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In this edition of “How I will treat my next patient,” I examine two recently published efforts to enlighten our sensitivity to the seriousness of immune-related adverse events (IrAEs) in patients on immune checkpoint inhibitors (ICIs) and the effect of delays in initiating systemic adjuvant therapy on the long-term outcomes of patients with resected pancreatic cancer.
IrAEs requiring hospitalization
Investigators led by Aanika Balaji of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, reviewed a 6-month audit of inpatient oncology admissions of solid-tumor patients who had ever received ICIs and ascertained the prevalence of hospitalization for management of IrAEs (J Oncol Pract. 2019 Aug 6. doi: 10.1200/JOP.18.00703). To determine that an IrAE had occurred they required: consensus among two oncologists, clinical improvement with immune-directed therapy, exclusion of alternative diagnoses or pathologic confirmation of an IrAE, or chronic management of an IrAE for more than 6 months.
The bottom line: They found a cumulative incidence of a confirmed IrAEs among hospitalized ICI-treated solid tumor patients of 23%. As expected, the majority (65%) were grade 3-4 in severity. In total, 91% required multidisciplinary management, and 65% improved or resolved. But 87% of patients never received an ICI again.
Patients with preexisting autoimmune disease (25% of patients, although they included hypothyroidism in that group) were not more vulnerable to an IrAE with ICI therapy (odds ratio, 1.0; 95% confidence interval, 0.3-4.0). Not unsurprisingly, the median age was higher for ICI-treated patients who were admitted for IrAEs than for those not admitted (68 years vs. 59 years; OR, 5.4; 95% CI, 1.6-17.8), and more admitted patients had received combination ICIs than single agents (OR, 6.8; 95% CI, 2.0-23.2).
The median time from beginning ICIs to an IrAE-related hospitalization was 64 days, and the median number of ICI doses was one, with a wide range for both days and doses. The authors were quick to comment that this is a small, academic, single-institution survey over a brief period of time and that the generalizability of the results is uncertain.
What this means in practice
This publication changes very little for most practicing oncologists, but it does reinforce that ICI therapy can cause unpredictable, severe IrAEs. Clinical markers for selecting patients at highest risk are imperfect. As with chemotherapy, the patients we worry about the most – older individuals and patients treated with drug combinations – are, in fact, the ones we should be worrying about the most.
In view of the potential severity and impact of IrAEs, research efforts should place equal priority on identifying biomarkers of toxicity, such as tumor mutation burden, and biomarkers of efficacy (JAMA Oncol. 2019 Aug 22. doi: 10.1001/jamaoncol.2019.3221). The potential financial and societal effects, as well as lost opportunity costs in the form of alternative therapies and early referral to hospice, demand no less, particularly in an era of value-based health care reimbursement.
Timing of adjuvant treatment
Sung Jun Ma, MD, department of radiation medicine at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues analyzed data from the more than 7,500 stage I-II resected pancreatic cancer patients in the National Cancer Database, of whom more than 5,400 ultimately received adjuvant therapy (chemotherapy with or without radiation). The patients were treated during 2004-2015. Appropriately, the investigators focused on correlating survival duration with the interval between surgery and initiation of adjuvant therapy. Other endpoints would be hard to accurately measure and verify without detailed clinical information (JAMA Network Open. 2019 Aug 14. doi: 10.1001/jamanetworkopen.2019.9126).
They found that the best overall survival was associated with starting adjuvant treatment 28-59 days after surgery – not earlier (17% higher mortality) and not later (9% higher). Patients who did not start adjuvant treatment until more than 90 days post operatively still had an overall survival benefit (hazard ratio, 0.75; 95% confidence interval, 0.66-0.85; P less than .001), a more impressive hazard ratio than that seen for any particular interval between surgery and adjuvant treatment. Overall survival at 2 years was 47.2% versus 38% for the adjuvant therapy and surgery alone cohorts, respectively, with no overlap in the 95% confidence intervals.
As expected, longer delays to receive adjuvant treatment were associated with longer inpatient surgical stays, advanced age, black race, lower income, and a readmission for a postoperative complication within 30 days.
What this means in practice
This is another study that verifies that the patients we worry about most – older patients, those with a complicated recovery from surgery, and those with fewer supportive resources – are exactly the patients we should worry about most. It changes very little for most practicing oncologists. The analysis validates the importance of adjuvant therapy for patients who are able to receive it – whenever that is.
The data collection in this publication precedes recent improvements in adjuvant chemotherapy for resected pancreatic cancer, such as FOLFIRINOX or gemcitabine plus capecitabine. In an era of improved treatment, delays in initiating therapy may be less important since better treatment overcomes many prognostic variables that are significant for less effective therapy.
In my opinion, this large-data analysis is not really hypothesis-generating or practice-changing, but it does compel us to continue research efforts to improve surgical morbidity, identify better adjuvant and advanced disease regimens, and consider neoadjuvant treatment so that more than 72% of patients can receive all components of the multimodality treatment they need.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I examine two recently published efforts to enlighten our sensitivity to the seriousness of immune-related adverse events (IrAEs) in patients on immune checkpoint inhibitors (ICIs) and the effect of delays in initiating systemic adjuvant therapy on the long-term outcomes of patients with resected pancreatic cancer.
IrAEs requiring hospitalization
Investigators led by Aanika Balaji of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, reviewed a 6-month audit of inpatient oncology admissions of solid-tumor patients who had ever received ICIs and ascertained the prevalence of hospitalization for management of IrAEs (J Oncol Pract. 2019 Aug 6. doi: 10.1200/JOP.18.00703). To determine that an IrAE had occurred they required: consensus among two oncologists, clinical improvement with immune-directed therapy, exclusion of alternative diagnoses or pathologic confirmation of an IrAE, or chronic management of an IrAE for more than 6 months.
The bottom line: They found a cumulative incidence of a confirmed IrAEs among hospitalized ICI-treated solid tumor patients of 23%. As expected, the majority (65%) were grade 3-4 in severity. In total, 91% required multidisciplinary management, and 65% improved or resolved. But 87% of patients never received an ICI again.
Patients with preexisting autoimmune disease (25% of patients, although they included hypothyroidism in that group) were not more vulnerable to an IrAE with ICI therapy (odds ratio, 1.0; 95% confidence interval, 0.3-4.0). Not unsurprisingly, the median age was higher for ICI-treated patients who were admitted for IrAEs than for those not admitted (68 years vs. 59 years; OR, 5.4; 95% CI, 1.6-17.8), and more admitted patients had received combination ICIs than single agents (OR, 6.8; 95% CI, 2.0-23.2).
The median time from beginning ICIs to an IrAE-related hospitalization was 64 days, and the median number of ICI doses was one, with a wide range for both days and doses. The authors were quick to comment that this is a small, academic, single-institution survey over a brief period of time and that the generalizability of the results is uncertain.
What this means in practice
This publication changes very little for most practicing oncologists, but it does reinforce that ICI therapy can cause unpredictable, severe IrAEs. Clinical markers for selecting patients at highest risk are imperfect. As with chemotherapy, the patients we worry about the most – older individuals and patients treated with drug combinations – are, in fact, the ones we should be worrying about the most.
In view of the potential severity and impact of IrAEs, research efforts should place equal priority on identifying biomarkers of toxicity, such as tumor mutation burden, and biomarkers of efficacy (JAMA Oncol. 2019 Aug 22. doi: 10.1001/jamaoncol.2019.3221). The potential financial and societal effects, as well as lost opportunity costs in the form of alternative therapies and early referral to hospice, demand no less, particularly in an era of value-based health care reimbursement.
Timing of adjuvant treatment
Sung Jun Ma, MD, department of radiation medicine at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues analyzed data from the more than 7,500 stage I-II resected pancreatic cancer patients in the National Cancer Database, of whom more than 5,400 ultimately received adjuvant therapy (chemotherapy with or without radiation). The patients were treated during 2004-2015. Appropriately, the investigators focused on correlating survival duration with the interval between surgery and initiation of adjuvant therapy. Other endpoints would be hard to accurately measure and verify without detailed clinical information (JAMA Network Open. 2019 Aug 14. doi: 10.1001/jamanetworkopen.2019.9126).
They found that the best overall survival was associated with starting adjuvant treatment 28-59 days after surgery – not earlier (17% higher mortality) and not later (9% higher). Patients who did not start adjuvant treatment until more than 90 days post operatively still had an overall survival benefit (hazard ratio, 0.75; 95% confidence interval, 0.66-0.85; P less than .001), a more impressive hazard ratio than that seen for any particular interval between surgery and adjuvant treatment. Overall survival at 2 years was 47.2% versus 38% for the adjuvant therapy and surgery alone cohorts, respectively, with no overlap in the 95% confidence intervals.
As expected, longer delays to receive adjuvant treatment were associated with longer inpatient surgical stays, advanced age, black race, lower income, and a readmission for a postoperative complication within 30 days.
What this means in practice
This is another study that verifies that the patients we worry about most – older patients, those with a complicated recovery from surgery, and those with fewer supportive resources – are exactly the patients we should worry about most. It changes very little for most practicing oncologists. The analysis validates the importance of adjuvant therapy for patients who are able to receive it – whenever that is.
The data collection in this publication precedes recent improvements in adjuvant chemotherapy for resected pancreatic cancer, such as FOLFIRINOX or gemcitabine plus capecitabine. In an era of improved treatment, delays in initiating therapy may be less important since better treatment overcomes many prognostic variables that are significant for less effective therapy.
In my opinion, this large-data analysis is not really hypothesis-generating or practice-changing, but it does compel us to continue research efforts to improve surgical morbidity, identify better adjuvant and advanced disease regimens, and consider neoadjuvant treatment so that more than 72% of patients can receive all components of the multimodality treatment they need.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I examine two recently published efforts to enlighten our sensitivity to the seriousness of immune-related adverse events (IrAEs) in patients on immune checkpoint inhibitors (ICIs) and the effect of delays in initiating systemic adjuvant therapy on the long-term outcomes of patients with resected pancreatic cancer.
IrAEs requiring hospitalization
Investigators led by Aanika Balaji of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, reviewed a 6-month audit of inpatient oncology admissions of solid-tumor patients who had ever received ICIs and ascertained the prevalence of hospitalization for management of IrAEs (J Oncol Pract. 2019 Aug 6. doi: 10.1200/JOP.18.00703). To determine that an IrAE had occurred they required: consensus among two oncologists, clinical improvement with immune-directed therapy, exclusion of alternative diagnoses or pathologic confirmation of an IrAE, or chronic management of an IrAE for more than 6 months.
The bottom line: They found a cumulative incidence of a confirmed IrAEs among hospitalized ICI-treated solid tumor patients of 23%. As expected, the majority (65%) were grade 3-4 in severity. In total, 91% required multidisciplinary management, and 65% improved or resolved. But 87% of patients never received an ICI again.
Patients with preexisting autoimmune disease (25% of patients, although they included hypothyroidism in that group) were not more vulnerable to an IrAE with ICI therapy (odds ratio, 1.0; 95% confidence interval, 0.3-4.0). Not unsurprisingly, the median age was higher for ICI-treated patients who were admitted for IrAEs than for those not admitted (68 years vs. 59 years; OR, 5.4; 95% CI, 1.6-17.8), and more admitted patients had received combination ICIs than single agents (OR, 6.8; 95% CI, 2.0-23.2).
The median time from beginning ICIs to an IrAE-related hospitalization was 64 days, and the median number of ICI doses was one, with a wide range for both days and doses. The authors were quick to comment that this is a small, academic, single-institution survey over a brief period of time and that the generalizability of the results is uncertain.
What this means in practice
This publication changes very little for most practicing oncologists, but it does reinforce that ICI therapy can cause unpredictable, severe IrAEs. Clinical markers for selecting patients at highest risk are imperfect. As with chemotherapy, the patients we worry about the most – older individuals and patients treated with drug combinations – are, in fact, the ones we should be worrying about the most.
In view of the potential severity and impact of IrAEs, research efforts should place equal priority on identifying biomarkers of toxicity, such as tumor mutation burden, and biomarkers of efficacy (JAMA Oncol. 2019 Aug 22. doi: 10.1001/jamaoncol.2019.3221). The potential financial and societal effects, as well as lost opportunity costs in the form of alternative therapies and early referral to hospice, demand no less, particularly in an era of value-based health care reimbursement.
Timing of adjuvant treatment
Sung Jun Ma, MD, department of radiation medicine at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues analyzed data from the more than 7,500 stage I-II resected pancreatic cancer patients in the National Cancer Database, of whom more than 5,400 ultimately received adjuvant therapy (chemotherapy with or without radiation). The patients were treated during 2004-2015. Appropriately, the investigators focused on correlating survival duration with the interval between surgery and initiation of adjuvant therapy. Other endpoints would be hard to accurately measure and verify without detailed clinical information (JAMA Network Open. 2019 Aug 14. doi: 10.1001/jamanetworkopen.2019.9126).
They found that the best overall survival was associated with starting adjuvant treatment 28-59 days after surgery – not earlier (17% higher mortality) and not later (9% higher). Patients who did not start adjuvant treatment until more than 90 days post operatively still had an overall survival benefit (hazard ratio, 0.75; 95% confidence interval, 0.66-0.85; P less than .001), a more impressive hazard ratio than that seen for any particular interval between surgery and adjuvant treatment. Overall survival at 2 years was 47.2% versus 38% for the adjuvant therapy and surgery alone cohorts, respectively, with no overlap in the 95% confidence intervals.
As expected, longer delays to receive adjuvant treatment were associated with longer inpatient surgical stays, advanced age, black race, lower income, and a readmission for a postoperative complication within 30 days.
What this means in practice
This is another study that verifies that the patients we worry about most – older patients, those with a complicated recovery from surgery, and those with fewer supportive resources – are exactly the patients we should worry about most. It changes very little for most practicing oncologists. The analysis validates the importance of adjuvant therapy for patients who are able to receive it – whenever that is.
The data collection in this publication precedes recent improvements in adjuvant chemotherapy for resected pancreatic cancer, such as FOLFIRINOX or gemcitabine plus capecitabine. In an era of improved treatment, delays in initiating therapy may be less important since better treatment overcomes many prognostic variables that are significant for less effective therapy.
In my opinion, this large-data analysis is not really hypothesis-generating or practice-changing, but it does compel us to continue research efforts to improve surgical morbidity, identify better adjuvant and advanced disease regimens, and consider neoadjuvant treatment so that more than 72% of patients can receive all components of the multimodality treatment they need.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.