend this same approach to younger patients with this disease and other cancers that are urgently treated as a single disease despite recognition of multiple subtypes, the authors concluded.

Dr. Burd is an employee of LLS, which received funding from AbbVie, Agios Pharmaceuticals, Alexion Pharmaceuticals, and a variety of other pharmaceutical and biotechnology companies. Dr. Byrd has received research support from Acerta Pharma, Genentech, Janssen Pharmaceutica, and Pharmacyclics and has served on the advisory board of Syndax Pharmaceuticals.

[email protected]

SOURCE: Burd A et al. Nature Medicine 2020 Oct 26. doi: 10.1038/s41591-020-1089-8.

Precision medicine therapy proved feasible and superior to standard-of-care (SOC) chemotherapy in patients with acute myeloid leukemia in the Beat AML Master Clinical Trial.

The 30-day mortality rates were 3.7% versus 20.4% in 224 patients who enrolled in the Beat AML trial precision medicine substudies within 7 days of prospective genomic profiling and 103 who elected SOC chemotherapy, respectively, Amy Burd, PhD, vice president of research strategy for the Leukemia & Lymphoma Society, Rye Brook, N.Y. and her colleagues reported online in Nature Medicine.

Overall survival (OS) at a median of 7.1 months was also significantly longer with precision medicine than with SOC chemotherapy (median, 12.8 vs. 3.9 months), the investigators found.

In an additional 28 patients who selected an investigational therapy rather than a precision medicine strategy or SOC chemotherapy, median OS was not reached, and in 38 who chose palliative care, median OS was 0.6 months, they noted. Care type was unknown in two patients.

The results were similar after controlling for demographic, clinical, and molecular variables and did not change when patients with adverse events of special interest were excluded from the analysis or when only those with survival greater than 2 weeks were included in the analysis.

AML confers an adverse outcome in older adults and therefore is typically treated rapidly after diagnosis. This has precluded consideration of patients’ mutational profile for treatment decisions.

Beat AML, however, sought to prospectively assess the feasibility of quickly ascertaining cytogenetic and mutational data for the purpose of improving outcomes through targeted treatment.

“The study shows that delaying treatment up to 7 days is feasible and safe, and that patients who opted for the precision medicine approach experienced a lower early death rate and superior overall survival, compared with patients who opted for standard of care,” lead study author John C. Byrd, MD, the D. Warren Brown Chair of Leukemia Research of the Ohio State University, Columbus, noted in a press statement from the Leukemia & Lymphoma Society, which conducted the trial. “This patient-centric study shows that we can move away from chemotherapy treatment for patients who won’t respond or can’t withstand the harsh effects of the same chemotherapies we’ve been using for 40 years and match them with a treatment better suited for their individual cases.”

The ongoing Beat AML trial was launched by LLS in 2016 to assess various novel targeted therapies in newly diagnosed AML patients aged 60 years and older. Participants underwent next-generation genomic sequencing, were matched to the appropriate targeted therapy, and were given the option of enrolling on the relevant substudy or selecting an alternate treatment strategy. There are currently 11 substudies assessing novel therapies that have emerged in the wake of “significant progress in understanding the molecular pathogenesis of AML.”

The current findings represent outcomes in patients enrolled between Nov. 2016 and Jan. 2018. The patients had a mean age of 72 years, and those selecting precision medicine vs. SOC had similar demographic and genetic features, the authors noted.

LLS president and chief executive officer Louis J. DeGennaro, PhD, said the findings are practice changing and provide a template for studying precision medicine in other cancers.

“The study is changing significantly the way we look at treating patients with AML, showing that precision medicine ... can improve short- and long-term outcomes for patients with this deadly blood cancer,” he said in the LLS statement. “Further, BEAT AML has proven to be a viable model for other cancer clinical trials to emulate.”

In fact, the model has been applied to the recently launched Beat COVID trial, which looks at acalabrutinib in patients with hematologic cancers and COVID-19 infection, and other trials, including the LLS PedAL global precision medicine trial for children with relapsed acute leukemia, are planned.

“This study sets the path to establish the safety of precision medicine in AML and sets the stage to extend this same approach to younger patients with this disease and other cancers that are urgently treated as a single disease despite recognition of multiple subtypes, the authors concluded.

Dr. Burd is an employee of LLS, which received funding from AbbVie, Agios Pharmaceuticals, Alexion Pharmaceuticals, and a variety of other pharmaceutical and biotechnology companies. Dr. Byrd has received research support from Acerta Pharma, Genentech, Janssen Pharmaceutica, and Pharmacyclics and has served on the advisory board of Syndax Pharmaceuticals.

[email protected]

SOURCE: Burd A et al. Nature Medicine 2020 Oct 26. doi: 10.1038/s41591-020-1089-8.

Precision medicine therapy proved feasible and superior to standard-of-care (SOC) chemotherapy in patients with acute myeloid leukemia in the Beat AML Master Clinical Trial.

The 30-day mortality rates were 3.7% versus 20.4% in 224 patients who enrolled in the Beat AML trial precision medicine substudies within 7 days of prospective genomic profiling and 103 who elected SOC chemotherapy, respectively, Amy Burd, PhD, vice president of research strategy for the Leukemia & Lymphoma Society, Rye Brook, N.Y. and her colleagues reported online in Nature Medicine.

Overall survival (OS) at a median of 7.1 months was also significantly longer with precision medicine than with SOC chemotherapy (median, 12.8 vs. 3.9 months), the investigators found.

In an additional 28 patients who selected an investigational therapy rather than a precision medicine strategy or SOC chemotherapy, median OS was not reached, and in 38 who chose palliative care, median OS was 0.6 months, they noted. Care type was unknown in two patients.

The results were similar after controlling for demographic, clinical, and molecular variables and did not change when patients with adverse events of special interest were excluded from the analysis or when only those with survival greater than 2 weeks were included in the analysis.

AML confers an adverse outcome in older adults and therefore is typically treated rapidly after diagnosis. This has precluded consideration of patients’ mutational profile for treatment decisions.

Beat AML, however, sought to prospectively assess the feasibility of quickly ascertaining cytogenetic and mutational data for the purpose of improving outcomes through targeted treatment.

“The study shows that delaying treatment up to 7 days is feasible and safe, and that patients who opted for the precision medicine approach experienced a lower early death rate and superior overall survival, compared with patients who opted for standard of care,” lead study author John C. Byrd, MD, the D. Warren Brown Chair of Leukemia Research of the Ohio State University, Columbus, noted in a press statement from the Leukemia & Lymphoma Society, which conducted the trial. “This patient-centric study shows that we can move away from chemotherapy treatment for patients who won’t respond or can’t withstand the harsh effects of the same chemotherapies we’ve been using for 40 years and match them with a treatment better suited for their individual cases.”

The ongoing Beat AML trial was launched by LLS in 2016 to assess various novel targeted therapies in newly diagnosed AML patients aged 60 years and older. Participants underwent next-generation genomic sequencing, were matched to the appropriate targeted therapy, and were given the option of enrolling on the relevant substudy or selecting an alternate treatment strategy. There are currently 11 substudies assessing novel therapies that have emerged in the wake of “significant progress in understanding the molecular pathogenesis of AML.”

The current findings represent outcomes in patients enrolled between Nov. 2016 and Jan. 2018. The patients had a mean age of 72 years, and those selecting precision medicine vs. SOC had similar demographic and genetic features, the authors noted.

LLS president and chief executive officer Louis J. DeGennaro, PhD, said the findings are practice changing and provide a template for studying precision medicine in other cancers.

“The study is changing significantly the way we look at treating patients with AML, showing that precision medicine ... can improve short- and long-term outcomes for patients with this deadly blood cancer,” he said in the LLS statement. “Further, BEAT AML has proven to be a viable model for other cancer clinical trials to emulate.”

In fact, the model has been applied to the recently launched Beat COVID trial, which looks at acalabrutinib in patients with hematologic cancers and COVID-19 infection, and other trials, including the LLS PedAL global precision medicine trial for children with relapsed acute leukemia, are planned.

“This study sets the path to establish the safety of precision medicine in AML and sets the stage to extend this same approach to younger patients with this disease and other cancers that are urgently treated as a single disease despite recognition of multiple subtypes, the authors concluded.

Dr. Burd is an employee of LLS, which received funding from AbbVie, Agios Pharmaceuticals, Alexion Pharmaceuticals, and a variety of other pharmaceutical and biotechnology companies. Dr. Byrd has received research support from Acerta Pharma, Genentech, Janssen Pharmaceutica, and Pharmacyclics and has served on the advisory board of Syndax Pharmaceuticals.

[email protected]

SOURCE: Burd A et al. Nature Medicine 2020 Oct 26. doi: 10.1038/s41591-020-1089-8.

A genomic study has revealed new insights into the pathogenesis of neuroblastoma as well as potential therapeutic targets.

Insights into the genetic drivers of the disease were identified based on data from whole-genome, whole-exome, and/or transcriptome sequencing of tumor samples.

“The comprehensive genome-wide analysis performed here allowed us to discover age-associated alterations in MYCN, TERT, PTPRD, and Ras pathway alterations, which, together with ATRX, represent the majority of common driver gene alterations in neuroblastoma,” wrote study author Samuel W. Brady, PhD, of St. Jude Children’s Research Hospital in Memphis, Tenn., and colleagues.

The group’s findings were published in Nature Communications.

The researchers integrated and analyzed data from 702 neuroblastomas encompassing all age and risk categories, with the goal of identifying rare driver events and age-related molecular aberrations. Among the samples, 23 were from patients who had relapsed.

The researchers found that 40% of samples had somatic alterations in known driver genes, with the most common alterations being MYCN (19%; primarily amplification), TERT (17%; structural variations [SVs]), SHANK2 (13%; SVs), PTPRD (11%; SVs and focal deletions), ALK (10%; single nucleotide variants [SNVs] and SVs), and ATRX (8%; multiple mutation types).

MYCN and TERT alterations were more common in younger children (median age of 2.3 years and 3.8 years, respectively), while ATRX alterations were more frequently seen in older patients (median age of 5.6 years).

“These findings suggest that the sympathetic nervous system, the tissue from which neuroblastoma arises, is susceptible to different oncogenic insults at different times during development, which could be explored in future investigations using animal models,” the researchers wrote.

Furthermore, they found evidence to suggest the COSMIC mutational signature 18 is the most common cause of driver SNVs in neuroblastoma, including most Ras-activating and ALK variants.

Signature 18 was enriched in neuroblastomas with increased expression of mitochondrial ribosome and electron transport–associated genes, 17q gain, and MYCN amplification.

“[T]his mutagenic process, which is caused by ROS [reactive oxygen species] in other settings (though not proven in neuroblastoma), may promote evolution and heterogeneity, as many driver SNVs, such as ALK mutations, are later events in neuroblastoma,” the researchers explained.

Based on these findings, the authors concluded that neuroblastomas with 17q gain may be amenable to precision medicines, possibly through targeting altered mitochondrial function.

“[Our] findings will identify patients who might be eligible for targeted therapy and those that may be at higher risk based on a combination of genetic alterations detected by these genome-wide sequencing methods,” commented study author Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital.

The study was supported by grants from the National Cancer Institute and by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital. One author disclosed financial affiliations with Y-mabs Therapeutics, Abpro-Labs, Eureka Therapeutics, and Biotec Pharmacon.

SOURCE: Brady SW et al. Nat Commun. 2020 Oct 14. doi: 10.1038/s41467-020-18987-4.

A genomic study has revealed new insights into the pathogenesis of neuroblastoma as well as potential therapeutic targets.

Insights into the genetic drivers of the disease were identified based on data from whole-genome, whole-exome, and/or transcriptome sequencing of tumor samples.

“The comprehensive genome-wide analysis performed here allowed us to discover age-associated alterations in MYCN, TERT, PTPRD, and Ras pathway alterations, which, together with ATRX, represent the majority of common driver gene alterations in neuroblastoma,” wrote study author Samuel W. Brady, PhD, of St. Jude Children’s Research Hospital in Memphis, Tenn., and colleagues.

The group’s findings were published in Nature Communications.

The researchers integrated and analyzed data from 702 neuroblastomas encompassing all age and risk categories, with the goal of identifying rare driver events and age-related molecular aberrations. Among the samples, 23 were from patients who had relapsed.

The researchers found that 40% of samples had somatic alterations in known driver genes, with the most common alterations being MYCN (19%; primarily amplification), TERT (17%; structural variations [SVs]), SHANK2 (13%; SVs), PTPRD (11%; SVs and focal deletions), ALK (10%; single nucleotide variants [SNVs] and SVs), and ATRX (8%; multiple mutation types).

MYCN and TERT alterations were more common in younger children (median age of 2.3 years and 3.8 years, respectively), while ATRX alterations were more frequently seen in older patients (median age of 5.6 years).

“These findings suggest that the sympathetic nervous system, the tissue from which neuroblastoma arises, is susceptible to different oncogenic insults at different times during development, which could be explored in future investigations using animal models,” the researchers wrote.

Furthermore, they found evidence to suggest the COSMIC mutational signature 18 is the most common cause of driver SNVs in neuroblastoma, including most Ras-activating and ALK variants.

Signature 18 was enriched in neuroblastomas with increased expression of mitochondrial ribosome and electron transport–associated genes, 17q gain, and MYCN amplification.

“[T]his mutagenic process, which is caused by ROS [reactive oxygen species] in other settings (though not proven in neuroblastoma), may promote evolution and heterogeneity, as many driver SNVs, such as ALK mutations, are later events in neuroblastoma,” the researchers explained.

Based on these findings, the authors concluded that neuroblastomas with 17q gain may be amenable to precision medicines, possibly through targeting altered mitochondrial function.

“[Our] findings will identify patients who might be eligible for targeted therapy and those that may be at higher risk based on a combination of genetic alterations detected by these genome-wide sequencing methods,” commented study author Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital.

The study was supported by grants from the National Cancer Institute and by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital. One author disclosed financial affiliations with Y-mabs Therapeutics, Abpro-Labs, Eureka Therapeutics, and Biotec Pharmacon.

SOURCE: Brady SW et al. Nat Commun. 2020 Oct 14. doi: 10.1038/s41467-020-18987-4.

A genomic study has revealed new insights into the pathogenesis of neuroblastoma as well as potential therapeutic targets.

Insights into the genetic drivers of the disease were identified based on data from whole-genome, whole-exome, and/or transcriptome sequencing of tumor samples.

“The comprehensive genome-wide analysis performed here allowed us to discover age-associated alterations in MYCN, TERT, PTPRD, and Ras pathway alterations, which, together with ATRX, represent the majority of common driver gene alterations in neuroblastoma,” wrote study author Samuel W. Brady, PhD, of St. Jude Children’s Research Hospital in Memphis, Tenn., and colleagues.

The group’s findings were published in Nature Communications.

The researchers integrated and analyzed data from 702 neuroblastomas encompassing all age and risk categories, with the goal of identifying rare driver events and age-related molecular aberrations. Among the samples, 23 were from patients who had relapsed.

The researchers found that 40% of samples had somatic alterations in known driver genes, with the most common alterations being MYCN (19%; primarily amplification), TERT (17%; structural variations [SVs]), SHANK2 (13%; SVs), PTPRD (11%; SVs and focal deletions), ALK (10%; single nucleotide variants [SNVs] and SVs), and ATRX (8%; multiple mutation types).

MYCN and TERT alterations were more common in younger children (median age of 2.3 years and 3.8 years, respectively), while ATRX alterations were more frequently seen in older patients (median age of 5.6 years).

“These findings suggest that the sympathetic nervous system, the tissue from which neuroblastoma arises, is susceptible to different oncogenic insults at different times during development, which could be explored in future investigations using animal models,” the researchers wrote.

Furthermore, they found evidence to suggest the COSMIC mutational signature 18 is the most common cause of driver SNVs in neuroblastoma, including most Ras-activating and ALK variants.

Signature 18 was enriched in neuroblastomas with increased expression of mitochondrial ribosome and electron transport–associated genes, 17q gain, and MYCN amplification.

“[T]his mutagenic process, which is caused by ROS [reactive oxygen species] in other settings (though not proven in neuroblastoma), may promote evolution and heterogeneity, as many driver SNVs, such as ALK mutations, are later events in neuroblastoma,” the researchers explained.

Based on these findings, the authors concluded that neuroblastomas with 17q gain may be amenable to precision medicines, possibly through targeting altered mitochondrial function.

“[Our] findings will identify patients who might be eligible for targeted therapy and those that may be at higher risk based on a combination of genetic alterations detected by these genome-wide sequencing methods,” commented study author Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital.

The study was supported by grants from the National Cancer Institute and by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital. One author disclosed financial affiliations with Y-mabs Therapeutics, Abpro-Labs, Eureka Therapeutics, and Biotec Pharmacon.

SOURCE: Brady SW et al. Nat Commun. 2020 Oct 14. doi: 10.1038/s41467-020-18987-4.

People whose treatment for cancer is delayed by even 1 month have a 6%-13% higher risk of dying, suggests research published online in the BMJ.

In light of the treatment delays resulting from the pandemic, Canadian and U.K. researchers carried out a review and analysis of relevant studies published between January 2000 and April 2020.

Included studies examined data on surgical interventions, systemic therapy, or radiotherapy for seven forms of cancer – bladder, breast, colon, rectum, lung, cervix, and head and neck. Delays were measured from diagnosis to the first treatment or from the completion of one treatment to the start of the next.

The search identified 34 suitable studies for 17 indications, with data from more than 1.2 million patients. The analysis identified a significant association between delay and increased mortality for 13 of the 17 indications (P < .05).

For surgery, there was a 6%-8% increase in the risk of death for every 4-week treatment delay. Estimates for systemic treatment varied (hazard ratio range, 1.01-1.28). Four-week delays in radiotherapy were for radical radiotherapy for head and neck cancer (HR, 1.09; 95% confidence interval, 1.05-1.14), adjuvant radiotherapy after breast-conserving surgery (HR, 0.98; 95% CI, 0.88-1.09), and cervical cancer adjuvant radiotherapy (HR, 1.23; 95% CI, 1.00-1.50).

Delays of up to 8 and 12 weeks further increased mortality. An 8-week delay in breast cancer surgery was linked to a 17% increased mortality, and a 12-week delay would increase mortality by 26%.

A surgical delay of 12 weeks for patients with breast cancer continuing for 1 year – which is likely to be the case as the pandemic continues – would lead to 1,400 excess deaths in the United Kingdom.

The authors said the results of this study could be used to guide policy making on the organization of cancer services, particularly as the pandemic continues and further delays are expected.

This article originally appeared on Univadis, part of the Medscape Professional Network.

People whose treatment for cancer is delayed by even 1 month have a 6%-13% higher risk of dying, suggests research published online in the BMJ.

In light of the treatment delays resulting from the pandemic, Canadian and U.K. researchers carried out a review and analysis of relevant studies published between January 2000 and April 2020.

Included studies examined data on surgical interventions, systemic therapy, or radiotherapy for seven forms of cancer – bladder, breast, colon, rectum, lung, cervix, and head and neck. Delays were measured from diagnosis to the first treatment or from the completion of one treatment to the start of the next.

The search identified 34 suitable studies for 17 indications, with data from more than 1.2 million patients. The analysis identified a significant association between delay and increased mortality for 13 of the 17 indications (P < .05).

For surgery, there was a 6%-8% increase in the risk of death for every 4-week treatment delay. Estimates for systemic treatment varied (hazard ratio range, 1.01-1.28). Four-week delays in radiotherapy were for radical radiotherapy for head and neck cancer (HR, 1.09; 95% confidence interval, 1.05-1.14), adjuvant radiotherapy after breast-conserving surgery (HR, 0.98; 95% CI, 0.88-1.09), and cervical cancer adjuvant radiotherapy (HR, 1.23; 95% CI, 1.00-1.50).

Delays of up to 8 and 12 weeks further increased mortality. An 8-week delay in breast cancer surgery was linked to a 17% increased mortality, and a 12-week delay would increase mortality by 26%.

A surgical delay of 12 weeks for patients with breast cancer continuing for 1 year – which is likely to be the case as the pandemic continues – would lead to 1,400 excess deaths in the United Kingdom.

The authors said the results of this study could be used to guide policy making on the organization of cancer services, particularly as the pandemic continues and further delays are expected.

This article originally appeared on Univadis, part of the Medscape Professional Network.

People whose treatment for cancer is delayed by even 1 month have a 6%-13% higher risk of dying, suggests research published online in the BMJ.

In light of the treatment delays resulting from the pandemic, Canadian and U.K. researchers carried out a review and analysis of relevant studies published between January 2000 and April 2020.

Included studies examined data on surgical interventions, systemic therapy, or radiotherapy for seven forms of cancer – bladder, breast, colon, rectum, lung, cervix, and head and neck. Delays were measured from diagnosis to the first treatment or from the completion of one treatment to the start of the next.

The search identified 34 suitable studies for 17 indications, with data from more than 1.2 million patients. The analysis identified a significant association between delay and increased mortality for 13 of the 17 indications (P < .05).

For surgery, there was a 6%-8% increase in the risk of death for every 4-week treatment delay. Estimates for systemic treatment varied (hazard ratio range, 1.01-1.28). Four-week delays in radiotherapy were for radical radiotherapy for head and neck cancer (HR, 1.09; 95% confidence interval, 1.05-1.14), adjuvant radiotherapy after breast-conserving surgery (HR, 0.98; 95% CI, 0.88-1.09), and cervical cancer adjuvant radiotherapy (HR, 1.23; 95% CI, 1.00-1.50).

Delays of up to 8 and 12 weeks further increased mortality. An 8-week delay in breast cancer surgery was linked to a 17% increased mortality, and a 12-week delay would increase mortality by 26%.

A surgical delay of 12 weeks for patients with breast cancer continuing for 1 year – which is likely to be the case as the pandemic continues – would lead to 1,400 excess deaths in the United Kingdom.

The authors said the results of this study could be used to guide policy making on the organization of cancer services, particularly as the pandemic continues and further delays are expected.

This article originally appeared on Univadis, part of the Medscape Professional Network.

Patients with metastatic castrate resistant prostate carcinoma (CRPC) have several treatment options, including radium-223 dichloride (Ra-223) radionuclide therapy, abiraterone, enzalutamide, and cabazitaxel. Ra-223 therapy has been reported to increase median survival in patients with bone metastatic prostate carcinoma.^1,2 However, ERA 223 trial data showed an increase of bone fractures with combination of Ra-223 and abiraterone.³

Agent Orange (AO) exposure has been studied as a potential risk factor for development of prostate carcinoma. AO was a commercially manufactured defoliate that was sprayed extensively during the Vietnam War. Due to a side product of chemical manufacturing, AO was contaminated with the toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin, a putative carcinogen. These dioxins can enter the food chain through soil contamination. There is enough evidence to link AO to hematologic malignancies and several solid tumors, including prostate carcinoma.⁴ Although no real estimates exist for what percentage of Vietnam veterans experienced AO exposure, Surveillance, Epidemiology, and End Results data showed that about 3 million veterans served in Southeast Asia where AO was used extensively in the combat theater. AO has been reported to be positively associated with a 52% increase in risk of prostate carcinoma detection at initial prostate biopsy.⁵

There has been no reported study of treatment efficacy in veterans with AO-related prostate carcinoma. We present a retrospective study of Ra-223 and other therapies in metastatic CRPC. The purpose of this study was to compare response to therapy and survival in veterans exposed to agent orange (AO+) vs veterans who were not exposed to (AO-) in a single US Department of Veteran Affairs (VA) medical center.

Methods

This was a retrospective study of veterans with metastatic CRPC to bones who received Ra-223 radionuclide therapy with standard dose of 50 kBq per kg of body weight and other sequential therapies at VA Pittsburgh Healthcare System (VAPHS) from January 2014 to January 2019. The purpose of this study was to measure difference in treatment outcome between AO+ veterans and AO- veterans.

Eligibility Criteria

All veterans had a history that included bone metastasis CRPC. They could have 2 to 3 small lymphadenopathies but not visceral metastasis. They received a minimum of 3 cycles and a maximum of 6 cycles of Ra-223 therapy, which was given in 4-week intervals. Pretreatment criteria was hemoglobin > 10 g/dL, platelet > 100 × 10⁹/L, and absolute neutrophil counts > 1.5 × 10⁹/L. Other therapies, such as abiraterone, enzalutamide, docetaxel, and cabazitaxel, were administered either after Ra-223 (Ra first) or before Ra-223 therapy (Ra later). Veterans also received androgen deprivation therapy (ADT) with luteinizing hormone releasing hormone (LHRH) agonist (leuprolide acetate) to maintain castrate level of testosterone and bisphosphonates for bone metastasis. Eligible veterans were divided into 2 groups: AO+ and AO-. AO+ veterans are those that were proven to be physically active during the Vietnam War and have been determined by the US government to receive service-connected compensation from the VA. AO- veterans were those who were not exposed to AO.

Statistics

Time to study was calculated from the initiation of Ra-223 therapy. Time to skeletal-related events (SRE), progression of prostate specific antigen (PSA), bone metastasis, and alkaline phosphatase (ALP) were calculated in months, using unpaired t test with 2-tailed P value. Median survival was calculated in months by Kaplan Meier R log-rank test Definition).

Results

Forty-eight veterans with bone metastasis CRPC received Ra-223 therapy. Of those, 34 veterans were eligible for this retrospective study: 17 AO+ veterans and 17 AO- veterans. Mean age of diagnosis was 62 years (AO+) and 69 years (AO-) (P = .005). Mean Gleason score was 8.2 (AO+) and 8.0 (AO-) (P = .705). Veterans received initial therapy at diagnosis of prostate carcinoma, including radical prostatectomy (6 AO+ and 3 AO-), localized radiation therapy (3 AO+ and 5 AO-), and ADT (8 AO+ and 9 AO-) (Table 1).

Mean PSA at the initiation of Ra-223 therapy for AO+ was 92.8 (range, 2-551) and for AO- was 102.3 (range, 4-639; P = .86). Mean Ra-223 dose per cycle for AO+ and AO- was 157 uCi and 113 uCi, respectively. All 34 veterans received ADT (leuprolide acetate), and 30 veterans (16 AO+ and 14 AO-) received bisphosphonates (zoledronic acid or denosumab). A total of 10 veterans (29%) received Ra-223 as a first-line therapy (4 AO+ and 6 AO-), and 24 veterans (71%) received Ra-223 after hormonal or chemotherapy (13 AO+ and 11 AO-).

Discussions

There has been no reported VA study of using Ra-223 and other therapies (hormonal and chemotherapy) in veterans exposed to AO. This is the first retrospective study to compare the response and survival between AO+ and AO- veterans. Even though this study featured a small sample, it is interesting to note the difference between those 2 populations. There was 1 prior study in veterans with prostate carcinoma using radiotherapy (brachytherapy) in early-stage disease. Everly and colleagues reported that AO+ veterans were less likely to remain biochemically controlled compared with AO- and nonveteran patients with prostate carcinoma.⁴

Ansbaugh and colleagues reported that AO was associated with a 75% increase in the risk of Gleason ≥ 7 and a 110% increase in Gleason ≥ 8. AO+ veterans are at risk for the detection of high-grade prostate carcinoma. They also tend to have an average age of diagnosis that is 4 to 5 years younger than AO- veterans.⁶

Our study revealed that AO+ veterans were diagnosed at a younger age (mean 62 years) compared with that of AO- veterans (mean 69 years, P = .005). We also proved that AO veterans have a higher mean Gleason score (8.2) compared with that of AO- veterans (8.0). Veterans received therapy at the time of diagnosis of prostate carcinoma with either radical prostatectomy, radiation therapy, or ADT with leuprolide acetate. Mean PSA at the start of Ra-223 therapy for AO+ was 92.8 (range, 2-551); for AO- was 102.3 (range, 4-639), which is not statistically significant.

Ra-223, an α-emitting radiopharmaceutical, mimics calcium in forming complexes with the bone mineral hydroxyapatite, which specifically targets bone metastases. Ra-223 preferentially targets new bone growth surrounding bone metastases while emitting α particles within the tumor microenvironment. α particles have high linear energy transfer with enhanced ability to induce lethal double-stranded DNA breaks, thus eliciting greater cytotoxic effects on bone-metastatic tumor sites.⁷

In a phase 3, randomized, double-blind, placebo-controlled study by Parker and colleagues (ALSYMPCA study), 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, were randomized to receive 6 injections of Ra-223 or matching placebo.² Ra-223 significantly improved overall survival (OS) (median, 14.9 months vs 11.3 months) compared with that of placebo. Ra-223 also prolonged the time to the first symptomatic SRE (median, 15.6 months vs 9.8 months), the time to an increase in the total ALP level (median 7.4 months vs 3.8 months), and the time to an increase in the PSA level (median 3.6 months vs 3.4 months).²

In our study, the mean time to SRE for AO+ was 10.6 months and AO- was 10.3 months (P = .93). Mean time to PSA progression for AO+ was 5.4 months and for AO- was 6.8 months (P = .28). Mean time to bone progression for AO+ and for AO- were 7.6 months and 10.1 months respectively (P = .16). Mean time to ALP progression for AO+ and AO- were 6.3 months and 8.7 months respectively (P = .05). There is a trend of shorter PSA progression, bone progression, and ALP progression in AO+ veterans, though these were not statistically significant due to small sample population. In our study the median survival in for AO- was 18 months and for AO+ was 12 months, which is comparable with median survival of 14.9 months from the ALSYMPCA study.

There were 12 veterans who developed SREs. All received radiation therapy due to bone progression or impending fracture. AO+ veterans developed more SREs (n = 8) when compared with AO- veterans (n = 4). There were more AO- veterans alive (n = 10) than there were AO+ veterans (n = 4). The plausible explanation of this may be due to the aggressive pattern of prostate carcinoma in AO+ veterans (younger age and higher Gleason score).

VAPHS participated in the ERA trial between 2014 and 2016. The trial enrolled 806 patients who were randomly assigned to receive first-line Ra-223 or placebo in addition to abiraterone acetate plus prednisone.³ The study was unblinded prematurely after more fractures and deaths were noted in the Ra-223 and abiraterone group than there were in the placebo and abiraterone group. Median symptomatic SRE was 22.3 months in the Ra-223 group and 26.0 months in the placebo group. Fractures (any grade) occurred in 29% in the Ra-223 group and 11% in the placebo group. It was suggested that Ra-223 could contribute to the risk of osteoporotic fractures in patients with bone metastatic prostate carcinoma. Median OS was 30.7 months in the Ra-223 group and 33.3 months in the placebo group.³

We enrolled 3 veterans in the ERA clinical trial. Two AO+ veterans had SREs at 7 months and 11 months. In our study, the median OS for Ra-223 first line was 32 months, which is comparable with median survival of 30.7 months from ERA-223 study. Median survival for Ra-223 later was only 15 months. We recommend veterans with at least 2 to 3-bone metastasis receive Ra-223 in the first-line setting rather than second- or third-line setting. In this retrospective study with Ra-223 and other therapies, we proved that AO+ veterans have a worse response and OS when compared with that of AO- veterans.

Conclusions

This is the first VA study to compare the efficacy of Ra-223 and other therapies in metastatic CRPC between AO+ and AO- veterans. AO+ veterans were diagnosed at a younger age and had higher Gleason scores. There was no statistical difference between AO+ and AO- veterans in terms of time to SRE, PSA progression, and bone and ALP progression even though there was a trend of shorter duration in AO+ veterans. There was no median survival difference between veterans who received Ra-223 first vs Ra-223 later as well as between AO+ and AO- veterans, but there was a trend of worse survival in veteran who received Ra-223 later and AO+ veterans.

This study showed that AO+ veterans have a shorter duration of response to therapy and shorter median survival compared with that of AO- veterans. We recommend that veterans should get Ra-223 in the first-line setting rather than after hormonal therapy and chemotherapy because their marrows are still intact. We need to investigate further whether veterans that exposed to carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) may have different molecular biology and as such may cause inferior efficacy in the treatment of prostate carcinoma.

Patients with metastatic castrate resistant prostate carcinoma (CRPC) have several treatment options, including radium-223 dichloride (Ra-223) radionuclide therapy, abiraterone, enzalutamide, and cabazitaxel. Ra-223 therapy has been reported to increase median survival in patients with bone metastatic prostate carcinoma.^1,2 However, ERA 223 trial data showed an increase of bone fractures with combination of Ra-223 and abiraterone.³

Agent Orange (AO) exposure has been studied as a potential risk factor for development of prostate carcinoma. AO was a commercially manufactured defoliate that was sprayed extensively during the Vietnam War. Due to a side product of chemical manufacturing, AO was contaminated with the toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin, a putative carcinogen. These dioxins can enter the food chain through soil contamination. There is enough evidence to link AO to hematologic malignancies and several solid tumors, including prostate carcinoma.⁴ Although no real estimates exist for what percentage of Vietnam veterans experienced AO exposure, Surveillance, Epidemiology, and End Results data showed that about 3 million veterans served in Southeast Asia where AO was used extensively in the combat theater. AO has been reported to be positively associated with a 52% increase in risk of prostate carcinoma detection at initial prostate biopsy.⁵

There has been no reported study of treatment efficacy in veterans with AO-related prostate carcinoma. We present a retrospective study of Ra-223 and other therapies in metastatic CRPC. The purpose of this study was to compare response to therapy and survival in veterans exposed to agent orange (AO+) vs veterans who were not exposed to (AO-) in a single US Department of Veteran Affairs (VA) medical center.

Methods

This was a retrospective study of veterans with metastatic CRPC to bones who received Ra-223 radionuclide therapy with standard dose of 50 kBq per kg of body weight and other sequential therapies at VA Pittsburgh Healthcare System (VAPHS) from January 2014 to January 2019. The purpose of this study was to measure difference in treatment outcome between AO+ veterans and AO- veterans.

Eligibility Criteria

All veterans had a history that included bone metastasis CRPC. They could have 2 to 3 small lymphadenopathies but not visceral metastasis. They received a minimum of 3 cycles and a maximum of 6 cycles of Ra-223 therapy, which was given in 4-week intervals. Pretreatment criteria was hemoglobin > 10 g/dL, platelet > 100 × 10⁹/L, and absolute neutrophil counts > 1.5 × 10⁹/L. Other therapies, such as abiraterone, enzalutamide, docetaxel, and cabazitaxel, were administered either after Ra-223 (Ra first) or before Ra-223 therapy (Ra later). Veterans also received androgen deprivation therapy (ADT) with luteinizing hormone releasing hormone (LHRH) agonist (leuprolide acetate) to maintain castrate level of testosterone and bisphosphonates for bone metastasis. Eligible veterans were divided into 2 groups: AO+ and AO-. AO+ veterans are those that were proven to be physically active during the Vietnam War and have been determined by the US government to receive service-connected compensation from the VA. AO- veterans were those who were not exposed to AO.

Statistics

Time to study was calculated from the initiation of Ra-223 therapy. Time to skeletal-related events (SRE), progression of prostate specific antigen (PSA), bone metastasis, and alkaline phosphatase (ALP) were calculated in months, using unpaired t test with 2-tailed P value. Median survival was calculated in months by Kaplan Meier R log-rank test Definition).

Results

Forty-eight veterans with bone metastasis CRPC received Ra-223 therapy. Of those, 34 veterans were eligible for this retrospective study: 17 AO+ veterans and 17 AO- veterans. Mean age of diagnosis was 62 years (AO+) and 69 years (AO-) (P = .005). Mean Gleason score was 8.2 (AO+) and 8.0 (AO-) (P = .705). Veterans received initial therapy at diagnosis of prostate carcinoma, including radical prostatectomy (6 AO+ and 3 AO-), localized radiation therapy (3 AO+ and 5 AO-), and ADT (8 AO+ and 9 AO-) (Table 1).

Mean PSA at the initiation of Ra-223 therapy for AO+ was 92.8 (range, 2-551) and for AO- was 102.3 (range, 4-639; P = .86). Mean Ra-223 dose per cycle for AO+ and AO- was 157 uCi and 113 uCi, respectively. All 34 veterans received ADT (leuprolide acetate), and 30 veterans (16 AO+ and 14 AO-) received bisphosphonates (zoledronic acid or denosumab). A total of 10 veterans (29%) received Ra-223 as a first-line therapy (4 AO+ and 6 AO-), and 24 veterans (71%) received Ra-223 after hormonal or chemotherapy (13 AO+ and 11 AO-).

Discussions

There has been no reported VA study of using Ra-223 and other therapies (hormonal and chemotherapy) in veterans exposed to AO. This is the first retrospective study to compare the response and survival between AO+ and AO- veterans. Even though this study featured a small sample, it is interesting to note the difference between those 2 populations. There was 1 prior study in veterans with prostate carcinoma using radiotherapy (brachytherapy) in early-stage disease. Everly and colleagues reported that AO+ veterans were less likely to remain biochemically controlled compared with AO- and nonveteran patients with prostate carcinoma.⁴

Ansbaugh and colleagues reported that AO was associated with a 75% increase in the risk of Gleason ≥ 7 and a 110% increase in Gleason ≥ 8. AO+ veterans are at risk for the detection of high-grade prostate carcinoma. They also tend to have an average age of diagnosis that is 4 to 5 years younger than AO- veterans.⁶

Our study revealed that AO+ veterans were diagnosed at a younger age (mean 62 years) compared with that of AO- veterans (mean 69 years, P = .005). We also proved that AO veterans have a higher mean Gleason score (8.2) compared with that of AO- veterans (8.0). Veterans received therapy at the time of diagnosis of prostate carcinoma with either radical prostatectomy, radiation therapy, or ADT with leuprolide acetate. Mean PSA at the start of Ra-223 therapy for AO+ was 92.8 (range, 2-551); for AO- was 102.3 (range, 4-639), which is not statistically significant.

Ra-223, an α-emitting radiopharmaceutical, mimics calcium in forming complexes with the bone mineral hydroxyapatite, which specifically targets bone metastases. Ra-223 preferentially targets new bone growth surrounding bone metastases while emitting α particles within the tumor microenvironment. α particles have high linear energy transfer with enhanced ability to induce lethal double-stranded DNA breaks, thus eliciting greater cytotoxic effects on bone-metastatic tumor sites.⁷

In a phase 3, randomized, double-blind, placebo-controlled study by Parker and colleagues (ALSYMPCA study), 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, were randomized to receive 6 injections of Ra-223 or matching placebo.² Ra-223 significantly improved overall survival (OS) (median, 14.9 months vs 11.3 months) compared with that of placebo. Ra-223 also prolonged the time to the first symptomatic SRE (median, 15.6 months vs 9.8 months), the time to an increase in the total ALP level (median 7.4 months vs 3.8 months), and the time to an increase in the PSA level (median 3.6 months vs 3.4 months).²

In our study, the mean time to SRE for AO+ was 10.6 months and AO- was 10.3 months (P = .93). Mean time to PSA progression for AO+ was 5.4 months and for AO- was 6.8 months (P = .28). Mean time to bone progression for AO+ and for AO- were 7.6 months and 10.1 months respectively (P = .16). Mean time to ALP progression for AO+ and AO- were 6.3 months and 8.7 months respectively (P = .05). There is a trend of shorter PSA progression, bone progression, and ALP progression in AO+ veterans, though these were not statistically significant due to small sample population. In our study the median survival in for AO- was 18 months and for AO+ was 12 months, which is comparable with median survival of 14.9 months from the ALSYMPCA study.

There were 12 veterans who developed SREs. All received radiation therapy due to bone progression or impending fracture. AO+ veterans developed more SREs (n = 8) when compared with AO- veterans (n = 4). There were more AO- veterans alive (n = 10) than there were AO+ veterans (n = 4). The plausible explanation of this may be due to the aggressive pattern of prostate carcinoma in AO+ veterans (younger age and higher Gleason score).

VAPHS participated in the ERA trial between 2014 and 2016. The trial enrolled 806 patients who were randomly assigned to receive first-line Ra-223 or placebo in addition to abiraterone acetate plus prednisone.³ The study was unblinded prematurely after more fractures and deaths were noted in the Ra-223 and abiraterone group than there were in the placebo and abiraterone group. Median symptomatic SRE was 22.3 months in the Ra-223 group and 26.0 months in the placebo group. Fractures (any grade) occurred in 29% in the Ra-223 group and 11% in the placebo group. It was suggested that Ra-223 could contribute to the risk of osteoporotic fractures in patients with bone metastatic prostate carcinoma. Median OS was 30.7 months in the Ra-223 group and 33.3 months in the placebo group.³

We enrolled 3 veterans in the ERA clinical trial. Two AO+ veterans had SREs at 7 months and 11 months. In our study, the median OS for Ra-223 first line was 32 months, which is comparable with median survival of 30.7 months from ERA-223 study. Median survival for Ra-223 later was only 15 months. We recommend veterans with at least 2 to 3-bone metastasis receive Ra-223 in the first-line setting rather than second- or third-line setting. In this retrospective study with Ra-223 and other therapies, we proved that AO+ veterans have a worse response and OS when compared with that of AO- veterans.

Conclusions

This is the first VA study to compare the efficacy of Ra-223 and other therapies in metastatic CRPC between AO+ and AO- veterans. AO+ veterans were diagnosed at a younger age and had higher Gleason scores. There was no statistical difference between AO+ and AO- veterans in terms of time to SRE, PSA progression, and bone and ALP progression even though there was a trend of shorter duration in AO+ veterans. There was no median survival difference between veterans who received Ra-223 first vs Ra-223 later as well as between AO+ and AO- veterans, but there was a trend of worse survival in veteran who received Ra-223 later and AO+ veterans.

This study showed that AO+ veterans have a shorter duration of response to therapy and shorter median survival compared with that of AO- veterans. We recommend that veterans should get Ra-223 in the first-line setting rather than after hormonal therapy and chemotherapy because their marrows are still intact. We need to investigate further whether veterans that exposed to carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) may have different molecular biology and as such may cause inferior efficacy in the treatment of prostate carcinoma.

Patients with metastatic castrate resistant prostate carcinoma (CRPC) have several treatment options, including radium-223 dichloride (Ra-223) radionuclide therapy, abiraterone, enzalutamide, and cabazitaxel. Ra-223 therapy has been reported to increase median survival in patients with bone metastatic prostate carcinoma.^1,2 However, ERA 223 trial data showed an increase of bone fractures with combination of Ra-223 and abiraterone.³

Agent Orange (AO) exposure has been studied as a potential risk factor for development of prostate carcinoma. AO was a commercially manufactured defoliate that was sprayed extensively during the Vietnam War. Due to a side product of chemical manufacturing, AO was contaminated with the toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin, a putative carcinogen. These dioxins can enter the food chain through soil contamination. There is enough evidence to link AO to hematologic malignancies and several solid tumors, including prostate carcinoma.⁴ Although no real estimates exist for what percentage of Vietnam veterans experienced AO exposure, Surveillance, Epidemiology, and End Results data showed that about 3 million veterans served in Southeast Asia where AO was used extensively in the combat theater. AO has been reported to be positively associated with a 52% increase in risk of prostate carcinoma detection at initial prostate biopsy.⁵

There has been no reported study of treatment efficacy in veterans with AO-related prostate carcinoma. We present a retrospective study of Ra-223 and other therapies in metastatic CRPC. The purpose of this study was to compare response to therapy and survival in veterans exposed to agent orange (AO+) vs veterans who were not exposed to (AO-) in a single US Department of Veteran Affairs (VA) medical center.

Methods

This was a retrospective study of veterans with metastatic CRPC to bones who received Ra-223 radionuclide therapy with standard dose of 50 kBq per kg of body weight and other sequential therapies at VA Pittsburgh Healthcare System (VAPHS) from January 2014 to January 2019. The purpose of this study was to measure difference in treatment outcome between AO+ veterans and AO- veterans.

Eligibility Criteria

All veterans had a history that included bone metastasis CRPC. They could have 2 to 3 small lymphadenopathies but not visceral metastasis. They received a minimum of 3 cycles and a maximum of 6 cycles of Ra-223 therapy, which was given in 4-week intervals. Pretreatment criteria was hemoglobin > 10 g/dL, platelet > 100 × 10⁹/L, and absolute neutrophil counts > 1.5 × 10⁹/L. Other therapies, such as abiraterone, enzalutamide, docetaxel, and cabazitaxel, were administered either after Ra-223 (Ra first) or before Ra-223 therapy (Ra later). Veterans also received androgen deprivation therapy (ADT) with luteinizing hormone releasing hormone (LHRH) agonist (leuprolide acetate) to maintain castrate level of testosterone and bisphosphonates for bone metastasis. Eligible veterans were divided into 2 groups: AO+ and AO-. AO+ veterans are those that were proven to be physically active during the Vietnam War and have been determined by the US government to receive service-connected compensation from the VA. AO- veterans were those who were not exposed to AO.

Statistics

Time to study was calculated from the initiation of Ra-223 therapy. Time to skeletal-related events (SRE), progression of prostate specific antigen (PSA), bone metastasis, and alkaline phosphatase (ALP) were calculated in months, using unpaired t test with 2-tailed P value. Median survival was calculated in months by Kaplan Meier R log-rank test Definition).

Results

Forty-eight veterans with bone metastasis CRPC received Ra-223 therapy. Of those, 34 veterans were eligible for this retrospective study: 17 AO+ veterans and 17 AO- veterans. Mean age of diagnosis was 62 years (AO+) and 69 years (AO-) (P = .005). Mean Gleason score was 8.2 (AO+) and 8.0 (AO-) (P = .705). Veterans received initial therapy at diagnosis of prostate carcinoma, including radical prostatectomy (6 AO+ and 3 AO-), localized radiation therapy (3 AO+ and 5 AO-), and ADT (8 AO+ and 9 AO-) (Table 1).

Mean PSA at the initiation of Ra-223 therapy for AO+ was 92.8 (range, 2-551) and for AO- was 102.3 (range, 4-639; P = .86). Mean Ra-223 dose per cycle for AO+ and AO- was 157 uCi and 113 uCi, respectively. All 34 veterans received ADT (leuprolide acetate), and 30 veterans (16 AO+ and 14 AO-) received bisphosphonates (zoledronic acid or denosumab). A total of 10 veterans (29%) received Ra-223 as a first-line therapy (4 AO+ and 6 AO-), and 24 veterans (71%) received Ra-223 after hormonal or chemotherapy (13 AO+ and 11 AO-).

Discussions

There has been no reported VA study of using Ra-223 and other therapies (hormonal and chemotherapy) in veterans exposed to AO. This is the first retrospective study to compare the response and survival between AO+ and AO- veterans. Even though this study featured a small sample, it is interesting to note the difference between those 2 populations. There was 1 prior study in veterans with prostate carcinoma using radiotherapy (brachytherapy) in early-stage disease. Everly and colleagues reported that AO+ veterans were less likely to remain biochemically controlled compared with AO- and nonveteran patients with prostate carcinoma.⁴

Ansbaugh and colleagues reported that AO was associated with a 75% increase in the risk of Gleason ≥ 7 and a 110% increase in Gleason ≥ 8. AO+ veterans are at risk for the detection of high-grade prostate carcinoma. They also tend to have an average age of diagnosis that is 4 to 5 years younger than AO- veterans.⁶

Our study revealed that AO+ veterans were diagnosed at a younger age (mean 62 years) compared with that of AO- veterans (mean 69 years, P = .005). We also proved that AO veterans have a higher mean Gleason score (8.2) compared with that of AO- veterans (8.0). Veterans received therapy at the time of diagnosis of prostate carcinoma with either radical prostatectomy, radiation therapy, or ADT with leuprolide acetate. Mean PSA at the start of Ra-223 therapy for AO+ was 92.8 (range, 2-551); for AO- was 102.3 (range, 4-639), which is not statistically significant.

Ra-223, an α-emitting radiopharmaceutical, mimics calcium in forming complexes with the bone mineral hydroxyapatite, which specifically targets bone metastases. Ra-223 preferentially targets new bone growth surrounding bone metastases while emitting α particles within the tumor microenvironment. α particles have high linear energy transfer with enhanced ability to induce lethal double-stranded DNA breaks, thus eliciting greater cytotoxic effects on bone-metastatic tumor sites.⁷

In a phase 3, randomized, double-blind, placebo-controlled study by Parker and colleagues (ALSYMPCA study), 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, were randomized to receive 6 injections of Ra-223 or matching placebo.² Ra-223 significantly improved overall survival (OS) (median, 14.9 months vs 11.3 months) compared with that of placebo. Ra-223 also prolonged the time to the first symptomatic SRE (median, 15.6 months vs 9.8 months), the time to an increase in the total ALP level (median 7.4 months vs 3.8 months), and the time to an increase in the PSA level (median 3.6 months vs 3.4 months).²

In our study, the mean time to SRE for AO+ was 10.6 months and AO- was 10.3 months (P = .93). Mean time to PSA progression for AO+ was 5.4 months and for AO- was 6.8 months (P = .28). Mean time to bone progression for AO+ and for AO- were 7.6 months and 10.1 months respectively (P = .16). Mean time to ALP progression for AO+ and AO- were 6.3 months and 8.7 months respectively (P = .05). There is a trend of shorter PSA progression, bone progression, and ALP progression in AO+ veterans, though these were not statistically significant due to small sample population. In our study the median survival in for AO- was 18 months and for AO+ was 12 months, which is comparable with median survival of 14.9 months from the ALSYMPCA study.

There were 12 veterans who developed SREs. All received radiation therapy due to bone progression or impending fracture. AO+ veterans developed more SREs (n = 8) when compared with AO- veterans (n = 4). There were more AO- veterans alive (n = 10) than there were AO+ veterans (n = 4). The plausible explanation of this may be due to the aggressive pattern of prostate carcinoma in AO+ veterans (younger age and higher Gleason score).

VAPHS participated in the ERA trial between 2014 and 2016. The trial enrolled 806 patients who were randomly assigned to receive first-line Ra-223 or placebo in addition to abiraterone acetate plus prednisone.³ The study was unblinded prematurely after more fractures and deaths were noted in the Ra-223 and abiraterone group than there were in the placebo and abiraterone group. Median symptomatic SRE was 22.3 months in the Ra-223 group and 26.0 months in the placebo group. Fractures (any grade) occurred in 29% in the Ra-223 group and 11% in the placebo group. It was suggested that Ra-223 could contribute to the risk of osteoporotic fractures in patients with bone metastatic prostate carcinoma. Median OS was 30.7 months in the Ra-223 group and 33.3 months in the placebo group.³

We enrolled 3 veterans in the ERA clinical trial. Two AO+ veterans had SREs at 7 months and 11 months. In our study, the median OS for Ra-223 first line was 32 months, which is comparable with median survival of 30.7 months from ERA-223 study. Median survival for Ra-223 later was only 15 months. We recommend veterans with at least 2 to 3-bone metastasis receive Ra-223 in the first-line setting rather than second- or third-line setting. In this retrospective study with Ra-223 and other therapies, we proved that AO+ veterans have a worse response and OS when compared with that of AO- veterans.

Conclusions

This is the first VA study to compare the efficacy of Ra-223 and other therapies in metastatic CRPC between AO+ and AO- veterans. AO+ veterans were diagnosed at a younger age and had higher Gleason scores. There was no statistical difference between AO+ and AO- veterans in terms of time to SRE, PSA progression, and bone and ALP progression even though there was a trend of shorter duration in AO+ veterans. There was no median survival difference between veterans who received Ra-223 first vs Ra-223 later as well as between AO+ and AO- veterans, but there was a trend of worse survival in veteran who received Ra-223 later and AO+ veterans.

This study showed that AO+ veterans have a shorter duration of response to therapy and shorter median survival compared with that of AO- veterans. We recommend that veterans should get Ra-223 in the first-line setting rather than after hormonal therapy and chemotherapy because their marrows are still intact. We need to investigate further whether veterans that exposed to carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) may have different molecular biology and as such may cause inferior efficacy in the treatment of prostate carcinoma.

The US Food and Drug Administration (FDA) approved the use of durvalumab for patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (CRT).¹ After 2 randomized phase 3 studies in 2017 and 2018 showed significant progression-free and overall survival respectively,^2,3 durvalumab became a category 1 recommendation for the above indication per National Comprehensive Cancer Network (NCCN) guidelines.⁴ Adherence to guidelines have been shown to improve patient survival across several cancer types.^5-7 However, guideline adherence rates have been variable across health institutions. Therefore, further study is warranted to evaluate nonadherent practices with the goal of improving the quality of cancer care delivery.^8,9

Stage III NSCLC is associated with poor survival rates.¹⁰ Concurrent CRT remains the standard of care in patients with good performance status based on clinical trial populations.⁴ Lung cancer remains a disease of the elderly, with a median age at diagnosis of 70 years.¹¹ Discrepancies in the treatment of lung cancer in older adults can vary widely due to a lack of evidence surrounding the treatment in those who have comorbidities and poor performance status, widening the gap between clinical trial and real-world populations.¹¹

A recent review by Passaro and colleagues revealed that at least 11 pivotal randomized controlled trials have shown the activity of immune checkpoint inhibitors (ICI) in locally advanced and metastatic lung cancer. However, these studies have mostly excluded patients with a performance status of the Eastern Cooperative Oncology Group (ECOG) level ≥ 2.¹¹

Durvalumab is one of many new therapies to enter clinical practice to demonstrate survival benefit, but its use among veterans with stage III NSCLC in adherence with National Comprehensive Cancer Network (NCCN) guidelines was not robust at the Birmingham Veterans Affairs Medical Center (VAMC) in Alabama. Therefore, we decided to study the level of adherence and to identify barriers to conformity to the category 1 NCCN recommendations.

Methods

The Birmingham VAMC Outpatient Oncology Clinic billing data identified all individuals diagnosed with lung cancer treated between October 2017 and August 2019. Patients who did not have NSCLC that was stage III and unresectable were excluded from our study. Patients who did not receive a majority of their treatment at US Department of Veterans Affairs (VA) facilities were excluded as well. Each patient’s demographic, functional level, and tumor characteristics during the treatment planning phase and follow-up visits were obtained. Two investigators who evaluated health care provider documentation using the VA Computerized Patient Record System (CPRS) conducted chart reviews.

The primary outcomes were the proportion of patients who received concurrent CRT and the proportion who received durvalumab consolidation. Our chart review also categorized reasons for nonreceipt of concurrent CRT and subsequent durvalumab. Documented reasons for guideline discordancy were generated empirically and broadly. We noted if documentation was unclear and included reasons for why a veteran was not a candidate for CRT, the presence of toxicities associated with CRT, and a patient’s refusal for therapy despite medical advice. Descriptive data were analyzed for all clinical or demographic characteristics and outcomes.

This was considered an internal quality improvement initiative. As such, Birmingham VAMC did not require institutional review board approval for the study. The facility is accredited by the American College of Surgeons Commission on Cancer.

Results

A total of 41 veterans with stage III NSCLC were identified to have established care in the Birmingham VAMC Oncology Clinic between October 2017 and August 2019. Of these, 7 received the majority of their treatment from community-based non-VA facilities and 14 were not candidates for CRT and were excluded from this study.

The mean (SD) age of study participants was 70.0 (8.4) years (range, 57 to 92 years). Most of the study veterans (33; 97.1%) were male and 20 (58.8%) were African American (Table). Eighteen (53%) of study participants had clinical stage IIIa NSCLC; 19 (56%) showed a squamous subtype of NSCLC. A majority (53%) of the veterans studied were evaluated to be functionally fit with an ECOG status of 0 to 1, although documentation of ECOG status was lacking in 5 (14.7%) patients in the initial treatment planning visit records. It was unclear if performance status had been reevaluated and changes noted over the course of concurrent CRT.

CRT Patients

The relative distribution of veterans who underwent CRT for stage III NSCLC plus the reasons they did not receive guideline-based treatment with durvalumab is shown in the Figure. Fourteen patients (41%) were inappropriate candidates for CRT; the most common reason for this was their poor performance status upon initial evaluation and 3 patients (8.8%) in the study had extensive disease or were upstaged upon follow-up clinic visit.

Twenty (59%) veterans in the study initiated CRT. However, only 16 (47.1%) completed CRT. Those who dropped out of CRT did so because of toxicities that included various cytopenia, gastrointestinal toxicities due to radiation and/or chemotherapy, or failure to thrive.

Durvalumab Treatment

After initiation of CRT, 9 (26.5%) patients did not go on to receive durvalumab. Three patients (8.8%) suffered toxicities during CRT. One study patient was found to have a severe respiratory infection requiring intensive care unit admission. Another study patient was found to have a new sternal lesion on follow-up positron emission tomography. One declined because of a history of severe antineutrophil cytoplasmic antibodies vasculitis, which made durvalumab use unsafe. Three patients (8.8%) declined treatment with CRT or durvalumab because of personal preference. Documentation was unclear as to why durvalumab was prescribed to one patient who had completed CRT.

Discussion

NCCN guidelines on the use of durvalumab in NSCLC are based on the phase 3 PACIFIC placebo-controlled randomized clinical trial. This trial, which included only patients with documented performance status of ECOG 0 or 1, reported that grade 3 or 4 events occurred in 30.5% of patients randomized to consolidative durvalumab. Treatment was discontinued in 15.4% of patients due to adverse events.³

Our study examined consolidation therapy with durvalumab in patients with unresectable stage III NSCLC with an ECOG performance status of 0 to 1 who had not progressed after 2 or more cycles of definitive concurrent CRT.⁴ Patients with previous exposure to immunotherapy, a history of immunodeficiency, active infection, unresolved toxicity from CRT, autoimmune disease, and patients who received sequential CRT were excluded.² Surprisingly, the adherence rate to guidelines was close to 100% with appropriate documentation and justification of CRT initiation and durvalumab use. Five (14.7%) of veterans with unresectable stage III NSCLC did not have clear documentation of ECOG status on initial visit and only 1 veteran who completed CRT did not have clear documentation as to why durvalumab was not provided. Unfortunately, 23 (68.6%) veterans in the study were unable to receive durvalumab, a potentially disease-modifying drug; nearly one-third (10) of veterans were deemed poor candidates for concurrent CRT despite the fact that 52.9% (18) of veterans in the study had a documented ECOG of 0 or 1 on initial evaluation.

Clinical Trials vs Real World

The heterogeneity between anticipated study populations, those who were able to receive durvalumab in the PACIFIC trial, compared with our observed real-world veteran population, likely stems from the lack of information about how comorbidity and fitness can affect the choice of therapeutic intervention in patients with lung cancer.¹² In addition, older adults who participated in randomized controlled trials (RCTs) are not representative of the average older adult who presents to medical oncology clinics, making the application of guideline concordant care difficult.¹³

Similar real-world observations parallel to our analyses have confirmed, complemented and/or refuted findings of RCTs, and have helped impact the treatment of multiple acute and chronic conditions including influenza, cardiovascular disease, and diabetes.¹⁴

A component of socioeconomic barriers and access to supportive care played roles in the decisions of certain patients who chose not to undergo concurrent CRT despite medical advice. These 2 obstacles also affected the decision making for some in the study when considering the use of durvalumab (administered by a 60-minute IV infusion every 2 weeks for 1 year) per recommended guidelines.¹ These hurdles need further study in the context of their effect on quality of life and the difficulties generated by various social determinants of health.

Limitations

Study limitations included the biased and confounding factors previously described about retrospective and nonrandomized observational studies that are controlled for during RCTs.¹⁵ Electronic health record data may have been incorrectly collected resulting in missing or wrong data points that affect the validity of our conclusion. Recall bias with regard to documentation by health care providers describing reasons why CRT or durvalumab were not initiated or the patient’s ability to recall previous treatments and report ECOG status or toxicities also may have impacted our findings. Comorbidities and poor performance status, frequently occurring among veterans, negatively impact cancer treatment decisions and may result in a detection bias. For example, tobacco use, cardiovascular disease, including heart failure, and chronic obstructive pulmonary disease, are notoriously higher in the US veteran population when compared with civilian cohorts.^16-18 Also, veterans with poorly controlled depression and posttraumatic stress disorder resulting in functional impairment are a factor.¹⁹ Steps were taken to address some of these biases by performing repeat checks of tabulated data and employing 2 independent reviewers to evaluate all relevant clinical documentation, compare results, and reach a consensus.

Conlcusions

This retrospective analysis of adherence to category 1 NCCN guidelines for durvalumab use among patients at the Birmingham VAMC Oncology Clinic reinforced our practice and identified minor deficiencies in documentation that would impact future clinical visits. More importantly, it depicted the massive disparity in treatment candidacy among Birmingham veterans compared with clinical trial populations. Efforts will be made to address factors impacting a veteran’s candidacy for CRT and explore other variables such as socioeconomic barriers to treatment. Multiple complementary tools to assess patients’ frailty, such as the Charlson Comorbidity Index (CCI), are now being used for a variety of disorders including cancers. More robust data and standardization are needed to validate the use of these assessments in predicting response to immune checkpoint inhibitors.

Immune checkpoint inhibitors are currently being evaluated in stage III NSCLC studies and may be implemented as routine practice in the future.¹² It is important to distinguish fit from frail veterans with lung cancer for treatment selection. We would like to see the expansion of the eligibility criteria for clinical trials to include patients with a performance status of ECOG 2 in order for results to be truly generalizable to the real-world population. Our hope is that such work will improve not only the quality of lung cancer care, but also the quality of care across multiple tumor types.

The US Food and Drug Administration (FDA) approved the use of durvalumab for patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (CRT).¹ After 2 randomized phase 3 studies in 2017 and 2018 showed significant progression-free and overall survival respectively,^2,3 durvalumab became a category 1 recommendation for the above indication per National Comprehensive Cancer Network (NCCN) guidelines.⁴ Adherence to guidelines have been shown to improve patient survival across several cancer types.^5-7 However, guideline adherence rates have been variable across health institutions. Therefore, further study is warranted to evaluate nonadherent practices with the goal of improving the quality of cancer care delivery.^8,9

Stage III NSCLC is associated with poor survival rates.¹⁰ Concurrent CRT remains the standard of care in patients with good performance status based on clinical trial populations.⁴ Lung cancer remains a disease of the elderly, with a median age at diagnosis of 70 years.¹¹ Discrepancies in the treatment of lung cancer in older adults can vary widely due to a lack of evidence surrounding the treatment in those who have comorbidities and poor performance status, widening the gap between clinical trial and real-world populations.¹¹

A recent review by Passaro and colleagues revealed that at least 11 pivotal randomized controlled trials have shown the activity of immune checkpoint inhibitors (ICI) in locally advanced and metastatic lung cancer. However, these studies have mostly excluded patients with a performance status of the Eastern Cooperative Oncology Group (ECOG) level ≥ 2.¹¹

Durvalumab is one of many new therapies to enter clinical practice to demonstrate survival benefit, but its use among veterans with stage III NSCLC in adherence with National Comprehensive Cancer Network (NCCN) guidelines was not robust at the Birmingham Veterans Affairs Medical Center (VAMC) in Alabama. Therefore, we decided to study the level of adherence and to identify barriers to conformity to the category 1 NCCN recommendations.

Methods

The Birmingham VAMC Outpatient Oncology Clinic billing data identified all individuals diagnosed with lung cancer treated between October 2017 and August 2019. Patients who did not have NSCLC that was stage III and unresectable were excluded from our study. Patients who did not receive a majority of their treatment at US Department of Veterans Affairs (VA) facilities were excluded as well. Each patient’s demographic, functional level, and tumor characteristics during the treatment planning phase and follow-up visits were obtained. Two investigators who evaluated health care provider documentation using the VA Computerized Patient Record System (CPRS) conducted chart reviews.

The primary outcomes were the proportion of patients who received concurrent CRT and the proportion who received durvalumab consolidation. Our chart review also categorized reasons for nonreceipt of concurrent CRT and subsequent durvalumab. Documented reasons for guideline discordancy were generated empirically and broadly. We noted if documentation was unclear and included reasons for why a veteran was not a candidate for CRT, the presence of toxicities associated with CRT, and a patient’s refusal for therapy despite medical advice. Descriptive data were analyzed for all clinical or demographic characteristics and outcomes.

This was considered an internal quality improvement initiative. As such, Birmingham VAMC did not require institutional review board approval for the study. The facility is accredited by the American College of Surgeons Commission on Cancer.

Results

A total of 41 veterans with stage III NSCLC were identified to have established care in the Birmingham VAMC Oncology Clinic between October 2017 and August 2019. Of these, 7 received the majority of their treatment from community-based non-VA facilities and 14 were not candidates for CRT and were excluded from this study.

The mean (SD) age of study participants was 70.0 (8.4) years (range, 57 to 92 years). Most of the study veterans (33; 97.1%) were male and 20 (58.8%) were African American (Table). Eighteen (53%) of study participants had clinical stage IIIa NSCLC; 19 (56%) showed a squamous subtype of NSCLC. A majority (53%) of the veterans studied were evaluated to be functionally fit with an ECOG status of 0 to 1, although documentation of ECOG status was lacking in 5 (14.7%) patients in the initial treatment planning visit records. It was unclear if performance status had been reevaluated and changes noted over the course of concurrent CRT.

CRT Patients

The relative distribution of veterans who underwent CRT for stage III NSCLC plus the reasons they did not receive guideline-based treatment with durvalumab is shown in the Figure. Fourteen patients (41%) were inappropriate candidates for CRT; the most common reason for this was their poor performance status upon initial evaluation and 3 patients (8.8%) in the study had extensive disease or were upstaged upon follow-up clinic visit.

Twenty (59%) veterans in the study initiated CRT. However, only 16 (47.1%) completed CRT. Those who dropped out of CRT did so because of toxicities that included various cytopenia, gastrointestinal toxicities due to radiation and/or chemotherapy, or failure to thrive.

Durvalumab Treatment

After initiation of CRT, 9 (26.5%) patients did not go on to receive durvalumab. Three patients (8.8%) suffered toxicities during CRT. One study patient was found to have a severe respiratory infection requiring intensive care unit admission. Another study patient was found to have a new sternal lesion on follow-up positron emission tomography. One declined because of a history of severe antineutrophil cytoplasmic antibodies vasculitis, which made durvalumab use unsafe. Three patients (8.8%) declined treatment with CRT or durvalumab because of personal preference. Documentation was unclear as to why durvalumab was prescribed to one patient who had completed CRT.

Discussion

NCCN guidelines on the use of durvalumab in NSCLC are based on the phase 3 PACIFIC placebo-controlled randomized clinical trial. This trial, which included only patients with documented performance status of ECOG 0 or 1, reported that grade 3 or 4 events occurred in 30.5% of patients randomized to consolidative durvalumab. Treatment was discontinued in 15.4% of patients due to adverse events.³

Our study examined consolidation therapy with durvalumab in patients with unresectable stage III NSCLC with an ECOG performance status of 0 to 1 who had not progressed after 2 or more cycles of definitive concurrent CRT.⁴ Patients with previous exposure to immunotherapy, a history of immunodeficiency, active infection, unresolved toxicity from CRT, autoimmune disease, and patients who received sequential CRT were excluded.² Surprisingly, the adherence rate to guidelines was close to 100% with appropriate documentation and justification of CRT initiation and durvalumab use. Five (14.7%) of veterans with unresectable stage III NSCLC did not have clear documentation of ECOG status on initial visit and only 1 veteran who completed CRT did not have clear documentation as to why durvalumab was not provided. Unfortunately, 23 (68.6%) veterans in the study were unable to receive durvalumab, a potentially disease-modifying drug; nearly one-third (10) of veterans were deemed poor candidates for concurrent CRT despite the fact that 52.9% (18) of veterans in the study had a documented ECOG of 0 or 1 on initial evaluation.

Clinical Trials vs Real World

The heterogeneity between anticipated study populations, those who were able to receive durvalumab in the PACIFIC trial, compared with our observed real-world veteran population, likely stems from the lack of information about how comorbidity and fitness can affect the choice of therapeutic intervention in patients with lung cancer.¹² In addition, older adults who participated in randomized controlled trials (RCTs) are not representative of the average older adult who presents to medical oncology clinics, making the application of guideline concordant care difficult.¹³

Similar real-world observations parallel to our analyses have confirmed, complemented and/or refuted findings of RCTs, and have helped impact the treatment of multiple acute and chronic conditions including influenza, cardiovascular disease, and diabetes.¹⁴

A component of socioeconomic barriers and access to supportive care played roles in the decisions of certain patients who chose not to undergo concurrent CRT despite medical advice. These 2 obstacles also affected the decision making for some in the study when considering the use of durvalumab (administered by a 60-minute IV infusion every 2 weeks for 1 year) per recommended guidelines.¹ These hurdles need further study in the context of their effect on quality of life and the difficulties generated by various social determinants of health.

Limitations

Study limitations included the biased and confounding factors previously described about retrospective and nonrandomized observational studies that are controlled for during RCTs.¹⁵ Electronic health record data may have been incorrectly collected resulting in missing or wrong data points that affect the validity of our conclusion. Recall bias with regard to documentation by health care providers describing reasons why CRT or durvalumab were not initiated or the patient’s ability to recall previous treatments and report ECOG status or toxicities also may have impacted our findings. Comorbidities and poor performance status, frequently occurring among veterans, negatively impact cancer treatment decisions and may result in a detection bias. For example, tobacco use, cardiovascular disease, including heart failure, and chronic obstructive pulmonary disease, are notoriously higher in the US veteran population when compared with civilian cohorts.^16-18 Also, veterans with poorly controlled depression and posttraumatic stress disorder resulting in functional impairment are a factor.¹⁹ Steps were taken to address some of these biases by performing repeat checks of tabulated data and employing 2 independent reviewers to evaluate all relevant clinical documentation, compare results, and reach a consensus.

Conlcusions

This retrospective analysis of adherence to category 1 NCCN guidelines for durvalumab use among patients at the Birmingham VAMC Oncology Clinic reinforced our practice and identified minor deficiencies in documentation that would impact future clinical visits. More importantly, it depicted the massive disparity in treatment candidacy among Birmingham veterans compared with clinical trial populations. Efforts will be made to address factors impacting a veteran’s candidacy for CRT and explore other variables such as socioeconomic barriers to treatment. Multiple complementary tools to assess patients’ frailty, such as the Charlson Comorbidity Index (CCI), are now being used for a variety of disorders including cancers. More robust data and standardization are needed to validate the use of these assessments in predicting response to immune checkpoint inhibitors.

Immune checkpoint inhibitors are currently being evaluated in stage III NSCLC studies and may be implemented as routine practice in the future.¹² It is important to distinguish fit from frail veterans with lung cancer for treatment selection. We would like to see the expansion of the eligibility criteria for clinical trials to include patients with a performance status of ECOG 2 in order for results to be truly generalizable to the real-world population. Our hope is that such work will improve not only the quality of lung cancer care, but also the quality of care across multiple tumor types.

The US Food and Drug Administration (FDA) approved the use of durvalumab for patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (CRT).¹ After 2 randomized phase 3 studies in 2017 and 2018 showed significant progression-free and overall survival respectively,^2,3 durvalumab became a category 1 recommendation for the above indication per National Comprehensive Cancer Network (NCCN) guidelines.⁴ Adherence to guidelines have been shown to improve patient survival across several cancer types.^5-7 However, guideline adherence rates have been variable across health institutions. Therefore, further study is warranted to evaluate nonadherent practices with the goal of improving the quality of cancer care delivery.^8,9

Stage III NSCLC is associated with poor survival rates.¹⁰ Concurrent CRT remains the standard of care in patients with good performance status based on clinical trial populations.⁴ Lung cancer remains a disease of the elderly, with a median age at diagnosis of 70 years.¹¹ Discrepancies in the treatment of lung cancer in older adults can vary widely due to a lack of evidence surrounding the treatment in those who have comorbidities and poor performance status, widening the gap between clinical trial and real-world populations.¹¹

A recent review by Passaro and colleagues revealed that at least 11 pivotal randomized controlled trials have shown the activity of immune checkpoint inhibitors (ICI) in locally advanced and metastatic lung cancer. However, these studies have mostly excluded patients with a performance status of the Eastern Cooperative Oncology Group (ECOG) level ≥ 2.¹¹

Durvalumab is one of many new therapies to enter clinical practice to demonstrate survival benefit, but its use among veterans with stage III NSCLC in adherence with National Comprehensive Cancer Network (NCCN) guidelines was not robust at the Birmingham Veterans Affairs Medical Center (VAMC) in Alabama. Therefore, we decided to study the level of adherence and to identify barriers to conformity to the category 1 NCCN recommendations.

Methods

The Birmingham VAMC Outpatient Oncology Clinic billing data identified all individuals diagnosed with lung cancer treated between October 2017 and August 2019. Patients who did not have NSCLC that was stage III and unresectable were excluded from our study. Patients who did not receive a majority of their treatment at US Department of Veterans Affairs (VA) facilities were excluded as well. Each patient’s demographic, functional level, and tumor characteristics during the treatment planning phase and follow-up visits were obtained. Two investigators who evaluated health care provider documentation using the VA Computerized Patient Record System (CPRS) conducted chart reviews.

The primary outcomes were the proportion of patients who received concurrent CRT and the proportion who received durvalumab consolidation. Our chart review also categorized reasons for nonreceipt of concurrent CRT and subsequent durvalumab. Documented reasons for guideline discordancy were generated empirically and broadly. We noted if documentation was unclear and included reasons for why a veteran was not a candidate for CRT, the presence of toxicities associated with CRT, and a patient’s refusal for therapy despite medical advice. Descriptive data were analyzed for all clinical or demographic characteristics and outcomes.

This was considered an internal quality improvement initiative. As such, Birmingham VAMC did not require institutional review board approval for the study. The facility is accredited by the American College of Surgeons Commission on Cancer.

Results

A total of 41 veterans with stage III NSCLC were identified to have established care in the Birmingham VAMC Oncology Clinic between October 2017 and August 2019. Of these, 7 received the majority of their treatment from community-based non-VA facilities and 14 were not candidates for CRT and were excluded from this study.

The mean (SD) age of study participants was 70.0 (8.4) years (range, 57 to 92 years). Most of the study veterans (33; 97.1%) were male and 20 (58.8%) were African American (Table). Eighteen (53%) of study participants had clinical stage IIIa NSCLC; 19 (56%) showed a squamous subtype of NSCLC. A majority (53%) of the veterans studied were evaluated to be functionally fit with an ECOG status of 0 to 1, although documentation of ECOG status was lacking in 5 (14.7%) patients in the initial treatment planning visit records. It was unclear if performance status had been reevaluated and changes noted over the course of concurrent CRT.

CRT Patients

The relative distribution of veterans who underwent CRT for stage III NSCLC plus the reasons they did not receive guideline-based treatment with durvalumab is shown in the Figure. Fourteen patients (41%) were inappropriate candidates for CRT; the most common reason for this was their poor performance status upon initial evaluation and 3 patients (8.8%) in the study had extensive disease or were upstaged upon follow-up clinic visit.

Twenty (59%) veterans in the study initiated CRT. However, only 16 (47.1%) completed CRT. Those who dropped out of CRT did so because of toxicities that included various cytopenia, gastrointestinal toxicities due to radiation and/or chemotherapy, or failure to thrive.

Durvalumab Treatment

After initiation of CRT, 9 (26.5%) patients did not go on to receive durvalumab. Three patients (8.8%) suffered toxicities during CRT. One study patient was found to have a severe respiratory infection requiring intensive care unit admission. Another study patient was found to have a new sternal lesion on follow-up positron emission tomography. One declined because of a history of severe antineutrophil cytoplasmic antibodies vasculitis, which made durvalumab use unsafe. Three patients (8.8%) declined treatment with CRT or durvalumab because of personal preference. Documentation was unclear as to why durvalumab was prescribed to one patient who had completed CRT.

Discussion

NCCN guidelines on the use of durvalumab in NSCLC are based on the phase 3 PACIFIC placebo-controlled randomized clinical trial. This trial, which included only patients with documented performance status of ECOG 0 or 1, reported that grade 3 or 4 events occurred in 30.5% of patients randomized to consolidative durvalumab. Treatment was discontinued in 15.4% of patients due to adverse events.³

Our study examined consolidation therapy with durvalumab in patients with unresectable stage III NSCLC with an ECOG performance status of 0 to 1 who had not progressed after 2 or more cycles of definitive concurrent CRT.⁴ Patients with previous exposure to immunotherapy, a history of immunodeficiency, active infection, unresolved toxicity from CRT, autoimmune disease, and patients who received sequential CRT were excluded.² Surprisingly, the adherence rate to guidelines was close to 100% with appropriate documentation and justification of CRT initiation and durvalumab use. Five (14.7%) of veterans with unresectable stage III NSCLC did not have clear documentation of ECOG status on initial visit and only 1 veteran who completed CRT did not have clear documentation as to why durvalumab was not provided. Unfortunately, 23 (68.6%) veterans in the study were unable to receive durvalumab, a potentially disease-modifying drug; nearly one-third (10) of veterans were deemed poor candidates for concurrent CRT despite the fact that 52.9% (18) of veterans in the study had a documented ECOG of 0 or 1 on initial evaluation.

Clinical Trials vs Real World

The heterogeneity between anticipated study populations, those who were able to receive durvalumab in the PACIFIC trial, compared with our observed real-world veteran population, likely stems from the lack of information about how comorbidity and fitness can affect the choice of therapeutic intervention in patients with lung cancer.¹² In addition, older adults who participated in randomized controlled trials (RCTs) are not representative of the average older adult who presents to medical oncology clinics, making the application of guideline concordant care difficult.¹³

Similar real-world observations parallel to our analyses have confirmed, complemented and/or refuted findings of RCTs, and have helped impact the treatment of multiple acute and chronic conditions including influenza, cardiovascular disease, and diabetes.¹⁴

A component of socioeconomic barriers and access to supportive care played roles in the decisions of certain patients who chose not to undergo concurrent CRT despite medical advice. These 2 obstacles also affected the decision making for some in the study when considering the use of durvalumab (administered by a 60-minute IV infusion every 2 weeks for 1 year) per recommended guidelines.¹ These hurdles need further study in the context of their effect on quality of life and the difficulties generated by various social determinants of health.

Limitations

Study limitations included the biased and confounding factors previously described about retrospective and nonrandomized observational studies that are controlled for during RCTs.¹⁵ Electronic health record data may have been incorrectly collected resulting in missing or wrong data points that affect the validity of our conclusion. Recall bias with regard to documentation by health care providers describing reasons why CRT or durvalumab were not initiated or the patient’s ability to recall previous treatments and report ECOG status or toxicities also may have impacted our findings. Comorbidities and poor performance status, frequently occurring among veterans, negatively impact cancer treatment decisions and may result in a detection bias. For example, tobacco use, cardiovascular disease, including heart failure, and chronic obstructive pulmonary disease, are notoriously higher in the US veteran population when compared with civilian cohorts.^16-18 Also, veterans with poorly controlled depression and posttraumatic stress disorder resulting in functional impairment are a factor.¹⁹ Steps were taken to address some of these biases by performing repeat checks of tabulated data and employing 2 independent reviewers to evaluate all relevant clinical documentation, compare results, and reach a consensus.

Conlcusions

This retrospective analysis of adherence to category 1 NCCN guidelines for durvalumab use among patients at the Birmingham VAMC Oncology Clinic reinforced our practice and identified minor deficiencies in documentation that would impact future clinical visits. More importantly, it depicted the massive disparity in treatment candidacy among Birmingham veterans compared with clinical trial populations. Efforts will be made to address factors impacting a veteran’s candidacy for CRT and explore other variables such as socioeconomic barriers to treatment. Multiple complementary tools to assess patients’ frailty, such as the Charlson Comorbidity Index (CCI), are now being used for a variety of disorders including cancers. More robust data and standardization are needed to validate the use of these assessments in predicting response to immune checkpoint inhibitors.

Immune checkpoint inhibitors are currently being evaluated in stage III NSCLC studies and may be implemented as routine practice in the future.¹² It is important to distinguish fit from frail veterans with lung cancer for treatment selection. We would like to see the expansion of the eligibility criteria for clinical trials to include patients with a performance status of ECOG 2 in order for results to be truly generalizable to the real-world population. Our hope is that such work will improve not only the quality of lung cancer care, but also the quality of care across multiple tumor types.

A short course of radiation therapy followed by neoadjuvant chemotherapy resulted in a clinical complete response (CR) in almost half of 90 patients with locally advanced rectal cancer, allowing the majority of responders to skip surgical resection, a retrospective study indicates.

Specifically, at a median follow-up of 16.6 months for living patients, the initial clinical CR rate was 48% overall.

“While we do not have enough follow-up yet to know the late side-effect profile of this regimen, our preliminary results are promising,” Re-I Chin, MD, of Washington University School of Medicine, St. Louis, Missouri, told Medscape Medical News in an email.

The study was presented at the virtual 2020 meeting of the American Society of Radiation Oncology (ASTRO).

“Certainly, longer follow-up will be needed in this study, but none of the observed patients to date has experienced an unsalvageable failure,” said meeting discussant Amol Narang, MD, of Johns Hopkins University, Baltimore, Maryland.

He reminded conference attendees that, despite good evidence supporting equivalency in oncologic outcomes between short-course radiation and long-course chemoradiation, the former is “highly underutilized in the US” with a mere 1% usage rate between 2004 and 2014.

The current study’s short-course treatment approach was compared in this setting to long-course chemoradiation and adjuvant chemotherapy in the RAPIDO trial reported at the 2020 annual meeting of the American Society of Clinical Oncology (ASCO), Narang pointed out.

Short-course patients had a higher rate of pathological complete response (pCR) and a lower rate of treatment failure compared with patients who received long-course chemoradiation and adjuvant chemotherapy; both patient groups underwent total mesorectal excision — which is different from the current analysis. The RAPIDO investigators concluded that the approach featuring the short course “can be considered as a new standard of care.”

Narang said the data collectively “begs the question as to whether the superiority of long-course chemoradiation should really have to be demonstrated to justify its use.”

But Chin highlighted toxicity issues. “Historically, there have been concerns regarding toxicity with short-course radiation therapy since it requires larger doses of radiation given over a shorter period of time,” Chin explained. “But [the short course] is particularly convenient for patients since it saves them more than a month of daily trips to the radiation oncology department.”
 

Seven local failures

The single-center study involved patients with newly diagnosed, nonmetastatic rectal adenocarcinoma treated with short-course radiation therapy followed by chemotherapy in 2018 and 2019. Nearly all (96%) had locally advanced disease, with either a T3/T4 tumor or node-positive disease. Median tumor size was 4.6 cm.

“Many of the patients in the study had low lying tumors,” Chin reported, with a median distance from the anal verge of 7 cm.

Radiation therapy was delivered in 25 Gy given in five fractions over 5 consecutive days, with the option to boost the dose to 30 Gy or 35 Gy in five fractions if extra-mesorectal lymph nodes were involved. Conventional 3D or intensity-modulated radiation was used and all patients completed treatment.

The median interval between diagnosis of rectal cancer and initiation of radiation therapy was 1.4 months, while the median interval between completion of radiation to initiation of chemotherapy was 2.7 weeks.

The most common chemotherapy regimen was FOLFOX – consisting of leucovorin, fluorouracil (5-FU), and oxaliplatin – or modified FOLFOX. For patients who received six or more cycles of chemotherapy, the median time spent on treatment was 3.9 months.

For those who completed at least six cycles of chemotherapy, the overall clinical CR was 51%, and, for patients with locally advanced disease, the clinical CR rate was 49%. Five of the 43 patients who achieved an initial clinical CR still underwent surgical resection because of patient or physician preference. Among this small group of patients, 4 of the 5 achieved a pCR, and the remaining patient achieved a pathological partial response (pPR).

A total of 42 patients (47% of the group) achieved a partial response following the radiation plus chemotherapy paradigm, and one patient had progressive disease. All underwent surgical resection. One patient did not complete chemotherapy and did not get surgery and subsequently died.

This left 38 patients to be managed nonoperatively. In this nonoperative cohort, 79% of patients continued to have a clinical CR at the end of follow-up. Of the 7 patients with local failure, 6 were salvaged by surgery, one was salvaged by chemotherapy, and all 7 treatment failures had no evidence of disease at last follow-up.

Of the small group of 5 patients who achieved an initial clinical CR following short-course radiation therapy and neoadjuvant chemotherapy, there were no further events in this group, whereas, for patients who achieved only an initial partial response or who had progressive disease, 72% remained event-free.

Approximately half of those who achieved a clinical CR to the treatment regimen had no late gastrointestinal toxicities, and no grade 3 or 4 toxicities were observed. “Surgical resection of tumors — even without a permanent stoma — can result in significantly decreased bowel function, so our goal is to treat patients without surgery and maintain good bowel function,” Chin noted.

“For rectal cancer, both short-course radiation therapy and nonoperative management are emerging treatment paradigms that may be more cost-effective and convenient compared to long-course chemoradiation followed by surgery, [especially since] the COVID-19 pandemic...has spurred changes in clinical practices in radiation oncology,” she said.

Chin has disclosed no relevant financial relationships. Narang reports receiving research support from Boston Scientific.
 

This article first appeared on Medscape.com.

A short course of radiation therapy followed by neoadjuvant chemotherapy resulted in a clinical complete response (CR) in almost half of 90 patients with locally advanced rectal cancer, allowing the majority of responders to skip surgical resection, a retrospective study indicates.

Specifically, at a median follow-up of 16.6 months for living patients, the initial clinical CR rate was 48% overall.

“While we do not have enough follow-up yet to know the late side-effect profile of this regimen, our preliminary results are promising,” Re-I Chin, MD, of Washington University School of Medicine, St. Louis, Missouri, told Medscape Medical News in an email.

The study was presented at the virtual 2020 meeting of the American Society of Radiation Oncology (ASTRO).

“Certainly, longer follow-up will be needed in this study, but none of the observed patients to date has experienced an unsalvageable failure,” said meeting discussant Amol Narang, MD, of Johns Hopkins University, Baltimore, Maryland.

He reminded conference attendees that, despite good evidence supporting equivalency in oncologic outcomes between short-course radiation and long-course chemoradiation, the former is “highly underutilized in the US” with a mere 1% usage rate between 2004 and 2014.

The current study’s short-course treatment approach was compared in this setting to long-course chemoradiation and adjuvant chemotherapy in the RAPIDO trial reported at the 2020 annual meeting of the American Society of Clinical Oncology (ASCO), Narang pointed out.

Short-course patients had a higher rate of pathological complete response (pCR) and a lower rate of treatment failure compared with patients who received long-course chemoradiation and adjuvant chemotherapy; both patient groups underwent total mesorectal excision — which is different from the current analysis. The RAPIDO investigators concluded that the approach featuring the short course “can be considered as a new standard of care.”

Narang said the data collectively “begs the question as to whether the superiority of long-course chemoradiation should really have to be demonstrated to justify its use.”

But Chin highlighted toxicity issues. “Historically, there have been concerns regarding toxicity with short-course radiation therapy since it requires larger doses of radiation given over a shorter period of time,” Chin explained. “But [the short course] is particularly convenient for patients since it saves them more than a month of daily trips to the radiation oncology department.”
 

Seven local failures

The single-center study involved patients with newly diagnosed, nonmetastatic rectal adenocarcinoma treated with short-course radiation therapy followed by chemotherapy in 2018 and 2019. Nearly all (96%) had locally advanced disease, with either a T3/T4 tumor or node-positive disease. Median tumor size was 4.6 cm.

“Many of the patients in the study had low lying tumors,” Chin reported, with a median distance from the anal verge of 7 cm.

Radiation therapy was delivered in 25 Gy given in five fractions over 5 consecutive days, with the option to boost the dose to 30 Gy or 35 Gy in five fractions if extra-mesorectal lymph nodes were involved. Conventional 3D or intensity-modulated radiation was used and all patients completed treatment.

The median interval between diagnosis of rectal cancer and initiation of radiation therapy was 1.4 months, while the median interval between completion of radiation to initiation of chemotherapy was 2.7 weeks.

The most common chemotherapy regimen was FOLFOX – consisting of leucovorin, fluorouracil (5-FU), and oxaliplatin – or modified FOLFOX. For patients who received six or more cycles of chemotherapy, the median time spent on treatment was 3.9 months.

For those who completed at least six cycles of chemotherapy, the overall clinical CR was 51%, and, for patients with locally advanced disease, the clinical CR rate was 49%. Five of the 43 patients who achieved an initial clinical CR still underwent surgical resection because of patient or physician preference. Among this small group of patients, 4 of the 5 achieved a pCR, and the remaining patient achieved a pathological partial response (pPR).

A total of 42 patients (47% of the group) achieved a partial response following the radiation plus chemotherapy paradigm, and one patient had progressive disease. All underwent surgical resection. One patient did not complete chemotherapy and did not get surgery and subsequently died.

This left 38 patients to be managed nonoperatively. In this nonoperative cohort, 79% of patients continued to have a clinical CR at the end of follow-up. Of the 7 patients with local failure, 6 were salvaged by surgery, one was salvaged by chemotherapy, and all 7 treatment failures had no evidence of disease at last follow-up.

Of the small group of 5 patients who achieved an initial clinical CR following short-course radiation therapy and neoadjuvant chemotherapy, there were no further events in this group, whereas, for patients who achieved only an initial partial response or who had progressive disease, 72% remained event-free.

Approximately half of those who achieved a clinical CR to the treatment regimen had no late gastrointestinal toxicities, and no grade 3 or 4 toxicities were observed. “Surgical resection of tumors — even without a permanent stoma — can result in significantly decreased bowel function, so our goal is to treat patients without surgery and maintain good bowel function,” Chin noted.

“For rectal cancer, both short-course radiation therapy and nonoperative management are emerging treatment paradigms that may be more cost-effective and convenient compared to long-course chemoradiation followed by surgery, [especially since] the COVID-19 pandemic...has spurred changes in clinical practices in radiation oncology,” she said.

Chin has disclosed no relevant financial relationships. Narang reports receiving research support from Boston Scientific.
 

This article first appeared on Medscape.com.

A short course of radiation therapy followed by neoadjuvant chemotherapy resulted in a clinical complete response (CR) in almost half of 90 patients with locally advanced rectal cancer, allowing the majority of responders to skip surgical resection, a retrospective study indicates.

Specifically, at a median follow-up of 16.6 months for living patients, the initial clinical CR rate was 48% overall.

“While we do not have enough follow-up yet to know the late side-effect profile of this regimen, our preliminary results are promising,” Re-I Chin, MD, of Washington University School of Medicine, St. Louis, Missouri, told Medscape Medical News in an email.

The study was presented at the virtual 2020 meeting of the American Society of Radiation Oncology (ASTRO).

“Certainly, longer follow-up will be needed in this study, but none of the observed patients to date has experienced an unsalvageable failure,” said meeting discussant Amol Narang, MD, of Johns Hopkins University, Baltimore, Maryland.

He reminded conference attendees that, despite good evidence supporting equivalency in oncologic outcomes between short-course radiation and long-course chemoradiation, the former is “highly underutilized in the US” with a mere 1% usage rate between 2004 and 2014.

The current study’s short-course treatment approach was compared in this setting to long-course chemoradiation and adjuvant chemotherapy in the RAPIDO trial reported at the 2020 annual meeting of the American Society of Clinical Oncology (ASCO), Narang pointed out.

Short-course patients had a higher rate of pathological complete response (pCR) and a lower rate of treatment failure compared with patients who received long-course chemoradiation and adjuvant chemotherapy; both patient groups underwent total mesorectal excision — which is different from the current analysis. The RAPIDO investigators concluded that the approach featuring the short course “can be considered as a new standard of care.”

Narang said the data collectively “begs the question as to whether the superiority of long-course chemoradiation should really have to be demonstrated to justify its use.”

But Chin highlighted toxicity issues. “Historically, there have been concerns regarding toxicity with short-course radiation therapy since it requires larger doses of radiation given over a shorter period of time,” Chin explained. “But [the short course] is particularly convenient for patients since it saves them more than a month of daily trips to the radiation oncology department.”
 

Seven local failures

The single-center study involved patients with newly diagnosed, nonmetastatic rectal adenocarcinoma treated with short-course radiation therapy followed by chemotherapy in 2018 and 2019. Nearly all (96%) had locally advanced disease, with either a T3/T4 tumor or node-positive disease. Median tumor size was 4.6 cm.

“Many of the patients in the study had low lying tumors,” Chin reported, with a median distance from the anal verge of 7 cm.

Radiation therapy was delivered in 25 Gy given in five fractions over 5 consecutive days, with the option to boost the dose to 30 Gy or 35 Gy in five fractions if extra-mesorectal lymph nodes were involved. Conventional 3D or intensity-modulated radiation was used and all patients completed treatment.

The median interval between diagnosis of rectal cancer and initiation of radiation therapy was 1.4 months, while the median interval between completion of radiation to initiation of chemotherapy was 2.7 weeks.

The most common chemotherapy regimen was FOLFOX – consisting of leucovorin, fluorouracil (5-FU), and oxaliplatin – or modified FOLFOX. For patients who received six or more cycles of chemotherapy, the median time spent on treatment was 3.9 months.

For those who completed at least six cycles of chemotherapy, the overall clinical CR was 51%, and, for patients with locally advanced disease, the clinical CR rate was 49%. Five of the 43 patients who achieved an initial clinical CR still underwent surgical resection because of patient or physician preference. Among this small group of patients, 4 of the 5 achieved a pCR, and the remaining patient achieved a pathological partial response (pPR).

A total of 42 patients (47% of the group) achieved a partial response following the radiation plus chemotherapy paradigm, and one patient had progressive disease. All underwent surgical resection. One patient did not complete chemotherapy and did not get surgery and subsequently died.

This left 38 patients to be managed nonoperatively. In this nonoperative cohort, 79% of patients continued to have a clinical CR at the end of follow-up. Of the 7 patients with local failure, 6 were salvaged by surgery, one was salvaged by chemotherapy, and all 7 treatment failures had no evidence of disease at last follow-up.

Of the small group of 5 patients who achieved an initial clinical CR following short-course radiation therapy and neoadjuvant chemotherapy, there were no further events in this group, whereas, for patients who achieved only an initial partial response or who had progressive disease, 72% remained event-free.

Approximately half of those who achieved a clinical CR to the treatment regimen had no late gastrointestinal toxicities, and no grade 3 or 4 toxicities were observed. “Surgical resection of tumors — even without a permanent stoma — can result in significantly decreased bowel function, so our goal is to treat patients without surgery and maintain good bowel function,” Chin noted.

“For rectal cancer, both short-course radiation therapy and nonoperative management are emerging treatment paradigms that may be more cost-effective and convenient compared to long-course chemoradiation followed by surgery, [especially since] the COVID-19 pandemic...has spurred changes in clinical practices in radiation oncology,” she said.

Chin has disclosed no relevant financial relationships. Narang reports receiving research support from Boston Scientific.
 

This article first appeared on Medscape.com.

Hepatocellular carcinoma (HCC) has a poor prognosis and remains an important cause of cancer-related morbidity and mortality.^1,2 Potentially curative interventions include surgical resection, radiofrequency ablation, and liver transplantation. However, the majority of patients are not eligible for these procedures because they are diagnosed at an advanced stage, when locoregional therapies are much more limited.^3,4 Although the kinase inhibitors sorafenib and lenvatinib are approved as first-line systemic treatment, at the US Department of Veterans Affairs (VA) Kansas City VA Medical Center (KCVAMC) in Missouri, nivolumab was used instead because of concerns for the tolerability of the kinase inhibitors. Locoregional therapies, resection, and transplantation options were either not appropriate or had been exhausted for these patients. The objective of this retrospective study was to determine the outcomes of those veteran patients in a small cohort.

Methods

The KCVAMC Institutional Review Board approved this retrospective chart review. Patients were selected from pharmacy records at KCVAMC. We identified all patients with a diagnosis of HCC who received nivolumab from January 2016 to December 2019. We then included only the patients that had nivolumab in the front-line setting for our final analysis. At the time of initiation of treatment, all patients were informed that immunotherapy was not approved for front-line treatment, but available evidence suggested that it would be easier to tolerate than sorafenib or lenvatinib. These patients were determined to be either ineligible for sorafenib or lenvatinib therapy or expected to tolerate it poorly, and hence they consented to the use of nivolumab. Tumor response and progression were assessed by the investigator according to iRECIST (Immune Response Evaluation Criteria in Solid Tumors) criteria.⁵ Data were obtained from retrospective health record review.

Results

Fourteen men received nivolumab in the front-line systemic therapy setting from January 2016 to December 2019 at KCVAMC. The median age was 63.5 years (range, 58-72 years), and the median Eastern Cooperative Oncology Group score was 1. The Table highlights patient characteristics.

Of the 14 patients included in the review, 2 patients had a response to nivolumab (14.3%) and 1 patient had a complete response (7.1%). The median duration of immunotherapy was 4.5 months. Immunotherapy was discontinued due to disease progression in 10 patients and toxicity in 3 patients.

The median progression-free survival (PFS) from initiation of immunotherapy was 4 months; median overall survival (OS) was 8 months. The median time from diagnosis to survival was 41 months. Only 1 patient received a second-line treatment.

Incidence of grade 3 or higher toxicity was 35%. Three deaths resulted from auto-immune hepatitis (grade 5 toxicity), as well as 1 grade 3 skin toxicity, and 1 grade 4 liver toxicity.

Discussion

Immunotherapy has shown promise in patients with HCC based on the results of the KEYNOTE-224 and Checkmate-040 studies,^6,7 which led to an accelerated US Food and Drug Administration approval of nivolumab and pembrolizumab for HCC following failure of first-line sorafenib.^8,9

Several clinical trials are evaluating front-line immunotherapy for HCC. The Checkmate 459 study demonstrated the median OS to be 16.4 months for nivolumab vs 14.7 months for sorafenib, a difference that was not statistically significant. However, tolerability of nivolumab was better than it was for sorafenib, thus positioning it as a potentially attractive first-line option.¹⁰ The GO30140 study evaluated atezolizumab and bevacizumab vs atezolizumab with results positive for a survival benefit in favor of combination.¹¹ This combination of atezolizumab and bevacizumab vs sorafenib also has been evaluated in the phase 3 IMbrave150 trial. Results from this trial show statistically significant improvement in the coprimary endpoints of OS and PFS in patients who were treated with atezolizumab and bevacizumab when compared with those who were treated with sorafenib. The median OS had not been reached for atezolizumab and bevacizumab vs 13.2 months for patients randomized to sorafenib, with a higher PFS and response rate also noted with combination treatment.¹²

The results from our study differed from the previous studies and raise concern for the applicability of these trials to a real-world population. For example, both the GO30140 and IMbrave150 excluded patients with untreated varices.^11,12 Both IMbrave150 and Checkmate 459 limited enrollment only to patients with a Child-Pugh A score for liver disease; 36% of the KCVAMC patients had a Child-Pugh B score. Three patients (21.4%) were homeless, 6 patients (42.8%) had substance abuse history and 5 patients (35.7%) had mental illness. Several psychosocial factors present in our patients, such as substance abuse, mental illness, and homelessness, would have excluded them from clinical trials. Our small cohort of patients, thus, represents a frail real-world population due to multiple medical and psychosocial comorbidities. Real-world experience with immunotherapy as second-line therapy after treatment with sorafenib has been reported, but this is the first reported real-world experience of immunotherapy in the front-line setting for HCC.^13,14

Large differences in sociodemographic status and health status exist between the veteran population and typical clinical trial populations. Veterans are predominantly male and older than a clinical trial population. Veterans are more likely to belong to a minority group, more likely to have lower level education and more likely to be poor than a clinical trial population. They are more likely to have poorer health status with higher number of medical conditions and psychosocial conditions.¹⁵

Limitations

We acknowledge several limitations to our study, such as the small number of patients and the retrospective single center nature of this study. Patients were older men with multiple psychosocial comorbitities like mental illness, substance abuse, and homelessness. This cohort may not represent the non-VA population, but is an excellent representation of a frail, real-world veteran population.

Conclusions

Despite clinical trials showing the promise of immunotherapy as an attractive front-line systemic treatment option for HCC, our results show poor outcomes in a frail real-world population. In a cohort of patients who received immunotherapy as a front-line systemic treatment for HCC, results were poor with a response rate of 14.3%, a median PFS of 4 months, and a median OS of 8 months. We noted a significantly higher number of adverse effects, including 21% incidence of grade 5 hepatotoxicity. There remains an urgent need to develop more effective and safer therapies for this patient population as well as validation from larger real-world studies.

Hepatocellular carcinoma (HCC) has a poor prognosis and remains an important cause of cancer-related morbidity and mortality.^1,2 Potentially curative interventions include surgical resection, radiofrequency ablation, and liver transplantation. However, the majority of patients are not eligible for these procedures because they are diagnosed at an advanced stage, when locoregional therapies are much more limited.^3,4 Although the kinase inhibitors sorafenib and lenvatinib are approved as first-line systemic treatment, at the US Department of Veterans Affairs (VA) Kansas City VA Medical Center (KCVAMC) in Missouri, nivolumab was used instead because of concerns for the tolerability of the kinase inhibitors. Locoregional therapies, resection, and transplantation options were either not appropriate or had been exhausted for these patients. The objective of this retrospective study was to determine the outcomes of those veteran patients in a small cohort.

Methods

The KCVAMC Institutional Review Board approved this retrospective chart review. Patients were selected from pharmacy records at KCVAMC. We identified all patients with a diagnosis of HCC who received nivolumab from January 2016 to December 2019. We then included only the patients that had nivolumab in the front-line setting for our final analysis. At the time of initiation of treatment, all patients were informed that immunotherapy was not approved for front-line treatment, but available evidence suggested that it would be easier to tolerate than sorafenib or lenvatinib. These patients were determined to be either ineligible for sorafenib or lenvatinib therapy or expected to tolerate it poorly, and hence they consented to the use of nivolumab. Tumor response and progression were assessed by the investigator according to iRECIST (Immune Response Evaluation Criteria in Solid Tumors) criteria.⁵ Data were obtained from retrospective health record review.

Results

Fourteen men received nivolumab in the front-line systemic therapy setting from January 2016 to December 2019 at KCVAMC. The median age was 63.5 years (range, 58-72 years), and the median Eastern Cooperative Oncology Group score was 1. The Table highlights patient characteristics.

Of the 14 patients included in the review, 2 patients had a response to nivolumab (14.3%) and 1 patient had a complete response (7.1%). The median duration of immunotherapy was 4.5 months. Immunotherapy was discontinued due to disease progression in 10 patients and toxicity in 3 patients.

The median progression-free survival (PFS) from initiation of immunotherapy was 4 months; median overall survival (OS) was 8 months. The median time from diagnosis to survival was 41 months. Only 1 patient received a second-line treatment.

Incidence of grade 3 or higher toxicity was 35%. Three deaths resulted from auto-immune hepatitis (grade 5 toxicity), as well as 1 grade 3 skin toxicity, and 1 grade 4 liver toxicity.

Discussion

Immunotherapy has shown promise in patients with HCC based on the results of the KEYNOTE-224 and Checkmate-040 studies,^6,7 which led to an accelerated US Food and Drug Administration approval of nivolumab and pembrolizumab for HCC following failure of first-line sorafenib.^8,9

Several clinical trials are evaluating front-line immunotherapy for HCC. The Checkmate 459 study demonstrated the median OS to be 16.4 months for nivolumab vs 14.7 months for sorafenib, a difference that was not statistically significant. However, tolerability of nivolumab was better than it was for sorafenib, thus positioning it as a potentially attractive first-line option.¹⁰ The GO30140 study evaluated atezolizumab and bevacizumab vs atezolizumab with results positive for a survival benefit in favor of combination.¹¹ This combination of atezolizumab and bevacizumab vs sorafenib also has been evaluated in the phase 3 IMbrave150 trial. Results from this trial show statistically significant improvement in the coprimary endpoints of OS and PFS in patients who were treated with atezolizumab and bevacizumab when compared with those who were treated with sorafenib. The median OS had not been reached for atezolizumab and bevacizumab vs 13.2 months for patients randomized to sorafenib, with a higher PFS and response rate also noted with combination treatment.¹²

The results from our study differed from the previous studies and raise concern for the applicability of these trials to a real-world population. For example, both the GO30140 and IMbrave150 excluded patients with untreated varices.^11,12 Both IMbrave150 and Checkmate 459 limited enrollment only to patients with a Child-Pugh A score for liver disease; 36% of the KCVAMC patients had a Child-Pugh B score. Three patients (21.4%) were homeless, 6 patients (42.8%) had substance abuse history and 5 patients (35.7%) had mental illness. Several psychosocial factors present in our patients, such as substance abuse, mental illness, and homelessness, would have excluded them from clinical trials. Our small cohort of patients, thus, represents a frail real-world population due to multiple medical and psychosocial comorbidities. Real-world experience with immunotherapy as second-line therapy after treatment with sorafenib has been reported, but this is the first reported real-world experience of immunotherapy in the front-line setting for HCC.^13,14

Large differences in sociodemographic status and health status exist between the veteran population and typical clinical trial populations. Veterans are predominantly male and older than a clinical trial population. Veterans are more likely to belong to a minority group, more likely to have lower level education and more likely to be poor than a clinical trial population. They are more likely to have poorer health status with higher number of medical conditions and psychosocial conditions.¹⁵

Limitations

We acknowledge several limitations to our study, such as the small number of patients and the retrospective single center nature of this study. Patients were older men with multiple psychosocial comorbitities like mental illness, substance abuse, and homelessness. This cohort may not represent the non-VA population, but is an excellent representation of a frail, real-world veteran population.

Conclusions

Despite clinical trials showing the promise of immunotherapy as an attractive front-line systemic treatment option for HCC, our results show poor outcomes in a frail real-world population. In a cohort of patients who received immunotherapy as a front-line systemic treatment for HCC, results were poor with a response rate of 14.3%, a median PFS of 4 months, and a median OS of 8 months. We noted a significantly higher number of adverse effects, including 21% incidence of grade 5 hepatotoxicity. There remains an urgent need to develop more effective and safer therapies for this patient population as well as validation from larger real-world studies.

Hepatocellular carcinoma (HCC) has a poor prognosis and remains an important cause of cancer-related morbidity and mortality.^1,2 Potentially curative interventions include surgical resection, radiofrequency ablation, and liver transplantation. However, the majority of patients are not eligible for these procedures because they are diagnosed at an advanced stage, when locoregional therapies are much more limited.^3,4 Although the kinase inhibitors sorafenib and lenvatinib are approved as first-line systemic treatment, at the US Department of Veterans Affairs (VA) Kansas City VA Medical Center (KCVAMC) in Missouri, nivolumab was used instead because of concerns for the tolerability of the kinase inhibitors. Locoregional therapies, resection, and transplantation options were either not appropriate or had been exhausted for these patients. The objective of this retrospective study was to determine the outcomes of those veteran patients in a small cohort.

Methods

The KCVAMC Institutional Review Board approved this retrospective chart review. Patients were selected from pharmacy records at KCVAMC. We identified all patients with a diagnosis of HCC who received nivolumab from January 2016 to December 2019. We then included only the patients that had nivolumab in the front-line setting for our final analysis. At the time of initiation of treatment, all patients were informed that immunotherapy was not approved for front-line treatment, but available evidence suggested that it would be easier to tolerate than sorafenib or lenvatinib. These patients were determined to be either ineligible for sorafenib or lenvatinib therapy or expected to tolerate it poorly, and hence they consented to the use of nivolumab. Tumor response and progression were assessed by the investigator according to iRECIST (Immune Response Evaluation Criteria in Solid Tumors) criteria.⁵ Data were obtained from retrospective health record review.

Results

Fourteen men received nivolumab in the front-line systemic therapy setting from January 2016 to December 2019 at KCVAMC. The median age was 63.5 years (range, 58-72 years), and the median Eastern Cooperative Oncology Group score was 1. The Table highlights patient characteristics.

Of the 14 patients included in the review, 2 patients had a response to nivolumab (14.3%) and 1 patient had a complete response (7.1%). The median duration of immunotherapy was 4.5 months. Immunotherapy was discontinued due to disease progression in 10 patients and toxicity in 3 patients.

The median progression-free survival (PFS) from initiation of immunotherapy was 4 months; median overall survival (OS) was 8 months. The median time from diagnosis to survival was 41 months. Only 1 patient received a second-line treatment.

Incidence of grade 3 or higher toxicity was 35%. Three deaths resulted from auto-immune hepatitis (grade 5 toxicity), as well as 1 grade 3 skin toxicity, and 1 grade 4 liver toxicity.

Discussion

Immunotherapy has shown promise in patients with HCC based on the results of the KEYNOTE-224 and Checkmate-040 studies,^6,7 which led to an accelerated US Food and Drug Administration approval of nivolumab and pembrolizumab for HCC following failure of first-line sorafenib.^8,9

Several clinical trials are evaluating front-line immunotherapy for HCC. The Checkmate 459 study demonstrated the median OS to be 16.4 months for nivolumab vs 14.7 months for sorafenib, a difference that was not statistically significant. However, tolerability of nivolumab was better than it was for sorafenib, thus positioning it as a potentially attractive first-line option.¹⁰ The GO30140 study evaluated atezolizumab and bevacizumab vs atezolizumab with results positive for a survival benefit in favor of combination.¹¹ This combination of atezolizumab and bevacizumab vs sorafenib also has been evaluated in the phase 3 IMbrave150 trial. Results from this trial show statistically significant improvement in the coprimary endpoints of OS and PFS in patients who were treated with atezolizumab and bevacizumab when compared with those who were treated with sorafenib. The median OS had not been reached for atezolizumab and bevacizumab vs 13.2 months for patients randomized to sorafenib, with a higher PFS and response rate also noted with combination treatment.¹²

The results from our study differed from the previous studies and raise concern for the applicability of these trials to a real-world population. For example, both the GO30140 and IMbrave150 excluded patients with untreated varices.^11,12 Both IMbrave150 and Checkmate 459 limited enrollment only to patients with a Child-Pugh A score for liver disease; 36% of the KCVAMC patients had a Child-Pugh B score. Three patients (21.4%) were homeless, 6 patients (42.8%) had substance abuse history and 5 patients (35.7%) had mental illness. Several psychosocial factors present in our patients, such as substance abuse, mental illness, and homelessness, would have excluded them from clinical trials. Our small cohort of patients, thus, represents a frail real-world population due to multiple medical and psychosocial comorbidities. Real-world experience with immunotherapy as second-line therapy after treatment with sorafenib has been reported, but this is the first reported real-world experience of immunotherapy in the front-line setting for HCC.^13,14

Large differences in sociodemographic status and health status exist between the veteran population and typical clinical trial populations. Veterans are predominantly male and older than a clinical trial population. Veterans are more likely to belong to a minority group, more likely to have lower level education and more likely to be poor than a clinical trial population. They are more likely to have poorer health status with higher number of medical conditions and psychosocial conditions.¹⁵

Limitations

We acknowledge several limitations to our study, such as the small number of patients and the retrospective single center nature of this study. Patients were older men with multiple psychosocial comorbitities like mental illness, substance abuse, and homelessness. This cohort may not represent the non-VA population, but is an excellent representation of a frail, real-world veteran population.

Conclusions

Despite clinical trials showing the promise of immunotherapy as an attractive front-line systemic treatment option for HCC, our results show poor outcomes in a frail real-world population. In a cohort of patients who received immunotherapy as a front-line systemic treatment for HCC, results were poor with a response rate of 14.3%, a median PFS of 4 months, and a median OS of 8 months. We noted a significantly higher number of adverse effects, including 21% incidence of grade 5 hepatotoxicity. There remains an urgent need to develop more effective and safer therapies for this patient population as well as validation from larger real-world studies.